CN111132997A - 包含fgf-18部分的融合蛋白 - Google Patents
包含fgf-18部分的融合蛋白 Download PDFInfo
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- CN111132997A CN111132997A CN201880061326.1A CN201880061326A CN111132997A CN 111132997 A CN111132997 A CN 111132997A CN 201880061326 A CN201880061326 A CN 201880061326A CN 111132997 A CN111132997 A CN 111132997A
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Abstract
本发明涉及新的融合蛋白，其包含与抗NGF部分融合的FGF‑18部分。所述融合蛋白可以用于治疗软骨疾病，例如骨关节炎或软骨损伤。
Description
发明领域
本发明涉及新的融合蛋白，其包含与抗NGF部分融合的FGF-18部分。所述融合蛋白可以用于治疗软骨疾病，例如骨关节炎或软骨损伤。
背景技术
软骨由分散在基质(一种坚固的凝胶状物质)中的软骨细胞(来源于间充质细胞的细胞)组成。软骨基质由这些细胞产生，主要包括II型胶原纤维(除了还包含I型胶原蛋白纤维的纤维软骨)、蛋白多糖和弹性蛋白纤维。在关节，肋骨，耳朵，鼻子，喉咙，气管和椎间盘等处都发现了软骨。软骨主要有三种类型：透明软骨，弹性软骨和纤维软骨，根据其组织学形态提供不同的功能特性。例如，关节软骨是具有粘弹性的，覆盖骨关节表面的透明软骨。关节软骨的主要目的是提供光滑的表面，以确保关节骨几乎无摩擦的运动。
软骨疾病广义上指以软骨退化/解体为特征的疾病和由受影响的身体部分的炎症、疼痛、僵硬和运动受限所表现的结缔组织异常。这些疾病可能是由于病变或可能是创伤或损伤的结果。成熟的软骨自我修复的能力非常有限，这主要是因为成熟软骨细胞几乎没有增殖潜力，因为软骨中缺乏血管导致营养供应有限。由损伤或疾病引起的受损软骨，特别是关节软骨的置换是医师的一大挑战，可用的外科治疗程序被认为是不可预测的且仅在在没有骨关节炎改变的年轻患者中起效有限的时间。因此，大多数患者要么不寻求治疗，要么被建议尽可能长时间地推迟治疗。当需要治疗时，标准程序取决于年龄并且不外乎全部或部分关节置换，软骨或软骨细胞碎片的移植或骨髓刺激技术(例如微骨折)。微骨折是一种廉价且常见的程序，涉及软骨下骨穿刺以刺激骨髓衍生干细胞的软骨沉积。然而，已经表明，该技术不能充分修复软骨缺损，并且形成的新软骨主要是纤维软骨，导致修复组织寿命短。实际上，纤维软骨不具有与透明关节软骨相同的生物力学特性，并且通常缺乏适当的横向整合入周围软骨的能力。因此，新合成的纤维软骨可能更容易破损(预期时间范围：5-10年)。
对于骨关节炎(OA)患者，所有这些软骨修复技术都失败了。其余的非手术治疗主要由物理疗法，改变生活方式(例如减轻体重)，支持装置，口服药物(例如非甾体类抗炎药)和药物注射(例如透明质酸和皮质类固醇)以及食物补充组成。所有这些治疗均不能阻止OA疾病的进展。如果疼痛治疗也失败，则患者可以选择手术，例如膝关节置换或胫骨高位截骨术。胫骨或股骨截骨术(切开骨头以重新平衡关节磨损)可以减轻症状，帮助维持积极的生活方式，并延迟全关节置换的需要。全关节置换可以缓解晚期骨关节炎的症状，但通常需要对患者的生活方式和/或活动水平进行重大改变。
当前可用的药物治疗主要针对疼痛缓解。目前还没有市售的治疗方法可以恢复软骨损伤(参见Lotz，2010)。
抗NGF化合物是在与OA有关的疼痛的情况中描述的一类分子。目前，正在开发他尼珠单抗(tanezumab)，法希姆单抗(fasinumab)或富拉单抗(fulranumab)来治疗OA患者的疼痛，基于I至III期临床试验的有希望的结果，目前都处于针对关节炎和/或慢性疼痛的II/III期临床试验中(Sanga等，2013；Tiseo等，2014；Brown等，2012)。
成纤维细胞生长因子18(FGF-18)是成纤维细胞生长因子(FGF)蛋白质家族的成员。已经显示出FGF-18是软骨细胞和成骨细胞的增殖剂(Ellsworth等，2002；Shimoaka等，2002)。已经提出FGF-18可单独(WO2008023063)或与透明质酸组合(WO2004032849)用于治疗软骨疾病，例如骨关节炎和软骨损伤。FGF-18目前正在临床试验中研究治疗OA。
尽管FGF18在关节软骨修复中提供了良好的结果，但仍需要能够减轻疼痛/改善功能，同时保持用于治疗软骨疾病的功效的其他分子。实际上，疼痛不仅经常与软骨疾病相关，而且代表了临床上检测这些疾病的主要症状。
发明内容
本发明的一个目的是提供新的融合蛋白，其包含与抗NGF部分(即NGF的抑制剂)融合的FGF-18部分。融合蛋白可用于治疗软骨疾病。所述软骨疾病是例如骨关节炎或软骨损伤。
本发明还提供了所述融合蛋白的优选氨基酸序列。
还包括编码本发明融合蛋白的多核苷酸序列，包含所述多核苷酸序列的载体和细胞系。
还描述了产生根据本发明的融合蛋白的方法。
本发明的另一个实施方式是药物组合物，其包含根据本发明的融合蛋白与至少一种赋形剂。
在另一个实施方式中，根据本发明的融合蛋白用于治疗软骨疾病，例如骨关节炎或软骨损伤。
定义
-本文中所用的术语“FGF-18部分”、“FGF18部分”、“FGF-18”或“FGF18”意指，保留了人FGF-18蛋白(即成纤维细胞生长因子18)的至少一种生物活性的蛋白质。FGF-18可以是天然的，可以是其成熟形式，重组形式或截短形式。人FGF-18蛋白的生物活性特别包括软骨细胞或成骨细胞增殖(参见WO9816644)或软骨形成(参见WO2008023063)的增加。天然或野生型人FGF-18是主要在骨骼发育过程中产生的蛋白质，并参与骨骼和软骨的形成(请参阅Haque等，2007)。人FGF-18首先被命名为zFGF-5，并在WO9816644中有完整描述。SEQ ID NO:1对应于原始人FGF-18的氨基酸序列，其具有由氨基酸残基1(Met)至27(Ala)组成的信号肽。人FGF-18的成熟形式对应于SEQ ID NO:1的残基28(Glu)至残基207(Ala)的氨基酸序列(180个氨基酸)。根据本发明的FGF-18部分还包括FGF-18的活性片段，例如但不限于包含SEQ ID NO：1的残基28(Glu)至196(Lys)或由其组成的截短形式(所述截短形式复制成SEQID NO：2)，或FGF-18的突变体(例如与SEQ ID NO：1或SEQ ID NO：2的成熟形式具有至少80％序列相同性的突变体)。如果FGF-18部分是FGF-18的活性片段(或FGF-18的截短形式)，则所述FGF-18片段(或所述FGF-18的截短形式)优选包含至少150个氨基酸残基。已经显示出包含SEQ ID NO：2的FGF-18部分显示出与成熟的人FGF-18类似的活性，例如，它增加了软骨细胞的增殖和软骨沉积，从而导致多种软骨组织的修复和重建(参见WO2008023063)。
-本文中所用的术语“FGF-8部分”、“FGF8部分”、“FGF-8”或“FGF8”意指，保留了人FGF-8蛋白(即成纤维细胞生长因子8)的至少一种生物活性的蛋白质。FGF-8可以是天然的，可以是其成熟形式，重组形式，截短形式或突变体形式。天然形式表示为SEQ ID NO：121。
-本文中所用的术语“FGF-9部分”、“FGF9部分”、“FGF-9”或“FGF9”意指，保留了人FGF-9蛋白(即成纤维细胞生长因子9)的至少一种生物活性的蛋白质。FGF-9可以是天然的，可以是其成熟形式，重组形式，截短形式或突变体形式。天然形式表示为SEQ ID NO：122。FGF9被证明可减弱DMM小鼠模型中的软骨降解，降低MMP13表达并促进OA软骨中II型胶原的表达(Zhou等，2016)。
-本文中所用的术语“FGF-17部分”、“FGF17部分”、“FGF-17”或“FGF17”意指，保留了人FGF-17蛋白(即成纤维细胞生长因子17)的至少一种生物活性的蛋白质。FGF-17可以是天然的，可以是其成熟形式，重组形式，截短形式或突变体形式。天然形式表示为SEQ IDNO：123。
-本文所用的术语“NGF的抑制剂”或“抗NGF部分”是指能够结合NGF(神经生长因子)并且部分或完全抑制所述NGF活性的化合物。根据本发明的优选的“NGF的抑制剂”是抗NGF抗体或其活性片段或活性变体，以及纳米抗体。此类化合物例如但不限于他尼珠单抗(参见SEQ ID No：9-11)或其活性片段或活性变体，法希姆单抗(参见SEQ ID No：12-13))或其活性片段或活性变体，富拉单抗(参见SEQ ID No：14-15)或其活性片段或活性变体。ANA-02，ABT-110，ALD-906或MEDI-578是已知NGF受体抑制剂的其他实例。
-本文所用术语“抗体”及其复数形式包括但不限于多克隆抗体、亲和纯化的多克隆抗体、单克隆抗体和抗原结合片段，如F(ab')2、Fab片段、单链可变区片段(scFv或鲨鱼VNAR)以及单域抗体(例如骆驼科VHH)。它既指单臂(单价；一对免疫球蛋白链)，也指两臂(二价；两对免疫球蛋白链)抗体。该术语还包括称为基于杵臼(knobs-into-holes)的抗体(Ridgway等，1996)和SEED体(Davis等，2010或US 8,871,912)的变体。还包括遗传工程改造的完整抗体或活性片段，例如嵌合抗体、scFv和Fab片段，以及合成的抗原结合肽和多肽。抗体的基础结构单元是四聚体，由两对相同的免疫球蛋白链组成，每一对具有一条轻链和一条重链。轻链具有两部分：可变结构域(VL)和恒定结构域(CL)，其在轻链的上下文中也称为恒定区。重链也具有两部分：可变结构域(VH)和恒定区(CH)。在各对中，轻链和重链可变结构域共同主要负责结合抗原，且恒定区负责抗体效应功能。全长免疫球蛋白轻链摂(通常约25kDa)由N末端处的可变结构域基因(通常约110个氨基酸)和C末端处的κ或λ恒定区结构域(分别为CK和Cλ)编码。全长免疫球蛋白重链摂(通常约50kDa)类似地由可变结构域基因(通常约116个氨基酸)和后文所述其他恒定区基因之一(通常约330个氨基酸)编码。存在五种类型的哺乳动物重链，其由希腊字母命名：[α]、[δ]、[ε]、[γ]和[μ]。重链类型分别将抗体的同种型限定为IgA、IgD、IgE、IgG和IgM。恒定区在相同同种型的所有抗体中都相同，但在不同同种型的抗体中不同。重链[γ]、[α]和[δ]的恒定区由三个Ig恒定结构域(CH1、CH2和CH3)和一个铰链区(用于增加挠性)组成；重链[ε]和[μ]的恒定区由四个Ig恒定结构域(CH1、CH2、CH3和CH4)和一个铰链区组成。
轻链或重链可变结构域由“构架”区组成，其被三个高变区打断。其负责抗原结合。高变区包含来自“互补决定区”或“CDR(Kabat等，1991)的氨基酸残基和/或来自“高变环”(Chothia和Lesk 1987)的那些残基。“构架区”或“FR”残基是除了本文所限定的超变区残基之外的那些可变区残基。不同的轻链或重链的框架区序列在物种内是相对保守的。因此，“人构架区”是与天然产生的人免疫球蛋白的构架区基本相同(约85％或更高，通常约90-95％或更高)的构架区。抗体的构架区即组成轻链和重链的组合的构架区，其用作定位和对齐CDR。CDR主要负责与抗原表位的结合。所述抗体(或免疫球蛋白)可以是嵌合的，人源化的，也可以是完全人的。它们大多数时间是重组的(即重组抗体)。
-术语“重组抗体”指其中氨基酸序列不同于天然抗体的抗体。由于抗体生成中重组DNA技术的相关性，无需限制于天然抗体中发现的氨基酸的序列；可以重新设计抗体以获得所需的特性。可能的变化是多种多样的，范围从仅改变一个或几个氨基酸到完全重新设计例如可变结构域或恒定区。通常，进行恒定区的改变以改善、减少或改变特征，例如补体固定(例如补体依赖性细胞毒性，CDC)，与Fc受体的相互作用，以及其他效应子功能(例如抗体依赖性细胞毒性，ADCC)，药物动力学特性(例如，与新生儿Fc受体FcRn结合)。为了改善抗原结合特性，对可变结构域进行改变。除抗体外，免疫球蛋白还可以多种其他形式存在，包括例如单链或Fv、Fab和(Fab')2以及双抗体、线性抗体、多价或多特异性杂交抗体。
-本文所用术语“片段”指完整或全长链抗体(本文中抗NGF抗体)的活性片段，通常是结合或可变区。所述部分或片段应保留完整链/抗体的至少一种活性，即其是“功能性部分”或“功能性片段”或“活性片段”。如果其保留至少一种活性，则优选保留靶标结合特性。抗体部分(或抗体片段)的示例包括但不限于单链Fv、Fab、单链抗体、Fv或scFv、VHH或vNAR。这些术语指在单个多肽链内包含来自重链和轻链的可变结构域但缺少恒定区的抗体片段。通常，单链抗体还包含VH和VL结构域之间的多肽接头，其能够令单链抗体形成抗原结合所需的结构。在具体的实施方式中，单链抗体还可以是双特异性和/或人源化的。
-术语“片段”也指“Fab片段”，其包含一条轻链和一条重链的可变结构域和CH1结构域。Fab分子的重链无法与另一重链分子形成二硫键。含有一条轻链和一条重链且含有更多恒定区(CH1和CH2结构域之间部分)从而在两条重链之间形成链间二硫键的“Fab’片段”称作F(ab')2分子。“F(ab')2”含有两条轻链和两条重链，其含有恒定区中CH1和CH2结构域之间的部分，使得两条重链之间形成链间二硫键。
-术语“SEED体”(SEED表示链交换工程改造的结构域；复数形式：SEED体)，是指包含人IgG和IgA CH3结构域衍生物的特定类型的抗体，产生由人IgG和IgA CH3序列的交替区段组成的互补人SEED CH3异二聚体(所得异二聚体被称为AG部分和GA部分，如图1所示)。它们是不对称融合蛋白。Davis等，2010或US 8,871,912描述了SEED体和SEED技术，其全部内容纳入本文。它们可以是单价或二价的。
-术语基于“杵臼”的抗体是指Carter及其同事在1996年开发的重链异二聚技术(Ridgway等，1996)。在这种方法中，CH3域的指定“杵”变体包含一个小氨基酸被一个较大的氨基酸(T366Y)取代。相反，设计用于异二聚并称为“臼”变体的相反的CH3结构域包含Y407T突变，即用较小的残基代替大残基。
-在本发明的上下文中，术语“治疗”指对于疾病进展的任何有利影响，包括在疾病开始后减弱、减少和降低或缓解疾病发展。
-术语“药学上可接受的”旨在涵盖任何运载体，其不干扰活性成分的生物学活性的有效性并且对给予的宿主无毒。例如，对于关节内给药，活性蛋白质可配制为用于在载剂中注射的单位剂型，载剂例如但不限于盐水、右旋糖溶液、血清白蛋白和林格氏溶液。
-本文中所用的术语“软骨疾病”涵盖由因损伤(例如创伤性损伤或软骨病疾病或关节炎)造成的损害所致的疾病。可以通过给予本文所述的融合蛋白来治疗的软骨疾病的实例包括但不限于关节炎，例如骨关节炎和软骨损伤。该措词还包括软骨或关节的退行性疾病/病症，例如软骨钙化病，多发性软骨炎，复发性多发性软骨炎，强直性脊柱炎或肋软骨炎。国际软骨修复协会提出了评估软骨缺损严重程度的关节镜分级系统：0级：(正常)健康软骨，1级：软骨具有软斑或水疱，2级：软骨中可见微小的撕裂，3级：病灶具有深裂缝(超过软骨层的50％)和4级：软骨撕裂暴露下面的(亚软骨)骨骼(参见ICRS出版物：http://www.cartilage.org/_files/contentmanagement/ICRS_evaluation.pdf，第13页)。
-本文使用的术语“关节炎”包括例如骨关节炎、类风湿性关节炎、青少年类风湿性关节炎、感染性关节炎、银屑病关节炎、斯蒂尔病(幼年类风湿性关节炎发作)或剥脱性骨软骨炎的疾病。它优选包括软骨受损的疾病或病症。
-所用术语“骨关节炎”意指关节炎的最常见形式。术语“骨关节炎”包括原发性骨关节炎和继发性骨关节炎(参见例如《默克手册》，第17版，第449页)。骨关节炎可能是由软骨分解引起的。少量的软骨可能会脱落，从而造成骨与骨之间的关节中的疼痛和膨胀。随时间推移，该软骨可能会完全磨损，使得骨与骨在一起摩擦。骨关节炎可以影响任何关节，但通常涉及手，肩膀和承重关节，例如臀部，膝盖，脚和脊柱。在一个优选的示例中，骨关节炎可以是膝盖骨关节炎或髋骨关节炎。该措词尤其包括骨关节炎的形式，根据OARSI分类系统，骨关节炎的形式分为1级至4级或1级至6级。技术人员完全知道本领域中使用的骨关节炎分类，特别是所述的OARSI评估系统(也称为OOCHAS；参见例如Custers等，2007)。骨关节炎是可通过给予本发明的融合蛋白治疗的优选的软骨疾病之一。
-本文中所用的术语“软骨损伤”是主要由创伤造成的软骨疾病或软骨损伤。在创伤性机械破坏之后，尤其是在意外事故或手术(例如微骨折手术)之后，可能会发生软骨损伤。术语“软骨损伤”还包括软骨或骨软骨骨折和半月板损伤。该定义中还考虑运动相关损伤或运动相关的关节组织磨损。该术语还包括微损伤或钝伤，软骨骨折，骨软骨骨折或半月板损伤。
-术语“对象”或“患者”旨在包括(但不限于)哺乳动物，例如人、狗、牛、马、绵羊、山羊、猫、小鼠、兔或大鼠。更优选地，对象(或患者)是人。
具体实施方式
发明人惊奇地发现，根据本发明的融合蛋白(即具有FGF-18部分和抗NGF部分两者)保持FGF-18对软骨的活性和NGF抑制剂对疼痛的活性。事实上，在体外发现，总体而言，1)FGF-18部分的作用通过与NGF抑制剂的融合而得以保留，并且2)FGF-18部分不影响抗NGF部分的中和作用。由于融合蛋白每个部分的分子量都很高，并且众所周知，由于例如不同的重折叠，融合蛋白可能不会表现出预期的活性，因此无法预期该发现。同样令人惊讶的是，所述活性得到维持，即使每种化合物的剂量非常低。在疾病情况下，本发明的优点将是减轻疼痛/改善功能，同时保持FGF-18部分对软骨结构的功效。
在第一个实施方式中，本发明提供了新的融合蛋白，其包含与抗NGF部分(即NGF的抑制剂，优选抗NGF抗体或其片段)融合的FGF-18部分。任选地，融合蛋白在两个部分之间包含接头。
整体上，根据本发明的FGF-18部分可以是SEQ ID NO：1所示的FGF-18的天然形式或其成熟形式(对应于SEQ ID NO：1的氨基酸残基28至残基207)。或者，其可以是截短形式，优选包含至少150个氨基酸残基，例如SEQ ID NO：2所示的截短形式(SEQ ID No：2是没有任何前导序列的截短的FGF-18的成熟形式)。当在其N-末端部分中具有额外的一个甲硫氨酸残基表达时，所述截短形式被称为司瑞菲敏(sprifermin)。也可以使用其他截短形式，优选包含至少150个氨基酸残基，例如包含或由SEQ ID No：2的氨基酸1(Glu)至167(Thr)组成的形式，包含或由SEQ ID No：2氨基的酸1(Glu)至161(Pro)组成的形式(如SEQ ID NO：3所示)或诸如与SEQ ID No：2相比在N端和/或C端中具有1至15个氨基酸残基缺失和/或具有一些突变(例如，降低蛋白酶活性)的任何形式。可以使用此类截短和/或突变形式，只要它们保留天然FGF-18或司瑞菲敏的全部生物活性即可。这种其他截短和/或突变形式的实例是例如选自(但不限于)SEQ ID No：4至8或87的氨基酸序列或包含SEQ ID NO：1至8或87中任何一个的至少150个连续氨基酸残基的多肽。在另一个替代方案中，FGF18部分可以是与SEQID NO：1的氨基酸残基28至残基207或与SEQ ID NO：2具有至少80％的序列相同性的活性变体。优选地，所述FGF18变体与SEQ ID NO：1的氨基酸残基28至残基207或与SEQ ID NO：2具有至少85％，至少90％，至少91％，至少92％，至少93％，至少94％，至少95％，至少96％，至少97％，至少98％或至少99％的序列相同性。所述(活性)变体可以是FGF18部分与来自另一FGF部分，例如来自FGF8，FGF9或FGF19部分的部分序列融合或精确突变的结果。此类变体的实例显示在SEQID NO：83-86中。
本发明的抗NGF部分必须结合并中和NGF。优选地，所述抗NGF部分基于抗NGF抗体，并且优选地是其活性片段或活性变体。可以根据本发明使用的抗NGF抗体是例如他尼珠单抗，法希姆单抗或富拉单抗，但不限于这些抗体。优选地，这些抗NGF部分是抗NGF抗体的活性片段，例如scFv，Fab活性片段，VHH或vNAR，或者是所述抗NGF抗体的活性变体，例如SEED体或基于杵臼的抗体。例如，抗NGF抗体的(活性)片段可以选自氨基酸序列：SEQ ID NO：22(他尼珠单抗的scFv)，SEQ ID NO：23(法希姆单抗的scFv)，SEQ ID NO：24(富拉单抗的scFv)，SEQ ID NO：16(他尼珠单抗的VH-Fab)，SEQ ID NO：18(法希姆单抗的VH-Fab)，SEQID NO：20(富拉单抗的VH-Fab)，SEQ ID NO：17(他尼珠单抗的VL-Fab)，SEQ ID NO：19(法希姆单抗的VL-Fab)和SEQ ID NO：21(富拉单抗的VL-Fab)。
或者，根据本发明的抗NGF抗体或其与NGF结合的部分包含HCDR1，H-CDR2和H-CDR3的重链可变结构域和包含L-CDR1，L-CDR2和L-CDR3的轻链可变结构域，其中，1)H-CDR1包含SEQ ID NO：135的氨基酸序列或由其组成，2)H-CDR2包含SEQ ID NO：136的氨基酸序列或由其组成，3)H-CDR3包含SEQ ID NO：137的氨基酸序列或由其组成，4)L-CDR1包含SEQ ID NO：138的氨基酸序列或由其组成，5)L-CDR2包含SEQ IDNO：139的氨基酸序列或由其组成，和6)L-CDR3包含SEQ ID NO：140的氨基酸序列或由其组成。
本发明的FGF-18部分可以通过其N端或C端直接或通过接头与抗NGF部分连接(见图1)。SEQ ID No：118-120或127-131表示可以在任何构建体中无差别使用的接头的实例。技术人员将理解，在根据本发明的用于融合蛋白的任何SEQ ID NO中，他可以用他选择的任何其他接头来改变接头。
当根据本发明的融合蛋白是与scFv部分融合的FGF-18部分时，该连接可以通过抗NGF scFv部分的游离VH-末端或游离VL-末端进行。此类融合蛋白的实例例如包含：1)选自包含SEQ ID No：1至8中的任何一个或由其组成的氨基酸序列作为FGF-18部分，和2)选自包含SEQ ID No：22至24中的任何一个或由其组成的氨基酸序列作为抗NGF部分，和任选地3)FGF-18部分和抗NGF部分之间的接头。特异性融合蛋白的实例例如选自(但不限于)下组的氨基酸序列：SEQ ID No：25-27。
当根据本发明的构建体(或融合蛋白)基于Fab作为抗NGF部分时，它将同时包含VH-Fab结构域和VL-Fab结构域，FGF-18通过所述Fab部分的C端和/或N端融合至VH-Fab结构域和/或VL-Fab结构域中的任一个。此类融合蛋白的实例例如包含：1)选自包含SEQ ID No：1至8或83-87中的任何一个或由其组成的氨基酸序列作为FGF-18部分，和2)选自包含SEQID No：16至21中的任何一个或由其组成的氨基酸序列作为抗NGF部分，和任选地3)FGF-18部分和抗NGF部分之间的接头，其可以选自包含SEQ ID No：118-120或127-131中的任一个或由其组成的组。特异性融合蛋白的实例例如选自(但不限于)下组的氨基酸序列：SEQ IDNo：28至53。如果FGF-18部分连接至VH-Fab，则融合蛋白将还包含常规的VL-Fab。这样的分子的实例是例如但不限于SEQ ID No：37和SEQ ID No：17，SEQ ID NO：40和SEQ ID No：17或SEQ ID NO：46和SEQ ID No：17的组合。如果FGF-18部分连接至VL-Fab，则融合蛋白将还包含常规的VH-Fab。由于Fab分子同时包含VH-Fab结构域和VL-Fab结构域，因此所述分子可包含i)VH-Fab结构域包含选自下组的氨基酸序列，该组包含SEQ ID NO：1至8或83-87中的任一个或由其组成，其融合至选自下组的氨基酸序列，该组包含SEQ ID NO：16、18或20中的任一个或由其组成，任选地在两个氨基酸序列部分之间具有接头；并且VL-Fab结构域包含选自下组的氨基酸序列，该组包含SEQ ID NO：17、19或21中的任一个或由其组成，ii)VL-Fab结构域包含选自下组的氨基酸序列，该组包含SEQ ID NO：1至8或83-87中的任一个或由其组成，其融合至选自下组的氨基酸序列，该组包含SEQ ID NO：17、19或21中的任一个或由其组成，任选地在两个氨基酸序列部分之间具有接头；并且VH-Fab结构域包含选自下组的氨基酸序列，该组包含SEQ ID NO：16、18或21中的任一个或由其组成，iii)VH-Fab结构域包含选自下组的氨基酸序列，该组包含SEQ ID NO：34至39、45至49、51或53中的任一个或由其组成；并且VL-Fab结构域包含选自下组的氨基酸序列，该组包含SEQ ID NO：17、19或21中的任一个或由其组成，或者iv)VL-Fab结构域包含选自下组的氨基酸序列，该组包含SEQ ID NO：28至33、40至44、50或52中的任一个或由其组成；并且VH-Fab结构域包含选自下组的氨基酸序列，该组包含SEQ ID NO：16、18或21中的任一个或由其组成。该分子的实例例如但不限于以下组合：1)SEQ ID No：28和SEQ ID No：16，2)SEQ ID NO：31和SEQ ID No：16，3)SEQ IDNO：40和SEQ ID No：16，4)SEQ ID NO：41和SEQ ID No：16或4)SEQ ID NO：42和SEQ ID No：16(HOF3)。
或者，当根据本发明的融合蛋白是与抗NGF抗体的SEED体形式融合的FGF-18部分时，将优选使用SEED体的单价形式(即它们通常不会形成包含两条完整重链和两条轻链的同二聚体)。SEED体(作为单体)由一条包含可变结构域和恒定结构域的完整轻链(例如SEQID NO：11、13或15公开)，一条包含可变结构域和恒定结构域的完整重链(例如SEQ ID No：56、58、60、65、71或96公开)以及仅包含SEED体的恒定结构域CH2和CH3的一条部分重链(例如SEQ ID No：54的氨基酸残基185至414，SEQ ID NO：55的氨基酸残基180至409、57的氨基酸残基180至409或SEQ ID No：102，SEQ IDNO：107，或SEQ ID No：59的氨基酸残基180至409)组成。部分重链与其在完整重链上的对应部分不对称(例如，如果完整重链为GA形式，则部分重链将为AG形式，反之亦然)。FGF-18部分将在C端或N端通过部分重链(见图1B或1D)，其完整重链或轻链(见图1C)连接到SEED体。与AG形式融合的这种FGF-18部分的非限制性实例例如选自氨基酸序列SEQ ID NO：54、55、57、59、62、66-70、77-82、91-95、101或103-106。与GA形式融合的这种FGF-18部分的非限制性实例例如选自氨基酸序列SEQ ID NO：72-76、90、97-100或108。此类FGF的非限制性实例-18-SEED抗体例如选自氨基酸序列(每个SEED体由三个序列组成，此处分别为FGF-18部分重链；完整重链和轻链)：1)SEQ ID No：54，56和11(MBE626)，2)SEQ ID No：55、56和11、3)SEQ ID No：57、58和13、4)SEQ ID No：59、60和15、5)SEQID No：90、71和11(HO124)，6)SEQ ID No：97、96和11(HO110)，或7)SEQ ID No：100、96和11(HO113)。融合至轻链的FGF-18部分的实例例如选自氨基酸序列：40-44或124-126。此类FGF-18-SEED体的非限制性实例例如选自氨基酸序列(每个SEED体由三个序列组成，此处分别为完整重链；部分重链和FGF-18-轻链)：1)SEQ ID No：71、102和126(HO114)，2)SEQ ID No：96、102和40-44或124-126中的任一个，3)56，107和40或124，4)58，107和40或124或5)60、107和40或124。
在另一个替代方案中，当根据本发明的融合蛋白是与抗NGF抗体的活性IgG变体形式融合的FGF-18部分时，FGF-18部分将通过其重链或其轻链在C端或N端与活性IgG变体连接。此类FGF-18-IgG融合体的实例例如选自氨基酸序列(每种融合蛋白由两个序列，即一个重链和一个轻链形成)：1)SEQ ID No：9或10和61，2)SEQ ID No：62和11，3)SEQ ID No：63和9或10，4)SEQ ID No：64和11，5)SEQ ID No：88或89和11，6)SEQ ID No：9或10和124或7)5)SEQ ID No：9或10和125。
整体上，根据本发明的融合蛋白可以在N端带有分子引导的方式表达。另外，还提供了与本文公开的完整或部分重链氨基酸序列或者重链可变区序列具有至少80％或更多，至少85％或更多，至少90％或更多，至少95％或更多，或至少99％或更多的序列相同性的氨基酸序列。类似地，还提供了与本文公开的轻链可变区序列具有至少85％或更多，至少90％或更多，至少95％或更多，或至少99％或更多的序列相同性的氨基酸序列。
本发明的另一个实施方式是一种分离的核酸分子或多核苷酸，其编码本发明所述任意融合蛋白，或其互补链或简并序列。在这一方面，术语“核酸分子”或可互换的“多核苷酸”涵盖所有不同类型的核酸，包括但不限于脱氧核糖核酸(例如DNA、cDNA、gDNA、合成的DNA等)、核糖核酸(如RNA)和肽核酸(PNA)。在优选的实施方式中，该核酸分子是DNA分子，例如双链DNA分子或cDNA分子。术语“分离的”指核酸分子已经鉴定并与至少一种污染核酸分子分离，所述污染核酸分子通常在天然来源中与所述核酸分子结合。分离的核酸分子不同于其在天然中发现的形式或状态。因此，分离的核酸分子与天然细胞中存在的特定核酸分子不同。简并序列指编码与参考核苷酸序列相同的氨基酸序列的任意核苷酸序列，但其因为遗传密码简并性而包含不同的核苷酸序列。
在一个特定的实施方式中，当根据本发明的融合蛋白是与活性抗NGF部分的活性scFv片段连接的FGF-18部分时，所述融合蛋白被编码为单个分子，即核苷酸序列整体包含编码的两个部分所需要的核苷酸。
或者，当根据本发明的融合蛋白是与Fab部分或活性IgG变体连接的FGF-18部分时，一个多核苷酸编码本发明的任何一种融合蛋白的重链，另一个多核苷酸编码本发明的任何一种融合蛋白的轻链。取决于FGF-18部分与Fab连接的方式，其编码序列将在其N端或在其C端连接至重链或轻链的编码序列。或者，当根据本发明的融合蛋白是与SEED体连接的FGF-18部分时，一个多核苷酸编码本发明的任何一种融合蛋白的完整重链，另一个多核苷酸编码与本发明的任何一种融合蛋白的FGF-18部分融合的部分重链，并且另一个编码本发明的任何一种融合蛋白的轻链。编码所述蛋白质的多核苷酸序列通常在前导序列之后。可以根据本发明使用的多核苷酸序列的非限制性实例是例如SEQ ID No：109-117和132的那些。
由于遗传密码子的简并性，应理解可优化编码本发明所述融合蛋白的多核苷酸。因此，还提供了与编码本发明所述重链可变区序列(例如上文列举的优选的多核苷酸序列)至少90％或以上相同、至少95％或以上相同或至少99％或以上相同的多核苷酸序列。类似地，还提供了与编码本发明所述轻链可变区序列(例如上文列举的优选的多核苷酸序列)至少90％或以上相同、至少95％或以上相同或至少99％或以上相同的多核苷酸序列。
本发明的另一个实施方式是一种载体，其包含编码本文所述的任何一种融合蛋白的DNA。该载体可以是任意克隆或表达载体，整合或自主复制，在任何原核或真核细胞中起作用。具体而言，该载体可以是质粒、粘粒、病毒、噬菌体、原生质体、人工染色体等。该载体可包含重链和轻链的整个或部分编码序列，或轻链和重链编码序列中的任一种，或其任何部分。如果载体包含重链和轻链的编码序列(例如在Fab融合蛋白或SEED体融合蛋白的情况下)，则这些编码序列可各自与启动子可操作地连接。对于重链和轻链编码序列，该启动子可以是相同的或不同的。重链和轻链编码序列还可可操作地连接单个启动子，此时重链和轻链的编码序列可优选由内部核糖体进入位点(IRES)或病毒2A肽隔开。用于真核基因表达的合适的启动子是例如衍生自病毒基因如鼠或人巨细胞病毒(CMV)的启动子，小鼠双向CMV启动子，劳斯肉瘤病毒(RSV)启动子或人延伸因子-1α(EF-1α)启动子，这是本领域技术人员众所周知的。该载体可包含调控元件，例如启动子、终止子、增强子、选择标志物、复制起点、绝缘子等。可以通过多种方法将合适的核酸序列插入载体。通常，使用本领域已知的方法将DNA插入适当限制性内切酶位点。包含一种或多种这些成分的合适载体的构建采用技术人员已知的标准连接技术。
本发明的另一个实施方式是一种重组宿主细胞，所述细胞包含一种或多种上文所述核酸分子/多核苷酸或一种或多种上文所述载体。宿主细胞可以是原核或真核细胞。原核细胞的示例包括细菌，例如大肠杆菌。真核细胞的示例是酵母细胞、植物细胞、哺乳动物细胞和昆虫细胞，包括任何原代细胞培养物或建立的细胞系(例如3T3、Vero、HEK293、TN5等)。用于表达糖基化蛋白的合适宿主细胞衍生自多细胞生物。优选的有用哺乳动物宿主细胞系的实例包括CHO(例如CHO-S，ExpiCHOTM，CHO-k1或CHO-LF)，HEK293(例如293，293-6E或Expi293TM)，NS0，SP2/0和COS细胞。本发明的融合蛋白可通过本领域已知的任何技术生产，例如通过重组技术、化学合成、克隆、连接或其组合。许多书和综述教导了如何使用载体和原核或真核宿主细胞来克隆和生产重组蛋白。如果需要获得具有较低糖基化水平的融合蛋白或无糖基化融合蛋白，则可以有利地使用酵母表达系统或工程改造/糖工程改造CHO细胞系。类似地，如果需要获得具有较低岩藻糖基化水平的融合蛋白或岩藻糖基化的融合蛋白，则可以有利地使用工程改造/糖工程改造的酵母表达系统或工程改造/糖工程改造CHO细胞系。
因此，本发明的另一个实施方式是产生本发明的融合蛋白的方法，该方法包括在允许表达编码本文所述任何融合蛋白或其部分的核酸分子的条件下培养本发明的重组宿主细胞，并回收/分离产生的融合蛋白。生产的融合蛋白可以是糖基化或去糖基化的，可以是岩藻糖基化或去岩藻糖基化的，或可含有其他翻译后修饰，这取决于使用的宿主细胞类型。本发明的产生融合蛋白的方法可以进一步包括纯化所述融合蛋白和/或将所述融合蛋白配制成药物组合物的步骤。
用于制备编码本文所述融合蛋白的多核苷酸(包括DNA和RNA)的其他方法是本领域众所周知的。可使用异硫氰酸胍提取并随后在CsCI梯度中提供离心分离来制备总RNA(Chirgwin等1979)。使用Aviv和Leder(Aviv和Leder 1972)的方法从总RNA制备多聚(A)+RNA。使用已知方法由多聚(A)+RNA制备互补DNA(cDNA)。或者，可分离基因组DNA。编码融合蛋白的多核苷酸可随后通过例如杂交或PCR进行鉴定和分离。
总体上，在本发明的上下文中，融合蛋白是药物制剂的一部分。本发明的融合蛋白可以配制成药物组合物，即与至少一种药学上可接受的运载体，赋形剂等一起配制。定义“药学上可接受的”旨在涵盖任何运载体，赋形剂等，其不干扰活性成分的生物学活性的有效性并且对给予的患者无毒。所述至少一种赋形剂例如选自缓冲剂，表面活性剂，盐，抗氧化剂，等张剂，填充剂，稳定剂或其任何组合。例如，对于胃肠道外给药，融合蛋白可配制为用于在载剂中注射的单位剂型，载剂例如盐水、右旋糖溶液、血清白蛋白和林格氏溶液或任何类型的已知缓冲剂。用于关节内施用的制剂将符合大部分要求，其也适用于其他注射制剂，即它们需要是无菌的并且与施用部位(例如膝关节，滑液)处的生理条件相容。用于关节内注射的赋形剂也可以存在于其他注射制剂中，例如用于静脉内或皮下施用。融合蛋白的此类制剂，包括至少一种其他药学上可接受的运载体，赋形剂等，也可用于本发明。
总体上，在本发明的上下文中，融合蛋白用于治疗软骨疾病，例如骨关节炎或软骨损伤。特别地，它们可用于治疗滑膜关节的关节软骨缺损，例如，由于表面纤维性颤动(早期骨关节炎)，由于骨关节炎引起的软骨变性，以及由于损伤或疾病引起的软骨或骨软骨缺损。融合蛋白还可以用于治疗由分离性骨软骨炎和退化性关节疾病引起的关节疾病。在重建和整形外科领域，融合蛋白将用于自体或同种异体软骨的扩张和转移，以重建广泛的组织缺损。根据本发明的融合蛋白可以与关节的灌洗，刺激骨髓，磨损性关节置换术，软骨下钻孔或软骨下骨的微骨折一起用于修复软骨损伤。
在一个优选的实施方式中，待根据本发明治疗的软骨疾病是骨关节炎，例如膝骨关节炎或髋关节骨关节炎。待治疗的骨关节炎可以是例如但不限于原发性骨关节炎或继发性骨关节炎，以及根据OARSI分类系统分类为1至4级或1至6级的骨关节炎。
在另一个优选的实施方式中，根据本发明待治疗的软骨疾病是在有或没有手术介入如微骨折的情况下的软骨损伤。另外，在由于给予根据本发明的融合蛋白而导致软骨生长之后，可能需要外科手术治疗以适当地使新形成的软骨表面轮廓化。
在一个优选的实施方式中，治疗包括根据本发明的融合蛋白的滑膜周围给药，滑膜内给药，关节周围给药或关节内给药。所述融合蛋白可通过直接注射到关节的滑液中或直接注射到缺损中，单独或与合适的运载体复合以延长蛋白质的释放(例如持续释放的制剂)或限制局部释放。关节内给药是在选自髋，膝，肘，腕，踝，脊柱，脚，手指，脚趾，手，肩，肋骨，肩胛骨，大腿，小腿，脚跟和沿脊柱骨点的关节中进行的。在另一个优选的实施方式中，关节内给药在髋或膝的关节中进行。
附图描述：
图1：A)经由所述ScFv部分的游离VL部分与scFv部分连接的FGF-18部分的结构。B)经由所述SEED体的部分重链的N端，在此为AG部分与SEED体部分连接的FGF-18部分的结构。C)经由所述SEED体的轻链的C端与SEED体部分连接的FGF-18部分的结构。D)经由所述SEED体的部分重链的C端，在此为AG部分与SEED体部分连接的FGF-18部分的结构。E)经由轻链融合的N端与Fab部分连接的FGF-18部分的结构。F)经由N端重链融合与Fab部分连接的FGF-18部分的结构。G)经由C端轻链融合与Fab部分连接的FGF-18部分的结构。H)经由C端重链融合与Fab部分连接的FGF-18部分的结构。I)经由N端轻链融合与IgG部分连接的FGF-18部分的结构。J)经由N端重链融合与IgG部分连接的FGF-18部分的结构。K)经由C端轻链融合与IgG部分连接的FGF-18部分的结构。L)经由C端重链融合与IgG部分连接的FGF-18部分的结构。
图2：A)在用rhFGF18，构建体FGF18 scFv他尼珠单抗或MBE626培养7天的单层中，猪软骨细胞中的细胞增殖和I型胶原蛋白表达。B)用50.04nM的rhFGF18、构建体FGF18 scFv他尼珠单抗或MBE626培养5天的单层中，猪软骨细胞的细胞形态(肌动蛋白染色)。
图3：A)设计用于分析MIA大鼠模型中步态异常的体内研究。在3mg/关节MIA引起骨关节炎疼痛后的第1天进行关节内注射。同时静脉内注射他尼珠单抗。步态异常已通过猫步(catwalk)分析进行了分析。B)MIA引起的骨关节炎疼痛期间，FGF18-scFv-他尼珠单抗的剂量依赖性症状益处。显示的是7-8只大鼠/组的对侧后爪印百分比平均值±SEM的时程±SEM。
图4：A)设计用于分析慢性骨关节炎的ACLT tMx大鼠模型中的步态异常的体内研究。(B)随时间推移的步态异常。100％步态的质量相当于两个后爪的负重相等。(C)注射后3周内的步态异常表示为曲线上方的面积(AAC；100％＝基线)。显示的是9-10只动物的平均值±SEM。显著性已通过采用Dunnett事后检验的双向方差分析确定。
图5：A)用MBE626进行的关于结构和症状益处的长期研究干预方案。B)在慢性骨关节炎期间，MBE626随时间推移对步态表现的治疗效果。显示的是参数爪印长度的对侧百分比。100％表示相等负重。减小的值表示由于膝盖疼痛而减轻了对患肢的负重。数据代表n＝10-18只动物/组的平均值±SEM。
图6：相对于安慰剂的益处百分比：已确定从第13天到第98天(结束)的曲线下面积。接下来，健康+载剂组的AUC均值已设置为100％益处，而ACLTpMx+载剂组的AUC均值已设置为0％益处。基于此归一化，已计算出每只动物相对于载剂(安慰剂)的益处百分比，并显示了平均值±SEM(n＝10-18只动物/组)。
图7：通过组织学评分确定的软骨结构。显示的是18只动物/组的平均值±SEM。
氨基酸序列的列表和说明
SEQ ID NO：1：天然人FGF-18的氨基酸序列
MYSAPSACTCLCLHFLLLCFQVQVLVAEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKRSRRIRPTHPA
SEQ ID NO：2：重组截短的FGF-18(trFGF-18)的氨基酸序列
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTK
SEQ ID NO：3：FGF18_delta8的氨基酸序列
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKP
SEQ ID NO：4：FGF18_TF的氨基酸序列
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPGGGGSGGGGS
SEQ ID NO：5：FGF18_QNQS的氨基酸序列
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQQNFQSTTVTK
SEQ ID NO：6：FGF18_Y191P的氨基酸序列
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKPTTVTK
SEQ ID NO：7：FGF18_3Ala的氨基酸序列
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQAAFAYTTVTK
SEQ ID NO：8：FGF18_VS的氨基酸序列
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFVSTTVTK
SEQ ID NO：9：他尼珠单抗的完整重链的氨基酸序列
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO：10：他尼珠单抗的完整重链的氨基酸序列，具有点突变
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO：11：他尼珠单抗的完整轻链的氨基酸序列
DIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：12：法希姆单抗的完整重链的氨基酸序列
QVQLVQSGAEVKKPGASVKVSCKVSGFTLTELSIHWVRQAPGKGLEWMGGFDPEDGETIYAQKFQGRVTMTEDTSTDTAYMELTSLRSEDTAVYYCSTIFGVVTNFDNWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO：13：法希姆单抗的完整轻链的氨基酸序列
DIQMTQSPSSLSASAGDRVTITCRASQAIRNDLGWYQQKPGKAPKRLIYAAFNLQSGVPSRFSGSGSGTEFTLTISSLQPEDLASYYCQQYNRYPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：14：富拉单抗的重链的氨基酸序列
EVQLVESGGGLVQPGGSLRLSCAASGFTLRSYSMNWVRQAPGKGLEWVSYISRSSHTIFYADSVKGRFTISRDNAKNSLYLQMDSLRDEDTAMYYCARVYSSGWHVSDYFDYWGQGILVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO：15：富拉单抗的轻链的氨基酸序列
AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：16：他尼珠单抗的重链Fab片段的氨基酸序列
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
SEQ ID NO：17：他尼珠单抗的轻链Fab片段的氨基酸序列
DIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：18：法希姆单抗的重链Fab片段的氨基酸序列
QVQLVQSGAEVKKPGASVKVSCKVSGFTLTELSIHWVRQAPGKGLEWMGGFDPEDGETIYAQKFQGRVTMTEDTSTDTAYMELTSLRSEDTAVYYCSTIFGVVTNFDNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
SEQ ID NO：19：法希姆单抗的轻链Fab片段的氨基酸序列
DIQMTQSPSSLSASAGDRVTITCRASQAIRNDLGWYQQKPGKAPKRLIYAAFNLQSGVPSRFSGSGSGTEFTLTISSLQPEDLASYYCQQYNRYPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：20：富拉单抗的重链Fab片段的氨基酸序列
EVQLVESGGGLVQPGGSLRLSCAASGFTLRSYSMNWVRQAPGKGLEWVSYISRSSHTIFYADSVKGRFTISRDNAKNSLYLQMDSLRDEDTAMYYCARVYSSGWHVSDYFDYWGQGILVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
SEQ ID NO：21：富拉单抗的轻链Fab片段的氨基酸序列
AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：22：他尼珠单抗的scFv的氨基酸序列
DIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSS
SEQ ID NO：23：法希姆单抗的scFv的氨基酸序列
DIQMTQSPSSLSASAGDRVTITCRASQAIRNDLGWYQQKPGKAPKRLIYAAFNLQSGVPSRFSGSGSGTEFTLTISSLQPEDLASYYCQQYNRYPWTFGQGTKVEIKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKVSGFTLTELSIHWVRQAPGKGLEWMGGFDPEDGETIYAQKFQGRVTMTEDTSTDTAYMELTSLRSEDTAVYYCSTIFGVVTNFDNWGQGTLVTVSS
SEQ ID NO：24：富拉单抗的scFv的氨基酸序列
AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTLRSYSMNWVRQAPGKGLEWVSYISRSSHTIFYADSVKGRFTISRDNAKNSLYLQMDSLRDEDTAMYYCARVYSSGWHVSDYFDYWGQGILVTVSS
SEQ ID NO：25：FGF-18-scFv-他尼珠单抗的氨基酸序列，经由轻链结构域N端融合(残基1-169＝FGF-18部分；170-184＝接头；185-427＝scFv他尼珠单抗作为抗-NGF抑制剂部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSS
SEQ ID NO：26：FGF-18-scFv-法希姆单抗的氨基酸序列，经由轻链结构域N端融合(残基1-169＝FGF-18部分；170-184＝接头；185-425＝scFv法希姆单抗作为抗-NGF抑制剂部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKGGGGSGGGGSGGGGSDIQMTQSPSSLSASAGDRVTITCRASQAIRNDLGWYQQKPGKAPKRLIYAAFNLQSGVPSRFSGSGSGTEFTLTISSLQPEDLASYYCQQYNRYPWTFGQGTKVEIKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKVSGFTLTELSIHWVRQAPGKGLEWMGGFDPEDGETIYAQKFQGRVTMTEDTSTDTAYMELTSLRSEDTAVYYCSTIFGVVTNFDNWGQGTLVTVSS
SEQ ID NO：27：FGF-18-scFv-富拉单抗的氨基酸序列，经由轻链结构域N端融合(残基1-169＝FGF-18部分；170-184＝接头；185-429＝scFv富拉单抗作为抗-NGF抑制剂部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKGGGGSGGGGSGGGGSAIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTLRSYSMNWVRQAPGKGLEWVSYISRSSHTIFYADSVKGRFTISRDNAKNSLYLQMDSLRDEDTAMYYCARVYSSGWHVSDYFDYWGQGILVTVSS
SEQ ID NO：28：FGF-18-抗NGF的Fab的氨基酸序列，经由轻链N端融合(残基1-169＝FGF-18部分；170-184＝接头；185-398＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：29：FGF18TF-抗NGF的Fab的氨基酸序列，经由轻链N端融合(残基1-161＝FGF-18部分；162-186＝接头；187-400＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPGGGGSGGGGSEPKSSDKTHTGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：30：FGF18QNQS–抗-NGF的Fab的氨基酸序列，经由轻链N端融合(残基1-169＝FGF-18部分；1170-184＝接头；185-398＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQQNFQSTTVTKEPKSSDKTHTGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：31：FGF18Y191P–抗NGF抗体的Fab的氨基酸序列，经由轻链N端融合(残基1-169＝FGF-18部分；170-184＝接头；185-398＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKPTTVTKEPKSSDKTHTGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：32：FGF18_3Ala–抗NGF的Fab的氨基酸序列，经由轻链N端融合(残基1-169＝FGF-18部分；170-184＝接头；185-398＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQAAFAYTTVTKEPKSSDKTHTGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：33：FGF18VS-抗NGF的Fab的氨基酸序列，经由轻链N端融合(残基1-169＝FGF-18部分；170-184＝接头；185-398＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFVSTTVTKEPKSSDKTHTGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：34：FGF18-抗NGF的Fab的氨基酸序列，经由重链N端融合(残基1-169＝FGF-18部分；170-179＝接头；180-403＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
SEQ ID NO：35：FGF18TF-抗NGF的Fab的氨基酸序列，经由重链N端融合(残基1-161＝FGF-18部分；162-186＝接头；187-410＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPGGGGSGGGGSEPKSSDKTHTGGGGSQVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
SEQ ID NO：36：FGF18QNQS–抗NGF的Fab的氨基酸序列，经由重链N端融合(残基1-169＝FGF-18部分；170-184＝接头；185-408＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQQNFQSTTVTKEPKSSDKTHTGGGGSQVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
SEQ ID NO：37：FGF18Y191P–抗NGF的Fab的氨基酸序列，经由重链N端融合(残基1-169＝FGF-18部分；170-184＝接头；185-408＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKPTTVTKEPKSSDKTHTGGGGSQVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
SEQ ID NO：38：FGF18_3Ala–抗NGF的Fab的氨基酸序列，经由重链N端融合(残基1-169＝FGF-18部分；170-184＝接头；185-408＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQAAFAYTTVTKEPKSSDKTHTGGGGSQVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
SEQ ID NO：39：FGF18VS–抗NGF的Fab的氨基酸序列，经由重链N端融合(残基1-169＝FGF-18部分；170-184＝接头；185-408＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFVSTTVTKEPKSSDKTHTGGGGSQVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
SEQ ID NO：40：抗NGF的Fab-FGF18_delta8的氨基酸序列，经由轻链C端融合(残基1-214＝Fab部分；215-234＝接头；235-395＝FGF-18部分)
DIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKP
SEQ ID NO：41：抗NGF的Fab-FGF18QNQS的氨基酸序列，经由轻链C端融合(残基1-214＝Fab部分；215-234＝接头；235-403＝FGF-18部分)
DIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQQNFQSTTVTK
SEQ ID NO：42：抗NGF的Fab-FGF18Y191P的氨基酸序列，经由轻链C端融合(残基1-214＝Fab部分；215-234＝接头；235-403＝FGF-18部分)
DIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKPTTVTK
SEQ ID NO：43：抗NGF的Fab-FGF18_3Ala的氨基酸序列，经由轻链C端融合(残基1-214＝Fab部分；215-234＝接头；235-403＝FGF-18部分)
DIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQAAFAYTTVTK
SEQ ID NO：44：抗NGF的Fab-FGF18VS的氨基酸序列，经由轻链C端融合(残基1-214＝Fab部分；215-234＝接头；235-403＝FGF-18部分)
DIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFVSTTVTK
SEQ ID NO：45：抗NGF的Fab-FGF18TF的氨基酸序列，经由重链C端融合(残基1-224＝Fab部分；225-244＝接头；245-405＝FGF-18部分)
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKP
SEQ ID NO：46：抗NGF的Fab-FGF18QNQS的氨基酸序列，经由重链C端融合(残基1-224＝Fab部分；225-244＝接头；245-413＝FGF-18部分)
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQQNFQSTTVTK
SEQ ID NO：47：抗NGF的Fab-FGF18Y191P的氨基酸序列，经由重链C端融合(残基1-224＝Fab部分；225-244＝接头；245-413＝FGF-18部分)
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKPTTVTK
SEQ ID NO：48：抗NGF的Fab-FGF18_3Ala的氨基酸序列，经由重链C端融合(残基1-224＝Fab部分；225-244＝接头；245-413＝FGF-18部分)
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQAAFAYTTVTK
SEQ ID NO：49：抗NGF的Fab-FGF18VS的氨基酸序列，经由重链C端融合(残基1-224＝Fab部分；225-244＝接头；245-413＝FGF-18部分)
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFVSTTVTK
SEQ ID NO：50：FGF-18-抗NGF的Fab的氨基酸序列，经由法希姆单抗轻链N端融合(残基1-169＝FGF-18部分；170-179＝接头；180-393＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKGGGGSGGGGSDIQMTQSPSSLSASAGDRVTITCRASQAIRNDLGWYQQKPGKAPKRLIYAAFNLQSGVPSRFSGSGSGTEFTLTISSLQPEDLASYYCQQYNRYPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：51：FGF-18-抗NGF的Fab的氨基酸序列，经由法希姆单抗重链N端融合(残基1-169＝FGF-18部分；170-179＝接头；180-401＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKVSGFTLTELSIHWVRQAPGKGLEWMGGFDPEDGETIYAQKFQGRVTMTEDTSTDTAYMELTSLRSEDTAVYYCSTIFGVVTNFDNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
SEQ ID NO：52：FGF-18-抗NGF的Fab的氨基酸序列，经由富拉单抗轻链N端融合(残基1-169＝FGF-18部分；170-179＝接头；180-393＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKGGGGSGGGGSAIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：53：FGF-18-抗NGF的Fab的氨基酸序列，经由富拉单抗重链N端融合(残基1-169＝FGF-18部分；170-179＝接头；180-405＝Fab部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTLRSYSMNWVRQAPGKGLEWVSYISRSSHTIFYADSVKGRFTISRDNAKNSLYLQMDSLRDEDTAMYYCARVYSSGWHVSDYFDYWGQGILVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
SEQ ID NO：54：FGF18-SEED，AG链的氨基酸序列(在序列的N端连接了FGF-18部分；残基1-169＝FGF-18部分；170-184＝接头；185-414＝AG链部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKGGSGGSGSGSEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：55：FGF18-SEED，AG链的氨基酸序列(在序列的N端连接了FGF-18部分；残基1-169＝FGF-18部分；170-179＝接头；180-409＝AG链部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：56：抗NGF GA链的氨基酸序列
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGK
SEQ ID NO：57：FGF18-SEED，AG链的氨基酸序列(在序列的N端连接了FGF-18部分；残基1-169＝FGF-18部分；170-179＝接头；180-409＝AG链部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：58：抗NGF GA链的氨基酸序列
QVQLVQSGAEVKKPGASVKVSCKVSGFTLTELSIHWVRQAPGKGLEWMGGFDPEDGETIYAQKFQGRVTMTEDTSTDTAYMELTSLRSEDTAVYYCSTIFGVVTNFDNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGK
SEQ ID NO：59：FGF18-SEED，AG链的氨基酸序列(在序列的N端连接了FGF-18部分；残基1-169＝FGF-18部分；170-179＝接头；180-409＝AG链部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：60：抗NGF GA链的氨基酸序列
EVQLVESGGGLVQPGGSLRLSCAASGFTLRSYSMNWVRQAPGKGLEWVSYISRSSHTIFYADSVKGRFTISRDNAKNSLYLQMDSLRDEDTAMYYCARVYSSGWHVSDYFDYWGQGILVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGK
SEQ ID NO：61：FGF18_3Ala_IgG-轻链的氨基酸序列，经由该序列的N端融合；残基1-169＝FGF-18部分；170-184＝接头；185-398＝轻链部分
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQAAFAYTTVTKEPKSSDKTHTGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：62：FGF18_3Ala_IgG重链的氨基酸序列，经由该序列的N端融合；残基1-169＝FGF-18部分；170-184＝接头；185-635＝AG链部分
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQAAFAYTTVTKEPKSSDKTHTGGGGSQVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO：63：IgG轻链-FGF18_3Ala的氨基酸序列，经由该序列的C端融合；残基1-214＝轻链部分；215-234＝接头；235-403＝FGF-18部分。
DIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQAAFAYTTVTK
SEQ ID NO：64：IgG重链-FGF18_3Ala的氨基酸序列，经由该序列的C端融合；残基1-451＝重链部分；452-471＝接头；472-640＝FGF-18部分。
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQAAFAYTTVTK
SEQ ID NO：65：具有点突变的抗NGF GA链的氨基酸序列
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGK
SEQ ID NO：66：FGF18TF_SEED，AG链的氨基酸序列(作为SEED体的部分重链)(在序列的N端连接了FGF-18部分；残基1-162＝FGF-18部分；163-176＝接头；177-406＝AG链部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPGGGGSGGGGSEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：67：FGF18QNQS_SEED，AG链(作为SEED体的部分重链)的氨基酸序列(在序列的N端连接了FGF-18部分；残基1-169＝FGF-18部分；170-174＝接头；175-404＝AG链部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQQNFQSTTVTKEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：68：FGF18Y191P_SEED，AG链(作为SEED体的部分重链)的氨基酸序列(在序列的N端连接了FGF-18部分；残基1-169＝FGF-18部分；170-174＝接头；175-404＝AG链部分)。
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKPTTVTKEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：69：FGF18_3Ala_SEED，AG链(作为SEED体的部分重链)的氨基酸序列(在序列的N端连接了FGF-18部分；残基1-169＝FGF-18部分；170-174＝接头；175-404＝AG链部分)。
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQAAFAYTTVTKEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：70：FGF18VS_SEED，AG链(作为SEED体的部分重链)的氨基酸序列(在序列的N端连接了FGF-18部分；残基1-169＝FGF-18部分；170-174＝接头；175-404＝AG链部分)。
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFVSTTVTKEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：71：抗NGF AG链的氨基酸序列(作为SEED体的完整重链)
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：72：SEED_FGF18TF，GA链(作为SEED体的部分重链)的氨基酸序列(在序列的N端连接了FGF-18部分；残基1-161＝FGF-18部分；162-176＝接头；177-406＝GA链部分)。
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPGGGGSGGGGSEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGK
SEQ ID NO：73：SEED_FGF18QNQS，GA链(作为SEED体的部分重链)的氨基酸序列(在序列的N端连接了FGF-18部分；残基1-169＝FGF-18部分；170-174＝接头；175-404＝GA链部分)。
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQQNFQSTTVTKEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGK
SEQ ID NO：74：SEED_FGF18Y191P，GA链的氨基酸序列(在序列的N端连接了FGF-18部分)(作为SEED体的部分重链；残基1-169＝FGF-18部分；170-174＝接头；175-404＝GA链部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKPTTVTKEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGK
SEQ ID NO：75：SEED_FGF18_3Ala，GA链的氨基酸序列(在序列的N端连接了FGF-18部分)。(作为SEED体的部分重链；残基1-169＝FGF-18部分；170-174＝接头；175-404＝GA链部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQAAFAYTTVTKEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGK
SEQ ID NO：76：SEED_FGF18VS，GA链的氨基酸序列(在序列的N端连接了FGF-18部分)。(作为SEED体的部分重链；残基1-169＝FGF-18部分；170-174＝接头；175-404＝GA链部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFVSTTVTKEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGK
SEQ ID NO：77：FGF18_SEED_GS，AG链的氨基酸序列(FGF-18部分在序列的N端连接)。(作为SEED体的部分重链；残基1-169＝FGF-18部分；170-179＝接头；180-409＝AG链部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKGGSGGSGSGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：78：FGF18_SEED_CH2，AG链的氨基酸序列(在序列的N端连接了FGF-18部分)。(作为SEED体的部分重链；残基1-169＝FGF-18部分；170-177＝接头；178-407＝AG链部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKPAPEAAGGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：79：FGF18_SEED_YOL，AG链的氨基酸序列(在序列的N端连接了FGF-18部分)。(作为SEED体的部分重链；残基1-169＝FGF-18部分；170-178＝接头；179-408＝AG链部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKEEGEFSEARDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：80：FGF18_SEED_铰链，AG链的氨基酸序列(在序列的N端连接了FGF-18部分)。(作为SEED体的部分重链；残基1-169＝FGF-18部分；170-174＝接头；175-404＝AG链部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：81：FGF18_SEED_shin，AG链的氨基酸序列(在序列的N端连接了FGF-18部分)。(作为SEED体的部分重链；残基1-169＝FGF-18部分；170-399＝AG链部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：82：FGF18_SEED_3Ala，AG链的氨基酸序列(在序列的N端连接了FGF-18部分)。(作为SEED体的部分重链；残基1-169＝FGF-18部分；170-172＝接头；173-402＝AG链部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKAAADKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：83：FGF18CFGF8的氨基酸序列(残基1-155＝FGF18部分；156-188＝FGF8部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQHTTEQSLRFEFLNYPPFTRSLRGSQRTWAPEPR
SEQ ID NO：84：FGF18CFGF8T的氨基酸序列(残基1-155＝FGF18部分；156-173＝FGF8T部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQHTTEQSLRFEFLNYPPFT
SEQ ID NO：85：FGF18CFGF17T的氨基酸序列(残基1-155＝FGF18部分；156-177＝FGF17T部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQLPFPNHAEKQKQFEFVGSAPTR
SEQ ID NO：86：FGF18CFGF9的氨基酸序列(残基1-147＝FGF18部分；148-168＝FGF9部分)
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFLPRPVDPDKVPELYKDILSQS
SEQ ID NO：87：FGF18Y191F的氨基酸序列
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKFTTVTK
SEQ ID NO：88：IgG重链-野生型FGF18的氨基酸序列，经由该序列C端融合；残基1-451＝重链部分；452-471＝接头；472-651＝FGF-18部分。
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKRSRRIRPTHPA
SEQ ID NO：89：IgG重链-司瑞菲敏的氨基酸序列，经由该序列C端融合；残基1-451＝重链部分；452-471＝接头；472-640＝FGF-18部分。
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTK
SEQ ID NO：90：SEED_司瑞菲敏，GA链(作为SEED体的部分重链)的氨基酸序列(在序列的N端连接了FGF-18部分；残基1-169＝FGF-18部分；170-184＝接头；185-414＝GA链部分)。
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKGGSGGSGSGSEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGK
SEQ ID NO：91：SEED_野生型FGF18，GA链(作为SEED体的部分重链)的氨基酸序列(在序列的N端连接了FGF-18部分；残基1-180＝FGF-18部分；181-185＝接头；186-415＝GA链部分)。
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKRSRRIRPTHPAEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：92：SEED_FGF18CFGF8，AG链(作为SEED体的部分重链)的氨基酸序列(在序列的N端连接了FGF-18部分；残基1-188＝FGF-18部分；189-193＝接头；194-423＝AG链部分)。
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQHTTEQSLRFEFLNYPPFTRSLRGSQRTWAPEPREPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：93：SEED_FGF18CFGF8T，AG链的氨基酸序列(作为SEED体的部分重链)(在序列的N端连接了FGF-18部分；残基1-173＝FGF-18部分；174-178＝接头；179-408＝AG链部分)。
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQHTTEQSLRFEFLNYPPFTEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：94：SEED_FGF18CFGF17，AG链(作为SEED体的部分重链)的氨基酸序列(在序列的N端连接了FGF-18部分；残基1-177＝FGF-18部分；178-182＝接头；183-412＝AG链部分)。
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQLPFPNHAEKQKQFEFVGSAPTREPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：95：SEED_FGF18CFGF9，AG链的氨基酸序列(作为SEED体的部分重链)(在序列的N端连接了FGF-18部分；残基1-168＝FGF-18部分；169-173＝接头；174-403＝AG链部分)。
EENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFLPRPVDPDKVPELYKDILSQSEPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO：96：突变的AG链的氨基酸序列
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGK
SEQ ID NO：97：SEED_司瑞菲敏，GA链(作为SEED体的部分重链)的氨基酸序列(FGF-18部分在序列的C端连接；残基1-235＝GA链部分；236-245＝接头；246-414＝FGF-18部分)。
EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGKEPKSSDKTHTEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTK
SEQ ID NO：98：SEED_司瑞菲敏，GA链(作为SEED体的部分重链)的氨基酸序列(FGF-18部分在序列的C端连接；残基1-235＝GA链部分；236-255＝接头；256-424＝FGF-18部分)。
EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGKGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTK
SEQ ID NO：99：SEED_司瑞菲敏，GA链(作为SEED体的部分重链)的氨基酸序列(FGF-18部分在序列的C端连接；残基1-235＝GA链部分；236-250＝接头；251-419＝FGF-18部分)
EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGKGGGGSGGGGSGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTK
SEQ ID NO：100：SEED_野生型FGF18，GA链(作为SEED体的部分重链)的氨基酸序列(在该序列的C端连接了FGF-18部分；残基1-235＝GA链部分；236-255＝接头；256-435＝FGF-18部分)
EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGKGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKRSRRIRPTHPA
SEQ ID NO：101：SEED_司瑞菲敏，AG链(作为SEED体的部分重链)的氨基酸序列(FGF-18部分在该序列的C端连接；残基1-235＝AG链部分；236-255＝接头；256-424＝FGF-18部分)
EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGKGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTK
SEQ ID NO：102：GA链的CH2-CH3结构域(即部分GA链)的氨基酸序列
EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGK
SEQ ID NO：103：SEED_司瑞菲敏，AG链(作为SEED体的完整重链)的氨基酸序列(FGF-18部分在序列的C端连接；残基1-454＝AG链部分；455-474＝接头；475-643＝FGF-18部分)
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGKGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTK
SEQ ID NO：104：SEED_FGF18Y191P，AG链(作为SEED体的完整重链)的氨基酸序列(在该序列的C端连接了FGF-18部分；残基1-454＝AG链部分；455-474＝接头；475-643＝FGF-18部分)
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGKGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKPTTVTK
SEQ ID NO：105：SEED_FGF18Y191F，AG链(作为SEED体的完整重链)的氨基酸序列(在该序列的C端连接了FGF-18部分；残基1-454＝AG链部分；455-474＝接头；475-643＝FGF-18部分)
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGKGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKFTTVTK
SEQ ID NO：106：SEED_FGF18VS，AG链(作为SEED体的完整重链)的氨基酸序列(在该序列的C端连接了FGF-18部分；残基1-454＝AG链部分；455-474＝接头；475-643＝FGF-18部分)
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGKGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFVSTTVTK
SEQ ID NO：107：AG链的CH2-CH3结构域(部分AG链)的氨基酸序列
EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPFRPEVHLLPPSREEMTKNQVSLTCLARGFYPKDIAVEWESNGQPENNYKTTPSRQEPSQGTTTFAVTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKTISLSPGK
SEQ ID NO:108：SEED_FGF18VS，GA链(作为SEED体的完整重链)的氨基酸序列(FGF-18部分在序列的C端连接；残基1-454＝GA链部分；455-474＝接头；475-643＝FGF-18部分)
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPPSEELALNELVTLTCLVKGFYPSDIAVEWLQGSQELPREKYLTWAPVLDSDGSFFLYSILRVAAEDWKKGDTFSCSVMHEALHNRFTQKSLDRSPGKGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTK
SEQ ID NO：118：接头的氨基酸序列
GGGGSEPKSSDKTHTGGGGS
SEQ ID NO:119：接头的氨基酸序列
GGGGSGGGGSGGGGS
SEQ ID NO：120：接头的氨基酸序列
EPKSSDKTHT
SEQ ID NO：121：人FGF8前体的氨基酸序列(GenBank参考：AAC50785.1)
MGSPRSALSCLLLHLLVLCLQAQVTVQSSPNFTQHVREQSLVTDQLSRRLIRTYQLYSRTSGKHVQVLANKRINAMAEDGDPFAKLIVETDTFGSRVRVRGAETGLYICMNKKGKLIAKSNGKGKDCVFTEIVLENNYTALQNAKYEGWYMAFTRKGRPRKGSKTRQHQREVHFMKRLPRGHHTTEQSLRFEFLNYPPFTRSLRGSQRTWAPEPR
SEQ ID NO：122：人FGF9前体的氨基酸序列(GenBank参考：NP_002001.1)
MAPLGEVGNYFGVQDAVPFGNVPVLPVDSPVLLSDHLGQSEAGGLPRGPAVTDLDHLKGILRRRQLYCRTGFHLEIFPNGTIQGTRKDHSRFGILEFISIAVGLVSIRGVDSGLYLGMNEKGELYGSEKLTQECVFREQFEENWYNTYSSNLYKHVDTGRRYYVALNKDGTPREGTRTKRHQKFTHFLPRPVDPDKVPELYKDILSQS
SEQ ID NO：123：人FGF17的氨基酸序列(GenBank参考：AAI43790.1)
MGAARLLPNLTLCLQLLILCCQTQYVRDQGAMTDQLSRRQIREYQLYSRTSGKHVQVTGRRISATAEDGNKFAKLIVETDTFGSRVRIKGAESEKYICMNKRGKLIGKPSGKSKDCVFTEIVLENNYTAFQNARHEGWFMAFTRQGRPRQASRSRQNQREAHFIKRLYQGQLPFPNHAEKQKQFEFVGSAPTRRTKRTRRPQPLT
SEQ ID NO：124：C端带有司瑞菲敏的轻链的氨基酸序列(残基1-214＝轻链；215-234＝接头；235-403＝司瑞菲敏部分)
DIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTK
SEQ ID NO：125：具有野生型FGF18末端的轻链的氨基酸序列(残基1-214＝轻链；215-234＝接头；235-414＝FGF18部分)
DIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTKRSRRIRPTHPA
SEQ ID NO：126：C端带有FGF18的轻链的氨基酸序列(残基1-214＝轻链；215-234＝接头；235-414＝FGF18部分)
DIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSEPKSSDKTHTGGGGSEENVDFRIHVENQTRARDDVSRKQLRLYQLYSRTSGKHIQVLGRRISARGEDGDKYAQLLVETDTFGSQVRIKGKETEFYLCMNRKGKLVGKPDGTSKECVFIEKVLENNYTALMSAKYSGWYVGFTKKGRPRKGPKTRENQQDVHFMKRYPKGQPELQKPFKYTTVTK
SEQ ID NO：127：接头的氨基酸序列
GGSGGSGSGSEPKSS
SEQ ID NO：128：接头的氨基酸序列
GGGGSGGGGS
SEQ ID NO：129：接头的氨基酸序列
EPKSS
SEQ ID NO：130：接头的氨基酸序列
GGGGSGGGGSEPKSSDKTHTGGGGS
SEQ ID NO：131：接头的氨基酸序列
EPKSSDKTHT
SEQ ID NO：135：抗NGF变体CDR-H1的氨基酸序列
TVSGFSLIGYDLN
SEQ ID NO：136：抗NGF变体CDR-H2的氨基酸序列，X1＝D或E；X2＝N或H；X3＝S，P，H，或Q；X4＝A或S；X5是V或L
IIWGX1GTTDYX2X3X4X5KS
SEQ ID NO：137：抗NGF变体CDR-H3的氨基酸序列
ARGGYWYATSYYFDY
SEQ ID NO：138：抗NGF变体CDR-L1的氨基酸序列，X1＝N或Q；X2＝N或H
RASQSISX1X2LN
SEQ ID NO：139：抗NGF变体CDR-L2的氨基酸序列
YYTSRFHS
SEQ ID NO：140：抗NGF变体CDR-L3的氨基酸序列
QQEHTLPYT
实施例
材料
用作对照的FGF18部分是司瑞菲敏。它对应于具有根据SEQ ID NO：2的氨基酸序列的多肽，其在N端具有额外的Met残基(因为其在大肠杆菌中表达)。用作对照的抗NGF部分是他尼珠单抗。
实施例1-构建体
使用ExpiFectamineTM试剂以1升规模瞬时转染ExpiCHOTM细胞来表达蛋白质。在ExpiCHOTM表达培养基中以3.0x 106vc/ml转染前20±2小时，接种ExpiCHOTM细胞(vc＝活菌计数)。转染当天的细胞计数在7.0x 106vc/ml和10.0x 106vc/ml之间，并且活力高于95％。将培养物在750ml中稀释至6×106vc/ml。ExpiCHOTM表达培养基用作转染培养基。在28mlOptiProTM中稀释2.4ml ExpiFectamineTM并轻轻混合。将编码目标蛋白质(编码具有选自SEQ ID No：1-82的氨基酸序列的任何一种蛋白质)的DNA分子添加到30ml OptiProTM中并轻轻混合。将ExpiFectamineTM和DNA溶液混合，然后将复合物立即添加到细胞中。不需要复合物形成时间。将细胞在36.5℃和5％CO2下孵育。转染后20小时，在培养物中添加4.5μl增强剂和180ml饲料。转染六天后，收获细胞并通过在4℃下以4300x g离心20分钟与上清液分离。将包含目标蛋白质的上清液转移到下游处理中进行纯化。使用标准方法纯化目标蛋白质。
实施例2-融合蛋白的生物活性
BaF3/FGFR3细胞测定：表达FGFR3且仅在FGFR3激活后生长的BaF3细胞。代谢活性是通过ATP(使用ATP lite)测量的，与细胞数量成正比。将BaF3/FGFR3细胞在含有2mM L-谷氨酰胺，1mM丙酮酸钠，青霉素/链霉素1X，0.6mg/mL G-418、50nMβ-巯基乙醇和50ng/mL IL3的RPMI 1640培养基中进行培养和传代。为了进行测定，首先将细胞在测定培养基中(不含IL3但含有1μg/mL肝素的相同培养基)培养24小时，然后以20000细胞/孔在白色96孔板中接种在100μL测定培养基中，该测定培养基含有递增浓度的测试化合物。将细胞在37℃下进一步培养48小时。然后根据制造商的建议，使用ATPlite试剂盒(珀金埃尔默(Perkin Elmer)，目录号6016731)评估ATP含量(与细胞含量成比例)。rhFGF18作为对照以0.001、0.01、0.1、1、10、100和1000ng/mL(对应于5.04x10-5至50.4nM)进行了测试。在相同的等摩尔浓度下测试了FGF18_抗NGF构建体。使用PadPrism软件v7.0计算得出的EC50。
U2OS TrkA-P75测定：使用表达TrkA和p75(NGF受体)的U2OS细胞。在NGF存在下，受体二聚并发光。将U2OS TrkA-p75细胞(Discoverx，目录号93-0529C3)在含有遗传霉素0.2mg/ml，潮霉素0.1mg/mL和FCS 10％的McCoy培养基中培养。为了进行测定，将50 000个细胞/孔在白色96孔板中接种在90μL的测定培养基(含有HEPES 10mM，青霉素/链霉素0.5X，FCS 2％的MEMα)中，并在37℃下过夜培养。然后将NGF 600ng/mL以1:1v/v与浓度递增的测试化合物(孔中最终所需浓度的20X)混合，并在室温下孵育1小时。然后在室温下将10μLNGF/测试化合物混合物添加到细胞中3小时。根据制造商的建议，使用Pathhunter生物测定检测试剂盒(Discoverx，目录号93-0933E)测量受体的激活。他尼珠单抗作为对照以0.457、1.37、4.12、12.36、37、111.1、333.3和1000ng/mL(对应于0.003至6.86nM)进行了测试。在相同的等摩尔浓度下测试了FGF18_抗NGF构建体。使用PadPrism软件v7.0计算得出的IC50。
结果：所有测试的构建体在BaF3/FGFR3和U2OS Trka_p75细胞测定中均具有活性，表明对于所有构建体，两个部分(FGF18和抗NGF)均具有生物活性(见表1)。
表1：分别在BaF3/FGFR3测定(监测FGFR3激活)和U2OS TrkA_p75测定(监测NGF抑制)中针对每种构建体获得的EC50和IC50。
实施例3-融合蛋白对原代软骨细胞的活性
原代软骨细胞的分离：猪软骨细胞从猪髋部股骨头的软骨中分离出来。首先以20000细胞/cm2接种细胞，并在含有10％FCS，50μg/mL抗坏血酸-2-磷酸酯和0.4mM L-脯氨酸的DMEMHG中培养一周。
用于基因表达和细胞计数的细胞培养：将软骨细胞以15000个细胞/孔接种于24孔板中的一毫升相同培养基中，或补充不同浓度的rhFGF18或FGF18_抗NGF构建体(与rhFGF18等摩尔)。将细胞培养7天。培养结束时，用ViCellTM细胞分析仪(来自贝克曼库尔特公司(Beckman Coulter))对细胞计数，或裂解细胞以进行RNA分离和基因表达。根据制造商的建议，使用RNeasy小试剂盒(凯杰公司(Qiagen)，目录号74104)分离RNA。然后，通过具有安捷伦RNA 6000纳米芯片(安捷伦，目录号G2938-80023)的安捷伦生物分析仪分析mRNA的浓度和质量。逆转录是用SuperScript III第一链合成超混合物实现的。然后用RNA酶H消化cDNA以消化RNA，并用SYBRGreen Jumpstart Taq即用混合物，在各200nM的I型胶原的反向引物和正向引物的存在下通过qPCR分析(正向(SEQ ID NO：133)：5'-AAAGGATCTCCTGGTGAAGC-3'和反向(SEQ ID NO：134)：5'-CCTGAGTGGAAGAGTGTGGAGA-3')。该反应在安捷伦科技公司的热循环仪Mx3000P中进行。
用于细胞形态分析的细胞培养：将软骨细胞以1000个细胞/孔在96孔板中接种于200μL相同培养基中，或补充不同浓度的rhFGF18(10、100和1000ng/mL)或FGF18_抗NGF构建体(与rhFGF18等摩尔)。将细胞培养5天。随后，将细胞用PBS中的4％(w/v)低聚甲醛固定15分钟，在PBS中洗涤3次，然后用PBS中的0.2％(v/v)曲通X100在室温下透化5分钟。固定和透化的细胞用PBS洗涤3次，并用PBS中的Hoechst 33342(1/400，英杰公司，目录号H1399)和Phalloidin-Alex 488(1/40，英杰公司，目录号A12379)在室温下染色1小时。最后，将细胞用PBS洗涤3次。使用倒置显微镜(蔡司(Zeiss)，Axio Observer)使用绿色和蓝色荧光滤光片组采集图像。
FGF18 scFv他尼珠单抗的结果：rhFGF18和FGF18scFv-他尼珠单抗以0.015、0.05、0.15、0.5、1.5、5、15和50nM进行了测试。构建体FGF18 scFv他尼珠单抗的作用不如rhFGF18的作用那么明显。但是，这两种分子剂量依赖性地增加了细胞增殖，并降低了I型胶原蛋白的表达(图2A)。还观察到，rhFGF18对软骨细胞的形态有影响并有利于细胞圆化，而FGF18scFv他尼珠单抗构建体对某些细胞(但不是全部)具有类似的作用，展示圆形形态(图2B)。这些结果表明，构建体FGF18 scFv他尼珠单抗与rhFGF18具有相似的作用。
MBE626的结果：rhFGF18和MBE626在0.504、5.04和50.4nM下进行测试。MBE626对软骨细胞增殖的影响不如rhFGF18那么明显，但在50.04nM时达到了rhFGF18的65％。关于I型胶原蛋白表达的抑制，两种分子表现相似。此外，MBE626诱导的细胞圆化与rhFGF18一样(图2B)。这些结果表明，构建体MBE626发挥与rhFGF18相似的作用。
实施例4-融合蛋白在强OA疼痛体内模型(MIA模型)中的活性
这项研究的目的是确定与静脉内注射他尼珠单抗相比，关节内(i.art.)FGF18-scFv(与针对NGF的抗体的单链片段融合的人重组FGF18)对单碘乙酸酯(MIA)引起的步态异常(疼痛样行为)的剂量反应(效力)。
实验：将来自查尔斯河的雄性李斯特顶罩大鼠(250-350克)饲养在4个平置群体笼(storied colony cage)中由48个个体组成的相连群体(connected colony)中。在这个笼里，大鼠有机会在各层之间跳跃并走过楼梯，以进行自然的身体活动。为了诱导软骨降解并随后发炎，关节内注射30μl溶于0.9％NaCl的100μg/μl MIA(西格玛奥德里奇公司(SigmaAldrich)，产品编号I9148，批号LBB0968V)到异氟烷麻醉大鼠的右膝关节中。为了评估对疼痛的潜在影响，使用Noldus猫步XT 10.0系统(诺达思公司(Noldus)，瓦赫宁根，荷兰)进行了纵向步态分析。该系统使用带照明的玻璃底部通道，玻璃上的爪子接触区域被明亮地照亮，并由摄像机从下方记录下来。大鼠是昼夜颠倒的，并在黑暗中活跃阶段进行分析。必须在10秒的时间内完全自愿走过隧道(拍摄区域)。对于每只动物，获得三次独立的运行。如果动物在视频采集过程中停下脚步或站起来，则该运行的数据将被删除。如果大鼠在5分钟内没有走猫步，则将对下一只动物进行测试，而不会获得任何数据。然后Noldus猫步XT 10.0软件将爪印分配到某个位置(例如左前爪)。为了描述步态性能/异常，将参数爪印长度计算为对侧的百分比。将每次运行的对侧值的百分比平均，以获得单个动物的值。为了评估药物作用，在MIA注射后第1天，将不同剂量的FGF18-scFv-他尼珠单抗(从0.03至100μg/关节)或PBS关节内注射到患病的右膝关节中。同时静脉内注射他尼珠单抗(1mg/kg的高剂量)。载剂组接受了30μg/关节的关节内PBS。每组由7只动物组成。图3A示出了研究的原理。
结果：关节内注射FGF18-scFv他尼珠单抗达到的改善步态异常的效力与高剂量静脉内给予(i.v.)的临床证实的他尼珠单抗相同(图3B)。使用3μg/关节的FGF18-scFv他尼珠单抗已达到全部效果。
结论：关节内注射3μg/关节的FGF-18-scFv和更高剂量产生与阳性对照他尼珠单抗i.v相同的功效。该结果表明，利用其中抗NGF部分与FGF18融合的新的双功能分子，可以实现有意义的症状益处。由于FGF18在大鼠体内在1μg/关节(甚至更高)下也有活性，因此该实验的结果表明，使用新型双功能(>3μg/关节)分子，在一定剂量下可能对疼痛产生影响，该剂量也诱导了FGF18部分的结构益处。
实施例5-在慢性OA模型(ACLT
tMx模型)中一次关节内注射后融合蛋白的症状益
处的持续时间
这项研究的目的是确定一种高剂量下测试的新型双功能分子对手术引起的慢性骨关节炎后步态异常的益处。
实验：动物，饲养条件和步态分析与实施例4中描述的相同。OA的发展是通过前十字韧带横断和半月板切除(ACLT+pMx)手术(即手术诱发的关节不稳定模型以诱导慢性骨关节炎)诱导的。用异氟烷麻醉大鼠，并剃除右膝关节周围的毛。用解剖刀在髌骨侧面内侧关节上纵向皮肤切片。然后纵向切断股四头肌内侧区域，将髌骨移至前部，并打开关节囊。膝关节屈曲时，前交叉韧带被一个小钩破坏。然后，用手术刀解剖前粘膜胫骨肌腱，并切开其内侧部分的内侧半月板，并从关节上取下一半。最后，将关节囊，相关的肌肉和结缔组织分层缝合。骨关节炎是由于关节力学受损而引起的。群体笼中高水平的自发活动加速了这种情况。为了测试药物效果，在ACLT pMx后第16天，将30μg/关节(30μl PBS中1μg/μl)的FGF18-SEED(MBE626)或FGF18-scFv-他尼珠单抗关节内注射到患病的右膝关节中。载剂组接受了30μg/关节的关节内PBS。作为阳性参照，同时静脉内注射他尼珠单抗。每组动物包括9至10只动物。图4A示出了研究的原理。
结果：MBE626和FGF18-scFv-他尼珠单抗均在ACLT tMx后第16天关节内注射后对步态异常产生立即益处。所述益处对于FGF18-Seed稳定≥3周，并且对于FGF18-scFv-他尼珠单抗稳定≥1周(图4)。应当指出的是，静脉内他尼珠单抗对疼痛的效果不能直接与关节内载剂的效果相比，因为众所周知关节内注射本身会引起疼痛，而这不适用于静脉组。
结论：当已经建立ACLT pMx诱导的慢性骨关节炎时，一次关节内注射MBE626或FGF18-scFv-他尼珠单抗可以显著改善疼痛样症状。益处是立即的(4小时后)，持续至少3周。在此期间，症状益处与高剂量静脉内他尼珠单抗后的症状益处相当，表明通过关节内途径施用的双功能蛋白可以对疼痛症状产生有意义且持久的益处。由于仅使用FGF18，每月的治疗方案即可获得结构性益处，因此持续3周的症状益处可能会覆盖治疗期的3/4。
实施例6-在慢性OA模型(ACLT
pMx模型)中每隔一月的三次关节内注射后融合蛋
白MBE626的剂量依赖性症状和结构益处
这项研究的目的是确定在同一实验中长期重复施用新型双功能分子对结构和症状的益处。
实验：动物，饲养条件，手术和步态分析与实施例4中描述的相同。通过组织学用甲苯胺蓝和番红花染色来研究软骨结构。通过对胫骨内侧隔室的分数研究了同化作用，该分数考虑了表面的结构，基质染色，潮痕，基础整合，骨骼异常和软骨骨赘。为了测试药物效果，在ACLT pMx后第15天，第43天和第71天，向患病的右膝关节内关节内注射2.7μg/关节，7μg/关节，27μg/关节或90μg/关节的MBE626(全部n＝18)。载剂组接受了30μg/关节的关节内PBS(n＝18)。为了确定疾病窗口，健康的动物接受了载剂PBS(n＝14)。作为疼痛治疗的阳性参照在同一时间点，静脉内注射他尼珠单抗(0.3mg/kg)(n＝10)。图5A示出了研究的原理。
结果：所有测试剂量的MBE626对步态异常均引起了即时且持久的益处(图5B)。第一次注射后，这种效果是剂量依赖性的，不同的是27μg/关节在几个时间点上效果稍差。与安慰剂相比，最高剂量(90μg/关节)的益处最大，达到40％益处(图6)。相比之下，阳性参照他尼珠单抗(i.v.)与安慰剂相比有87％的益处。在终点(第98天)，组织学调查显示，随着MBE626剂量的增加，促代谢分数升高的趋势(图7)。
结论：结果表明，用新型双功能蛋白MBE626进行慢性治疗可同时改善软骨结构和疼痛症状，从而长期受益。
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<120> 包含FGF-18部分的融合蛋白
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Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 11
<211> 214
<212> PRT
<213> 人工
<220>
<223> 人工序列
<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 Ser Ile Ser Asn Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Phe His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Glu His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 12
<211> 446
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 12
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Thr Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn 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 Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 13
<211> 214
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 13
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Phe Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Ser Tyr Tyr Cys Gln Gln Tyr Asn Arg Tyr Pro Trp
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> 14
<211> 449
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 14
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 Leu Arg Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Arg Ser Ser His Thr Ile Phe Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Asp Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Val Tyr Ser Ser Gly Trp His Val Ser Asp Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Ile Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
210 215 220
Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 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 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
290 295 300
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Thr 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 Met 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> 15
<211> 214
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 15
Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly 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> 16
<211> 224
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 16
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
<210> 17
<211> 214
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 17
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 Ser Ile Ser Asn Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Phe His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Glu His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 18
<211> 222
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 18
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Thr Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn 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 Lys Val Glu Pro Lys Ser Cys
210 215 220
<210> 19
<211> 214
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 19
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Phe Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Ser Tyr Tyr Cys Gln Gln Tyr Asn Arg Tyr Pro Trp
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> 20
<211> 226
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 20
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 Leu Arg Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Arg Ser Ser His Thr Ile Phe Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Asp Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Val Tyr Ser Ser Gly Trp His Val Ser Asp Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Ile Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
210 215 220
Ser Cys
225
<210> 21
<211> 214
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 21
Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly 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> 22
<211> 243
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 22
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 Ser Ile Ser Asn Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Phe His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Glu His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu
115 120 125
Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys
130 135 140
Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr Asp Leu Asn Trp Ile Arg
145 150 155 160
Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Ile Ile Trp Gly Asp
165 170 175
Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys Ser Arg Val Thr Ile Ser
180 185 190
Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr
195 200 205
Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Gly Tyr Trp Tyr
210 215 220
Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
225 230 235 240
Val Ser Ser
<210> 23
<211> 241
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 23
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Phe Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Ser Tyr Tyr Cys Gln Gln Tyr Asn Arg Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln
115 120 125
Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys
130 135 140
Lys Val Ser Gly Phe Thr Leu Thr Glu Leu Ser Ile His Trp Val Arg
145 150 155 160
Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Gly Phe Asp Pro Glu
165 170 175
Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met
180 185 190
Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr Met Glu Leu Thr Ser Leu
195 200 205
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ser Thr Ile Phe Gly Val
210 215 220
Val Thr Asn Phe Asp Asn Trp Gly Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ser
<210> 24
<211> 245
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 24
Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu
115 120 125
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
130 135 140
Ala Ala Ser Gly Phe Thr Leu Arg Ser Tyr Ser Met Asn Trp Val Arg
145 150 155 160
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr Ile Ser Arg Ser
165 170 175
Ser His Thr Ile Phe Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asp Ser Leu
195 200 205
Arg Asp Glu Asp Thr Ala Met Tyr Tyr Cys Ala Arg Val Tyr Ser Ser
210 215 220
Gly Trp His Val Ser Asp Tyr Phe Asp Tyr Trp Gly Gln Gly Ile Leu
225 230 235 240
Val Thr Val Ser Ser
245
<210> 25
<211> 427
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 25
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Gly Gly Gly Gly Ser Gly Gly
165 170 175
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
180 185 190
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
195 200 205
Ala Ser Gln Ser Ile Ser Asn Asn Leu Asn Trp Tyr Gln Gln Lys Pro
210 215 220
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Phe His Ser
225 230 235 240
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
245 250 255
Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
260 265 270
Gln Gln Glu His Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu
275 280 285
Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
290 295 300
Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro
305 310 315 320
Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile
325 330 335
Gly Tyr Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
340 345 350
Trp Ile Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala
355 360 365
Val Lys Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe
370 375 380
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
385 390 395 400
Cys Ala Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr
405 410 415
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
420 425
<210> 26
<211> 425
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 26
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Gly Gly Gly Gly Ser Gly Gly
165 170 175
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
180 185 190
Ser Ser Leu Ser Ala Ser Ala Gly Asp Arg Val Thr Ile Thr Cys Arg
195 200 205
Ala Ser Gln Ala Ile Arg Asn Asp Leu Gly Trp Tyr Gln Gln Lys Pro
210 215 220
Gly Lys Ala Pro Lys Arg Leu Ile Tyr Ala Ala Phe Asn Leu Gln Ser
225 230 235 240
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
245 250 255
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Leu Ala Ser Tyr Tyr Cys
260 265 270
Gln Gln Tyr Asn Arg Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
275 280 285
Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
290 295 300
Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
305 310 315 320
Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr
325 330 335
Glu Leu Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
340 345 350
Trp Met Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln
355 360 365
Lys Phe Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr
370 375 380
Ala Tyr Met Glu Leu Thr Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
385 390 395 400
Tyr Cys Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly
405 410 415
Gln Gly Thr Leu Val Thr Val Ser Ser
420 425
<210> 27
<211> 429
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 27
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Gly Gly Gly Gly Ser Gly Gly
165 170 175
Gly Gly Ser Gly Gly Gly Gly Ser Ala Ile Gln Leu Thr Gln Ser Pro
180 185 190
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
195 200 205
Ala Ser Gln Gly Ile Ser Ser Ala Leu Ala Trp Tyr Gln Gln Lys Pro
210 215 220
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu Glu Ser
225 230 235 240
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
245 250 255
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
260 265 270
Gln Gln Phe Asn Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val
275 280 285
Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
290 295 300
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
305 310 315 320
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Arg
325 330 335
Ser Tyr Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
340 345 350
Trp Val Ser Tyr Ile Ser Arg Ser Ser His Thr Ile Phe Tyr Ala Asp
355 360 365
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser
370 375 380
Leu Tyr Leu Gln Met Asp Ser Leu Arg Asp Glu Asp Thr Ala Met Tyr
385 390 395 400
Tyr Cys Ala Arg Val Tyr Ser Ser Gly Trp His Val Ser Asp Tyr Phe
405 410 415
Asp Tyr Trp Gly Gln Gly Ile Leu Val Thr Val Ser Ser
420 425
<210> 28
<211> 398
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 28
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Gly Gly Gly Gly Ser Gly Gly
165 170 175
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
180 185 190
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
195 200 205
Ala Ser Gln Ser Ile Ser Asn Asn Leu Asn Trp Tyr Gln Gln Lys Pro
210 215 220
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Phe His Ser
225 230 235 240
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
245 250 255
Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
260 265 270
Gln Gln Glu His Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu
275 280 285
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
290 295 300
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
305 310 315 320
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
325 330 335
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
340 345 350
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
355 360 365
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
370 375 380
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
385 390 395
<210> 29
<211> 400
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 29
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
165 170 175
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln
180 185 190
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
195 200 205
Cys Arg Ala Ser Gln Ser Ile Ser Asn Asn Leu Asn Trp Tyr Gln Gln
210 215 220
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Phe
225 230 235 240
His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
245 250 255
Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr
260 265 270
Tyr Cys Gln Gln Glu His Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr
275 280 285
Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
290 295 300
Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys
305 310 315 320
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
325 330 335
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
340 345 350
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
355 360 365
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
370 375 380
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
385 390 395 400
<210> 30
<211> 398
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 30
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Gln
145 150 155 160
Asn Phe Gln Ser Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
180 185 190
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
195 200 205
Ala Ser Gln Ser Ile Ser Asn Asn Leu Asn Trp Tyr Gln Gln Lys Pro
210 215 220
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Phe His Ser
225 230 235 240
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
245 250 255
Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
260 265 270
Gln Gln Glu His Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu
275 280 285
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
290 295 300
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
305 310 315 320
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
325 330 335
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
340 345 350
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
355 360 365
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
370 375 380
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
385 390 395
<210> 31
<211> 398
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 31
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Pro Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
180 185 190
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
195 200 205
Ala Ser Gln Ser Ile Ser Asn Asn Leu Asn Trp Tyr Gln Gln Lys Pro
210 215 220
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Phe His Ser
225 230 235 240
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
245 250 255
Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
260 265 270
Gln Gln Glu His Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu
275 280 285
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
290 295 300
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
305 310 315 320
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
325 330 335
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
340 345 350
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
355 360 365
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
370 375 380
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
385 390 395
<210> 32
<211> 398
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 32
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Ala
145 150 155 160
Ala Phe Ala Tyr Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
180 185 190
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
195 200 205
Ala Ser Gln Ser Ile Ser Asn Asn Leu Asn Trp Tyr Gln Gln Lys Pro
210 215 220
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Phe His Ser
225 230 235 240
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
245 250 255
Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
260 265 270
Gln Gln Glu His Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu
275 280 285
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
290 295 300
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
305 310 315 320
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
325 330 335
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
340 345 350
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
355 360 365
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
370 375 380
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
385 390 395
<210> 33
<211> 398
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 33
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Val Ser Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
180 185 190
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
195 200 205
Ala Ser Gln Ser Ile Ser Asn Asn Leu Asn Trp Tyr Gln Gln Lys Pro
210 215 220
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Phe His Ser
225 230 235 240
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
245 250 255
Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
260 265 270
Gln Gln Glu His Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu
275 280 285
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
290 295 300
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
305 310 315 320
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
325 330 335
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
340 345 350
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
355 360 365
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
370 375 380
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
385 390 395
<210> 34
<211> 403
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 34
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Gly Gly Gly Gly Ser Gly Gly
165 170 175
Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys
180 185 190
Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu
195 200 205
Ile Gly Tyr Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu
210 215 220
Glu Trp Ile Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser
225 230 235 240
Ala Val Lys Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln
245 250 255
Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr
260 265 270
Tyr Cys Ala Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp
275 280 285
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
290 295 300
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
305 310 315 320
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
325 330 335
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
340 345 350
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
355 360 365
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
370 375 380
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
385 390 395 400
Lys Ser Cys
<210> 35
<211> 410
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 35
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
165 170 175
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu
180 185 190
Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys
195 200 205
Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr Asp Leu Asn Trp Ile Arg
210 215 220
Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Ile Ile Trp Gly Asp
225 230 235 240
Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys Ser Arg Val Thr Ile Ser
245 250 255
Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr
260 265 270
Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Gly Tyr Trp Tyr
275 280 285
Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
290 295 300
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
305 310 315 320
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
325 330 335
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
340 345 350
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
355 360 365
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
370 375 380
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
385 390 395 400
Val Asp Lys Lys Val Glu Pro Lys Ser Cys
405 410
<210> 36
<211> 408
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 36
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Gln
145 150 155 160
Asn Phe Gln Ser Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly
180 185 190
Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val
195 200 205
Ser Gly Phe Ser Leu Ile Gly Tyr Asp Leu Asn Trp Ile Arg Gln Pro
210 215 220
Pro Gly Lys Gly Leu Glu Trp Ile Gly Ile Ile Trp Gly Asp Gly Thr
225 230 235 240
Thr Asp Tyr Asn Ser Ala Val Lys Ser Arg Val Thr Ile Ser Lys Asp
245 250 255
Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala
260 265 270
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Gly Tyr Trp Tyr Ala Thr
275 280 285
Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
290 295 300
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
305 310 315 320
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
325 330 335
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
340 345 350
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
355 360 365
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
370 375 380
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
385 390 395 400
Lys Lys Val Glu Pro Lys Ser Cys
405
<210> 37
<211> 408
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 37
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Pro Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly
180 185 190
Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val
195 200 205
Ser Gly Phe Ser Leu Ile Gly Tyr Asp Leu Asn Trp Ile Arg Gln Pro
210 215 220
Pro Gly Lys Gly Leu Glu Trp Ile Gly Ile Ile Trp Gly Asp Gly Thr
225 230 235 240
Thr Asp Tyr Asn Ser Ala Val Lys Ser Arg Val Thr Ile Ser Lys Asp
245 250 255
Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala
260 265 270
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Gly Tyr Trp Tyr Ala Thr
275 280 285
Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
290 295 300
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
305 310 315 320
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
325 330 335
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
340 345 350
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
355 360 365
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
370 375 380
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
385 390 395 400
Lys Lys Val Glu Pro Lys Ser Cys
405
<210> 38
<211> 408
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 38
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Ala
145 150 155 160
Ala Phe Ala Tyr Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly
180 185 190
Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val
195 200 205
Ser Gly Phe Ser Leu Ile Gly Tyr Asp Leu Asn Trp Ile Arg Gln Pro
210 215 220
Pro Gly Lys Gly Leu Glu Trp Ile Gly Ile Ile Trp Gly Asp Gly Thr
225 230 235 240
Thr Asp Tyr Asn Ser Ala Val Lys Ser Arg Val Thr Ile Ser Lys Asp
245 250 255
Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala
260 265 270
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Gly Tyr Trp Tyr Ala Thr
275 280 285
Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
290 295 300
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
305 310 315 320
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
325 330 335
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
340 345 350
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
355 360 365
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
370 375 380
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
385 390 395 400
Lys Lys Val Glu Pro Lys Ser Cys
405
<210> 39
<211> 408
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 39
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Val Ser Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly
180 185 190
Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val
195 200 205
Ser Gly Phe Ser Leu Ile Gly Tyr Asp Leu Asn Trp Ile Arg Gln Pro
210 215 220
Pro Gly Lys Gly Leu Glu Trp Ile Gly Ile Ile Trp Gly Asp Gly Thr
225 230 235 240
Thr Asp Tyr Asn Ser Ala Val Lys Ser Arg Val Thr Ile Ser Lys Asp
245 250 255
Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala
260 265 270
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Gly Tyr Trp Tyr Ala Thr
275 280 285
Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
290 295 300
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
305 310 315 320
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
325 330 335
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
340 345 350
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
355 360 365
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
370 375 380
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
385 390 395 400
Lys Lys Val Glu Pro Lys Ser Cys
405
<210> 40
<211> 395
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 40
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 Ser Ile Ser Asn Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Phe His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Glu His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
210 215 220
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe
225 230 235 240
Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg
245 250 255
Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
260 265 270
Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp
275 280 285
Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val
290 295 300
Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys
305 310 315 320
Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe
325 330 335
Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys
340 345 350
Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys
355 360 365
Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg
370 375 380
Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys Pro
385 390 395
<210> 41
<211> 403
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 41
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 Ser Ile Ser Asn Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Phe His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Glu His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
210 215 220
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe
225 230 235 240
Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg
245 250 255
Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
260 265 270
Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp
275 280 285
Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val
290 295 300
Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys
305 310 315 320
Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe
325 330 335
Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys
340 345 350
Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys
355 360 365
Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg
370 375 380
Tyr Pro Lys Gly Gln Pro Glu Leu Gln Gln Asn Phe Gln Ser Thr Thr
385 390 395 400
Val Thr Lys
<210> 42
<211> 403
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 42
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 Ser Ile Ser Asn Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Phe His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Glu His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
210 215 220
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe
225 230 235 240
Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg
245 250 255
Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
260 265 270
Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp
275 280 285
Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val
290 295 300
Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys
305 310 315 320
Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe
325 330 335
Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys
340 345 350
Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys
355 360 365
Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg
370 375 380
Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys Pro Phe Lys Pro Thr Thr
385 390 395 400
Val Thr Lys
<210> 43
<211> 403
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 43
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 Ser Ile Ser Asn Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Phe His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Glu His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
210 215 220
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe
225 230 235 240
Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg
245 250 255
Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
260 265 270
Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp
275 280 285
Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val
290 295 300
Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys
305 310 315 320
Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe
325 330 335
Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys
340 345 350
Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys
355 360 365
Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg
370 375 380
Tyr Pro Lys Gly Gln Pro Glu Leu Gln Ala Ala Phe Ala Tyr Thr Thr
385 390 395 400
Val Thr Lys
<210> 44
<211> 403
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 44
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 Ser Ile Ser Asn Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Phe His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Glu His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
210 215 220
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe
225 230 235 240
Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg
245 250 255
Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
260 265 270
Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp
275 280 285
Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val
290 295 300
Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys
305 310 315 320
Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe
325 330 335
Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys
340 345 350
Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys
355 360 365
Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg
370 375 380
Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys Pro Phe Val Ser Thr Thr
385 390 395 400
Val Thr Lys
<210> 45
<211> 405
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 45
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Gly
225 230 235 240
Gly Gly Gly Ser Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn
245 250 255
Gln Thr Arg Ala Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr
260 265 270
Gln Leu Tyr Ser Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg
275 280 285
Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu
290 295 300
Val Glu Thr Asp Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu
305 310 315 320
Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys
325 330 335
Pro Asp Gly Thr Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu
340 345 350
Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val
355 360 365
Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu
370 375 380
Asn Gln Gln Asp Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro
385 390 395 400
Glu Leu Gln Lys Pro
405
<210> 46
<211> 413
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 46
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Gly
225 230 235 240
Gly Gly Gly Ser Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn
245 250 255
Gln Thr Arg Ala Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr
260 265 270
Gln Leu Tyr Ser Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg
275 280 285
Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu
290 295 300
Val Glu Thr Asp Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu
305 310 315 320
Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys
325 330 335
Pro Asp Gly Thr Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu
340 345 350
Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val
355 360 365
Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu
370 375 380
Asn Gln Gln Asp Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro
385 390 395 400
Glu Leu Gln Gln Asn Phe Gln Ser Thr Thr Val Thr Lys
405 410
<210> 47
<211> 413
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 47
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Gly
225 230 235 240
Gly Gly Gly Ser Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn
245 250 255
Gln Thr Arg Ala Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr
260 265 270
Gln Leu Tyr Ser Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg
275 280 285
Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu
290 295 300
Val Glu Thr Asp Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu
305 310 315 320
Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys
325 330 335
Pro Asp Gly Thr Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu
340 345 350
Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val
355 360 365
Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu
370 375 380
Asn Gln Gln Asp Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro
385 390 395 400
Glu Leu Gln Lys Pro Phe Lys Pro Thr Thr Val Thr Lys
405 410
<210> 48
<211> 413
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 48
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Gly
225 230 235 240
Gly Gly Gly Ser Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn
245 250 255
Gln Thr Arg Ala Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr
260 265 270
Gln Leu Tyr Ser Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg
275 280 285
Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu
290 295 300
Val Glu Thr Asp Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu
305 310 315 320
Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys
325 330 335
Pro Asp Gly Thr Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu
340 345 350
Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val
355 360 365
Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu
370 375 380
Asn Gln Gln Asp Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro
385 390 395 400
Glu Leu Gln Ala Ala Phe Ala Tyr Thr Thr Val Thr Lys
405 410
<210> 49
<211> 413
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 49
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Gly
225 230 235 240
Gly Gly Gly Ser Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn
245 250 255
Gln Thr Arg Ala Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr
260 265 270
Gln Leu Tyr Ser Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg
275 280 285
Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu
290 295 300
Val Glu Thr Asp Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu
305 310 315 320
Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys
325 330 335
Pro Asp Gly Thr Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu
340 345 350
Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val
355 360 365
Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu
370 375 380
Asn Gln Gln Asp Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro
385 390 395 400
Glu Leu Gln Lys Pro Phe Val Ser Thr Thr Val Thr Lys
405 410
<210> 50
<211> 393
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 50
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Gly Gly Gly Gly Ser Gly Gly
165 170 175
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
180 185 190
Ser Ala Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile
195 200 205
Arg Asn Asp Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
210 215 220
Arg Leu Ile Tyr Ala Ala Phe Asn Leu Gln Ser Gly Val Pro Ser Arg
225 230 235 240
Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser
245 250 255
Leu Gln Pro Glu Asp Leu Ala Ser Tyr Tyr Cys Gln Gln Tyr Asn Arg
260 265 270
Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr
275 280 285
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
290 295 300
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
305 310 315 320
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
325 330 335
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
340 345 350
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
355 360 365
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
370 375 380
Thr Lys Ser Phe Asn Arg Gly Glu Cys
385 390
<210> 51
<211> 401
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 51
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Gly Gly Gly Gly Ser Gly Gly
165 170 175
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
180 185 190
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu
195 200 205
Thr Glu Leu Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
210 215 220
Glu Trp Met Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala
225 230 235 240
Gln Lys Phe Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp
245 250 255
Thr Ala Tyr Met Glu Leu Thr Ser Leu Arg Ser Glu Asp Thr Ala Val
260 265 270
Tyr Tyr Cys Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp
275 280 285
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
290 295 300
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
305 310 315 320
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
325 330 335
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
340 345 350
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
355 360 365
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
370 375 380
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
385 390 395 400
Cys
<210> 52
<211> 393
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 52
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Gly Gly Gly Gly Ser Gly Gly
165 170 175
Gly Gly Ser Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala
180 185 190
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile
195 200 205
Ser Ser Ala Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
210 215 220
Leu Leu Ile Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg
225 230 235 240
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
245 250 255
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser
260 265 270
Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr
275 280 285
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
290 295 300
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
305 310 315 320
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
325 330 335
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
340 345 350
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
355 360 365
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
370 375 380
Thr Lys Ser Phe Asn Arg Gly Glu Cys
385 390
<210> 53
<211> 405
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 53
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Gly Gly Gly Gly Ser Gly Gly
165 170 175
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
180 185 190
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu
195 200 205
Arg Ser Tyr Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
210 215 220
Glu Trp Val Ser Tyr Ile Ser Arg Ser Ser His Thr Ile Phe Tyr Ala
225 230 235 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
245 250 255
Ser Leu Tyr Leu Gln Met Asp Ser Leu Arg Asp Glu Asp Thr Ala Met
260 265 270
Tyr Tyr Cys Ala Arg Val Tyr Ser Ser Gly Trp His Val Ser Asp Tyr
275 280 285
Phe Asp Tyr Trp Gly Gln Gly Ile Leu Val Thr Val Ser Ser Ala Ser
290 295 300
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
305 310 315 320
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
325 330 335
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
340 345 350
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
355 360 365
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
370 375 380
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
385 390 395 400
Glu Pro Lys Ser Cys
405
<210> 54
<211> 414
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 54
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Gly Gly Ser Gly Gly Ser Gly
165 170 175
Ser Gly Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro
180 185 190
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
195 200 205
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
210 215 220
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
225 230 235 240
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
245 250 255
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
260 265 270
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
275 280 285
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
290 295 300
Gly Gln Pro Phe Arg Pro Glu Val His Leu Leu Pro Pro Ser Arg Glu
305 310 315 320
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Ala Arg Gly Phe
325 330 335
Tyr Pro Lys Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
340 345 350
Asn Asn Tyr Lys Thr Thr Pro Ser Arg Gln Glu Pro Ser Gln Gly Thr
355 360 365
Thr Thr Phe Ala Val Thr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
370 375 380
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
385 390 395 400
Asn His Tyr Thr Gln Lys Thr Ile Ser Leu Ser Pro Gly Lys
405 410
<210> 55
<211> 409
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 55
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Gly Gly Gly Gly Ser Gly Gly
165 170 175
Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
180 185 190
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
195 200 205
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
210 215 220
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
225 230 235 240
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
245 250 255
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
260 265 270
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
275 280 285
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg
290 295 300
Pro Glu Val His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
305 310 315 320
Gln Val Ser Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile
325 330 335
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
340 345 350
Thr Pro Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val
355 360 365
Thr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
370 375 380
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
385 390 395 400
Lys Thr Ile Ser Leu Ser Pro Gly Lys
405
<210> 56
<211> 454
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 56
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu Leu Val
355 360 365
Thr Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys Tyr Leu Thr
385 390 395 400
Trp Ala Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ile
405 410 415
Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly Asp Thr Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu
435 440 445
Asp Arg Ser Pro Gly Lys
450
<210> 57
<211> 409
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 57
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Gly Gly Gly Gly Ser Gly Gly
165 170 175
Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
180 185 190
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
195 200 205
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
210 215 220
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
225 230 235 240
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
245 250 255
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
260 265 270
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
275 280 285
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg
290 295 300
Pro Glu Val His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
305 310 315 320
Gln Val Ser Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile
325 330 335
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
340 345 350
Thr Pro Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val
355 360 365
Thr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
370 375 380
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
385 390 395 400
Lys Thr Ile Ser Leu Ser Pro Gly Lys
405
<210> 58
<211> 452
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 58
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Thr Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn 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 Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 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 Pro Ser Glu Glu Leu Ala Leu Asn Glu Leu Val Thr Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys Tyr Leu Thr Trp Ala
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ile Leu Arg
405 410 415
Val Ala Ala Glu Asp Trp Lys Lys Gly Asp Thr Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Asp Arg
435 440 445
Ser Pro Gly Lys
450
<210> 59
<211> 409
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 59
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Gly Gly Gly Gly Ser Gly Gly
165 170 175
Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
180 185 190
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
195 200 205
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
210 215 220
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
225 230 235 240
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
245 250 255
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
260 265 270
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
275 280 285
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg
290 295 300
Pro Glu Val His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
305 310 315 320
Gln Val Ser Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile
325 330 335
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
340 345 350
Thr Pro Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val
355 360 365
Thr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
370 375 380
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
385 390 395 400
Lys Thr Ile Ser Leu Ser Pro Gly Lys
405
<210> 60
<211> 456
<212> PRT
<213> 人工
<220>
<223> 人工序列
<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 Leu Arg Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Arg Ser Ser His Thr Ile Phe Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Asp Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Val Tyr Ser Ser Gly Trp His Val Ser Asp Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Ile Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu
355 360 365
Leu Val Thr Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys Tyr
385 390 395 400
Leu Thr Trp Ala Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
405 410 415
Ser Ile Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly Asp Thr Phe
420 425 430
Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys
435 440 445
Ser Leu Asp Arg Ser Pro Gly Lys
450 455
<210> 61
<211> 398
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 61
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Ala
145 150 155 160
Ala Phe Ala Tyr Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
180 185 190
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
195 200 205
Ala Ser Gln Ser Ile Ser Asn Asn Leu Asn Trp Tyr Gln Gln Lys Pro
210 215 220
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Phe His Ser
225 230 235 240
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
245 250 255
Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
260 265 270
Gln Gln Glu His Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu
275 280 285
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
290 295 300
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
305 310 315 320
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
325 330 335
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
340 345 350
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
355 360 365
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
370 375 380
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
385 390 395
<210> 62
<211> 635
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 62
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Ala
145 150 155 160
Ala Phe Ala Tyr Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly
180 185 190
Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val
195 200 205
Ser Gly Phe Ser Leu Ile Gly Tyr Asp Leu Asn Trp Ile Arg Gln Pro
210 215 220
Pro Gly Lys Gly Leu Glu Trp Ile Gly Ile Ile Trp Gly Asp Gly Thr
225 230 235 240
Thr Asp Tyr Asn Ser Ala Val Lys Ser Arg Val Thr Ile Ser Lys Asp
245 250 255
Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala
260 265 270
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Gly Tyr Trp Tyr Ala Thr
275 280 285
Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
290 295 300
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
305 310 315 320
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
325 330 335
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
340 345 350
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
355 360 365
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
370 375 380
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
385 390 395 400
Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
405 410 415
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
420 425 430
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
435 440 445
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
450 455 460
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
465 470 475 480
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
485 490 495
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
500 505 510
Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
515 520 525
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
530 535 540
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
545 550 555 560
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
565 570 575
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
580 585 590
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
595 600 605
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
610 615 620
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
625 630 635
<210> 63
<211> 403
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 63
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 Ser Ile Ser Asn Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Phe His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Glu His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
210 215 220
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe
225 230 235 240
Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg
245 250 255
Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
260 265 270
Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp
275 280 285
Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val
290 295 300
Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys
305 310 315 320
Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe
325 330 335
Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys
340 345 350
Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys
355 360 365
Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg
370 375 380
Tyr Pro Lys Gly Gln Pro Glu Leu Gln Ala Ala Phe Ala Tyr Thr Thr
385 390 395 400
Val Thr Lys
<210> 64
<211> 640
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 64
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp Lys Thr
450 455 460
His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe Arg Ile His
465 470 475 480
Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg Lys Gln Leu
485 490 495
Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His Ile Gln Val
500 505 510
Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp Lys Tyr Ala
515 520 525
Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val Arg Ile Lys
530 535 540
Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys Gly Lys Leu
545 550 555 560
Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe Ile Glu Lys
565 570 575
Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys Tyr Ser Gly
580 585 590
Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys Gly Pro Lys
595 600 605
Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg Tyr Pro Lys
610 615 620
Gly Gln Pro Glu Leu Gln Ala Ala Phe Ala Tyr Thr Thr Val Thr Lys
625 630 635 640
<210> 65
<211> 454
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 65
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu Leu Val
355 360 365
Thr Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys Tyr Leu Thr
385 390 395 400
Trp Ala Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ile
405 410 415
Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly Asp Thr Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu
435 440 445
Asp Arg Ser Pro Gly Lys
450
<210> 66
<211> 406
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 66
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
165 170 175
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
180 185 190
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
195 200 205
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
210 215 220
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
225 230 235 240
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
245 250 255
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
260 265 270
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
275 280 285
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro Glu Val
290 295 300
His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
305 310 315 320
Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala Val Glu
325 330 335
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Ser
340 345 350
Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser Lys
355 360 365
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
370 375 380
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Thr Ile
385 390 395 400
Ser Leu Ser Pro Gly Lys
405
<210> 67
<211> 404
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 67
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Gln
145 150 155 160
Asn Phe Gln Ser Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
180 185 190
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
195 200 205
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
210 215 220
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
225 230 235 240
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
245 250 255
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
260 265 270
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
275 280 285
Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro Glu Val His Leu
290 295 300
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
305 310 315 320
Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala Val Glu Trp Glu
325 330 335
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Ser Arg Gln
340 345 350
Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser Lys Leu Thr
355 360 365
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
370 375 380
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Thr Ile Ser Leu
385 390 395 400
Ser Pro Gly Lys
<210> 68
<211> 404
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 68
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Pro Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
180 185 190
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
195 200 205
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
210 215 220
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
225 230 235 240
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
245 250 255
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
260 265 270
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
275 280 285
Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro Glu Val His Leu
290 295 300
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
305 310 315 320
Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala Val Glu Trp Glu
325 330 335
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Ser Arg Gln
340 345 350
Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser Lys Leu Thr
355 360 365
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
370 375 380
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Thr Ile Ser Leu
385 390 395 400
Ser Pro Gly Lys
<210> 69
<211> 404
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 69
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Ala
145 150 155 160
Ala Phe Ala Tyr Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
180 185 190
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
195 200 205
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
210 215 220
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
225 230 235 240
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
245 250 255
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
260 265 270
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
275 280 285
Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro Glu Val His Leu
290 295 300
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
305 310 315 320
Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala Val Glu Trp Glu
325 330 335
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Ser Arg Gln
340 345 350
Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser Lys Leu Thr
355 360 365
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
370 375 380
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Thr Ile Ser Leu
385 390 395 400
Ser Pro Gly Lys
<210> 70
<211> 404
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 70
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Val Ser Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
180 185 190
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
195 200 205
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
210 215 220
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
225 230 235 240
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
245 250 255
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
260 265 270
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
275 280 285
Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro Glu Val His Leu
290 295 300
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
305 310 315 320
Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala Val Glu Trp Glu
325 330 335
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Ser Arg Gln
340 345 350
Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser Lys Leu Thr
355 360 365
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
370 375 380
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Thr Ile Ser Leu
385 390 395 400
Ser Pro Gly Lys
<210> 71
<211> 454
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 71
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro Glu Val
340 345 350
His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Ser
385 390 395 400
Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Thr Ile
435 440 445
Ser Leu Ser Pro Gly Lys
450
<210> 72
<211> 406
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 72
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
165 170 175
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
180 185 190
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
195 200 205
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
210 215 220
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
225 230 235 240
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
245 250 255
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
260 265 270
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
275 280 285
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
290 295 300
Tyr Thr Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu Leu Val
305 310 315 320
Thr Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
325 330 335
Glu Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys Tyr Leu Thr
340 345 350
Trp Ala Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ile
355 360 365
Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly Asp Thr Phe Ser Cys
370 375 380
Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu
385 390 395 400
Asp Arg Ser Pro Gly Lys
405
<210> 73
<211> 404
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 73
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Gln
145 150 155 160
Asn Phe Gln Ser Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
180 185 190
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
195 200 205
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
210 215 220
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
225 230 235 240
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
245 250 255
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
260 265 270
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
275 280 285
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
290 295 300
Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu Leu Val Thr Leu
305 310 315 320
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
325 330 335
Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys Tyr Leu Thr Trp Ala
340 345 350
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ile Leu Arg
355 360 365
Val Ala Ala Glu Asp Trp Lys Lys Gly Asp Thr Phe Ser Cys Ser Val
370 375 380
Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Asp Arg
385 390 395 400
Ser Pro Gly Lys
<210> 74
<211> 404
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 74
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Pro Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
180 185 190
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
195 200 205
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
210 215 220
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
225 230 235 240
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
245 250 255
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
260 265 270
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
275 280 285
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
290 295 300
Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu Leu Val Thr Leu
305 310 315 320
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
325 330 335
Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys Tyr Leu Thr Trp Ala
340 345 350
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ile Leu Arg
355 360 365
Val Ala Ala Glu Asp Trp Lys Lys Gly Asp Thr Phe Ser Cys Ser Val
370 375 380
Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Asp Arg
385 390 395 400
Ser Pro Gly Lys
<210> 75
<211> 404
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 75
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Ala
145 150 155 160
Ala Phe Ala Tyr Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
180 185 190
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
195 200 205
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
210 215 220
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
225 230 235 240
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
245 250 255
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
260 265 270
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
275 280 285
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
290 295 300
Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu Leu Val Thr Leu
305 310 315 320
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
325 330 335
Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys Tyr Leu Thr Trp Ala
340 345 350
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ile Leu Arg
355 360 365
Val Ala Ala Glu Asp Trp Lys Lys Gly Asp Thr Phe Ser Cys Ser Val
370 375 380
Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Asp Arg
385 390 395 400
Ser Pro Gly Lys
<210> 76
<211> 404
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 76
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Val Ser Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
180 185 190
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
195 200 205
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
210 215 220
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
225 230 235 240
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
245 250 255
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
260 265 270
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
275 280 285
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
290 295 300
Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu Leu Val Thr Leu
305 310 315 320
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
325 330 335
Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys Tyr Leu Thr Trp Ala
340 345 350
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ile Leu Arg
355 360 365
Val Ala Ala Glu Asp Trp Lys Lys Gly Asp Thr Phe Ser Cys Ser Val
370 375 380
Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Asp Arg
385 390 395 400
Ser Pro Gly Lys
<210> 77
<211> 409
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 77
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Gly Gly Ser Gly Gly Ser Gly
165 170 175
Ser Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
180 185 190
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
195 200 205
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
210 215 220
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
225 230 235 240
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
245 250 255
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
260 265 270
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
275 280 285
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg
290 295 300
Pro Glu Val His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
305 310 315 320
Gln Val Ser Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile
325 330 335
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
340 345 350
Thr Pro Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val
355 360 365
Thr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
370 375 380
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
385 390 395 400
Lys Thr Ile Ser Leu Ser Pro Gly Lys
405
<210> 78
<211> 407
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 78
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Pro Ala Pro Glu Ala Ala Gly
165 170 175
Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
180 185 190
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
195 200 205
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
210 215 220
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
225 230 235 240
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
245 250 255
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
260 265 270
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
275 280 285
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro Glu
290 295 300
Val His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
305 310 315 320
Ser Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala Val
325 330 335
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
340 345 350
Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser
355 360 365
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
370 375 380
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Thr
385 390 395 400
Ile Ser Leu Ser Pro Gly Lys
405
<210> 79
<211> 408
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 79
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Glu Glu Gly Glu Phe Ser Glu
165 170 175
Ala Arg Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
180 185 190
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
195 200 205
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
210 215 220
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
225 230 235 240
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
245 250 255
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
260 265 270
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
275 280 285
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro
290 295 300
Glu Val His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
305 310 315 320
Val Ser Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala
325 330 335
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
340 345 350
Pro Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr
355 360 365
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
370 375 380
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
385 390 395 400
Thr Ile Ser Leu Ser Pro Gly Lys
405
<210> 80
<211> 404
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 80
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Glu Pro Lys Ser Ser Asp Lys
165 170 175
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
180 185 190
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
195 200 205
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
210 215 220
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
225 230 235 240
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
245 250 255
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
260 265 270
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
275 280 285
Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro Glu Val His Leu
290 295 300
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
305 310 315 320
Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala Val Glu Trp Glu
325 330 335
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Ser Arg Gln
340 345 350
Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser Lys Leu Thr
355 360 365
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
370 375 380
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Thr Ile Ser Leu
385 390 395 400
Ser Pro Gly Lys
<210> 81
<211> 399
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 81
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Asp Lys Thr His Thr Cys Pro
165 170 175
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
180 185 190
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
195 200 205
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
210 215 220
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
225 230 235 240
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
245 250 255
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
260 265 270
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
275 280 285
Lys Gly Gln Pro Phe Arg Pro Glu Val His Leu Leu Pro Pro Ser Arg
290 295 300
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Ala Arg Gly
305 310 315 320
Phe Tyr Pro Lys Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
325 330 335
Glu Asn Asn Tyr Lys Thr Thr Pro Ser Arg Gln Glu Pro Ser Gln Gly
340 345 350
Thr Thr Thr Phe Ala Val Thr Ser Lys Leu Thr Val Asp Lys Ser Arg
355 360 365
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
370 375 380
His Asn His Tyr Thr Gln Lys Thr Ile Ser Leu Ser Pro Gly Lys
385 390 395
<210> 82
<211> 402
<212> PRT
<213> 人工
<220>
<223> 人工序列
<400> 82
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Ala Ala Ala Asp Lys Thr His
165 170 175
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
180 185 190
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
195 200 205
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
210 215 220
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
225 230 235 240
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
245 250 255
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
260 265 270
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
275 280 285
Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro Glu Val His Leu Leu Pro
290 295 300
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
305 310 315 320
Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala Val Glu Trp Glu Ser Asn
325 330 335
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Ser Arg Gln Glu Pro
340 345 350
Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser Lys Leu Thr Val Asp
355 360 365
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
370 375 380
Glu Ala Leu His Asn His Tyr Thr Gln Lys Thr Ile Ser Leu Ser Pro
385 390 395 400
Gly Lys
<210> 83
<211> 188
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 83
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln His Thr Thr Glu Gln
145 150 155 160
Ser Leu Arg Phe Glu Phe Leu Asn Tyr Pro Pro Phe Thr Arg Ser Leu
165 170 175
Arg Gly Ser Gln Arg Thr Trp Ala Pro Glu Pro Arg
180 185
<210> 84
<211> 173
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 84
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln His Thr Thr Glu Gln
145 150 155 160
Ser Leu Arg Phe Glu Phe Leu Asn Tyr Pro Pro Phe Thr
165 170
<210> 85
<211> 177
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 85
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Leu Pro Phe Pro Asn
145 150 155 160
His Ala Glu Lys Gln Lys Gln Phe Glu Phe Val Gly Ser Ala Pro Thr
165 170 175
Arg
<210> 86
<211> 168
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 86
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Leu Pro Arg Pro Val Asp Pro Asp Lys Val Pro Glu Leu
145 150 155 160
Tyr Lys Asp Ile Leu Ser Gln Ser
165
<210> 87
<211> 169
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 87
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Phe Thr Thr Val Thr Lys
165
<210> 88
<211> 651
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 88
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp Lys Thr
450 455 460
His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe Arg Ile His
465 470 475 480
Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg Lys Gln Leu
485 490 495
Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His Ile Gln Val
500 505 510
Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp Lys Tyr Ala
515 520 525
Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val Arg Ile Lys
530 535 540
Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys Gly Lys Leu
545 550 555 560
Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe Ile Glu Lys
565 570 575
Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys Tyr Ser Gly
580 585 590
Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys Gly Pro Lys
595 600 605
Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg Tyr Pro Lys
610 615 620
Gly Gln Pro Glu Leu Gln Lys Pro Phe Lys Tyr Thr Thr Val Thr Lys
625 630 635 640
Arg Ser Arg Arg Ile Arg Pro Thr His Pro Ala
645 650
<210> 89
<211> 640
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 89
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp Lys Thr
450 455 460
His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe Arg Ile His
465 470 475 480
Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg Lys Gln Leu
485 490 495
Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His Ile Gln Val
500 505 510
Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp Lys Tyr Ala
515 520 525
Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val Arg Ile Lys
530 535 540
Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys Gly Lys Leu
545 550 555 560
Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe Ile Glu Lys
565 570 575
Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys Tyr Ser Gly
580 585 590
Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys Gly Pro Lys
595 600 605
Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg Tyr Pro Lys
610 615 620
Gly Gln Pro Glu Leu Gln Lys Pro Phe Lys Tyr Thr Thr Val Thr Lys
625 630 635 640
<210> 90
<211> 414
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 90
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Gly Gly Ser Gly Gly Ser Gly
165 170 175
Ser Gly Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro
180 185 190
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
195 200 205
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
210 215 220
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
225 230 235 240
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
245 250 255
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
260 265 270
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
275 280 285
Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
290 295 300
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Pro Ser Glu
305 310 315 320
Glu Leu Ala Leu Asn Glu Leu Val Thr Leu Thr Cys Leu Val Lys Gly
325 330 335
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Leu Gln Gly Ser Gln Glu
340 345 350
Leu Pro Arg Glu Lys Tyr Leu Thr Trp Ala Pro Val Leu Asp Ser Asp
355 360 365
Gly Ser Phe Phe Leu Tyr Ser Ile Leu Arg Val Ala Ala Glu Asp Trp
370 375 380
Lys Lys Gly Asp Thr Phe Ser Cys Ser Val Met His Glu Ala Leu His
385 390 395 400
Asn Arg Phe Thr Gln Lys Ser Leu Asp Arg Ser Pro Gly Lys
405 410
<210> 91
<211> 415
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 91
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys
145 150 155 160
Pro Phe Lys Tyr Thr Thr Val Thr Lys Arg Ser Arg Arg Ile Arg Pro
165 170 175
Thr His Pro Ala Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro
180 185 190
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
195 200 205
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
210 215 220
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
225 230 235 240
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
245 250 255
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
260 265 270
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
275 280 285
Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
290 295 300
Lys Gly Gln Pro Phe Arg Pro Glu Val His Leu Leu Pro Pro Ser Arg
305 310 315 320
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Ala Arg Gly
325 330 335
Phe Tyr Pro Lys Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
340 345 350
Glu Asn Asn Tyr Lys Thr Thr Pro Ser Arg Gln Glu Pro Ser Gln Gly
355 360 365
Thr Thr Thr Phe Ala Val Thr Ser Lys Leu Thr Val Asp Lys Ser Arg
370 375 380
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
385 390 395 400
His Asn His Tyr Thr Gln Lys Thr Ile Ser Leu Ser Pro Gly Lys
405 410 415
<210> 92
<211> 423
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 92
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln His Thr Thr Glu Gln
145 150 155 160
Ser Leu Arg Phe Glu Phe Leu Asn Tyr Pro Pro Phe Thr Arg Ser Leu
165 170 175
Arg Gly Ser Gln Arg Thr Trp Ala Pro Glu Pro Arg Glu Pro Lys Ser
180 185 190
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
195 200 205
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
210 215 220
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
225 230 235 240
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
245 250 255
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
260 265 270
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
275 280 285
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro
290 295 300
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro Glu
305 310 315 320
Val His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
325 330 335
Ser Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala Val
340 345 350
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
355 360 365
Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser
370 375 380
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
385 390 395 400
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Thr
405 410 415
Ile Ser Leu Ser Pro Gly Lys
420
<210> 93
<211> 408
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 93
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln His Thr Thr Glu Gln
145 150 155 160
Ser Leu Arg Phe Glu Phe Leu Asn Tyr Pro Pro Phe Thr Glu Pro Lys
165 170 175
Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
180 185 190
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
195 200 205
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
210 215 220
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
225 230 235 240
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
245 250 255
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
260 265 270
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala
275 280 285
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro
290 295 300
Glu Val His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
305 310 315 320
Val Ser Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala
325 330 335
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
340 345 350
Pro Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr
355 360 365
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
370 375 380
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
385 390 395 400
Thr Ile Ser Leu Ser Pro Gly Lys
405
<210> 94
<211> 412
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 94
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln Leu Pro Phe Pro Asn
145 150 155 160
His Ala Glu Lys Gln Lys Gln Phe Glu Phe Val Gly Ser Ala Pro Thr
165 170 175
Arg Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
180 185 190
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
195 200 205
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
210 215 220
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
225 230 235 240
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
245 250 255
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
260 265 270
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
275 280 285
Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
290 295 300
Pro Phe Arg Pro Glu Val His Leu Leu Pro Pro Ser Arg Glu Glu Met
305 310 315 320
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro
325 330 335
Lys Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
340 345 350
Tyr Lys Thr Thr Pro Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr
355 360 365
Phe Ala Val Thr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
370 375 380
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
385 390 395 400
Tyr Thr Gln Lys Thr Ile Ser Leu Ser Pro Gly Lys
405 410
<210> 95
<211> 403
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 95
Glu Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala
1 5 10 15
Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser
20 25 30
Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala
35 40 45
Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp
50 55 60
Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr
65 70 75 80
Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr
85 90 95
Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr
100 105 110
Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys
115 120 125
Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp
130 135 140
Val His Phe Leu Pro Arg Pro Val Asp Pro Asp Lys Val Pro Glu Leu
145 150 155 160
Tyr Lys Asp Ile Leu Ser Gln Ser Glu Pro Lys Ser Ser Asp Lys Thr
165 170 175
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
180 185 190
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
195 200 205
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
210 215 220
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
225 230 235 240
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
245 250 255
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
260 265 270
Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr
275 280 285
Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro Glu Val His Leu Leu
290 295 300
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
305 310 315 320
Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala Val Glu Trp Glu Ser
325 330 335
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Ser Arg Gln Glu
340 345 350
Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser Lys Leu Thr Val
355 360 365
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
370 375 380
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Thr Ile Ser Leu Ser
385 390 395 400
Pro Gly Lys
<210> 96
<211> 454
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 96
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu Leu Val
355 360 365
Thr Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys Tyr Leu Thr
385 390 395 400
Trp Ala Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ile
405 410 415
Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly Asp Thr Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu
435 440 445
Asp Arg Ser Pro Gly Lys
450
<210> 97
<211> 414
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 97
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala 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 Gly 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 Pro Ser Glu Glu Leu Ala
130 135 140
Leu Asn Glu Leu Val Thr Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
145 150 155 160
Ser Asp Ile Ala Val Glu Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg
165 170 175
Glu Lys Tyr Leu Thr Trp Ala Pro Val Leu Asp Ser Asp Gly Ser Phe
180 185 190
Phe Leu Tyr Ser Ile Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly
195 200 205
Asp Thr Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe
210 215 220
Thr Gln Lys Ser Leu Asp Arg Ser Pro Gly Lys Glu Pro Lys Ser Ser
225 230 235 240
Asp Lys Thr His Thr Glu Glu Asn Val Asp Phe Arg Ile His Val Glu
245 250 255
Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg Lys Gln Leu Arg Leu
260 265 270
Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His Ile Gln Val Leu Gly
275 280 285
Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu
290 295 300
Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val Arg Ile Lys Gly Lys
305 310 315 320
Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys Gly Lys Leu Val Gly
325 330 335
Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe Ile Glu Lys Val Leu
340 345 350
Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr
355 360 365
Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg
370 375 380
Glu Asn Gln Gln Asp Val His Phe Met Lys Arg Tyr Pro Lys Gly Gln
385 390 395 400
Pro Glu Leu Gln Lys Pro Phe Lys Tyr Thr Thr Val Thr Lys
405 410
<210> 98
<211> 424
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 98
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala 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 Gly 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 Pro Ser Glu Glu Leu Ala
130 135 140
Leu Asn Glu Leu Val Thr Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
145 150 155 160
Ser Asp Ile Ala Val Glu Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg
165 170 175
Glu Lys Tyr Leu Thr Trp Ala Pro Val Leu Asp Ser Asp Gly Ser Phe
180 185 190
Phe Leu Tyr Ser Ile Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly
195 200 205
Asp Thr Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe
210 215 220
Thr Gln Lys Ser Leu Asp Arg Ser Pro Gly Lys Gly Gly Gly Gly Ser
225 230 235 240
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu
245 250 255
Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg
260 265 270
Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg
275 280 285
Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg
290 295 300
Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr
305 310 315 320
Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu
325 330 335
Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser
340 345 350
Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala
355 360 365
Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys
370 375 380
Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val
385 390 395 400
His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys Pro
405 410 415
Phe Lys Tyr Thr Thr Val Thr Lys
420
<210> 99
<211> 419
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 99
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala 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 Gly 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 Pro Ser Glu Glu Leu Ala
130 135 140
Leu Asn Glu Leu Val Thr Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
145 150 155 160
Ser Asp Ile Ala Val Glu Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg
165 170 175
Glu Lys Tyr Leu Thr Trp Ala Pro Val Leu Asp Ser Asp Gly Ser Phe
180 185 190
Phe Leu Tyr Ser Ile Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly
195 200 205
Asp Thr Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe
210 215 220
Thr Gln Lys Ser Leu Asp Arg Ser Pro Gly Lys Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe
245 250 255
Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg
260 265 270
Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
275 280 285
Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp
290 295 300
Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val
305 310 315 320
Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys
325 330 335
Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe
340 345 350
Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys
355 360 365
Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys
370 375 380
Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg
385 390 395 400
Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys Pro Phe Lys Tyr Thr Thr
405 410 415
Val Thr Lys
<210> 100
<211> 435
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 100
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala 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 Gly 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 Pro Ser Glu Glu Leu Ala
130 135 140
Leu Asn Glu Leu Val Thr Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
145 150 155 160
Ser Asp Ile Ala Val Glu Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg
165 170 175
Glu Lys Tyr Leu Thr Trp Ala Pro Val Leu Asp Ser Asp Gly Ser Phe
180 185 190
Phe Leu Tyr Ser Ile Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly
195 200 205
Asp Thr Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe
210 215 220
Thr Gln Lys Ser Leu Asp Arg Ser Pro Gly Lys Gly Gly Gly Gly Ser
225 230 235 240
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu
245 250 255
Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg
260 265 270
Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg
275 280 285
Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg
290 295 300
Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr
305 310 315 320
Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu
325 330 335
Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser
340 345 350
Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala
355 360 365
Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys
370 375 380
Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val
385 390 395 400
His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys Pro
405 410 415
Phe Lys Tyr Thr Thr Val Thr Lys Arg Ser Arg Arg Ile Arg Pro Thr
420 425 430
His Pro Ala
435
<210> 101
<211> 424
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 101
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala 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 Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Phe Arg Pro Glu Val His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys
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 Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe
180 185 190
Ala Val Thr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
195 200 205
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
210 215 220
Thr Gln Lys Thr Ile Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser
225 230 235 240
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu
245 250 255
Glu Asn Val Asp Phe Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg
260 265 270
Asp Asp Val Ser Arg Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg
275 280 285
Thr Ser Gly Lys His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg
290 295 300
Gly Glu Asp Gly Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr
305 310 315 320
Phe Gly Ser Gln Val Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu
325 330 335
Cys Met Asn Arg Lys Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser
340 345 350
Lys Glu Cys Val Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala
355 360 365
Leu Met Ser Ala Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys
370 375 380
Gly Arg Pro Arg Lys Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val
385 390 395 400
His Phe Met Lys Arg Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys Pro
405 410 415
Phe Lys Tyr Thr Thr Val Thr Lys
420
<210> 102
<211> 235
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 102
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala 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 Gly 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 Pro Ser Glu Glu Leu Ala
130 135 140
Leu Asn Glu Leu Val Thr Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
145 150 155 160
Ser Asp Ile Ala Val Glu Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg
165 170 175
Glu Lys Tyr Leu Thr Trp Ala Pro Val Leu Asp Ser Asp Gly Ser Phe
180 185 190
Phe Leu Tyr Ser Ile Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly
195 200 205
Asp Thr Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe
210 215 220
Thr Gln Lys Ser Leu Asp Arg Ser Pro Gly Lys
225 230 235
<210> 103
<211> 643
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 103
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro Glu Val
340 345 350
His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Ser
385 390 395 400
Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Thr Ile
435 440 445
Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
450 455 460
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe
465 470 475 480
Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg
485 490 495
Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
500 505 510
Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp
515 520 525
Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val
530 535 540
Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys
545 550 555 560
Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe
565 570 575
Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys
580 585 590
Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys
595 600 605
Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg
610 615 620
Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys Pro Phe Lys Tyr Thr Thr
625 630 635 640
Val Thr Lys
<210> 104
<211> 643
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 104
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro Glu Val
340 345 350
His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Ser
385 390 395 400
Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Thr Ile
435 440 445
Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
450 455 460
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe
465 470 475 480
Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg
485 490 495
Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
500 505 510
Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp
515 520 525
Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val
530 535 540
Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys
545 550 555 560
Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe
565 570 575
Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys
580 585 590
Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys
595 600 605
Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg
610 615 620
Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys Pro Phe Lys Pro Thr Thr
625 630 635 640
Val Thr Lys
<210> 105
<211> 643
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 105
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro Glu Val
340 345 350
His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Ser
385 390 395 400
Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Thr Ile
435 440 445
Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
450 455 460
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe
465 470 475 480
Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg
485 490 495
Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
500 505 510
Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp
515 520 525
Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val
530 535 540
Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys
545 550 555 560
Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe
565 570 575
Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys
580 585 590
Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys
595 600 605
Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg
610 615 620
Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys Pro Phe Lys Phe Thr Thr
625 630 635 640
Val Thr Lys
<210> 106
<211> 643
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 106
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Phe Arg Pro Glu Val
340 345 350
His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Ser
385 390 395 400
Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Thr Ile
435 440 445
Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
450 455 460
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe
465 470 475 480
Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg
485 490 495
Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
500 505 510
Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp
515 520 525
Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val
530 535 540
Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys
545 550 555 560
Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe
565 570 575
Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys
580 585 590
Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys
595 600 605
Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg
610 615 620
Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys Pro Phe Val Ser Thr Thr
625 630 635 640
Val Thr Lys
<210> 107
<211> 235
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 107
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala 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 Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Phe Arg Pro Glu Val His Leu Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Ala Arg Gly Phe Tyr Pro Lys
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 Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe
180 185 190
Ala Val Thr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
195 200 205
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
210 215 220
Thr Gln Lys Thr Ile Ser Leu Ser Pro Gly Lys
225 230 235
<210> 108
<211> 643
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 108
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr
20 25 30
Asp Leu Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Gly Asp Gly Thr Thr Asp Tyr Asn Ser Ala Val Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu Leu Val
355 360 365
Thr Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys Tyr Leu Thr
385 390 395 400
Trp Ala Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ile
405 410 415
Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly Asp Thr Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu
435 440 445
Asp Arg Ser Pro Gly Lys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
450 455 460
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe
465 470 475 480
Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg
485 490 495
Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
500 505 510
Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp
515 520 525
Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val
530 535 540
Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys
545 550 555 560
Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe
565 570 575
Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys
580 585 590
Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys
595 600 605
Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg
610 615 620
Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys Pro Phe Lys Tyr Thr Thr
625 630 635 640
Val Thr Lys
<210> 109
<211> 1362
<212> DNA
<213> 人工
<220>
<223> 人工
<400> 109
caggtccagc tgcaagaatc tggccctggc ctggtcaagc cttccgagac actgtctctg 60
acctgcaccg tgtctggctt ctccctgatc ggctacgacc tgaactggat cagacagcct 120
cctggcaaag gcctggaatg gatcggaatc atctggggcg acggcaccac cgactacaac 180
tctgccgtga agtccagagt gaccatctcc aaggacacct ccaagaacca gttcagcctg 240
aagctgtcct ccgtgaccgc tgctgatacc gccgtgtact actgtgccag aggcggctat 300
tggtacgcca cctcctacta cttcgactac tggggccagg gcaccctggt cacagtttct 360
tccgcttcca ccaagggacc cagcgtgttc cctctggctc cttccagcaa gtctacctct 420
ggcggaacag ctgctctggg ctgtctggtc aaggactact tccctgagcc tgtgaccgtg 480
tcctggaact ctggcgctct gacatctggc gtgcacacct ttccagctgt gctgcagtcc 540
tccggcctgt actctctgtc ctctgtcgtg accgtgcctt ccagctctct gggaacccag 600
acctacatct gcaatgtgaa ccacaagcct agcaacacca aggtggacaa gaaggtggaa 660
cccaagtcct gcgacaagac ccacacctgt cctccatgtc ctgctccaga agctgctggc 720
ggcccttccg tgtttctgtt ccctccaaag cctaaggaca ccctgatgat ctctcggacc 780
cctgaagtga cctgcgtggt ggtggatgtg tctcacgagg acccagaagt gaagttcaat 840
tggtacgtgg acggcgtgga agtgcacaac gccaagacca agcctagaga ggaacagtac 900
aactccacct acagagtggt gtccgtgctg accgtgctgc accaggattg gctgaacggc 960
aaagagtaca agtgcaaggt gtccaacaag gccctgggcg ctcccatcga aaagaccatc 1020
agcaaggcta agggccagcc tttccggcct gaagtgcatc tgctgcctcc aagcagagaa 1080
gagatgacca agaatcaggt gtccctgacc tgtctggcca ggggcttcta ccctaaggat 1140
atcgccgtgg aatgggagtc caacggccag cctgagaaca actacaagac aacccctagc 1200
cggcaagagc cctctcaggg caccacaacc tttgccgtga cctccaagct gacagtggac 1260
aagtccagat ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 1320
aaccactaca cccagaaaac catttctctg agccccggca ag 1362
<210> 110
<211> 1242
<212> DNA
<213> 人工
<220>
<223> 人工
<400> 110
gaggaaaacg tggactttag aatccacgtc gagaaccaga ccagagccag ggacgacgtg 60
tccagaaagc agctgagact gtaccagctg tactcccgga cctccggcaa gcacattcag 120
gtgctgggca gaagaatctc cgccagaggc gaggacggcg ataagtatgc acagctgctg 180
gtggaaaccg acaccttcgg aagccaagtg cggatcaagg gcaaagagac agagttctac 240
ctgtgcatga accggaaggg caagctcgtg ggcaagcctg acggcacctc taaagaatgc 300
gtgttcatcg agaaggtgct cgagaacaac tacaccgctc tgatgtccgc caagtactcc 360
ggatggtacg tgggcttcac caagaagggc agacccagaa agggccccaa gaccagagaa 420
aaccagcagg acgtgcactt tatgaagcgc taccccaagg gccagcctga gctgcagaag 480
ccctttaagt acaccaccgt gaccaaaggc ggctccggcg gaagtggatc tggatctgaa 540
cctaagtcct ccgacaagac ccacacctgt cctccatgtc ctgctccaga agctgctggc 600
ggcccttccg tgtttctgtt ccctccaaag cctaaggaca ccctgatgat ctctcggacc 660
cctgaagtga cctgcgtggt ggtggatgtg tctcacgagg acccagaagt gaagttcaat 720
tggtacgtcg acggcgtgga agtgcacaac gccaagacca agcctagaga ggaacagtac 780
aactccacct acagagtggt gtccgtgctg accgtgctgc accaggattg gctgaacggc 840
aaagagtaca agtgcaaggt gtccaacaag gccctgggcg ctcccatcga aaagaccatc 900
tctaaggcca agggacagcc ccgggaacct caggtttaca cactgcctcc accttccgag 960
gaactggccc tgaatgagct ggtcaccctg acctgtctgg tcaagggctt ttacccctcc 1020
gatatcgccg tggaatggct gcagggatct caagagctgc ccagagagaa gtacctgacc 1080
tgggctcctg tgctggactc cgacggctct ttcttcctgt actccatcct gagagtggcc 1140
gccgaggatt ggaagaaggg cgataccttc tcctgctccg tgatgcacga ggccctgcac 1200
aacagattca cacagaagtc cctggacaga tcccctggca ag 1242
<210> 111
<211> 642
<212> DNA
<213> 人工
<220>
<223> 人工
<400> 111
gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60
atcacctgta gagccagcca gagcatctcc aacaacctga actggtatca gcagaagccc 120
ggcaaggccc ctaagctgct gatctactac accagcagat tccacagcgg cgtgccctct 180
agattttctg gcagcggctc tggcaccgac ttcaccttca ccataagcag cctgcagcct 240
gaggatatcg ccacctacta ctgccagcaa gagcacaccc tgccttacac ctttggccag 300
ggcaccaagc tggaaatcaa gcggacagtg gccgctccta gcgtgttcat ctttccacct 360
agcgacgagc agctgaagtc cggcacagcc tctgttgtgt gcctgctgaa caacttctac 420
cccagagaag ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caatagccaa 480
gagagcgtga ccgagcagga cagcaaggac tctacctact ctctgagcag caccctgaca 540
ctgagcaagg ccgactacga gaagcacaaa gtgtacgcct gcgaagtgac ccaccagggc 600
ctttctagcc ctgtgaccaa gagcttcaac cggggcgagt gc 642
<210> 112
<211> 1362
<212> DNA
<213> 人工
<220>
<223> 人工
<400> 112
caggtccagc tgcaagaatc tggccctggc ctggtcaagc cttccgagac actgtctctg 60
acctgcaccg tgtctggctt ctccctgatc ggctacgacc tgaactggat cagacagcct 120
cctggcaaag gcctggaatg gatcggaatc atctggggcg acggcaccac cgactacaac 180
tctgccgtga agtccagagt gaccatctcc aaggacacct ccaagaacca gttcagcctg 240
aagctgtcct ccgtgaccgc tgctgatacc gccgtgtact actgtgccag aggcggctat 300
tggtacgcca cctcctacta cttcgactac tggggccagg gcaccctggt cacagtttct 360
tccgcttcca ccaagggacc cagcgtgttc cctctggctc cttccagcaa gtctacctct 420
ggcggaacag ctgctctggg ctgtctggtc aaggactact tccctgagcc tgtgaccgtg 480
tcctggaact ctggcgctct gacatctggc gtgcacacct ttccagctgt gctgcagtcc 540
tccggcctgt actctctgtc ctctgtcgtg accgtgcctt ccagctctct gggaacccag 600
acctacatct gcaatgtgaa ccacaagcct agcaacacca aggtggacaa gaaggtggaa 660
cccaagtcct gcgacaagac ccacacctgt cctccatgtc ctgctccaga agctgctggc 720
ggcccttccg tgtttctgtt ccctccaaag cctaaggaca ccctgatgat ctctcggacc 780
cctgaagtga cctgcgtggt ggtggatgtg tctcacgagg acccagaagt gaagttcaat 840
tggtacgtgg acggcgtgga agtgcacaac gccaagacca agcctagaga ggaacagtac 900
aactccacct acagagtggt gtccgtgctg accgtgctgc accaggattg gctgaacggc 960
aaagagtaca agtgcaaggt gtccaacaag gccctgggcg ctcccatcga aaagaccatc 1020
agcaaggcta agggccagcc tttccggcct gaagtgcatc tgctgcctcc aagcagagaa 1080
gagatgacca agaatcaggt gtccctgacc tgtctggcca ggggcttcta ccctaaggat 1140
atcgccgtgg aatgggagtc caacggccag cctgagaaca actacaagac aacccctagc 1200
cggcaagagc cctctcaggg caccacaacc tttgccgtga cctccaagct gacagtggac 1260
aagtccagat ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 1320
aaccactaca cccagaaaac catttctctg agccccggca ag 1362
<210> 113
<211> 1242
<212> DNA
<213> 人工
<220>
<223> 人工
<400> 113
gagcctaagt cctccgataa gacccacacc tgtcctccat gtcctgctcc agaagctgct 60
ggcggccctt ccgtgtttct gttccctcca aagcctaagg acaccctgat gatctctcgg 120
acccctgaag tgacctgcgt ggtggtggat gtgtctcacg aggacccaga agtgaagttc 180
aattggtacg tggacggcgt ggaagtgcac aacgccaaga ccaagcctag agaggaacag 240
tacaactcca cctacagagt ggtgtccgtg ctgaccgtgc tgcaccagga ttggctgaac 300
ggcaaagagt acaagtgcaa ggtgtccaac aaggccctgg gcgctcccat cgaaaagacc 360
atctctaagg ccaagggcca gcctcgggaa ccccaggttt acacattgcc tccaccttcc 420
gaggaactgg ccctgaatga gctggtcacc ctgacctgtc tggtcaaggg cttctacccc 480
tccgatatcg ccgtggaatg gctgcaggga agccaagagc tgcccagaga gaagtacctg 540
acctgggctc ctgtgctgga ctccgacggc tctttcttcc tgtactccat cctgagagtg 600
gccgccgagg attggaagaa gggcgacacc ttcagctgct ccgtgatgca cgaggccctg 660
cacaacagat tcacacagaa gtccctggac agatcccctg gcaaagagcc caagtccagc 720
gacaagacac ataccgagga aaacgtggac ttccgcatcc acgtcgagaa ccagaccaga 780
gccagagatg acgtgtcccg gaagcagctg agactgtacc agctgtactc tagaacctcc 840
ggcaagcaca tccaggtgct gggcagaaga atctccgcca gaggcgagga cggcgataag 900
tatgcacagc tgctggtgga aaccgacacc tttggctccc aagtgcggat caagggcaaa 960
gagacagagt tctacctgtg catgaaccgg aagggcaagc tcgtgggcaa gcctgacggc 1020
acctctaaag aatgcgtgtt catcgagaag gtgctcgaga acaactacac cgctctgatg 1080
tccgccaagt actccggatg gtacgtcggc ttcaccaaga agggcagacc cagaaagggc 1140
cccaagacca gagaaaacca gcaggacgtg cactttatga agcgctaccc caagggacag 1200
cccgagctgc agaagccttt caagtacacc accgtgacca ag 1242
<210> 114
<211> 1305
<212> DNA
<213> 人工
<220>
<223> 人工
<400> 114
gagcctaagt cctccgataa gacccacacc tgtcctccat gtcctgctcc agaagctgct 60
ggcggccctt ccgtgtttct gttccctcca aagcctaagg acaccctgat gatctctcgg 120
acccctgaag tgacctgcgt ggtggtggat gtgtctcacg aggacccaga agtgaagttc 180
aattggtacg tggacggcgt ggaagtgcac aacgccaaga ccaagcctag agaggaacag 240
tacaactcca cctacagagt ggtgtccgtg ctgaccgtgc tgcaccagga ttggctgaac 300
ggcaaagagt acaagtgcaa ggtgtccaac aaggccctgg gcgctcccat cgaaaagacc 360
atctctaagg ccaagggcca gcctcgggaa ccccaggttt acacattgcc tccaccttcc 420
gaggaactgg ccctgaatga gctggtcacc ctgacctgtc tggtcaaggg cttctacccc 480
tccgatatcg ccgtggaatg gctgcaggga agccaagagc tgcccagaga gaagtacctg 540
acctgggctc ctgtgctgga ctccgacggc tctttcttcc tgtactccat cctgagagtg 600
gccgccgagg attggaagaa gggcgacacc ttcagctgct ccgtgatgca cgaggccctg 660
cacaacagat tcacacagaa gtccctggac agatcccctg gcaaaggtgg cggaggatct 720
gagcccaagt ctagcgacaa gacccataca ggcggaggcg gctctgagga aaacgtggac 780
tttagaatcc acgtcgagaa ccagaccaga gccagggacg acgtgtccag aaagcagctg 840
agactgtacc agctgtactc ccggacctcc ggcaagcaca ttcaggtgct gggcagaaga 900
atctccgcca gaggcgagga cggcgataag tatgcacagc tgctggtgga aaccgacacc 960
tttggctccc aagtgcggat caagggcaaa gagacagagt tctacctgtg catgaaccgg 1020
aagggcaagc tcgtgggcaa gcctgacggc acctctaaag aatgcgtgtt catcgagaag 1080
gtgctcgaga acaactacac cgctctgatg tccgccaagt actccggatg gtacgtcggc 1140
ttcaccaaga agggcagacc cagaaagggc cccaagacca gagaaaacca gcaggacgtg 1200
cactttatga agcgctaccc caagggacag cccgagctgc agaagccttt caagtacacc 1260
accgtgacca agcggtcccg gcggatcaga cctacacacc ctgct 1305
<210> 115
<211> 705
<212> DNA
<213> 人工
<220>
<223> 人工
<400> 115
gagcctaagt cctccgataa gacccacacc tgtcctccat gtcctgctcc agaagctgct 60
ggcggccctt ccgtgtttct gttccctcca aagcctaagg acaccctgat gatctctcgg 120
acccctgaag tgacctgcgt ggtggtggat gtgtctcacg aggacccaga agtgaagttc 180
aattggtacg tggacggcgt ggaagtgcac aacgccaaga ccaagcctag agaggaacag 240
tacaactcca cctacagagt ggtgtccgtg ctgaccgtgc tgcaccagga ttggctgaac 300
ggcaaagagt acaagtgcaa ggtgtccaac aaggccctgg gcgctcccat cgaaaagacc 360
atctctaagg ccaagggcca gcctcgggaa ccccaggttt acacattgcc tccaccttcc 420
gaggaactgg ccctgaatga gctggtcacc ctgacctgtc tggtcaaggg cttctacccc 480
tccgatatcg ccgtggaatg gctgcaggga agccaagagc tgcccagaga gaagtacctg 540
acctgggctc ctgtgctgga ctccgacggc tctttcttcc tgtactccat cctgagagtg 600
gccgccgagg attggaagaa gggcgacacc ttcagctgct ccgtgatgca cgaggccctg 660
cacaacagat tcacacagaa gtccctggac agatcccctg gcaag 705
<210> 116
<211> 1209
<212> DNA
<213> 人工
<220>
<223> 人工
<400> 116
gacatccaga tgacccagtc tccatcctct ctgtccgcct ctgtgggcga cagagtgacc 60
atcacctgtc gggcctctca gtccatctcc aacaacctga actggtatca gcagaagccc 120
ggcaaggccc ctaagctgct gatctactac accagccggt tccactctgg cgtgccctct 180
agattttccg gctctggctc tggcaccgac tttaccttta caatctccag cctgcagcct 240
gaggatatcg ccacctacta ctgccagcaa gagcacaccc tgccttacac ctttggccag 300
ggcaccaagc tggaaatcaa gcggacagtg gccgctcctt ccgtgttcat cttcccacct 360
tccgacgagc agctgaagtc cggcacagct tctgtcgtgt gcctgctgaa caacttctac 420
cctcgggaag ccaaggtgca gtggaaggtg gacaatgccc tgcagtccgg caactcccaa 480
gagtctgtga ccgagcagga ctccaaggac agcacctaca gcctgagcag caccctgaca 540
ctgtccaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccatcagggc 600
ctgtctagcc ctgtgaccaa gtctttcaac agaggcgagt gtggcggcgg aggctctgaa 660
cctaagtcct ctgataagac ccacactggc ggaggcggct ccgaggaaaa cgtggacttt 720
agaatccacg tcgagaacca gaccagggcc agagatgacg tgtcccggaa acagctgaga 780
ctgtaccagc tgtactcccg gacctccggc aagcacattc aggtgctggg cagaagaatc 840
tccgctagag gcgaggacgg cgataagtac gctcagctcc tggtggaaac cgacaccttc 900
ggatctcaag tgcggatcaa gggcaaagag acagagttct acctgtgcat gaatcggaag 960
ggcaagctcg tgggcaagcc tgacggcacc tctaaagaat gcgtgttcat tgagaaggtg 1020
ctcgagaaca actacaccgc tctgatgtcc gccaagtact ccggatggta cgtgggcttc 1080
accaagaagg gcagacccag aaagggcccc aagaccagag aaaaccagca ggacgtgcac 1140
tttatgaagc gctaccccaa gggccagcca gagctgcaga agcctttcaa gtacaccacc 1200
gtgacaaag 1209
<210> 117
<211> 672
<212> DNA
<213> 人工
<220>
<223> 人工
<400> 117
caggtgcagc tgcaggagtc tggacctgga ctggtgaagc ctagcgagac actgtccctg 60
acctgcacag tgtctggctt tagcctgatc ggctacgacc tgaactggat caggcagccc 120
cctggcaagg gactggagtg gatcggcatc atctggggcg acggcaccac agattataac 180
tctgccgtga agagcagggt gaccatctcc aaggacacat ctaagaatca gttctccctg 240
aagctgagct ccgtgaccgc cgctgataca gccgtgtact attgcgctag gggcggctac 300
tggtatgcta ccagctacta tttcgactac tggggccagg gcaccctggt gacagtgtct 360
agcgccagca caaagggccc ctccgtgttt cctctggctc catcctctaa gagcacctcc 420
ggcggcacag ccgctctggg ctgtctggtg aaggattatt tcccagagcc cgtgaccgtg 480
tcctggaact ctggcgccct gacctccgga gtgcacacat ttcccgctgt gctgcagagc 540
tccggcctgt actctctgtc tagcgtggtg accgtgcctt cctctagcct gggcacccag 600
acatatatct gcaacgtgaa tcacaagcct tctaatacaa aggtggataa gaaggtggag 660
ccaaagagct gt 672
<210> 118
<211> 20
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 118
Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 119
<211> 15
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 119
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 120
<211> 10
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 120
Glu Pro Lys Ser Ser Asp Lys Thr His Thr
1 5 10
<210> 121
<211> 215
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 121
Met Gly Ser Pro Arg Ser Ala Leu Ser Cys Leu Leu Leu His Leu Leu
1 5 10 15
Val Leu Cys Leu Gln Ala Gln Val Thr Val Gln Ser Ser Pro Asn Phe
20 25 30
Thr Gln His Val Arg Glu Gln Ser Leu Val Thr Asp Gln Leu Ser Arg
35 40 45
Arg Leu Ile Arg Thr Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
50 55 60
Val Gln Val Leu Ala Asn Lys Arg Ile Asn Ala Met Ala Glu Asp Gly
65 70 75 80
Asp Pro Phe Ala Lys Leu Ile Val Glu Thr Asp Thr Phe Gly Ser Arg
85 90 95
Val Arg Val Arg Gly Ala Glu Thr Gly Leu Tyr Ile Cys Met Asn Lys
100 105 110
Lys Gly Lys Leu Ile Ala Lys Ser Asn Gly Lys Gly Lys Asp Cys Val
115 120 125
Phe Thr Glu Ile Val Leu Glu Asn Asn Tyr Thr Ala Leu Gln Asn Ala
130 135 140
Lys Tyr Glu Gly Trp Tyr Met Ala Phe Thr Arg Lys Gly Arg Pro Arg
145 150 155 160
Lys Gly Ser Lys Thr Arg Gln His Gln Arg Glu Val His Phe Met Lys
165 170 175
Arg Leu Pro Arg Gly His His Thr Thr Glu Gln Ser Leu Arg Phe Glu
180 185 190
Phe Leu Asn Tyr Pro Pro Phe Thr Arg Ser Leu Arg Gly Ser Gln Arg
195 200 205
Thr Trp Ala Pro Glu Pro Arg
210 215
<210> 122
<211> 208
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 122
Met Ala Pro Leu Gly Glu Val Gly Asn Tyr Phe Gly Val Gln Asp Ala
1 5 10 15
Val Pro Phe Gly Asn Val Pro Val Leu Pro Val Asp Ser Pro Val Leu
20 25 30
Leu Ser Asp His Leu Gly Gln Ser Glu Ala Gly Gly Leu Pro Arg Gly
35 40 45
Pro Ala Val Thr Asp Leu Asp His Leu Lys Gly Ile Leu Arg Arg Arg
50 55 60
Gln Leu Tyr Cys Arg Thr Gly Phe His Leu Glu Ile Phe Pro Asn Gly
65 70 75 80
Thr Ile Gln Gly Thr Arg Lys Asp His Ser Arg Phe Gly Ile Leu Glu
85 90 95
Phe Ile Ser Ile Ala Val Gly Leu Val Ser Ile Arg Gly Val Asp Ser
100 105 110
Gly Leu Tyr Leu Gly Met Asn Glu Lys Gly Glu Leu Tyr Gly Ser Glu
115 120 125
Lys Leu Thr Gln Glu Cys Val Phe Arg Glu Gln Phe Glu Glu Asn Trp
130 135 140
Tyr Asn Thr Tyr Ser Ser Asn Leu Tyr Lys His Val Asp Thr Gly Arg
145 150 155 160
Arg Tyr Tyr Val Ala Leu Asn Lys Asp Gly Thr Pro Arg Glu Gly Thr
165 170 175
Arg Thr Lys Arg His Gln Lys Phe Thr His Phe Leu Pro Arg Pro Val
180 185 190
Asp Pro Asp Lys Val Pro Glu Leu Tyr Lys Asp Ile Leu Ser Gln Ser
195 200 205
<210> 123
<211> 205
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 123
Met Gly Ala Ala Arg Leu Leu Pro Asn Leu Thr Leu Cys Leu Gln Leu
1 5 10 15
Leu Ile Leu Cys Cys Gln Thr Gln Tyr Val Arg Asp Gln Gly Ala Met
20 25 30
Thr Asp Gln Leu Ser Arg Arg Gln Ile Arg Glu Tyr Gln Leu Tyr Ser
35 40 45
Arg Thr Ser Gly Lys His Val Gln Val Thr Gly Arg Arg Ile Ser Ala
50 55 60
Thr Ala Glu Asp Gly Asn Lys Phe Ala Lys Leu Ile Val Glu Thr Asp
65 70 75 80
Thr Phe Gly Ser Arg Val Arg Ile Lys Gly Ala Glu Ser Glu Lys Tyr
85 90 95
Ile Cys Met Asn Lys Arg Gly Lys Leu Ile Gly Lys Pro Ser Gly Lys
100 105 110
Ser Lys Asp Cys Val Phe Thr Glu Ile Val Leu Glu Asn Asn Tyr Thr
115 120 125
Ala Phe Gln Asn Ala Arg His Glu Gly Trp Phe Met Ala Phe Thr Arg
130 135 140
Gln Gly Arg Pro Arg Gln Ala Ser Arg Ser Arg Gln Asn Gln Arg Glu
145 150 155 160
Ala His Phe Ile Lys Arg Leu Tyr Gln Gly Gln Leu Pro Phe Pro Asn
165 170 175
His Ala Glu Lys Gln Lys Gln Phe Glu Phe Val Gly Ser Ala Pro Thr
180 185 190
Arg Arg Thr Lys Arg Thr Arg Arg Pro Gln Pro Leu Thr
195 200 205
<210> 124
<211> 403
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 124
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 Ser Ile Ser Asn Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Phe His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Glu His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
210 215 220
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe
225 230 235 240
Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg
245 250 255
Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
260 265 270
Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp
275 280 285
Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val
290 295 300
Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys
305 310 315 320
Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe
325 330 335
Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys
340 345 350
Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys
355 360 365
Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg
370 375 380
Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys Pro Phe Lys Tyr Thr Thr
385 390 395 400
Val Thr Lys
<210> 125
<211> 414
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 125
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 Ser Ile Ser Asn Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Phe His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Glu His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
210 215 220
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe
225 230 235 240
Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg
245 250 255
Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
260 265 270
Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp
275 280 285
Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val
290 295 300
Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys
305 310 315 320
Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe
325 330 335
Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys
340 345 350
Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys
355 360 365
Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg
370 375 380
Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys Pro Phe Lys Tyr Thr Thr
385 390 395 400
Val Thr Lys Arg Ser Arg Arg Ile Arg Pro Thr His Pro Ala
405 410
<210> 126
<211> 403
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 126
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 Ser Ile Ser Asn Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Phe His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Glu His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
210 215 220
Asp Lys Thr His Thr Gly Gly Gly Gly Ser Glu Glu Asn Val Asp Phe
225 230 235 240
Arg Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser Arg
245 250 255
Lys Gln Leu Arg Leu Tyr Gln Leu Tyr Ser Arg Thr Ser Gly Lys His
260 265 270
Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg Gly Glu Asp Gly Asp
275 280 285
Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln Val
290 295 300
Arg Ile Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg Lys
305 310 315 320
Gly Lys Leu Val Gly Lys Pro Asp Gly Thr Ser Lys Glu Cys Val Phe
325 330 335
Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu Met Ser Ala Lys
340 345 350
Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg Lys
355 360 365
Gly Pro Lys Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys Arg
370 375 380
Tyr Pro Lys Gly Gln Pro Glu Leu Gln Lys Pro Phe Lys Tyr Thr Thr
385 390 395 400
Val Thr Lys
<210> 127
<211> 15
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 127
Gly Gly Ser Gly Gly Ser Gly Ser Gly Ser Glu Pro Lys Ser Ser
1 5 10 15
<210> 128
<211> 10
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 128
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 129
<211> 5
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 129
Glu Pro Lys Ser Ser
1 5
<210> 130
<211> 25
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 130
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp
1 5 10 15
Lys Thr His Thr Gly Gly Gly Gly Ser
20 25
<210> 131
<211> 10
<212> PRT
<213> 人工
<220>
<223> 人工
<400> 131
Glu Pro Lys Ser Ser Asp Lys Thr His Thr
1 5 10
<210> 132
<211> 1209
<212> DNA
<213> 人工
<220>
<223> 人工
<400> 132
gacatccaga tgacccagtc tccatcctct ctgtccgcct ctgtgggcga cagagtgacc 60
atcacctgtc gggcctctca gtccatctcc aacaacctga actggtatca gcagaagccc 120
ggcaaggccc ctaagctgct gatctactac accagccggt tccactctgg cgtgccctct 180
agattttccg gctctggctc tggcaccgac tttaccttta caatctccag cctgcagcct 240
gaggatatcg ccacctacta ctgccagcaa gagcacaccc tgccttacac ctttggccag 300
ggcaccaagc tggaaatcaa gcggacagtg gccgctcctt ccgtgttcat cttcccacct 360
tccgacgagc agctgaagtc cggcacagct tctgtcgtgt gcctgctgaa caacttctac 420
cctcgggaag ccaaggtgca gtggaaggtg gacaatgccc tgcagtccgg caactcccaa 480
gagtctgtga ccgagcagga ctccaaggac agcacctaca gcctgagcag caccctgaca 540
ctgtccaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccatcagggc 600
ctgtctagcc ctgtgaccaa gtctttcaac agaggcgagt gtggcggcgg aggctctgaa 660
cctaagtcct ctgataagac ccacactggc ggaggcggct ccgaggaaaa cgtggacttt 720
agaatccacg tcgagaacca gaccagggcc agagatgacg tgtcccggaa acagctgaga 780
ctgtaccagc tgtactcccg gacctccggc aagcacattc aggtgctggg cagaagaatc 840
tccgctagag gcgaggacgg cgataagtac gctcagctcc tggtggaaac cgacaccttc 900
ggatctcaag tgcggatcaa gggcaaagag acagagttct acctgtgcat gaatcggaag 960
ggcaagctcg tgggcaagcc tgacggcacc tctaaagaat gcgtgttcat tgagaaggtg 1020
ctcgagaaca actacaccgc tctgatgtcc gccaagtact ccggatggta cgtgggcttc 1080
accaagaagg gcagacccag aaagggcccc aagaccagag aaaaccagca ggacgtgcac 1140
tttatgaagc gctaccccaa gggccagcca gagctgcaga agccttttaa gcctaccacc 1200
gtgacaaag 1209
<210> 133
<211> 20
<212> DNA
<213> 人工
<220>
<223> 人工
<400> 133
aaaggatctc ctggtgaagc 20
<210> 134
<211> 20
<212> DNA
<213> 人工
<220>
<223> 人工
<400> 134
cctgagtgga agagtggaga 20
<210> 135
<211> 13
<212> PRT
<213> 人工序列
<400> 135
Thr Val Ser Gly Phe Ser Leu Ile Gly Tyr Asp Leu Asn
1 5 10
<210> 136
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列
<220>
<221> misc_feature
<222> (5)..(5)
<223> Xaa可以是D或E中的任一个
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa可以是N或H中的任一个
<220>
<221> misc_feature
<222> (12)..(12)
<223> Xaa可以是S, P, H, 或Q中的任一个
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa可以是A或S中的任一个
<220>
<221> misc_feature
<222> (14)..(14)
<223> Xaa可以是V或L中的任一个
<400> 136
Ile Ile Trp Gly Xaa Gly Thr Thr Asp Tyr Xaa Xaa Xaa Xaa Lys Ser
1 5 10 15
<210> 137
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列
<400> 137
Ala Arg Gly Gly Tyr Trp Tyr Ala Thr Ser Tyr Tyr Phe Asp Tyr
1 5 10 15
<210> 138
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列
<220>
<221> misc_feature
<222> (8)..(8)
<223> Xaa可以是N或Q中的任一个
<220>
<221> misc_feature
<222> (9)..(9)
<223> Xaa可以是N或H中的任一个
<400> 138
Arg Ala Ser Gln Ser Ile Ser Xaa Xaa Leu Asn
1 5 10
<210> 139
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列
<400> 139
Tyr Tyr Thr Ser Arg Phe His Ser
1 5
<210> 140
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列
<400> 140
Gln Gln Glu His Thr Leu Pro Tyr Thr
1 5
Claims (16)
1.一种融合蛋白，包含与抗NGF部分融合的FGF-18部分，并且任选地包含两个部分之间的接头。
2.如权利要求1所述的融合蛋白，其中所述FGF-18部分选自下组：
a)选自下组的氨基酸序列，所述组包含SEQ ID NO：1至8或83-87中的任一个或由其组成，
b)活性片段，其包含来自SEQ ID NO：1至8或83-87中的任一个的至少150的连续氨基酸残基或由其组成，或，
c)活性变体，其与选自下组的氨基酸序列具有至少85％的序列相同性，所述组包含SEQID NO：1和2中的任一个或由其组成。
3.如前述权利要求中任一项所述的融合蛋白，其中所述抗NGF部分选自下组：
a)NGF中和部分，
b)选自下组的他尼珠单抗部分，所述组包含他尼珠单抗的活性片段或其活性变体或由其组成，
c)选自下组的富拉单抗部分，所述组包含富拉单抗的活性片段或其活性变体或由其组成，或
d)选自下组的法希姆单抗部分，所述组包含法希姆单抗的活性片段或其活性变体或由其组成，或
e)包含重链可变结构域和轻链可变结构域的抗NGF抗体，所述重链可变结构域包含H-CDR1、H-CDR2和H-CDR3，所述轻链包含L-CDR1、L-CDR2和L-CDR3，其中H-CDR1包含SEQ IDNO:135的氨基酸序列或由其组成，H-CDR2包含SEQ ID NO:136的氨基酸序列或由其组成，H-CDR3包含SEQ ID NO:137的氨基酸序列或由其组成，L-CDR1包含SEQ ID NO:138的氨基酸序列或由其组成，L-CDR2包含SEQ ID NO:139的氨基酸序列或由其组成，并且L-CDR3包含SEQID NO:140的氨基酸序列或由其组成。
4.如权利要求1-3中任一项所述的融合蛋白，其中所述抗NGF部分是选自下组的活性抗NGF片段：scFv、Fab、VHH或vNAR。
5.如权利要求3所述的融合蛋白，其中所述抗NGF部分是选自下组的活性变体：SEED体或基于IgG的部分。
6.如权利要求1-4中任一项所述的融合蛋白，其中所述融合蛋白选自下组：
a)选自下组的氨基酸序列，所述组包含SEQ ID NO：1至8或83-87中的任一个或由其组成，其融合至选自下组的氨基酸序列，所述组包含SEQ ID NO：22至24中的任一个或由其组成，任选地在两个氨基酸序列部分之间具有接头；
b)选自下组的氨基酸序列，所述组包含SEQ ID NO：25至27中的任一个或由其组成；
c)Fab分子，其包含VH-Fab结构域和VL-Fab结构域，其中
i)VH-Fab结构域包含选自下组的氨基酸序列，所述组包含SEQ ID NO：1至8或83-87中的任一个或由其组成，其融合至选自下组的氨基酸序列，所述组包含SEQ ID NO：16、18或20中的任一个或由其组成，任选地在两个氨基酸序列部分之间具有接头；并且VL-Fab结构域包含选自下组的氨基酸序列，所述组包含SEQ ID NO：17、19或21中的任一个或由其组成，或
ii)VL-Fab结构域包含选自下组的氨基酸序列，所述组包含SEQ ID NO：1至8或83-87中的任一个或由其组成，其融合至选自下组的氨基酸序列，所述组包含SEQ ID NO：17、19或21中的任一个或由其组成，任选地在两个氨基酸序列部分之间具有接头；并且VH-Fab结构域包含选自下组的氨基酸序列，所述组包含SEQ ID NO：16、18或21中的任一个或由其组成，
iii)VH-Fab结构域包含选自下组的氨基酸序列，所述组包含SEQ ID NO：34至39、45至49、51或53中的任一个或由其组成；并且VL-Fab结构域包含选自下组的氨基酸序列，所述组包含SEQ ID NO：17、19或21中的任一个或由其组成，
iv)VL-Fab结构域包含选自下组的氨基酸序列，所述组包含SEQ ID NO：28至33、40至44、50或52中的任一个或由其组成；并且VH-Fab结构域包含选自下组的氨基酸序列，所述组包含SEQ ID NO：16、18或21中的任一个或由其组成，
d)与a)、b)或c)中的任一个有至少85％的序列相同性的氨基酸序列。
7.如权利要求1-3或5中任一项所述的融合蛋白，其中所述融合蛋白选自下组：
a)包含FGF-18部分和抗NGF部分的SEED体，所述FGF-18部分由选自下组的氨基酸序列组成，所述组包含SEQ ID NO：1至8或83-87中的任一个或由其组成，所述抗NGF部分包含一条完整轻链、一条完整重链和一条部分轻链，其选自以下：
i.一条完整轻链，其包含选自SEQ ID NO：11、13或15的氨基酸序列或由其组成；
ii.一条完整重链，其包含选自SEQ ID NO：56、58、60、65、71或96的氨基酸序列或由其组成；
iii.一条部分轻链，其包含选自下组的氨基酸序列或由其组成：SEQ ID NO：54的185至414，SEQ ID NO：55的氨基酸残基180至409，57的氨基酸残基180至409，SEQ ID NO：102或SEQ ID NO：107或SEQ ID NO：59的氨基酸残基180至409，任选地在两个氨基酸序列部分之间具有接头；
b)SEED体，其包含SEQ ID NO：55、56和11的氨基酸序列或由其组成；
c)SEED体，其包含SEQ ID NO：57、58和13的氨基酸序列或由其组成；
d)SEED体，其包含SEQ ID NO：59、60和15的氨基酸序列或由其组成；
e)SEED体，其包含SEQ ID NO：90、71和11的氨基酸序列或由其组成；
f)SEED体，其包含SEQ ID NO：97或100，96和11的氨基酸序列或由其组成，
g)SEED体，其包含SEQ ID NO：71或96，102和126的氨基酸序列或由其组成，
h)SEED体，其包含SEQ ID NO：56或58或60，107和40的氨基酸序列或由其组成，
i)包含FGF-18部分和抗NGF部分的基于IgG的融合蛋白，所述FGF-18部分包含选自SEQID NO：1至8中的任一个的氨基酸序列或由其组成，所述抗NGF部分包含一条完整轻链和一条完整重链，其选自以下：
i.一条完整轻链，其包含选自SEQ ID NO：11、13或15的氨基酸序列或由其组成；
ii.一条完整重链，其包含选自SEQ ID NO：9-10、12或14的氨基酸序列或由其组成，任选地在两个氨基酸序列部分之间具有接头；
j)基于IgG的融合蛋白，其包含SEQ ID NO：61和SEQ ID NO：9或10的氨基酸序列或由其组成；
k)基于IgG的融合蛋白，其包含SEQ ID NO：62和SEQ ID NO：11的氨基酸序列或由其组成；
l)基于IgG的融合蛋白，其包含SEQ ID NO：63和SEQ ID NO：9或10的氨基酸序列或由其组成；
m)基于IgG的融合蛋白，其包含SEQ ID NO：64和SEQ ID NO：11的氨基酸序列或由其组成，
n)基于IgG的融合蛋白，其包含SEQ ID NO：88或89和11的氨基酸序列或由其组成，
o)基于IgG的融合蛋白，其包含SEQ ID NO：9或10和124的氨基酸序列或由其组成，
p)基于IgG的融合蛋白，其包含SEQ ID NO：9或10和125的氨基酸序列或由其组成，或
q)与a)至p)中的任一个有至少85％的序列相同性的氨基酸序列。
8.一种核酸序列，其编码如前述权利要求中任一项所述的融合蛋白。
9.一种表达载体，其包含如权利要求8所述的核酸序列。
10.一种宿主细胞，其用如权利要求9所述的表达载体转化。
11.一种产生如权利要求1-7中任一项所述的融合蛋白的方法，所述方法包括以下步骤：
a.培养如权利要求10所述的宿主细胞，以及
b.分离由所述宿主细胞产生的所述抗体。
12.一种药物组合物，其包含如权利要求1-7中任一项所述的融合蛋白或通过如权利要求11所述的方法产生的融合蛋白和至少一种赋形剂。
13.如权利要求1-7中任一项所述的融合蛋白，通过如权利要求11所述的方法产生的融合蛋白或如权利要求12所述的药物组合物，其用作药物。
14.如权利要求1-7中任一项所述的融合蛋白，通过如权利要求11所述的方法产生的融合蛋白或如权利要求12所述的药物组合物，其用于治疗软骨疾病。
15.如权利要求14所述的融合蛋白或药物组合物，其中所述软骨疾病是骨关节炎。
16.如权利要求14所述的融合蛋白或药物组合物，其中所述软骨疾病是软骨损伤。
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| PCT/EP2018/075432 WO2019057805A1 (en) | 2017-09-21 | 2018-09-20 | FUSION PROTEIN COMPRISING A FRACTION FGF-18 |
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| AU2019366956A1 (en) * | 2018-10-23 | 2021-05-20 | Dragonfly Therapeutics, Inc. | Heterodimeric Fc-fused proteins |
| CN113151185B (zh) * | 2020-11-17 | 2023-06-23 | 苏州仁端生物医药科技有限公司 | 分泌抗fgf18单克隆抗体杂交瘤细胞株及其单抗、应用 |
| IL310700A (en) * | 2021-08-09 | 2024-04-01 | Merck Patent Gmbh | Proteins that uncouple cell-mediated tumor cytotoxicity from proinflammatory cytokine release |
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| IL273271A (en) | 2020-04-30 |
| RU2020113713A3 (zh) | 2022-03-03 |
| MX2020003211A (es) | 2020-09-21 |
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| AU2018337686B2 (en) | 2023-04-20 |
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| RU2020113713A (ru) | 2021-10-21 |
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| PH12020550099A1 (en) | 2020-09-14 |
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