CN110831613A

CN110831613A - 因子ix融合蛋白及其制备和使用方法

Info

Publication number: CN110831613A
Application number: CN201880020779.XA
Authority: CN
Inventors: A·范德弗莱尔; 刘钱智; D·R·莱特; E·S·恰布拉; 刘童瑶; R·T·彼得斯; J·库尔曼; A·伊斯梅尔
Original assignee: Bioverativ Therapeutics Inc
Current assignee: Bioverativ Therapeutics Inc
Priority date: 2017-01-31
Filing date: 2018-01-31
Publication date: 2020-02-21
Also published as: AR110871A1; WO2018144623A1; PH12019501765A1; AU2018215092A1; MX2019009063A; EP3576762A1; SG11201906788XA; CL2019002155A1; US20210238259A1; EA201991768A1; CR20190389A; IL268234A; TW201831521A; BR112019015569A2; CA3051862A1; MA47416A; JP2020505424A; KR20190112763A

Abstract

本公开文本提供了包含至少一个异源部分如XTEN的因子IX(FIX)融合蛋白。本公开文本还公开了制备和使用所述FIX融合蛋白的方法。

Description

因子IX融合蛋白及其制备和使用方法

对以电子方式提交的序列表的引用

与本申请一起提交的ASCII文本文件(名称：4159_487PC01_SeqListing；大小：69,4504字节；以及创建日期：2018年1月29日)中电子提交的序列表的内容通过引用整体并入本文。

背景技术

血友病B(也称为克里斯马斯病)是世界上最常见的遗传性出血性障碍之一。它导致体内和体外血液凝固活性降低，并且在受影响个体的整个寿命期间需要进行广泛的医学监测。在没有干预的情况下，受困扰的个体将遭受关节自发性出血，这会产生严重的疼痛和使人虚弱的不动；出血流入肌肉会导致血液在这些组织中积聚；如果不立即治疗，喉咙和颈部自发性出血可引起窒息；肾出血；手术后严重出血，轻微意外伤害或拔牙也很普遍。

正常的体内血液凝固至少需要丝氨酸蛋白酶因子II(凝血酶原)、VII、IX、X和XI(可溶性血浆蛋白)；包括跨膜蛋白组织因子和血浆蛋白因子V和VIII的辅助因子；纤维蛋白原、转谷氨酰胺酶因子XIII、磷脂(包括活化的血小板)和钙。包括激肽释放酶、高分子量激肽原和因子XII在内的另外的蛋白质是一些体外凝血测试所必需的，并且可以在病理条件下在体内发挥作用。

在血友病中，血液凝固因缺乏某些血浆凝血因子而受到干扰。血友病B由因子IX(FIX)的缺乏引起，所述因子IX(FIX)的缺乏可能由FIX蛋白的合成减少或缺乏或者活性降低的缺陷分子导致。血友病的治疗通过用高度富集FIX的外源因子浓缩物替代缺失的凝血因子来进行。然而，如下所述，从血液中产生这种浓缩物充满了技术困难。

从血浆中纯化FIX(血浆衍生的FIX；pdFIX)几乎排外地产生完全γ羧化的FIX。然而，从血浆中纯化FIX是非常困难的，因为FIX仅在血浆中以低浓度存在(5μg/mL)。Andersson,Thrombosis Research 7:451 459(1975)。另外，从血液中纯化需要将感染因子如HIV和HCV除去或灭活。此外，pdFIX的半衰期短，因此需要频繁给药。重组因子IX(rFIX)也是可用的，但其与pdFIX具有相同的短半衰期并且同样需要频繁给药(例如，每周2-3次用于预防)。

由于血浆衍生的和重组的FIX的开发，降低的死亡率、关节损伤的预防和生活质量的改进已取得了重要成就。长期出血防护将代表血友病B受试者治疗的另一个关键进步。因此，仍然需要改进的重组FIX，其具有更长的半衰期，同时维持有效的活性。

发明内容

公开了将因子IX(FIX)融合蛋白给予有此需要的受试者的方法，其包括向受试者皮下给予FIX融合蛋白，其中

(a)所述FIX融合蛋白包含FIX多肽和至少一个XTEN，所述至少一个XTEN在插入位点处插入所述FIX多肽内，所述插入位点对应于选自以下的氨基酸：SEQ ID NO:2的氨基酸103、SEQ ID NO:2的氨基酸105、SEQ ID NO:2的氨基酸142、SEQ ID NO:2的氨基酸149、SEQID NO:2的氨基酸162、SEQ ID NO:2的氨基酸166、SEQ ID NO:2的氨基酸174、SEQ ID NO:2的氨基酸224、SEQ ID NO:2的氨基酸226、SEQ ID NO:2的氨基酸228、SEQ ID NO:2的氨基酸413及其任何组合，并且

(b)其中在给予后，所述FIX融合蛋白在所述受试者中展现出约5％至约30％的血浆活性。

本公开文本的其他方面涉及将因子IX(FIX)融合蛋白给予有此需要的受试者的方法，其包括向受试者皮下给予包含FIX多肽和Fc结构域的FIX融合蛋白，其中所述FIX融合蛋白包含与SEQ ID NO:229具有至少约80％，85％、90％、95％、96％、97％、98％、99％或100％序列同一性的氨基酸序列，其中在给予后，所述FIX融合蛋白在所述受试者中展现出约1％至约30％的血浆活性。

在一些实施方案中，所述FIX融合蛋白是以约50IU/kg至约400IU/kg的剂量给予，例如，以约50IU/kg、约100IU/kg、约200IU/kg，或约400IU/kg的剂量给予。

在一些实施方案中，所述FIX融合蛋白展现出约10％至约30％的血浆活性峰值。在一些实施方案中，所述FIX融合蛋白展现出约1％至约10％的血浆活性谷值。

在其他实施方案中，所述因子IX融合蛋白包括至少一个XTEN。在一个方面，所述因子IX(FIX)融合蛋白包含FIX多肽和至少一个XTEN，其在插入位点处插入FIX多肽内，所述插入位点对应于选自以下的氨基酸：SEQ ID NO:2的氨基酸103、SEQ ID NO:2的氨基酸105、SEQ ID NO:2的氨基酸142、SEQ ID NO:2的氨基酸149、SEQ ID NO:2的氨基酸162、SEQ IDNO:2的氨基酸166、SEQ ID NO:2的氨基酸174、SEQ ID NO:2的氨基酸224、SEQ ID NO:2的氨基酸226、SEQ ID NO:2的氨基酸228、SEQ ID NO:2的氨基酸413及其任何组合，并且其中所述FIX融合蛋白展现出促凝血活性。在某些实施方案中，所述插入位点对应于选自以下的氨基酸：SEQ ID NO:2的氨基酸149、SEQ ID NO:2的氨基酸162、SEQ ID NO:2的氨基酸166、SEQID NO:2的氨基酸174及其任何组合。

在一些实施方案中，所述XTEN包含至少约6个氨基酸、至少约12个氨基酸、至少约36个氨基酸、至少约42个氨基酸、至少约72个氨基酸、至少约144个氨基酸或至少约288个氨基酸。在某些实施方案中，所述XTEN包含与选自SEQ ID NO:34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、202、203、204、205、206、207、208、209、210、211、212、213、214、230及其任何组合的氨基酸序列至少约80％、至少约85％、至少约90％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％或约100％相同的氨基酸序列。在一些实施方案中，所述XTEN包含AE72。在一个具体实施方案中，所述XTEN包含SEQ ID NO:230。

在一些实施方案中，所述FIX融合蛋白还包含第二XTEN，其中所述XTEN在对应于SEQ ID NO:2的氨基酸166的插入位点处插入FIX多肽内，并且其中所述第二XTEN与所述FIX多肽的C端融合。

在一些实施方案中，所述FIX融合蛋白还包含Fc结构域。在某些实施方案中，所述Fc结构域与所述FIX多肽的C端融合。在某些实施方案中，所述FIX融合蛋白还包含第二Fc结构域。在一些实施方案中，所述FIX融合蛋白还包含两条多肽链，其中第一多肽链包含与Fc结构域融合的FIX多肽，并且第二多肽链包含第二Fc结构域，其中第一Fc结构域和第二Fc结构域通过共价键缔合。

在一些实施方案中，所述FIX多肽是R338L FIX(“Padua”)变体。

在一些实施方案中，所述FIX融合蛋白包含第一链和第二链，其中：(a)第一链包含：(i)具有338L突变的FIX多肽；(ii)任选地，XTEN，其中XTEN在对应于SEQ ID NO:2的氨基酸166的插入位点处插入FIX多肽内，并且其中所述XTEN包含具有至少约72个氨基酸的氨基酸序列；(iii)第一Fc结构域，其中第一Fc结构域与所述FIX多肽融合；并且(b)第二链包含第二Fc结构域；其中第一Fc结构域和第二Fc结构域通过共价键缔合。

本公开文本的方法还提供了FIX融合蛋白，其包含FIX多肽和含有XTEN的异源部分，其中所述XTEN与FIX多肽的C端融合且包含长于42个氨基酸且短于144个氨基酸的氨基酸序列。

本发明方法的FIX融合蛋白具有若干种用途，包括提供预防、治疗、改善或管理有此需要的患者的凝血疾病或病症的方法。

本公开文本还提供延长FIX多肽的半衰期的方法，所述方法包括在对应于选自SEQID NO:2的氨基酸103、SEQ ID NO:2的氨基酸105、SEQ ID NO:2的氨基酸142、SEQ ID NO:2的氨基酸149、SEQ ID NO:2的氨基酸162、SEQ ID NO:2的氨基酸166、SEQ ID NO:2的氨基酸174、SEQ ID NO:2的氨基酸224、SEQ ID NO:2的氨基酸226、SEQ ID NO:2的氨基酸228、SEQID NO:2的氨基酸413及其任何组合的氨基酸的插入位点处将XTEN插入FIX多肽内，从而构建FIX融合蛋白，其中所述FIX蛋白展现出促凝血活性。

本公开文本的另外的实施方案将从以下描述和附图中显而易见。

通过引用并入

本文公开的所有公开、专利和专利申请均通过引用并入，如同每个单独的公开、专利或专利申请被特别和单独地指出通过引用并入。

附图说明

图1是描绘FIX融合蛋白的活性的图，所述FIX融合蛋白包含具有42个氨基酸(例如AE42)的XTEN，所述XTEN在不同插入位点(例如，在与SEQ ID NO:2的氨基酸对应的氨基酸52、氨基酸59、氨基酸66、氨基酸80、氨基酸85、氨基酸89、氨基酸103、氨基酸105、氨基酸113、氨基酸129、氨基酸142、氨基酸149、氨基酸162、氨基酸166、氨基酸174、氨基酸188、氨基酸202、氨基酸224、氨基酸226、氨基酸228、氨基酸230、氨基酸240、氨基酸257、氨基酸265、氨基酸277、氨基酸283、氨基酸292、氨基酸316、氨基酸341、氨基酸354、氨基酸392、氨基酸403和氨基酸413)处插入或者与FIX多肽的C端(C-term)融合。C端融合的XTEN序列在FIX与C端融合之间含有凝血酶可切割位点。Y轴将FIX活性显示为通过显色测定获得的在条件培养基中碱基构建体(FIX-R338L)的活性的百分比。X轴将特定的插入位点显示为氨基酸编号(对应于SEQ ID NO:2)和单字母氨基酸缩写。FIX的相应结构域(例如，GLA、EGF1、EGF2、接头、AP和催化结构域)、接头区和C端(“C-term”)在X轴下方指示。

图2是描绘FIX融合蛋白的活性的图，所述FIX融合蛋白包含具有42个氨基酸(AE42)、72个氨基酸(AE72)、144个氨基酸(AE144)、288个氨基酸(AE288)和864个氨基酸(AE864)的XTEN，所述XTEN在不同插入位点(例如，与SEQ ID NO:2的氨基酸对应的氨基酸103、氨基酸105、氨基酸142、氨基酸149、氨基酸162、氨基酸166、氨基酸174、氨基酸224和氨基酸413)处插入或者与FIX多肽的C端(C-term，氨基酸415)融合。Y轴将FIX活性显示为通过显色测定获得的在条件培养基中碱基构建体(FIX-R338L)的活性的百分比。X轴将每个插入位点的结构域(例如，EGF2、AP和催化结构域)或区域(例如，接头和C端)和特定的插入位点显示为氨基酸编号(对应于SEQ ID NO:2)。箭头指示选择用于进一步实验的插入位点(参见图3A-3B)。

图3A是R338L FIX变体的区域和结构域的示意图。特定氨基酸残基(例如N105、D166和E224)和C端突出显示为潜在的异源部分例如XTEN插入位点。图3B显示了从三个不同角度的猪FIX(PDB:1PFX)的三维结构的图示。标记了插入位点N105、D166和E224，C端，以及R338L突变的位置(例如，在R338L FIX变体中)。

图4总结了包含一个或两个XTEN(例如42个、72个、144个和288个氨基酸的XTEN)，或包含一个XTEN和一个Fc结构域或FIXFc的FIX融合蛋白的相对活性。Y轴将FIX活性显示为通过显色测定在条件培养基中的碱基构建体(FIX-R338L)活性的百分比。X轴显示构建体编号，X轴下方的表显示测试的每种构建体的XTEN和Fc的组成。EGF2(105)、AP(166)、60环(224)和C端XTEN或Fc指示XTEN或Fc插入或融合的位置。X轴下方表格中每个框中的数字(例如42、72、144和288，指示XTEN的大小)和“Fc”指示哪个部分插入FIX多肽内或与FIX多肽的C端融合。

图5A提供了描绘与在血友病B小鼠中单次推注静脉内给药后测量的rFIX和rFIXFc相比，具有各种长度的凝血酶可切割C端XTEN融合的各种FIX融合蛋白(例如FIX-CT.288(具有288个氨基酸的XTEN，例如AE288)和FIX-CT.864(具有864个氨基酸的XTEN，例如AE864))的给药FIX凝固活性的血浆百分位数相对于时间的曲线图。图5B提供了描绘与在血友病B小鼠中单次推注静脉内给药后测量的rFIX和rFIXFc相比，具有插入活化肽(AP)结构域中的各种长度的XTEN融合的各种FIX融合蛋白(例如FIX-AP.144、FIX-AP.72和FIX-AP.42)的给药FIX凝固活性的血浆百分位数相对于时间的曲线图。图5C提供了图5A和5B中所示的单次静脉推注给药FIX融合蛋白的计算药代动力学参数的图形化汇编。在Y轴上指示的是每种指示分子的血浆活性回收率百分位数。X轴显示计算的平均停留时间(MRT，以小时计)，并且点的面积表示每剂量曲线下方相对计算面积(AUC/D，以h/kg/mL计)。

图6A提供了描绘与在血友病B小鼠中单次推注静脉内给药后测量的rFIX和rFIXFc相比，具有插入活化肽(AP)结构域(例如FIXFc-AP.72和FIXFc-AP.42)或EGF2结构域(例如FIXFc-EGF.42)中的的各种长度的XTEN融合的各种FIX融合蛋白的给药FIX凝固活性的血浆百分位数相对于时间的曲线图。图6B提供了图6A中所示的单次静脉推注给药FIX融合蛋白的计算药代动力学参数的图形化汇编。在Y轴上指示的是每种指示分子的血浆活性回收率百分位数。X轴显示计算的平均停留时间(MRT，以小时计)。点的面积表示每剂量曲线下相对计算面积(AUC/D，以h/kg/mL计)。

图7A提供了描绘与在血友病B小鼠中单次推注皮下给药后测量的rFIX和rFIXFc相比，包含与FIX多肽的C端融合的具有288个氨基酸的凝血酶可切割XTEN的FIX融合蛋白(rFIX-CT.288)、包含插入FIX多肽的AP结构域内的具有72个氨基酸的XTEN的FIX融合蛋白(rFIXFc-AP.72)以及包含插入FIX多肽的EGF2结构域内的具有42个氨基酸的XTEN的FIX融合蛋白(rFIXFc-EGF2.42)的给药FIX凝固活性的血浆百分位数相对于时间的曲线图。图7B提供了图7A中所示的单次皮内推注给药FIX融合蛋白的计算药代动力学参数的图形化汇编。在Y轴上指示的是每种指示分子的生物利用度的百分位数。X轴显示计算的平均停留时间(MRT，以小时计)。点的面积表示每剂量曲线下相对计算面积(AUC/D，以h/kg/mL计)。

图8A提供了通过旋转血栓弹力测定法(ROTEM)测量的人血友病B血液中rFIXFc和包含插入FIX的AP结构域内的具有72个氨基酸的XTEN的FIX融合蛋白(例如rFIXFc-AP-XTEN.72)的凝固时间(以秒计)的图形化描绘。图8B提供了人血友病B血液中rFIXFc和FIX融合蛋白(例如rFIXFc-AP-XTEN.72)的α角(以度计)的图形化描绘。图8C提供了人血友病B血液中rFIXFc和FIX融合蛋白(例如rFIXFc-AP-XTEN.72)的最大血凝块硬度(MCF)(以mm计)的图形化描绘。

图9是显示rFIXFc-AP.72与尾夹出血模型中的rFIXFc相比的急性功效的图。给出的结果是指示的给药后5分钟以及治疗和给药的30分钟时间内的个体和失血量中位数(μl)。星号指示媒介物对比所有其他治疗的显著性p值。数据指示与rFIXFc相比，rFIXFc-AP.72给药的小鼠中相似或改进的功效。

图10是显示HemB小鼠存活的百分比(Y轴)相对于尾静脉横切后的时间(以小时计)(X轴)的曲线图。所有小鼠在尾静脉切除前72小时，以指定IU/kg剂量用FIXFc(虚线)静脉内给药或用FIXFc-AP.72皮下给药(FIXFc-AP.72：100IU/kg(黑色实心圆)，50IU/kg(灰色实心三角形)和15IU/kg(灰色实心倒三角形)；rFIXFc：100IU/kg(空心圆)，50IU/kg(空心三角形)和15IU/kg(空心倒三角形)；以及媒介物(实心灰色圆圈)。与媒介物治疗的小鼠相比，rFIXFc或FIXFc-AP.72给药的小鼠的生存曲线都显著不同(p<0.0001，对数秩(Mantel-Cox)检验)。

图11A是显示对比时间绘制的通过一步血浆测定测量的血友病B小鼠血浆FX活性水平的图，所述血友病B小鼠通过静脉内(虚线)或皮下注射(实线)单次推注(200IU/kg)给药rFIX(灰色)或rFIXFc-AP.72融合蛋白(黑色)。图11B显示使用Phoenix WinNonLin 6.2.1软件(Pharsight，Certara)使用非房室分析(NCA)测定的药代动力学参数。

图12A是图示了rFIXFc-AP.72单链Fc的结构域结构的示意图。图12B是显示rFIXFc-AP.72双链Fc的结构域结构的示意图。“FIX HC”是指FIX的重链；“FIX LC”是指FIX的轻链，其包括FIX的EGF和GLA结构域；AP是指FIX的活化肽。

图13是总结如实施例中使用的FIX-XTEN构建体以及匹配的序列识别号、描述和质粒代码的表。

图14A和14B显示在HemB小鼠中给予单链rFIXFc-AP.72后FIX血浆活性的图形化表示。将给予50IU/kg(浅灰色圆圈)、100IU/kg(中灰色圆圈)、200IU/kg(深灰色圆圈)和400IU/kg(黑色圆圈)的rFIXFc-AP.72后的皮下药代动力学曲线显示为以IU/dL计的FIX血浆活性(图14A)和从注射剂量中回收的百分位数(图14B)。图14C显示了匹配表，使用Phoenix WinNonLin软件列出了图14A中所示的计算药理学参数。

图15A是在食蟹猴中通过静脉内(灰线)或皮下(黑线)注射(平均值±SD，n＝3)给予100IU/kg的单链rFIXFc-AP.72(pJH84；SEQ ID NO:151)的血浆活性(实线)和抗原(虚线)的图形化表示。图15B显示了匹配表，使用Phoenix WinNonLin软件列出了图15A中的计算的药理学参数。

图16是皮下(SQ)给予100IU/kg(深灰色填充)或200IU/kg(浅灰色填充)的rFIXFc-AP.72(pJH84；SEQ ID NO:151)后的HemB小鼠中和静脉内(IV)给予50IU/kg(实线)、100IU/kg(大虚线)或200IU/kg(小虚线)的rFIXFc后的HemB小鼠中血浆活性水平(IU/dL)的图形化表示。呈现从给药后1天直至7天低谷的数据。水平、重叠的线指示30％的峰值和5％的谷值，如图所示。

具体实施方式

本公开文本提供了包含FIX多肽和至少一个异源部分的FIX融合蛋白及其制备和使用方法。在某些方面，所述FIX融合蛋白包含插入FIX多肽内、与FIX多肽的C端融合或两者都有的至少一个异源部分，其中所述FIX融合蛋白展现出促凝血活性。在一个具体方面，所述异源部分是XTEN。

I.定义

在整个本公开文本中，术语“一个/一种(a或an)”实体是指该实体中的一个或多个；例如，“一种多核苷酸”应理解为代表一种或多种多核苷酸。因此，术语“一个/一种(a或an)”、“一个/一种或多个/多种(one or more)”以及“至少一个/一种(at least one)”在本文中可以互换使用。

此外，本文使用的“和/或”被视为两个指定特征或组分中的每一个与或不与其他特征或组分的特定公开。因此，如在本文中以短语如“A和/或B”使用的术语“和/或”旨在包括“A和B”、“A或B”、“A”(单独)和“B”(单独)。同样地，如以短语如“A、B和/或C”使用的术语“和/或”旨在涵盖以下方面中的每一个：A、B和C；A、B或C；A或C；A或B；B或C；A和C；A和B；B和C；A(单独)；B(单独)；以及C(单独)。

应当理解，本文中无论用语言“包括/包含(comprising)”描述任何方面，还提供了以“由...组成”和/或“基本上由...组成”描述的其他类似方面。

除非另外定义，否则本文中使用的所有技术术语和科学术语具有与本公开文本相关领域的普通技术人员通常所理解的相同的含义。例如，Concise Dictionary ofBiomedicine and Molecular Biology,Juo,Pei-Show,第2版,2002,CRC Press；TheDictionary of Cell and Molecular Biology,第3版,1999,Academic Press；以及OxfordDictionary Of Biochemistry And Molecular Biology,修订版,2000,OxfordUniversity Press为技术人员提供了本公开文本中所使用的许多术语的通用词典。

单位、前缀和符号以其国际单位制(SI)认可的形式表示。数值范围包括定义所述范围的数字。除非另有指示，氨基酸序列以氨基至羧基方向从左至右书写。本文提供的标题不是对本公开文本的各个方面的限制，所述各个方面可以通过参考说明书作为整体而获得。因此，通过从整体上参考说明书，可以更全面地定义下面紧接着定义的术语。

术语“约”在本文中用于表示大约、大致、大概或在其区域中。当术语“约”与数值范围结合使用时，它通过扩展所述数值的上下边界来修改该范围。通常，术语“约”可以通过方差(例如，10％，向上或向下)修改高于和低于所述值的数值(更高或更低)。

术语“多核苷酸”或“核苷酸”旨在包括单个核酸以及多个核酸，并且是指分离的核酸分子或构建体，例如，信使RNA(mRNA)或质粒DNA(pDNA)。在某些实施方案中，多核苷酸包含常规磷酸二酯键或非常规键(例如酰胺键，如见于肽核酸(PNA)中)。术语“核酸”是指存在于多核苷酸中的任何一个或多个核酸片段，例如DNA或RNA片段。“分离的”核酸或多核苷酸是指已从其原生环境中移除的核酸分子、DNA或RNA。例如，出于本公开文本的目的，认为编码载体中包含的FIX多肽的重组多核苷酸是分离的多核苷酸。分离的多核苷酸的其他例子包括在异源宿主细胞中维持或从溶液中的其他多核苷酸纯化(部分或基本)的重组多核苷酸。分离的RNA分子包括本公开文本的多核苷酸的体内或体内RNA转录物。根据本发明的分离的多核苷酸或核酸还包括合成产生的此类分子。另外，多核苷酸或核酸可包括调节元件，如启动子、增强子、核糖体结合位点或转录终止信号。

如本文所用，“编码区”或“编码序列”是多核苷酸的一部分，其由可翻译成氨基酸的密码子组成。尽管“终止密码子”(TAG、TGA或TAA)典型地不会翻译成氨基酸，它可以被认为是编码区的一部分，但是任何侧翼序列(例如启动子、核糖体结合位点、转录终止子、内含子等)不是编码区的一部分。编码区的边界典型地由编码所得多肽的氨基端的在5'端的起始密码子和编码所得多肽的羧基端的在3'端的翻译终止密码子确定。本公开文本的两个或更多个编码区可以存在于单个多核苷酸构建体中，例如在单个载体上，或在单独的多核苷酸构建体中，例如在分开的(不同的)载体上。因此，随后，单个载体可以仅包含单个编码区，或者包含两个或更多个编码区，例如，如下所述，单个载体可以分别编码结合结构域A和结合结构域B。另外，本公开文本的载体、多核苷酸或核酸可编码异源编码区，所述编码区与编码本公开文本的结合结构域的核酸融合或未融合。异源编码区包括但不限于特化元件或基序，如分泌信号肽或异源功能结构域。

哺乳动物细胞分泌的某些蛋白质与分泌信号肽相关，一旦开始通过粗面内质网输出生长的蛋白质链，所述分泌信号肽就从成熟蛋白上切割下来。本领域普通技术人员知道，信号肽通常与多肽的N端融合，并从完整或“全长”多肽切割，以产生多肽的分泌或“成熟”形式。在某些实施方案中，原生信号肽或该序列的功能衍生物保留指导多肽分泌的能力，所述多肽与其可操作地缔合。可替代地，可以使用异源哺乳动物信号肽，例如人组织型纤溶酶原激活物(TPA)或小鼠β-葡糖醛酸糖苷酶信号肽，或其功能衍生物。

术语“下游”是指位于参考核苷酸序列的3'处的核苷酸序列。在某些实施方案中，下游核苷酸序列涉及转录起始点之后的序列。例如，基因的翻译起始密码子位于转录起始位点的下游。“下游”还可以指位于参考肽序列的C端的肽序列。

术语“上游”是指位于参考核苷酸序列的5'处的核苷酸序列。在某些实施方案中，上游核苷酸序列涉及位于编码区的5'侧或转录起始点的序列。例如，大多数启动子位于转录起始位点的上游。“上游”还可以指位于参考肽序列的N端的肽序列。

如本文所用，术语“调节区”是指位于编码区上游(5'非编码序列)、内部或下游(3'非编码序列)的核苷酸序列，其影响转录、RNA加工、稳定性或相关编码区的翻译。调节区可包括启动子、翻译前导序列、内含子、多聚腺苷酸识别序列、RNA加工位点、效应子结合位点和茎-环结构。如果编码区预期在真核细胞中表达，聚腺苷酸化信号和转录终止序列通常将位于编码系列的3'方向。

编码基因产物(例如多肽)的多核苷酸可包括与一个或多个编码区可操作地缔合的启动子和/或其他转录或翻译控制元件。在可操作的缔合中，基因产物(例如多肽)的编码区与一个或多个调节区缔合，以便将基因产物的表达置于一个或多个调节区的影响或控制之下。例如，如果启动子功能的诱导导致编码基因产物(由编码区编码)的mRNA的转录，并且如果启动子与编码区之间的连接的性质确实不会干扰启动子指导基因产物表达的能力或干扰DNA模板转录的能力，则编码区和启动子是“可操作地缔合”。除启动子外，其他转录控制元件例如增强子、操纵子、阻遏物和转录终止信号也可与编码区可操作地缔合，以指导基因产物表达。

多种转录控制区域是本领域技术人员已知的。这些包括但不限于在脊椎动物细胞中起作用的转录控制区，诸如但不限于来自巨细胞病毒的启动子和增强子片段(立即早期启动子，与内含子A结合)、猿猴病毒40(早期启动子)和逆转录病毒(如劳氏肉瘤病毒)。其他转录控制区包括衍生自脊椎动物基因的那些，如肌动蛋白、热休克蛋白、牛生长激素和兔β珠蛋白，以及能够控制真核细胞中基因表达的其他序列。另外的合适的转录控制区包括组织特异性启动子和增强子以及淋巴因子诱导型启动子(例如可由干扰素或白细胞介素诱导的启动子)。

类似地，多种翻译控制元件是本领域普通技术人员已知的。这些包括但不限于核糖体结合位点、翻译起始和终止密码子，以及衍生自小核糖核酸病毒的元件(特别是内部核糖体进入位点，或IRES，也称为CITE序列)。

如本文所用的术语“表达”是指多核苷酸产生基因产物(例如RNA或多肽)的过程。它包括但不限于将多核苷酸转录成信使RNA(mRNA)、转移RNA(tRNA)、小发夹RNA(shRNA)、小干扰RNA(siRNA)或任何其他RNA产物以及将mRNA翻译为多肽。表达产生“基因产物”。如本文所用，基因产物可以是核酸，例如通过基因转录产生的信使RNA，或者是从转录物翻译的多肽。本文描述的基因产物还包括经过转录后修饰(例如聚腺苷酸化或剪接)的核酸，或经过翻译后修饰(例如甲基化、糖基化、脂质的添加、与其他蛋白质亚基缔合或蛋白水解切割)的多肽。

“载体”是指用于将核酸克隆和/或转移到宿主细胞中的任何媒介物。载体可以是复制子，另一个核酸片段可以附接于其上，以实现附接片段的复制。“复制子”是指在体内作为自主复制单元(即能够在其自身控制下复制)起作用的任何遗传元件(例如质粒、噬菌体、粘粒、染色体、病毒)。术语“载体”包括用于体外、离体或体内将核酸引入细胞的病毒载体和非病毒媒介物。很多载体是本领域已知和使用的，包括例如质粒、修饰的真核病毒或修饰的细菌病毒。通过将合适的多核苷酸片段连接到具有互补粘性末端的选择载体中，可将多核苷酸插入合适的载体中。

可以将载体工程化以编码提供对已掺入载体的细胞进行选择或鉴定的选择性标记物或报道分子。选择性标记物或报道分子的表达允许鉴定和/或选择掺入并表达载体上包含的其他编码区的宿主细胞。本领域已知和使用的选择性标记基因的例子包括：提供对氨苄青霉素、链霉素、庆大霉素、卡那霉素、潮霉素、新霉素、嘌呤霉素、双丙氨膦除草剂、磺胺类药物等的抗性的基因；用作表型标记的基因，即花色素苷调节基因、异戊烯基转移酶基因等。本领域已知和使用的报道分子的例子包括：荧光素酶(Luc)、绿色荧光蛋白(GFP)、氯霉素乙酰转移酶(CAT)、-半乳糖苷酶(LacZ)、-葡糖醛酸酶(Gus)等。选择性标记也可以视为报道分子。

术语“质粒”是指染色体外元件，其通常携带不是细胞中心代谢的一部分的基因，并且通常是环状双链DNA分子的形式。这些元件可以是衍生自任何来源的自主复制序列、基因组整合序列、噬菌体或核苷酸序列，线性、环状或超螺旋的单链或双链DNA或RNA，其中许多核苷酸序列已经连接或重组成独特的构造体，所述构造体能够将选择的基因产物的启动子片段和DNA序列以及合适的3'非翻译序列引入细胞中。

可以使用的真核病毒载体包括但不限于腺病毒载体、逆转录病毒载体、腺相关病毒载体和痘病毒，例如痘苗病毒载体、杆状病毒载体或疱疹病毒载体。非病毒载体包括质粒、脂质体、带电脂质(细胞转染素)、DNA-蛋白质复合物和生物聚合物。

“克隆载体”是指“复制子”，所述复制子是顺序复制并且包含复制起点的单位长度的核酸，如质粒、噬菌体或粘粒，其可以附接另一个核酸片段以实现附加片段的复制。某些克隆载体能够在一个细胞类型(例如细菌)中复制并在另一个细胞类型(例如真核细胞)中表达。克隆载体典型地包含一个或多个序列，所述序列可用于选择包含载体的细胞和/或用于插入目的核酸序列一个或多个多克隆位点的细胞。

术语“表达载体”是指设计用于在插入宿主细胞内后能够表达插入的核酸序列的媒介物。如上所述，插入的核酸序列以与调节区处于可操作缔合放置。

通过本领域熟知的方法将载体引入宿主细胞内，例如转染、电穿孔、显微注射、转导、细胞融合、DEAE葡聚糖、磷酸钙沉淀、脂质转染(溶酶体融合)、基因枪或DNA载体转运蛋白的使用。

如本文所用，“培养”(“culture”，“to culture”和“culturing”)意指在体外条件下温育细胞，所述条件允许细胞生长或分裂或使细胞维持存活状态。如本文所用，“培养的细胞”是指体外繁殖的细胞。

如本文所用，术语“多肽”意在涵盖单数“多肽”以及复数“多肽”，并且是指由通过酰胺键(也称为肽键)线性连接的单体(氨基酸)组成的分子。术语“多肽”是指两个或更多个氨基酸的任何单个链或多个链，而不是指特定长度的产物。因此，肽、二肽、三肽、寡肽、“蛋白质”、“氨基酸链”或用于指代两个或更多个氨基酸的单个或多个链的任何其他术语均包括在“多肽”的定义中，且术语“多肽”可以代替这些术语中的任何术语使用，或与这些术语中的任何术语互换使用。术语“多肽”还意指多肽的表达后修饰的产物，包括但不限于糖基化、乙酰化、磷酸化、酰胺化、通过已知保护/阻断基团的衍生化、蛋白水解切割或通过非天然存在氨基酸进行的修饰。多肽可以衍生自天然生物来源或由重组技术产生，但不一定从指定的核酸序列翻译。它可以以任何方式生成，包括化学合成。

“分离的”多肽或其片段、变体或衍生物是指不在其天然环境中的多肽。不要求具体纯化水平。例如，分离的多肽可以仅仅从其原生或天然环境中除去。为了本公开文本的目的，重组产生的多肽和宿主细胞中表达的蛋白质被视为是分离的，已经通过任何适当的技术分离、分馏或部分或基本上纯化的原生或重组多肽亦是如此。

如本文所用，术语“宿主细胞”是指携带或能够携带重组核酸的细胞或细胞群。宿主细胞可以是原核细胞(例如，大肠杆菌(E.coli))，或者可替代地，宿主细胞可以是真核细胞，例如真菌细胞(例如，酵母细胞如酿酒酵母(Saccharomyces cerevisiae)、毕赤酵母(Pichia pastoris)或粟酒裂殖酵母(Schizosaccharomyces pombe))，以及各种动物细胞，如昆虫细胞(例如Sf-9)或哺乳动物细胞(例如HEK293F、CHO、COS-7、NIH-3T3)。

本公开文本还包括多肽的片段或变体及其任何组合。当提及本公开文本的多肽结合结构域或结合分子时，术语“片段”或“变体”包括保留参考多肽的至少一些特性(例如对于FcRn结合结构域或Fc变体的FcRn结合亲和力，或对于FIX辩题的凝血活性)的任何多肽。除了本文其他地方讨论的特异性抗体片段之外，多肽的片段还包括蛋白水解片段以及缺失片段，但不包括天然存在的全长多肽(或成熟多肽)。本公开文本的多肽结合结构域或结合分子的变体包括如上所述的片段，以及由于氨基酸取代、缺失或插入而具有改变的氨基酸序列的多肽。变体可以是天然存在的或非天然存在的。可以使用本领域已知的诱变技术产生非天然存在的变体。变体多肽可包含保守性或非保守性氨基酸取代、缺失或添加。本文公开的一种具体FIX变体是R338L FIX(Padua)变体(SEQ ID NO:2)。参加，例如，Simioni,P.等,"X-Linked Thrombophilia with a Mutant Factor IX(Factor IX Padua),"NEJM361:1671-75(2009年10月)，其通过引用整体并入本文。

“保守性氨基酸取代”是其中用具有类似侧链的氨基酸残基替代氨基酸残基的取代。本领域已经定义了具有相似侧链的氨基酸残基家族，包括碱性侧链(例如赖氨酸、精氨酸、组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷的极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸)、非极性的侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸)、β-分支侧链(例如苏氨酸、缬氨酸、异亮氨酸)、以及芳香族侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。因此，如果多肽中的氨基酸被来自相同侧链家族的另一种氨基酸取代，则所述取代被认为是保守性的。在另一个实施方案中，一串氨基酸可以用结构相似、侧链家族成员的顺序和/或组成不同的串保守地替换。

术语两个多核苷酸或多肽序列之间的“序列同一性百分比”是指在比较窗口上序列共有的相同匹配位置的数目，考虑为实现两个序列的最佳比对必须引入的添加或缺失(即，缺口)。匹配位置是在靶序列和参考序列中存在相同核苷酸或氨基酸的任何位置。由于缺口不是核苷酸或氨基酸，因此靶序列中存在的缺口不计算在内。同样地，由于靶序列核苷酸或氨基酸计算在内而参考序列中的核苷酸或氨基酸不计算在内，因此参考序列中存在的缺口不计算在内。

通过以下方式计算序列同一性的百分比：确定在两个序列中出现相同氨基酸残基或核酸碱基的位置的数目以得到匹配的位置的数目，将匹配的位置的数目除以比较窗口中位置的总数目，然后将结果乘以100以得到序列同一性百分比。序列的比较和两个序列之间的序列同一性百分比的确定可以使用容易获得的软件在线使用和下载来完成。合适的软件程序可从各种来源获得，并用于蛋白质和核苷酸序列的比对。确定序列同一性百分比的一个合适程序是bl2seq，它是可从美国政府的国家生物技术信息中心BLAST网站(blast.ncbi.nlm.nih.gov)获得的BLAST程序套件的一部分。Bl2seq使用BLASTN或BLASTP算法在两个序列之间进行比较。BLASTN用于比较核酸序列，而BLASTP用于比较氨基酸序列。其他合适的程序是，例如Needle、Stretcher、Water或Matcher，EMBOSS生物信息学程序套件的一部分，也可从欧洲生物信息学研究所(EBI)网站www.ebi.ac.uk/Tools/psa上获得。

与多核苷酸或多肽参考序列比对的单个多核苷酸或多肽靶序列内的不同区域可各自具有其序列同一性百分比。应注意，序列同一性百分比值四舍五入到最接近的十分之一。例如，80.11、80.12、80.13和80.14向下舍入到80.1，而80.15、80.16、80.17、80.18和80.19向上舍入到80.2。还应注意，长度值将始终是整数。

本领域技术人员将理解，用于计算序列同一性百分比的序列比对的产生不限于仅由一级序列数据驱动的二元序列-序列比较。序列比对可以从多个序列比对中衍生。产生多序列比对的一个合适的程序是ClustalW2，可从www.clustal.org获得。另一个合适的程序是MUSCLE，可从www.drive5.com/muscle/获得。可替代地，ClustalW2和MUSCLE可从例如EBI获得。

还应当理解，序列比对可以通过将序列数据与来自异构数据源的数据整合来产生，如结构数据(例如，结晶蛋白质结构)、功能数据(例如，突变位置)或系统发育数据。整合异构数据以产生多序列比对的合适程序是T-Coffee，可从www.tcoffee.org获得，或者可替代地，例如，从EBI获得。还应当理解，用于计算序列同一性百分比的最终比对可以自动或手动选择。

如本文所用，通过比对鉴定因子IX蛋白质序列中的“对应氨基酸”，“对应位点”或“等效氨基酸”，以最大化第一FIX序列与第二FIX序列之间的同一性或相似性。用于鉴定第二FIX序列中的等效氨基酸的数目基于用于鉴定第一FIX序列中的相应氨基酸的数目。

如本文所用，术语“插入位点”是指FIX多肽(典型地成熟FIX多肽)或其片段、变体或衍生物中的氨基酸残基编号，其紧邻可插入异源部分的位置的上游。“插入位点”被指定为一个编号，所述编号是插入位点对应的R338L FIX(Padua)变体(SEQ ID NO:2)中的氨基酸编号，所述氨基酸位置紧邻插入位置的N端。例如，短语“EGF2结构域在对应于SEQ ID NO:2的氨基酸105的插入位点处包含XTEN”表示异源部分位于对应于SEQ ID NO:2的氨基酸105和氨基酸106的两个氨基酸之间。然而，本领域技术人员将能够容易地鉴定任何FIX变体中的相应位置，并且本公开文本不限于仅在R338L FIX(Padua)变体中进行的插入。相反，本文公开的插入可以在对应于R338L FIX变体位置的位置处具有促凝血活性的任何FIX变体或其片段中进行。

本文所用的短语“紧邻氨基酸下游”是指紧邻氨基酸末端羧基的位置。类似地，短语“紧邻氨基酸上游”是指紧邻氨基酸的末端胺基的位置。因此，如本文所用的短语“插入位点的两个氨基酸之间”是指XTEN或任何其他多肽在两个相邻氨基酸之间插入的位置。

如本文所用，术语“插入”(“inserted”，“is inserted”，“inserted into”)或语法上相关的术语是指融合多肽中相对于R338L FIX(Padua)变体(SEQ ID NO:2)中类似位置的XTEN的位置。本领域技术人员将理解如何鉴定相对于其他FIX多肽序列(如SEQ ID NO:1所示的序列)的对应插入位置。如本文所用的所述术语是指重组FIX多肽相对于R338L FIX(Padua)变体的特征，并不表示、暗示或推断制备融合多肽的任何方法或过程。例如，关于本文提供的融合多肽，短语“XTEN被插入紧邻FIX多肽的残基105下游的EGF2结构域中”指所述融合多肽包含紧邻氨基酸下游的XTEN，其对应于R338L FIX变体(SEQ ID NO:2)中的氨基酸105，例如，由对应于R338L FIX变体的氨基酸105和106的氨基酸限定。

“融合”或“嵌合”蛋白质包含与第二氨基酸序列连接的第一氨基酸序列，其在自然界中不天然连接。通常存在于分离的蛋白质中的氨基酸序列可以在融合多肽中聚集在一起，或者通常存在于相同蛋白质中的氨基酸序列可以以新的排列方式置于融合多肽中，例如，本公开文本的FIX结构域与Ig Fc结构域的融合。例如，通过化学合成，或通过产生和翻译多核苷酸来产生融合蛋白，所述多核苷酸中肽区域以理想的关系编码。融合蛋白可以还包含通过共价非肽键或非共价键与第一氨基酸序列缔合的第二氨基酸序列。

术语“异源”和“异源部分”是指多核苷酸、多肽或其他部分衍生自与其所比较的实体的不同的实体。例如，异源多肽可以是合成的，或衍生自个体的不同物质种类、不同细胞类型，或不同个体的相同或不同的细胞类型。在一个方面，异源部分是与另一多肽融合以产生融合多肽或蛋白质的多肽。在另一方面，异源部分是与多肽或蛋白质缀合的非多肽，如PEG。

如本文所用，术语“半衰期”是指体内具体多肽的生物半衰期。半衰期可以表示为从动物的循环和/或其他组织中清除给予受试者的一半量所需的时间。当给定多肽的清除曲线构建为时间的函数时，所述曲线通常是双相的，具有快速的α相和更长的β相。α相典型地代表给予的多肽在血管内空间与血管外空间之间的平衡，并且部分地由多肽的大小决定。β相典型地代表多肽在血管内空间中的分解代谢。在一些实施方案中，包含FIX的FIX和融合蛋白是单相的，因此不具有α相，而是仅具有单个β相。因此，在某些实施方案中，本文所用的术语半衰期是指多肽在β相中的半衰期。在人体中人抗体的典型β-相半衰期为21天。

本文所用的术语“连接”和“融合”是指分别与第二氨基酸序列或核苷酸序列共价或非共价连接的第一氨基酸序列或核苷酸序列。第一氨基酸或核苷酸序列可以与第二氨基酸或核苷酸序列直接连接或并置，或者可替代地，间插序列可以将第一个序列与第二个序列共价连接。术语“连接”不仅指在C端或N端的第一氨基酸序列与第二氨基酸序列的融合，还包括整个第一氨基酸序列(或第二氨基酸序列)插入第二氨基酸序列(或第一氨基酸序列，分别地)中的任何两个氨基酸中。在一个实施方案中，第一氨基酸序列通过肽键或接头与第二氨基酸序列连接。第一核苷酸序列可以通过磷酸二酯键或接头与第二核苷酸序列连接。接头可以是肽或多肽(对于多肽链)或者核苷酸或核苷酸链(对于核苷酸链)或任何化学部分(对于多肽和多核苷酸链)。术语“连接”也用连字符(-)表示。

如本文所用，术语“与...缔合”是指在第一氨基酸链与第二氨基酸链之间形成的共价或非共价键。在一个实施方案中，术语“与...缔合”是指共价、非肽键或非共价键。这种缔合可以用冒号表示，即(:)。在另一个实施方案中，它指除肽键外的共价键。例如，氨基酸半胱氨酸包含硫醇基，其可与第二个半胱氨酸残基上的硫醇基形成二硫键或桥接。在大多数天然存在的IgG分子中，CH1区域和CL区域通过二硫键缔合，并且这两个重链使用Kabat编号系统(位置226或229，EU编号系统)通过两个二硫键在对应于239和242的位置处缔合。共价键的例子包括但不限于肽键、金属键、氢键、二硫键、σ键、π键、δ键、糖苷键、抓氢键、弯曲键、偶极键、反馈π键、双键、三键、四键、五键、六键、共轭、超共轭、芳香、哈普托数或反键。非共价键的非限制性例子包括离子键(例如阳离子-π键或盐键)、金属键、氢键(例如二氢键、分子氢配合物、低势垒氢键或对称氢键)、范德华力、伦敦分散力、机械键、卤键、亲金作用、嵌入、堆积、熵力或化学极性。

如本文所用，术语“切割位点”或“酶促切割位点”是指由酶识别的位点。某些酶促切割位点包含细胞内加工位点。在一个实施方案中，多肽具有被凝血级联反应期间活化的酶切割的酶促切割位点，使得这些位点的切割发生在凝块形成的位点。示例性的此类位点包括，例如由凝血酶、因子XIa或因子Xa识别的那些位点。示例性的FXIa切割位点包括，例如TQSFNDFTR(SEQ ID NO:166)和SVSQTSKLTR(SEQ ID NO:167)。示例性凝血酶切割位点包括，例如DFLAEGGGVR(SEQ ID NO:168)，TTKIKPR(SEQ ID NO:169)，LVPRG(SEQ ID NO:170)和ALRPR(SEQ ID NO:171)。其他酶促切割位点是本领域已知的。

如本文所用，术语“加工位点”或“细胞内加工位点”是指多肽中的一种酶促切割位点，所述切割位点是在多肽翻译后起作用的酶的靶标。在一个实施方案中，此类酶在从高尔基体腔转运至高尔基体反面房室期间起作用。细胞内加工酶在从细胞中分泌蛋白质之前切割多肽。此类加工位点的例子包括，例如由肽链内切酶的PACE/弗林蛋白酶(其中PACE是配对碱性氨基酸裂解酶的首字母缩写)家族靶向的那些加工位点。这些酶定位于高尔基体膜上并切割序列基序Arg-[任何残基]-(Lys或Arg)-Arg序列羧基末端侧的蛋白质。如本文所用，“弗林蛋白酶”家族酶包括，例如PCSK1(也称为PC1/Pc3)、PCSK2(也称为PC2)、PCSK3(也称为弗林蛋白酶或PACE)、PCSK4(也称为PC4)、PCSK5(也称为PC5或PC6)、PCSK6(也称为PACE4)或PCSK7(也称为PC7/LPC、PC8或SPC7)。其他加工位点是本领域已知的。本文提及的术语“可加工的接头”是指包含细胞内加工位点的接头。

在包含多于一个加工或切割位点的构建体中，应理解这些位点可以相同或不同。

如本文所用的“可加工的接头”是指包含至少一个细胞内加工位点的接头，所述接头在本文其他地方描述。

如本文所用，“基线”是在给予剂量之前受试者中测得的最低血浆FIX水平。FIX血浆水平可以在给药前的两个时间点测量：在筛选访问时和在给药前即刻测量。可替代地，(a)治疗前FIX活性<1％、没有可检测的FIX抗原且具有无义基因型的受试者的基线可定义为0％，(b)治疗前FIX活性<1％且具有可检测的FIX抗原的受试者的基线可设定为0.5％，(c)治疗前FIX活性在1％-2％之间的受试者的基线为Cmin(整个PK研究中的最低活性)，且(d)治疗前FIX活性≥2％的受试者的基线可设定为2％。

如本文所用的“受试者”是指人。本文使用的受试者包括已知发生至少一次不受控制的出血事件的个体，所述个体被诊断患有与不受控制的出血事件相关的疾病或障碍，例如出血性疾病或障碍，例如血友病B，所述受试者易受不受控制的出血事件(例如血友病)或其任何组合的影响。受试者还可以包括在某种活动(例如手术、体育活动或任何剧烈活动)之前处于一种或多种不可控制的出血事件危险中的个体。受试者可具有低于1％、低于0.5％、低于2％、低于2.5％、低于3％或低于4％的基线FIX活性。受试者还包括儿科人类。儿科人类受试者为出生至20年，优选地为出生至18岁、出生至16岁、出生至15岁、出生至12岁、出生至11岁、出生至6岁、出生至5岁、出生至2岁、和2岁至11岁。

本文所用的治疗(treat/treatment/treating)是指，例如，疾病或病症严重程度的降低；病程持续时间的缩短；与疾病或病症有关的一种或多种症状的改善；为患有疾病或病症的受试者提供有益的效果而不一定治愈所述疾病或病症或与疾病或病症相关的一种或多种症状的预防。在一个实施方案中，术语“治疗”或“治疗”指通过给予本公开文本的融合蛋白，将受试者中FIX谷值水平维持在至少约1IU/dL、2IU/dL、3IU/dL、4IU/dL、5IU/dL、6IU/dL、7IU/dL、8IU/dL、9IU/dL、10IU/dL、11IU/dL、12IU/dL、13IU/dL、14IU/dL、15IU/dL、16IU/dL、17IU/dL、18IU/dL、19IU/dL或20IU/dL。在另一个实施方案中，治疗(treating或treatment)是指将FIX谷值水平维持在约1IU/dL至约20IU/dL、约2IU/dL至约20IU/dL、约3IU/dL至约20IU/dL、约4IU/dL至约20IU/dL、约5IU/dL至约20IU/dL、约6IU/dL至约20IU/dL、约7IU/dL至约20IU/dL、约8IU/dL至约20IU/dL、约9IU/dL至约20IU/dL、或约10IU/dL至约20IU/dL。疾病或病症的治疗(treatment或treating)还可以包括将受试者的FIX活性维持在相当于非血友病受试者中FIX活性的至少约1％、2％、3％、4％、5％、6％、7％、8％、9％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％或20％的水平。治疗所需的最低谷值水平可以通过一种或多种已知方法测量，并且可以针对每个人进行调整(增加或减少)。

如本文所用，止血障碍是指基因遗传性或获得性病症，其特征在于由于能力受损或不能形成纤维蛋白凝块而自发或由于创伤而容易出血的倾向。此类障碍的例子包括血友病。三种主要形式为血友病A(因子VIII缺乏)、血友病B(因子IX缺乏或“克里斯马斯病”)和血友病C(因子XI缺乏，轻度出血倾向)。其他止血障碍包括，例如血管性血友病，因子XI缺乏症(PTA缺乏症)，因子XII缺乏症，纤维蛋白原、凝血酶原、因子V、因子VII、因子X或因子XIII缺乏或结构异常，巨大血小板综合征(即GPIb缺陷或缺乏)。GPIb(VWF的受体)可能有缺陷并导致初期凝块形成(初期止血)不足和出血倾向增加，以及Glanzman和Naegeli的血小板无力(Glanzmann血小板无力症)。在肝衰竭(急性和慢性形式)中，肝脏产生的凝血因子不足；这可能会增加出血风险。

如本文所用，术语“急性出血”是指无论任何根本原因的出血事件。例如，受试者可能患有创伤、尿毒症、遗传性出血性障碍(例如因子VII缺乏症)、血小板障碍，或由于凝血因子抗体的产生而产生的抗性。

II.FIX融合蛋白

本公开文本涉及FIX融合蛋白的皮下给予，所述FIX融合蛋白包含FIX多肽和插入FIX多肽内、与FIX多肽的C端融合或两者都有的至少一个异源部分。本公开文本的某些方面涉及FIX融合蛋白的皮下给予，所述FIX融合蛋白包含FIX多肽和异源部分，例如Fc区域，其中所述FIX多肽包含R338L突变(Padua突变)。在插入异源部分或与异源部分融合后，所述FIX融合蛋白可保留一种或多种FIX活性。在一个实施方案中，所述FIX活性是促凝血活性。术语“促凝血活性”是指本公开文本的FIX蛋白参与血液中的凝血级联反应取代原生FIX的能力。例如，本发明的重组FIX蛋白在当其可以在因子VIII(FVIII)存在下将因子X(FX)转化为活化的因子X(FXa)时具有促凝血活性，正如在例如显色测定中测试的情况。在另一个实施方案中，所述FIX活性是产生Ⅹ酶复合物的能力。在其他实施方案中，所述FIX活性是产生凝血酶(或凝块)的能力。

本公开文本的重组FIX蛋白不需要展现出100％的原生成熟人FIX的促凝血活性。事实上，在某些方面，插入本公开文本的FIX多肽中的异源部分可显著增加蛋白质的半衰期或稳定性，使得较低活性是完全可接受的。因此，在某些方面，本公开文本的FIX融合蛋白具有至少约10％、约20％、约30％、约40％、约50％、约60％、约70％、约80％、约90％或约100％的原生FIX的促凝血活性。然而，在一些公开文本的实施方案中，本公开文本的重组FIX蛋白对于含有FIX Padua R338L高活性变体的蛋白质可具有大于100％的原生FIX活性，例如，所述活性的至少约105％、110％、120％、130％、140％、150％、160％、170％、180％、190％或200％或更多。

促凝血活性可以通过任何合适的体外或体内测定来测量。FIX的活性可以通过监测凝块的产生(凝血测定)在凝血级联反应的下游测量，或者通过在FVIII-FIX复合物激活后直接测量FX的酶活性(显色测定)在上游测量(参见，例如Barrowcliffe等,Semin.Thromb.Haemost.28:247-56(2002)；Lee等,Thromb.Haemost.82:1644-47(1999)；Lippi等,Clin.Chem.Lab.Med.45:2-12(2007)；Matsumoto等,J.Thromb.Haemost.4:377-84(2006))。因此，可以使用显色底物测定、凝血测定(例如，一步或两步凝血测定)或两者来测量促凝血活性。显色测定机制基于凝血级联反应的原理，其中活化的FIX在FVIII、磷脂和钙离子存在下将FX转化为FX_a。FX_a活性通过FX_a特异性对硝基苯胺(pNA)底物的水解来评估。在405nM处测量的对硝基苯胺的初始释放速率与FX_a活性成正比，因此与样品中的FIX活性成正比。显色测定是国际血栓和止血学会(ISTH)科学与标准化委员会(SSC)的因子VIII和因子IX分委员会建议的。

可用于确定促凝血活性的其他合适的测定包括在例如Scheiflinger和Dockal的美国申请公开号2010/0022445中公开的那些测定，其内容通过引用以其整体并入本文。

在某些方面，将本公开文本的重组FIX蛋白的促凝血活性与原生成熟FIX进行比较，在某些方面，将其与国际标准进行比较。

如下文更详细描述的，所述至少一个异源部分可包含任何异源部分或能够为FIX蛋白提供改进的特性的部分。例如，在一个方面，可用于本公开文本的异源部分可以是能够延长FIX蛋白半衰期的部分或能够改进FIX蛋白稳定性的部分。本公开文本的FIX融合蛋白可具有插入FIX多肽或与FIX多肽融合的多于一个异源部分。在一个实施方案中，所述多于一个的异源部分是相同的。在另一个实施方案中，所述多于一个的异源部分是不同的。在其他实施方案中，所述异源部分选自XTEN、白蛋白、白蛋白结合肽、白蛋白小结合分子、Fc结构域、FcRn结合配偶体、PAS、CTP、PEG、和HES、PSA或其任何组合。

在一些实施方案中，至少一个异源部分插入FIX多肽的结构域内，而不是结构域之间。FIX多肽包含多个结构域，例如γ-羧基谷氨酸(GLA)结构域、表皮生长因子样1(EGF1)结构域、表皮生长因子样2(EGF2)结构域、活化肽(AP)结构域、EGF2结构域与AP结构域之间的接头以及催化结构域(例如丝氨酸蛋白酶结构域)。FIX酶原包含461个氨基酸：氨基酸1-28(对应于SEQ ID NO:3)是信号肽；氨基酸29-46(对应于SEQ ID NO:3)是前肽；随后是415个氨基酸的FIX蛋白质序列。此415加工的FIX包含：氨基酸1-145(对应于SEQ ID NO:1或SEQID NO:2)是FIX轻链；氨基酸146-180是活化肽；氨基酸181至415(对应于SEQ ID NO:1或SEQID NO:2)是催化FIX重链。在轻链和重链内，GLA结构域对应于SEQ ID NO:1或SEQ ID NO:2的氨基酸1至46；EGF1结构域对应于SEQ ID NO:1或SEQ ID NO:2的氨基酸47至84；EGF2结构域对应于SEQ ID NO:1或SEQ ID NO:2的氨基酸85至127；EGF2结构域与AP结构域之间的接头对应于SEQ ID NO:1或SEQ ID NO:2的氨基酸128至145；AP结构域对应于SEQ ID NO:1或SEQ ID NO:2的氨基酸146至180；催化结构域对应于SEQ ID NO:1或SEQ ID NO:2的氨基酸181至415。

在某些实施方案中，至少一个异源部分被插入FIX多肽的一个或多个结构域内。例如，可以将至少一个异源部分(例如XTEN)插入选自GLA结构域、EGF1结构域、EGF2结构域、AP结构域、EGF2结构域与AP结构域之间的接头、催化结构域及其任何组合的结构域内。在一个具体实施方案中，所述至少一个异源部分(例如XTEN)被插入GLA结构域内，例如SEQ ID NO:1或SEQ ID NO:2的氨基酸1至46。在一个具体实施方案中，所述至少一个异源部分(例如XTEN)被插入EGF1结构域内，例如SEQ ID NO:1或SEQ ID NO:2的氨基酸47至83。在一个具体实施方案中，所述至少一个异源部分(例如XTEN)被插入EGF2结构域内，例如SEQ ID NO:1或SEQ ID NO:2的氨基酸84至125。在一些实施方案中，所述至少一个异源部分(例如XTEN)被插入EGF2结构域与AP结构域之间的接头内，例如SEQ ID NO:1或SEQ ID NO:2的氨基酸132至145。在一个具体实施方案中，所述至少一个异源部分(例如XTEN)被插入AP结构域内，例如SEQ ID NO:1或SEQ ID NO:2的氨基酸146至180。在一些实施方案中，所述至少一个异源部分(例如XTEN)被插入催化结构域内，例如SEQ ID NO:1或SEQ ID NO:2的氨基酸181至415。

在一些实施方案中，可以将一个或多个异源部分插入各插入位点内。在某些实施方案中，在这些位点中的一个或多个位点处插入至少一个异源部分(例如XTEN)不会导致FIX活性的丧失和/或诱导FIX蛋白质的改进特性。例如，至少一个异源部分可以在插入位点处插入FIX多肽内，所述插入位点对应于选自以下的氨基酸：SEQ ID NO:2的氨基酸103(即紧邻对应于SEQ ID NO:2的氨基酸103的氨基酸下游)、SEQ ID NO:2的氨基酸105(即紧邻对应于SEQ ID NO:2的氨基酸105的氨基酸的下游)、SEQ ID NO:2的氨基酸142(即紧邻对应于SEQ ID NO:2的氨基酸142的氨基酸的下游)、SEQ ID NO:2的氨基酸149(即紧邻对应于SEQID NO:2的氨基酸149的氨基酸的下游)、SEQ ID NO:2的氨基酸162(即紧邻对应于SEQ IDNO:2的氨基酸162的氨基酸的下游)、SEQ ID NO:2的氨基酸166(即紧邻对应于SEQ ID NO:2的氨基酸166的氨基酸的下游)、SEQ ID NO:2的氨基酸174(即紧邻对应于SEQ ID NO:2的氨基酸174的氨基酸的下游)、SEQ ID NO:2的氨基酸224(即紧邻对应于SEQ ID NO:2的氨基酸224的氨基酸的下游)、SEQ ID NO:2的氨基酸226(即紧邻对应于SEQ ID NO:2的氨基酸226的氨基酸的下游)、SEQ ID NO:2的氨基酸228(即紧邻对应于SEQ ID NO:2的氨基酸228的氨基酸的下游)、SEQ ID NO:2的氨基酸413(即紧邻对应于SEQ ID NO:2的氨基酸413的氨基酸的下游)及其任何组合，其中所述FIX融合蛋白展现出促凝血活性。

在一个实施方案中，所述异源部分(例如XTEN)在对应于选自SEQ ID NO:1或SEQID NO:2的氨基酸149、SEQ ID NO:1或SEQ ID NO:2的氨基酸162、SEQ ID NO:1或SEQ IDNO:2的氨基酸166、SEQ ID NO:1或SEQ ID NO:2的氨基酸174及其任何组合的氨基酸的插入位点处插入FIX多肽内。在另一个实施方案中，所述异源部分(例如XTEN)在对应于选自SEQID NO:1或SEQ ID NO:2的氨基酸224、SEQ ID NO:1或SEQ ID NO:2的氨基酸226、SEQ IDNO:1或SEQ ID NO:2的氨基酸228、SEQ ID NO:1或SEQ ID NO:2的氨基酸413及其任何组合的氨基酸的插入位点处插入FIX多肽内。在其他实施方案中，所述异源部分(例如XTEN)在对应于选自SEQ ID NO:1或SEQ ID NO:2的氨基酸103、SEQ ID NO:1或SEQ ID NO:2的氨基酸105或两者都有的氨基酸的插入位点处插入FIX多肽内。在另一个实施方案中，所述异源部分(例如XTEN)在对应于SEQ ID NO:1或SEQ ID NO:2的氨基酸142的插入位点处插入FIX多肽内。

正如下面更详细讨论的，所述异源部分可以是XTEN，其可以具有不同的长度。例如，所述XTEN可包含至少约42个氨基酸、至少约72个氨基酸、至少约144个氨基酸、至少约288个氨基酸或至少约864个氨基酸。在一些实施方案中，所述XTEN选自AE42、AG42、AE72、AG72、AE144、AG144、AE288、AG288、AE864和AG864。本文其他地方包括了可插入FIX多肽或与FIX多肽融合的XTEN的非限制性例子。

在一些实施方案中，包含42个氨基酸的XTEN(例如AE42或AG42)在插入位点处插入FIX多肽内，所述插入位点对应于选自以下的氨基酸：SEQ ID NO:1或2的氨基酸103、SEQ IDNO:1或2的氨基酸105、SEQ ID NO:1或2的氨基酸142、SEQ ID NO:1或2的氨基酸149、SEQ IDNO:1或2的氨基酸162、SEQ ID NO:1或2的氨基酸166、SEQ ID NO:1或2的氨基酸174、SEQ IDNO:1或2的氨基酸224、SEQ ID NO:1或2的氨基酸226、SEQ ID NO:1或2的氨基酸228、SEQ IDNO:1或2的氨基酸413及其任何组合，其中所述FIX融合蛋白展现出促凝血活性。

在一些实施方案中，包含72个氨基酸的XTEN(例如AE72或AG72)在插入位点处插入FIX多肽内，所述插入位点对应于选自以下的氨基酸：SEQ ID NO:1或2的氨基酸149、SEQ IDNO:1或2的氨基酸162、SEQ ID NO:1或2的氨基酸166、SEQ ID NO:1或2的氨基酸174、SEQ IDNO:1或2的氨基酸224、SEQ ID NO:1或2的氨基酸226、SEQ ID NO:1或2的氨基酸228、SEQ IDNO:1或2的氨基酸413及其任何组合，或者所述XTEN与所述C端融合，其中所述FIX融合蛋白展现出促凝血活性。

在一些实施方案中，包含144个氨基酸的XTEN(例如AE144或AG144)在插入位点处插入FIX多肽内，所述插入位点对应于选自以下的氨基酸：SEQ ID NO:1或2的氨基酸149、SEQ ID NO:1或2的氨基酸162、SEQ ID NO:1或2的氨基酸166、SEQ ID NO:1或2的氨基酸174、SEQ ID NO:1或2的氨基酸224、SEQ ID NO:1或2的氨基酸226、SEQ ID NO:1或2的氨基酸228、SEQ ID NO:1或2的氨基酸413及其任何组合，其中所述FIX融合蛋白展现出促凝血活性。

在一些实施方案中，包含288个氨基酸的XTEN(例如AE288或AG288)在插入位点处插入FIX多肽内，所述插入位点对应于选自以下的氨基酸：SEQ ID NO:1或2的氨基酸149、SEQ ID NO:1或2的氨基酸162、SEQ ID NO:1或2的氨基酸166、SEQ ID NO:1或2的氨基酸174、SEQ ID NO:1或2的氨基酸224、SEQ ID NO:1或2的氨基酸226、SEQ ID NO:1或2的氨基酸228、SEQ ID NO:1或2的氨基酸413及其任何组合，其中所述FIX融合蛋白展现出促凝血活性。

在仍其他实施方案中，包含864个氨基酸的XTEN(例如AE864或AG8648)在插入位点处插入FIX多肽内，所述插入位点对应于选自以下的氨基酸：SEQ ID NO:1或2的氨基酸149、SEQ ID NO:1或2的氨基酸162、SEQ ID NO:1或2的氨基酸166、SEQ ID NO:1或2的氨基酸174、SEQ ID NO:1或2的氨基酸224、SEQ ID NO:1或2的氨基酸226、SEQ ID NO:1或2的氨基酸228、SEQ ID NO:1或2的氨基酸413及其任何组合，其中所述FIX融合蛋白展现出促凝血活性。

本公开文本的FIX融合蛋白可以还包含插入FIX内、与FIX的C端融合或两者都有的第二异源部分，例如第二XTEN。第二异源部分可在插入位点处插入FIX多肽内，所述插入位点对应于选自以下的氨基酸：SEQ ID NO:1或2的氨基酸103、SEQ ID NO:1或2的氨基酸105、SEQ ID NO:1或2的氨基酸142、SEQ ID NO:1或2的氨基酸149、SEQ ID NO:1或2的氨基酸162、SEQ ID NO:1或2的氨基酸166、SEQ ID NO:1或2的氨基酸174、SEQ ID NO:1或2的氨基酸224、SEQ ID NO:1或2的氨基酸226、SEQ ID NO:1或2的氨基酸228、SEQ ID NO:1或2的氨基酸413及其任何组合，或者其中第二XTEN与FIX多肽的C端融合。在一些实施方案中，第一XTEN和第二XTEN分别在插入位点处插入FIX多肽内和/或与FIX多肽的C端融合，所述插入位点对应于选自以下的SEQ ID NO:1或2的氨基酸：SEQ ID NO:1或2的氨基酸105和SEQ IDNO:1或2的氨基酸166；SEQ ID NO:1或2的氨基酸105和SEQ ID NO:1或2的氨基酸224；SEQID NO:1或2的氨基酸105，并与所述C端融合；SEQ ID NO:1或2的氨基酸166和SEQ ID NO:1或2的氨基酸224；SEQ ID NO:1或2的氨基酸166，并与所述C端融合；SEQ ID NO:1的氨基酸224，并与所述C端融合。在一个实施方案中，第一XTEN在对应于SEQ ID NO:1或2的氨基酸166的插入位点处插入FIX多肽内，并且第二XTEN与所述FIX多肽的C端融合。

第二XTEN可包含至少约6个氨基酸、至少约12个氨基酸、至少约36个氨基酸、至少约42个氨基酸、至少约72个氨基酸、至少约144个氨基酸或至少约288个氨基酸。在一些实施方案中，第二XTEN包含6个氨基酸、12个氨基酸、36个氨基酸、42个氨基酸、72个氨基酸、144个氨基酸或288个氨基酸。第二XTEN可选自AE42、AE72、AE864、AE576、AE288、AE144、AG864、AG576、AG288、AG144及其任何组合。在一个具体实施方案中，第二XTEN是AE72或AE144。

在一个具体实施方案中，第二XTEN包含与选自SEQ ID NO:34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53及其任何组合的氨基酸序列至少约80％、至少约85％、至少约90％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％或约100％相同的氨基酸序列。

在一些实施方案中，所述FIX融合蛋白还包含第三、第四、第五和/或第六XTEN。

在一些实施方案中，所述FIX融合蛋白包含与选自SEQ ID NO:54至SEQ ID NO:153的序列约80％、至少约85％、至少约90％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％或约100％相同的氨基酸序列(不含信号肽和前肽序列)。在某些实施方案中，所述FIX融合蛋白包含选自SEQ ID NO:54至SEQ ID NO:153的氨基酸序列(不含信号肽和前肽序列)。在一个实施方案中，所述FIX融合蛋白包含与选自SEQ ID NO:119、120、121和123的序列至少约80％、至少约85％、至少约90％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％或约100％相同的氨基酸序列(不含信号肽和前肽序列)。在另一个实施方案中，所述FIX融合蛋白包含选自SEQ ID NO:119、120、123、121和226或122的氨基酸序列(不含信号肽和前肽序列)。在一些实施方案中，所述FIX融合蛋白选自FIX-AP.72、FIX-AP.144、FIX-CT.72、FIX-CT.144、FIX-AP.288和FIX-CT.288(不含信号肽和前肽序列)。

在一些实施方案中，所述FIX融合蛋白包含两个不同类型的异源部分。在一些实施方案中，所述FIX融合蛋白包含FIX多肽、XTEN和Fc结构域(或FcRn结合配偶体)或其片段。在一些实施方案中，所述XTEN插入所述FIX内，并且所述Fc结构域(或FcRn结合配偶体)或其片段与所述FIX的C端融合。在一些实施方案中，所述XTEN在选自表3中列出的插入位点的一个或多个插入位点处插入FIX多肽内。在一个实施方案中，XTEN在插入位点处插入FIX多肽内，所述插入位点对应于选自以下的氨基酸：SEQ ID NO:1或2的氨基酸103、SEQ ID NO:1或2的氨基酸105、SEQ ID NO:1或2的氨基酸142、SEQ ID NO:1或2的氨基酸149、SEQ ID NO:1或2的氨基酸162、SEQ ID NO:1或2的氨基酸166、SEQ ID NO:1或2的氨基酸174、SEQ ID NO:1或2的氨基酸224、SEQ ID NO:1或2的氨基酸226、SEQ ID NO:1或2的氨基酸228、以及SEQ IDNO:1或2的氨基酸413；并且所述Fc结构域(FcRn结合配偶体)或其片段与FIX多肽的C端融合。在某些实施方案中，所述XTEN在对应于选自SEQ ID NO:1或2的氨基酸105、SEQ ID NO:1或2的氨基酸166、SEQ ID NO:1或2的氨基酸224的氨基酸的插入位点处插入FIX多肽内；并且所述Fc结构域(或FcRn结合配偶体)或其片段与FIX多肽的C端融合。在一些实施方案中，所述XTEN选自AE42、AE72和AE144。

在本公开文本的某些方面，所述FIX融合蛋白包含一条或两条多肽链。在一个实施方案中，所述FIX融合蛋白包含两条多肽链，其中第一多肽链包含与Fc结构域(或FcRn结合配偶体)融合的FIX多肽，第二多肽链包含第二Fc结构域，其中第一Fc结构域(或FcRn结合配偶体)和第二Fc结构域(或FcRn结合配偶体)通过共价键缔合。

在另一个实施方案中，所述FIX融合蛋白包含单一多肽链，所述多肽链包含FIX多肽和Fc结构域(或FcRn结合配偶体)。在一个具体实施方案中，所述FIX融合蛋白还包含连接FIX多肽和Fc结构域(或FcRn结合配偶体)的接头。在另一个实施方案中，所述FIX融合蛋白包含FIX多肽、Fc结构域和第二Fc结构域(或FcRn结合配偶体)。在一个具体实施方案中，所述FIX融合蛋白还包含连接Fc结构域(或n结合配偶体)和第二Fc结构域(或n结合配偶体)的接头。在另一个实施方案中，所述FIX融合蛋白包含FIX多肽、Fc结构域(或FcRn结合配偶体)和第二Fc结构域(或FcRn结合配偶体)，其中所述FIX多肽与Fc结构域(或FcRn结合配偶体)通过接头连接。在另一个实施方案中，所述FIX融合蛋白包含FIX多肽、Fc结构域(或FcRn结合配偶体)和第二Fc结构域(或FcRn结合配偶体)，其中所述FIX多肽与Fc结构域(或FcRn结合配偶体)通过第一接头连接，并且其中所述Fc结构域(或FcRn结合配偶体)与第二Fc结构域(或FcRn结合配偶体)通过接头连接。在某些实施方案中，所述FIX融合蛋白包含选自以下的式：

(i)FIX(X)-F1；

(ii)FIX(X)-L1-F1；

(iii)FIX(X)-F1-F2；

(iv)FIX(X)-L1-F1-F2；

(v)FIX(X)-L1-F1-L2-F2；

(vi)FIX(X)-F1-L1-F2；

(vii)FIX(X)-F1:F2；

(viii)FIX(X)-L1-F1:F2；和

(ix)其任何组合，

其中FIX(X)是FIX多肽，其具有插入本文所述的一个或多个插入位点的XTEN；L1和L2中的每一个都是接头；F1是Fc结构域或FcRn结合配偶体；F2是第二Fc结构域或第二FcRn结合配偶体，(-)是肽键或一个或多个氨基酸；且(:)是共价键，例如二硫键。

所述接头(L1和L2)可以相同或不同。所述接头可以是可切割的或不可切割的，并且接头可包含一个或多个细胞内加工位点。本文其他地方描述了所述接头的非限制性例子。所述接头中任何一个可用于将FIX与异源部分(例如XTEN或Fc)或第一异源部分(例如第一Fc)与第二异源部分(例如第二Fc)组合。

在某些实施方案中，所述接头包含凝血酶切割位点。在一个具体实施方案中，所述凝血酶切割位点包含XVPR，其中X是任何脂族氨基酸(例如甘氨酸、丙氨酸、缬氨酸、亮氨酸或异亮氨酸)。在一个具体实施方案中，所述凝血酶切割位点包含LVPR。在一些实施方案中，所述接头包含PAR1外部位点相互作用基序，所述基序包含SFLLRN(SEQ ID NO:190)。在一些实施方案中，所述PAR1外部位点相互作用基序还包含选自以下的氨基酸序列；P、PN、PND、PNDK(SEQ ID NO:191)、PNDKY(SEQ ID NO:192)、PNDKYE(SEQ ID NO:193)、PNDKYEP(SEQ IDNO:194)、PNDKYEPF(SEQ ID NO:195)、PNDKYEPFW(SEQ ID NO:196)、PNDKYEPFWE(SEQ IDNO:197)、PNDKYEPFWED(SEQ ID NO:198)、PNDKYEPFWEDE(SEQ ID NO:199)、PNDKYEPFWEDEE(SEQ ID NO:200)、PNDKYEPFWEDEES(SEQ ID NO:201)或其任何组合。在其他实施方案中，所述接头包含FXIa切割位点LDPR。

在一个具体实施方案中，所述FIX融合蛋白包含FIX多肽和异源部分，其中所述异源部分包含XTEN，其中XTEN通过或不通过接头与FIX多肽的C端融合，所述接头可以是或不是可切割的，且所述XTEN包含长度超过42个氨基酸且短于864个氨基酸的氨基酸序列，优选地长度短于144个氨基酸。所述XTEN可包含长于42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70或71个氨基酸且短于140、139、138、137、136、135、134、133、132、131、130、129、128、127、126、125、124、123、122、121、120、119、118、117、116、115、114、113、112、111、110、109、108、107、106、105、104、103、102、101、100、99、98、97、96、95、94、93、92、91、90、89、88、87、86、85、84、83、82、81、80、79、78、76、75、74或73个氨基酸等或其任何组合的氨基酸序列。在一些实施方案中，所述XTEN的长度为72个氨基酸。在一个具体实施方案中，所述XTEN是AE72。在另一个实施方案中，所述XTEN包含与SEQ ID NO:35至少约80％、至少约85％、至少约90％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％或100％相同的氨基酸序列。

在一些实施方案中，所述FIX融合蛋白包含FIX多肽，其含有至少一个插入的XTEN序列和包含XTEN的异源部分，其中所述XTEN通过或不通过接头与FIX多肽的C端融合，所述接头可以是或不是可切割的。在一些实施方案中，所述XTEN的长度短于864个氨基酸，优选地长度短于144个氨基酸。在其他实施方案中，所述XTEN包含长度短于244、140、130、120、110、100、90、80或75个氨基酸的氨基酸序列。

在其他实施方案中，所述FIX融合蛋白包含选自以下的式：

(i)FIX-X

(ii)FIX-L1-X

(iii)FIX(X)-X

(iv)FIX(X)-L1-X

(v)FIX(X)-L1:X

(vi)其任何组合，

其中FIX是FIX多肽；FIX(X)是具有至少一个插入本文所述的一个或多个插入位点的XTEN的FIX多肽；(X)是长度长于42个氨基酸且短于144个氨基酸的XTEN；X是长度长于42个氨基酸且短于864个氨基酸的XTEN，如288个氨基酸，优选地短于144个氨基酸(例如，具有72个氨基酸的XTEN)；L1是接头；(-)是肽键或一个或多个氨基酸；并且(:)是共价键，例如二硫键。

所述接头(L1)可以相同或不同。根据需要，所述接头可以是可切割的或不可切割的，并且接头可包含一个或多个细胞内加工位点。本文其他地方描述了所述接头的非限制性例子。所述接头的任何一个可用于将FIX与异源部分(例如XTEN或Fc)组合。以下是适用于许多公开文本实施方案的接头的非限制性例子：

a)GPEGPSKLTRAETGAGSPGAETAEQKLISEEDLSPATGHHHHHHHH(SEQ ID NO:219，凝血酶)；

b)GAGSPGAETALVPRGAGSPGAETAG(SEQ ID NO:220，凝血酶-PAR1)；

c)GAGSPGAETALVPRSFLLRNPNDKYEPFWEDEESGAGSPGAETA(SEQ ID NO:221)；

d)GPEGPSKLTRAETGAGSPGAETA(SEQ ID NO:222)

e)GGGGALRPRVVGGAGSPGAETA(SEQ ID NO:223)

f)GGGGTLDPRSFLLRNPNDKYEPFWEDEEKGGAGSPGAETA(SEQ ID NO:224)

g)GGAGSPGAETA(SEQ ID NO:225)

在某些其他实施方案中，所述接头包含凝血酶切割位点。在一个具体实施方案中，所述凝血酶切割位点包含XVPR，其中X是任何脂肪族氨基酸(例如甘氨酸、丙氨酸、缬氨酸、亮氨酸或异亮氨酸)。在一个具体实施方案中，所述凝血酶切割位点包含LVPR。在一些实施方案中，所述接头包含PAR1外部位点相互作用基序，所述基序包含SFLLRN(SEQ ID NO:190)。在一些实施方案中，所述PAR1外部位点相互作用基序还包含选自以下的氨基酸序列；P、PN、PND、PNDK(SEQ ID NO:191)、PNDKY(SEQ ID NO:192)、PNDKYE(SEQ ID NO:193)、PNDKYEP(SEQ ID NO:194)、PNDKYEPF(SEQ ID NO:195)、PNDKYEPFW(SEQ ID NO:196)、PNDKYEPFWE(SEQ ID NO:197)、PNDKYEPFWED(SEQ ID NO:198)、PNDKYEPFWEDE(SEQ ID NO:199)、PNDKYEPFWEDEE(SEQ ID NO:200)、PNDKYEPFWEDEES(SEQ ID NO:201)或其任何组合。在某些其他实施方案中，所述接头包含含有LDPR的FXIa切割位点，其可以与PAR1外部位点相互作用基序组合。

在某些实施方案中，所述在C端与XTEN融合的FIX多肽可以还包含第二XTEN。所述第二XTEN可以与FIX融合蛋白的任何部分融合或插入FIX融合蛋白的任何部分，包括但不限于本文公开的插入位点。所述FIX融合蛋白还可包含第三XTEN、第四XTEN、第五XTEN或第六XTEN。

与原生FIX相比，本公开文本的FIX融合蛋白维持一定的活性水平。在一些实施方案中，所述FIX融合蛋白具有原生FIX的促凝血活性的至少约10％、至少约20％、至少约30％、至少约40％、至少约50％、至少约60％、至少约70％、至少约80％、至少约90％或100％。促凝血活性可通过本领域已知的任何方法测量，包括但不限于显色底物测定、一步凝固测定或两者。

II.A.因子IX

人因子IX(FIX)是丝氨酸蛋白酶，它是凝血级联反应内在途径的重要组分。如本文所用，“因子IX”或“FIX”是指凝血因子蛋白及其种类和序列变体，并且包括但不限于人FIX前体多肽(“prepro”)的461单链氨基酸序列，成熟人FIX(SEQ ID NO:1)的415单链氨基酸序列和R338L FIX(Padua)变体(SEQ ID NO:2)。FIX包括具有血液凝固FIX典型特征的任何形式的FIX分子。如本文所用，“因子IX”和“FIX”旨在涵盖包含结构域Gla(含有γ-羧基谷氨酸残基的区域)、EGF1和EGF2(含有与人表皮生长因子同源的序列的区域)、活化肽(“AP”，由成熟FIX的残基R136-R180形成)和C端蛋白酶结构域(“Pro”)，或本领域已知的这些结构域的同义词，或者可以是保留原生蛋白质的至少一部分生物活性的截短片段或序列变体。FIX或序列变体曾被克隆，如美国专利号4,770,999和7,700,734中所述，编码人因子IX的cDNA曾被分离、表征并克隆到表达载体中(参见，例如，Choo等,Nature 299:178-180(1982)；Fair等,Blood 64:194-204(1984)；及Kurachi等,Proc.Natl.Acad.Sci.,U.S.A.79:6461-6464(1982))。FIX的一种具体变体，R338L FIX(Padua)变体(SEQ ID NO:2)，其特征如Simioni等,2009中描述，包含功能获得性突变，其与Padua变体活性相对于原生FIX近8倍的增加有关(表1)。FIX变体还可以包括具有一个或多个保守氨基酸取代的任何FIX多肽，所述取代不影响FIX多肽的FIX活性。

表1：示例FIX序列

FIX多肽是55kDa，合成为由三个区域组成的前体多肽链(SEQ ID NO:1)：28个氨基酸的信号肽(SEQ ID NO:3的氨基酸1至28)、谷氨酸残基的γ-羧化所需的18个氨基酸的前肽(氨基酸29至46)和415个氨基酸的成熟因子IX(SEQ ID NO:1或2)。前肽是γ-羧基谷氨酸结构域N端的18个氨基酸的残基序列。前肽与维生素K依赖性γ羧化酶结合，然后通过内源性蛋白酶从FIX的前体多肽上切割，所述内源性蛋白酶最可能是PACE(配对碱性氨基酸切割酶)，也被称为弗林蛋白酶或PCSK3。在没有γ羧化的情况下，所述Gla结构域不能与钙结合以呈现将蛋白质锚定到带负电荷的磷脂表面所必需的正确构象，从而使因子IX无功能。即使它是羧化的，所述Gla结构域也依赖于前肽的切割以获得适当的功能，因为保留的前肽对与钙和磷脂的最佳结合所必需的Gla结构域的构象变化有干扰。在人类中，所得的成熟因子IX由肝细胞作为无活性酶原分泌到血流中，所述酶原是415个氨基酸残基的单链蛋白，其含有大约17％重量比的碳水化合物(Schmidt,A.E.等(2003)Trends Cardiovasc Med,13:39)。

所述成熟FIX由若干个结构域组成，其在N端至C端构型中是：GLA结构域、EGF1结构域、EGF2结构域、活化肽(AP)结构域和蛋白酶(或催化)结构域。短接头将EGF2结构域与AP结构域连接。FIX含有分别由R145-A146和R180-V181形成的两个活化肽。活化后，所述单链FIX变成2-链分子，其中两条链通过二硫键连接。凝血因子可以通过替换其活化肽进行工程化，从而带来改变的活化特异性。在哺乳动物中，成熟FIX必须被活化的因子XI激活以产生因子IXa。在FIX活化成FIXa后，蛋白酶结构域即提供FIX的催化活性。活化因子VIII(FVIIIa)是FIXa活性完全表达的特异性辅因子。

在其他实施方案中，FIX多肽包含Thr148等位形式的衍生自血浆的因子IX，并且具有与内源因子IX相似的结构和功能特征。

许多功能性FIX变体是已知的。国际公开号WO 02/040544A3在第4页第9-30行和第15页第6-31行公开了展现出对肝素抑制作用有增加的抗性的突变体。国际公开号WO 03/020764A2在表2和3(第14-24页)和第12页第1-27行公开了具有降低的T细胞免疫原性的FIX突变体。国际公开号WO2007/149406A2在第4页第1行至第19页第11行公开了功能性突变体FIX分子，所述FIX分子展现出增加的蛋白质稳定性、增加的体内和体外半衰期以及对蛋白酶的增加的抗性。WO 2007/149406A2还在第19页第12行至第20页第9行公开了嵌合和其他变体FIX分子。国际公开号WO 08/118507A2在第5页第14行至第6页第5行公开了展现出增加的凝血活性FIX突变体。国际公开号WO09/051717A2在第9页第11行至第20页第2行公开了具有增加数量的N-连接和/或O-连接的糖基化位点而导致半衰期和/或回收率增加的FIX突变体。国际公开号WO 09/137254A2在在第2页第[006]段至第5页第[011]段和第16页第[044]段至第24页第[057]段中还公开了具有增加的糖基化位点数的因子IX突变体。国际公开号WO 09/130198A2在第4页第26行至第12页第6行公开了功能性突变体FIX分子，所述FIX分子具有增加数量的糖基化位点而导致半衰期增加。国际公开号WO 09/140015A2在第11页第[0043]段至第13页第[0053]段公开了具有增加的Cys残基数的功能性FIX突变体，所述Cys残基可以用于聚合物(例如PEG)缀合。2011年7月11日提交并于2012年1月12日作为WO2012/006624公开的国际申请号PCT/US 2011/043569中描述的FIX多肽也通过引用以其整体并入本文。

此外，已在血友病受试者中鉴定出了数百种FIX中的非功能性突变，其中许多在在国际公开号WO 09/137254A2的第11-14页表5中公开。此类非功能性突变不包括在本公开文本中，但为哪些突变或多或少可能产生功能性FIX多肽提供了另外的指导。

在一个实施方案中，所述FIX多肽(或融合多肽的因子IX部分)包含与SEQ ID NO:1或2中所列出的序列(SEQ ID NO:1或2的氨基酸1至415)至少70％、至少80％、至少85％、至少90％、至少95％、至少96、至少97％、至少98％、至少99％或100％相同的氨基酸序列，或者可替代地，含有前肽序列，或含有前肽和信号序列(全长FIX)。在另一个实施方案中，所述FIX多肽包含与SEQ ID NO:2中所列出的序列至少70％、至少80％、至少85％、至少90％、至少95％、至少96、至少97％、至少98％、至少99％或100％相同的氨基酸序列。

因子IX凝血活性以国际单位(IU)表示。一个IU的FIX活性大约对应于1毫升正常人血浆中FIX的量。有若干种测定方法可用于测量因子IX活性，包括一步凝血测定(活化部分凝血活酶时间；aPTT)、凝血酶生成时间(TGA)和旋转血栓弹力测定法

本公开文本考虑了与FIX序列具有同源性的序列，天然的序列片段，如来自人、非人灵长类动物、哺乳动物(包括家畜)的序列片段，以及保留FIX的至少一部分生物活性或生物学功能和/或用于预防、治疗、介导或改善凝血因子相关疾病、缺陷、障碍或病症(例如与创伤、手术、凝血因子缺乏有关的出血事件)的非天然序列变体。可以通过标准同源性搜索技术(如NCBIBLAST)找到与人FIX具有同源性的序列。

II.B.异源部分

本公开文本的FIX融合蛋白可包含插入FIX多肽内一个或多个位点、与C端融合或两者都有的至少一个异源部分，其中所述FIX融合蛋白具有促凝血活性并且可在体内表达或在宿主细胞中体外表达。“异源部分”可包含异源多肽，或非多肽部分，或两者都有。在某些方面，所述异源部分是XTEN。在一些方面，本公开文本的FIX融合蛋白包含插入FIX多肽内一个或多个位点的至少一个XTEN。在一些方面，本公开文本的FIX融合蛋白包含至少一个与FIX多肽的C端融合的Fc区域。在其他方面，FIX融合蛋白包含插入FIX多肽内一个或多个位点的至少一个异源部分，其中所述异源部分是半衰期延长的部分(例如体内半衰期延长部分)。

据信，插入位点(其中所述FIX保留其至少一些促凝血活性)的发现也将允许具有非结构化或结构化特征的其他肽和多肽的插入，所述特征与当在一个或多个相同位点与FIX蛋白融合时半衰期延长相关。异源部分(例如，半衰期延长的部分)的非限制性例子包括白蛋白，白蛋白片段，免疫球蛋白的Fc片段，FcRn结合配偶体，人绒毛膜促性腺激素β亚单位的C端肽(CTP)，HAP序列，转铁蛋白，美国专利申请号20100292130的PAS多肽，聚甘氨酸接头，聚丝氨酸接头，具有选自甘氨酸(G)、丙氨酸(A)、丝氨酸(S)、苏氨酸(T)、谷氨酸(E)和脯氨酸(P)的两种类型的氨基酸的6-40个氨基酸的肽或短多肽(具有从小于50％到大于50％的不同程度的二级结构)，将尤其适合于插入鉴定出的FIX的活性插入位点。

在某些方面，异源部分增加FIX融合蛋白的体内或体外半衰期。在其他方面，异源部分促进FIX融合蛋白的可视化或定位。FIX融合蛋白的可视化和/或定位可以是体内、体外、离体或其组合。在其他方面，异源部分增加FIX融合蛋白的稳定性。如本文所用，术语“稳定性”是指本领域公认的为响应环境条件(例如升高或降低的温度)，所述FIX融合蛋白的一种或多种物理特性的维持的量度。在某些方面，所述物理特性是FIX融合蛋白的共价结构的维持(例如不存在蛋白水解切割，不需要的氧化或脱酰胺)。在其他方面，所述物理特性也可以是处于适当折叠状态的FIX融合蛋白的存在(例如，不存在可溶性或不溶性聚集体或沉淀物)。在一个方面，通过测定FIX融合蛋白的生物物理特性来测量所述FIX融合蛋白的稳定性，例如热稳定性、pH解折叠特征、聚糖的稳定去除、溶解度、生化功能(例如，与另一种蛋白质结合的能力)等，和/或其组合。在另一方面，通过相互作用的结合亲和力证明生化功能。在一个方面，蛋白质稳定性的量度是热稳定性，即对热激发的抗性。可以使用本领域已知的方法测量稳定性，如HPLC(高效液相色谱)、SEC(尺寸排阻色谱)、DLS(动态光散射)等。测量热稳定性的方法包括但不限于差示扫描量热法(DSC)、差示扫描荧光测定法(DSF)、圆二色性(CD)和热激发测定。

在一个特定方面，插入FIX融合蛋白中的一个或多个插入位点的异源部分保留了所述FIX融合蛋白的生物化学活性。在某些实施方案中，所述异源部分是XTEN。在一个实施方案中，所述生物化学活性是FIX活性，其可以通过显色测定来测量。

在一些实施方案中，通过位于异源部分的N端、C端或者N端和C端两者的接头在插入位点间接插入至少一个异源部分。所述异源部分的N端和C端的接头可以相同或不同。在一些实施方案中，若干个接头可以串联地位于异源部分的一个或两个末端的侧翼。在一些实施方案中，所述接头是“Gly-Ser肽接头”。术语“Gly-Ser肽接头”是指包含甘氨酸和丝氨酸残基的肽。

示例性Gly/Ser肽接头包括但不限于氨基酸序列(Gly₄Ser)_n(SEQ ID NO：161)，其中n是与1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、46、50、55、60、70、80、90或100相同或比其更高的整数。在一个实施方案中，n＝1，即所述接头是(Gly₄Ser)(SEQ ID NO:161)。在一个实施方案中，n＝2，即所述接头是(Gly₄Ser)₂(SEQ ID NO:162)。在另一个实施方案中，n＝3，即所述接头是(Gly₄Ser)₃(SEQ ID NO:172)。在另一个实施方案中，n＝4，即所述接头是(Gly₄Ser)₄(SEQ ID NO:173)。在另一个实施方案中，n＝5，即所述接头是(Gly₄Ser)₅(SEQID NO:174)。在又另一个实施方案中，n＝6，即所述接头是(Gly₄Ser)₆(SEQ ID NO:175)。在另一个实施方案中，n＝7，即所述接头是(Gly₄Ser)₇(SEQ ID NO:176)。在又另一个实施方案中，n＝8，即所述接头是(Gly₄Ser)₈(SEQ ID NO:177)。在另一个实施方案中，n＝9，即所述接头是(Gly₄Ser)₉(SEQ ID NO:178)。在又另一个实施方案中，n＝10，即所述接头是(Gly₄Ser)₁₀(SEQ ID NO:179)。

另一种示例性Gly/Ser肽接头包含氨基酸序列(Gly₄Ser)_n(SEQ ID NO:180)，其中n是与1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、46、50、55、60、70、80、90或100相同或比其更高的整数。在一个实施方案中，n＝1，即所述接头是Ser(Gly₄Ser)(SEQ ID NO:180)。在一个实施方案中，n＝2，即所述接头是Ser(Gly₄Ser)₂(SEQ ID NO:181)。在另一个实施方案中，n＝3，即所述接头是Ser(Gly₄Ser)₃(SEQ ID NO:182)。在另一个实施方案中，n＝4，即所述接头是Ser(Gly₄Ser)₄(SEQ ID NO:183)。在另一个实施方案中，n＝5，即所述接头是Ser(Gly₄Ser)₅(SEQ ID NO:184)。在又另一个实施方案中，n＝6，即所述接头是Ser(Gly₄Ser)₆(SEQ ID NO:185)。在又另一个实施方案中，n＝7，即所述接头是Ser(Gly₄Ser)₇(SEQ ID NO:186)。在又另一个实施方案中，n＝8，即所述接头是Ser(Gly₄Ser)₈(SEQ ID NO:187)。在又另一个实施方案中，n＝9，即所述接头是Ser(Gly₄Ser)₉(SEQ ID NO:188)。在又另一个实施方案中，n＝10，即所述接头是Ser(Gly₄Ser)₁₀(SEQ ID NO:189)。

在某些方面，FIX融合蛋白包含插入表7中列出的插入位点的一个异源部分。在其他方面，FIX融合蛋白包含插入表7中列出的两个插入位点的两个异源部分。在一个具体实施方案中，所述两个异源部分被插入表8中列出的两个插入位点。在某些方面，FIX融合蛋白包含插入表7中列出的三个插入位点的三个异源部分。在某些方面，FIX融合蛋白包含插入表7中列出的四个插入位点的四个异源部分。在某些方面，FIX融合蛋白包含插入表7中列出的五个插入位点的五个异源部分。在某些方面，FIX融合蛋白包含插入表7中列出的六个插入位点的六个异源部分。在一些方面，所有插入的异源部分是相同的。在其他方面，至少一个插入的异源部分与其余的插入的异源部分不同。

所述FIX多肽与所述至少一个异源部分(例如XTEN)的融合可以影响本公开文本的融合蛋白的物理或化学特性，例如药代动力学。在一个特定实施方案中，与FIX蛋白连接的异源部分增加至少一种药代动力学特性，例如，增加的终末半衰期或增加的曲线下方面积(AUC)，使得本文所述的融合蛋白与野生型FIX或缺乏异源部分的相应FIX相比，保持在体内的时间段增加。在另外的实施方案中，本公开文本中使用的XTEN序列增加至少一种药代动力学特性，例如，增加的终末半衰期、增加的回收率和/或增加的皮下给药的生物利用度、增加的曲线下方面积(AUC)，使得与野生型FIX或缺乏异源部分的相应FIX相比，FIX蛋白保持在体内的时间段增加。

在某些方面，增加本公开文本的FIX融合蛋白的半衰期的异源部分包括但不限于异源多肽，如白蛋白、免疫球蛋白Fc区、XTEN序列、人绒毛膜促性腺激素β亚单位的C端肽(CTP)、PAS序列、HAP序列、转铁蛋白、白蛋白结合部分，或这些多肽的任何片段、衍生物、变体或组合。在某些方面，本公开文本的FIX融合蛋白包含增加半衰期的异源多肽，其中所述异源多肽是XTEN序列。在其他相关方面，异源部分可包括非多肽部分的附接位点，如聚乙二醇(PEG)、羟乙基淀粉(HES)、聚唾液酸，或这些部分的任何衍生物、变体或组合。

在其他实施方案中，本公开文本的FIX融合蛋白与一种或多种聚合物缀合。所述聚合物可以是水溶性的或非水溶性的。所述聚合物可以共价或非共价附接到FIX或与FIX缀合的其他部分。聚合物的非限制性例子可以是聚(环氧烷)、聚(乙烯基吡咯烷酮)、聚(乙烯醇)、聚恶唑啉或聚(丙烯酰吗啉)。

在某些方面，本公开文本的FIX融合蛋白包含一个、两个、三个或更多个异源部分，其可各自为相同或不同的分子。在一些实施方案中，所述FIX融合蛋白包含一个或多个XTEN。在其他实施方案中，所述FIX融合蛋白包含一个或多个XTEN和一个或多个Fc结构域。在一个具体实施方案中，所述FIX融合蛋白可包含插入FIX内的XTEN和与FIX的C端融合的Fc。

与原生FIX、rFIXFc或FIX R338L相比，本公开文本的FIX融合蛋白可具有增加的体内半衰期。在一些实施方案中，与缺少异源部分的原生FIX相比或与缺少异源部分的FIXR338L相比，所述FIX融合蛋白可具有至少约1.5倍、至少约2倍、至少约3倍或至少约4倍的体内半衰期。在一个具体实施方案中，所述FIX融合蛋白的体内半衰期大于不含异源部分的FIX多肽超过2倍。

在其他实施方案中，所述FIX融合蛋白可以具有长于缺少异源部分的FIX多肽的体内半衰期至少约5小时、至少约6小时、至少约7小时、在至少约8小时、至少约9小时、至少约10小时、至少约11小时、至少约12小时、至少约13小时、至少约14小时、至少约15小时、至少约16小时、至少约17小时、至少约18小时、至少约19小时、至少约20小时、至少约21小时、至少约22小时、至少约23小时、至少约24小时、至少约25小时、至少约26小时、至少约27小时、至少约28小时、至少约29小时、至少约30小时、至少约31小时、至少约32小时、至少约33小时或至少约34小时的体内半衰期。

II.B.1.XTEN

在一些实施方案中，所述至少一个异源部分是XTEN。如本文所用，“XTEN序列”是指具有非天然存在的、基本上非重复的序列的延伸长度多肽，其主要由小的亲水性氨基酸组成，所述序列在生理条件下具有低度或者无二级或三级结构。作为融合蛋白配偶体，XTEN可以作为载体，当与本公开文本的FIX序列连接以产生融合蛋白时，赋予某些期望的药代动力学、理化和药学特性。这些期望的特性包括但不限于增强的药代动力学参数和溶解度特征。如本文所用，“XTEN”特别地排除抗体或抗体片段，如单链抗体或轻链或重链的Fc片段。

在某些方面，本公开文本的FIX融合蛋白包含插入所述FIX中的至少一个XTEN或其片段、变体或衍生物，其中所述FIX融合蛋白具有促凝血活性并且可以体内表达或在宿主细胞中体外表达。在某些方面，所述异源部分的两个是XTEN序列。在一些方面，所述异源部分的三个是XTEN序列。在一些方面，所述异源部分的四个是XTEN序列。在一些方面，所述异源部分的五个是XTEN序列。在一些方面，所述异源部分的六个或更多个是XTEN序列。

在一些实施方案中，可用于本公开文本的所述XTEN序列是具有大于约20、30、40、50、60、70、80、90、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1200、1400、1600、1800或2000个氨基酸残基的肽或多肽。在某些实施方案中，XTEN是具有大于约20至约3000个氨基酸残基、大于30至约2500个残基、大于40至约2000个残基、大于50至约1500个残基、大于60至约1000个残基、大于70至约900个残基、大于80至约800个残基、大于90至约700个残基、大于100至约600个残基、大于110至约500个残基、或大于120个至大约400个残基的肽或多肽。在一个具体实施方案中，所述XTEN包含长度长于42个氨基酸且短于144个氨基酸的氨基酸序列。

本公开文本的XTEN序列可包含一个或多个具有5至14个(例如9至14个)氨基酸残基的序列基序或与所述序列基序至少80％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％相同的氨基酸序列，其中所述基序包含、基本上由或由选自甘氨酸(G)、丙氨酸(A)、丝氨酸(S)、苏氨酸(T)、谷氨酸(E)和脯氨酸(P)的4-6种类型的氨基酸(例如5种氨基酸)组成。参见US2010-0239554A1。

在一些实施方案中，所述XTEN包含非重叠序列基序，其中所述序列的约80％、或至少约85％、或至少约90％、或约91％、或约92％、或约93％、或约94％、或约95％、或约96％、或约97％、或约98％、或约99％或约100％由选自表2A的单个基序家族的多个非重叠序列单元组成，产生家族序列。如本文所用，“家族”指所述XTEN具有仅从表2A中的单个基序类别中选择的基序；即AD、AE、AF、AG、AM、AQ、BC或BD XTEN，并且选择所述XTEN中不来自家族基序的任何其他氨基酸以实现所需的特性，如允许通过所述编码核苷酸掺入限制性位点、掺入切割序列、或实现与FIX的更好连接。在XTEN家族的一些实施方案中，XTEN序列包含AD基序家族、或AE基序家族、或AF基序家族、或AG基序家族、或AM基序家族、或AQ基序家族、或BC家族或BD家族的非重叠序列基序的多个单元，所得XTEN展现出上述同源性范围。在其他实施方案中，所述XTEN包含来自表2A的两个或更多个基序家族的多个基序序列单元。可以选择这些序列以实现所需的物理/化学特征，包括诸如净电荷、亲水性、二级结构缺少或重复性缺少等特性，这些特性由基序的氨基酸组成赋予，下面将更全面地描述。在本段上文所述的实施方案中，可以使用本文所述的方法选择和组装掺入XTEN中的基序，以实现具有约36至约3000个氨基酸残基的XTEN。

表2A.具有12个氨基酸的XTEN序列基序和基序家族

*表示单个基序序列，当在各种排列中一起使用时，产生“家族序列”

XTEN可以有不同的长度用于插入或连接至FIX。在一个实施方案中，基于所述融合蛋白中要实现的特性或功能来选择所述XTEN序列的长度。根据预期的特性或功能，XTEN可以是短序列或中等长度序列或更长的序列，可以作为载体。在某些实施方案中，所述XTEN包括约6至约99个氨基酸残基的短片段、约100至约399个氨基酸残基的中等长度片段、和约400至约1000及至多达约3000个氨基酸残基的较长长度片段。因此，插入或连接到FIX的XTEN可具有约6、约12、约36、约40、约42、约72、约96、约144、约288、约400、约500、约576、约600、约700、约800、约864、约900、约1000、约1500、约2000、约2500或多达约3000个氨基酸残基的长度。在其他实施方案中，所述XTEN序列为约6至约50、约50至约100、约100至150、约150至250、约250至400、约400至约500、约500至约900、约900至约1500、约1500至2000或约2000至约3000个氨基酸残基的长度。插入或连接至FIX的XTEN的精确长度可以变化，而不会对FIX的活性产生不利影响。在一个实施方案中，本文使用的一个或多个XTEN的长度为42个氨基酸、72个氨基酸、144个氨基酸、288个氨基酸、576个氨基酸或864个氨基酸，并且可以选自一个或多个XTEN家族序列；即AD、AE、AF、AG、AM、AQ、BC或BD。

在一些实施方案中，本公开文本中使用的XTEN序列与选自AE42、AG42、AE48、AM48、AE72、AG72、AE108、AG108、AE144、AF144、AG144、AE180、AG180、AE216、AG216、AE252、AG252、AE288、AG288、AE324、AG324、AE360、AG360、AE396、AG396、AE432、AG432、AE468、AG468、AE504、AG504、AF504、AE540、AG540、AF540、AD576、AE576、AF576、AG576、AE612、AG612、AE624、AE648、AG648、AG684、AE720、AG720、AE756、AG756、AE792、AG792、AE828、AG828、AD836、AE864、AF864、AG864、AM875、AE912、AM923、AM1318、BC864、BD864、AE948、AE1044、AE1140、AE1236、AE1332、AE1428、AE1524、AE1620、AE1716、AE1812、AE1908、AE2004A、AG948、AG1044、AG1140、AG1236、AG1332、AG1428、AG1524、AG1620、AG1716、AG1812、AG1908、AG2004及其任何组合的序列至少60％、70％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％相同。参见US2010-0239554A1。在一个具体实施方案中，XTEN包含AE42、AE72、AE144、AE288、AE576、AE864、AG42、AG72、AG144、AG288、AG576、AG864或其任何组合。

在一个实施方案中，所述XTEN序列与选自AE36(SEQ ID NO:217)、AE42(SEQ IDNO:34)、AE72(SEQ ID NO:35)、AE78(SEQ ID NO:218)、AE144(SEQ ID NO:36)、AE144_2A(SEQ ID NO:37)、AE144_3B(SEQ ID NO:38)、AE144_4A(SEQ ID NO:39)、AE144_5A(SEQ IDNO:40)、AE144_6B(SEQ ID NO:41)、AG144(SEQ ID NO:42)、AG144_A(SEQ ID NO:43)、AG144_B(SEQ ID NO:44)、AG144_C(SEQ ID NO:45)、AG144_F(SEQ ID NO:46)、AE288(SEQID NO:47)、AE288_2(SEQ ID NO:48)、AG288(SEQ ID NO:49)、AE576(SEQ ID NO:50)、AG576(SEQ ID NO:51)、AE864(SEQ ID NO:52)、AG864(SEQ ID NO:53)、XTEN_AE72_2A_1(SEQ IDNO:202)、XTEN_AE72_2A_2(SEQ ID NO:203)、XTEN_AE72_3B_1(SEQ ID NO:204)、XTEN_AE72_3B_2(SEQ ID NO:205)、XTEN_AE72_4A_2(SEQ ID NO:206)、XTEN_AE72_5A_2(SEQ IDNO:207)、XTEN_AE72_6B_1(SEQ ID NO:208)、XTEN_AE72_6B_2(SEQ ID NO:209)、XTEN_AE72_1A_1(SEQ ID NO:210)、XTEN_AE72_1A_2(SEQ ID NO:211)、XTEN_AE72_1A_3(SEQ IDNO:230)、XTEN_AE144_1A(SEQ ID NO:212)、AE150(SEQ ID NO:213)、AG150(SEQ ID NO:214)、AE294(SEQ ID NO:215)、AG294(SEQ ID NO:216)或其任何组合的氨基酸序列至少60％、70％、80％、90％、95％、96％、97％、98％、99％或100％相同。

在一些实施方案中，XTEN的少于100％的氨基酸选自甘氨酸(G)、丙氨酸(A)、丝氨酸(S)、苏氨酸(T)、谷氨酸(E)和脯氨酸(P)，或小于100％的序列由表2A的序列基序或表2B的XTEN序列组成。在此类实施方案中，所述XTEN的剩余氨基酸残基选自任何其他14种天然L-氨基酸，但可优选选自亲水性氨基酸，以使所述XTEN序列含有至少约90％、91％、92％、93％、94％、95％、96％、97％、98％或至少约99％的亲水性氨基酸。在缀合构建体中被利用的XTEN中的疏水氨基酸的含量可以小于疏水性氨基酸含量的5％，或小于2％，或小于1％。在XTEN构建中不太有利的疏水残基包括色氨酸、苯丙氨酸、酪氨酸、亮氨酸、异亮氨酸、缬氨酸和甲硫氨酸。另外，XTEN序列可含有少于5％或少于4％或少于3％或少于2％或少于1％或不含以下氨基酸：甲硫氨酸(例如为了避免氧化)或天冬酰胺和谷氨酰胺(为避免脱酰胺)。

在另一个实施方案中，所述XTEN序列选自AE36(SEQ ID NO:217)、AE42(SEQ IDNO:34)、AE72(SEQ ID NO:35)、AE78(SEQ ID NO:218)、AE144(SEQ ID NO:36)、AE144_2A(SEQ ID NO:37)、AE144_3B(SEQ ID NO:38)、AE144_4A(SEQ ID NO:39)、AE144_5A(SEQ IDNO:40)、AE144_6B(SEQ ID NO:41)、AG144(SEQ ID NO:42)、AG144_A(SEQ ID NO:43)、AG144_B(SEQ ID NO:44)、AG144_C(SEQ ID NO:45)、AG144_F(SEQ ID NO:46)、AE288(SEQID NO:47)、AE288_2(SEQ ID NO:48)、AG288(SEQ ID NO:49)、AE576(SEQ ID NO:50)、AG576(SEQ ID NO:51)、AE864(SEQ ID NO:52)、AG864(SEQ ID NO:53)、XTEN_AE72_2A_1(SEQ IDNO:202)、XTEN_AE72_2A_2(SEQ ID NO:203)、XTEN_AE72_3B_1(SEQ ID NO:204)、XTEN_AE72_3B_2(SEQ ID NO:205)、XTEN_AE72_4A_2(SEQ ID NO:206)、XTEN_AE72_5A_2(SEQ IDNO:207)、XTEN_AE72_6B_1(SEQ ID NO:208)、XTEN_AE72_6B_2(SEQ ID NO:209)、XTEN_AE72_1A_1(SEQ ID NO:210)、XTEN_AE72_1A_2(SEQ ID NO:211)、XTEN_AE72_1A_3(SEQ IDNO:230)、XTEN_AE144_1A(SEQ ID NO:212)、AE150(SEQ ID NO:213)、AG150(SEQ ID NO:214)、AE294(SEQ ID NO:215)、AG294(SEQ ID NO:216)或其任何组合。在一个特定实施方案中，所述XTEN序列选自AE72、AE144和AE288。本公开文本的某些XTEN序列的氨基酸序列显示在表2B中。

表2B.XTEN序列

在另外的实施方案中，本公开文本中使用的XTEN序列影响本公开文本的融合蛋白的物理或化学特性，例如药代动力学。本公开文本中使用的XTEN序列可以展现出一种或多种以下有利特性：构象灵活性、增强的水溶性、高度的蛋白酶抗性、低免疫原性、与哺乳动物受体的低结合或增加的流体动力学(或斯托克斯)半径。在一个特定实施方案中，与本公开文本中的FIX蛋白连接的XTEN序列增加了药代动力学特性，如更长的终末半衰期、增加的生物利用度或增加的曲线下方面积(AUC)，使得与野生型FIX相比，本文所述的蛋白质保持在体内的时间段增加。在另外的实施方案中，本公开文本中使用的XTEN序列增加了药代动力学特性，如更长的终末半衰期或增加的曲线下方面积(AUC)，使得与野生型相比，FIX蛋白保持在体内的时间段增加。

在一些实施方案中，所述FIX蛋白展现出大于原生FIX、rFIXFc、FIX R338L或缺少XTEN的相应FIX蛋白至少约1.5倍、至少约2倍、至少约3倍或至少约4倍的体内半衰期。在一个具体实施方案中，所述FIX融合蛋白的体内半衰期可以大于不含异源部分的FIX多肽超过2倍。

在其他实施方案中，所述FIX融合蛋白展现出长于缺少异源部分的FIX多肽的体内半衰期至少约5小时、至少约6小时、至少约7小时、在至少约8小时、至少约9小时、至少约10小时、至少约11小时、至少约12小时、至少约13小时、至少约14小时、至少约15小时、至少约16小时、至少约17小时、至少约18小时、至少约19小时、至少约20小时、至少约21小时、至少约22小时、至少约23小时、至少约24小时、至少约25小时、至少约26小时、至少约27小时、至少约28小时、至少约29小时、至少约30小时、至少约31小时、至少约32小时、至少约33小时或至少约34小时的体内半衰期。

可以采用多种方法和测定来确定包含XTEN序列的蛋白质的物理/化学特性。这些方法包括但不限于分析离心法、EPR、HPLC-离子交换、HPLC-尺寸排阻、HPLC-反相、光散射、毛细管电泳、圆二色性、差示扫描量热法、荧光、HPLC-离子交换、HPLC-尺寸排阻、IR、NMR、拉曼光谱、折光测定法和UV/可见光谱法。在Amau等,Prot Expr and Purif 48,1-13(2006)中公开了另外的方法。

XTEN序列的另外的例子可根据本公开文本使用并且在美国专利公开号2010/0239554 A1、2010/0323956 A1、2011/0046060 A1、2011/0046061 A1、2011/0077199 A1或2011/0172146 A1，或国际专利公开号WO 2010091122 A1、WO 2010144502 A2、WO2010144508 A1、WO 2011028228 A1、WO 2011028229A1、WO 2011028344 A2、WO 2014/011819 A2或WO 2015/023891中公开。

在一些方面，FIX融合蛋白包含插入FIX内、与FIX的C端融合或两者都有的一个或多个XTEN序列。在一个实施方案中，所述一个或多个XTEN序列被插入GLA结构域内。在另一个实施方案中，所述一个或多个XTEN序列被插入EGF1结构域内。在其他实施方案中，所述一个或多个XTEN序列被插入EGF2内。在仍其他实施方案中，所述一个或多个XTEN序列被插入AP内。在又其他实施方案中，所述一个或多个XTEN序列被插入催化结构域内。在一些实施方案中，所述一个或多个XTEN序列与FIX的C端融合。

在某些方面，FIX融合蛋白包含在表7中列出的插入位点处插入的一个XTEN序列。在其他方面，FIX融合蛋白包含在表7中列出的两个插入位点处插入的两个XTEN序列。在一个具体实施方案中，所述两个XTEN序列被插入表8中列出的两个插入位点。在某些方面，FIX融合蛋白包含插入表7中列出的三个插入位点的三个XTEN序列。在某些方面，FIX融合蛋白包含插入表7中列出的四个插入位点的四个XTEN序列。在某些方面，FIX融合蛋白包含插入表7中列出的五个插入位点的五个XTEN序列。在某些方面，FIX融合蛋白包含插入表7中列出的六个插入位点的六个XTEN序列。在一些方面，所有插入的XTEN序列是相同的。在其他方面，至少一个插入的XTEN序列与其余的插入的XTEN序列不同。

在一些方面，FIX融合蛋白包含在插入位点处插入FIX多肽内的一个XTEN序列，所述插入位点对应于选自以下的氨基酸：SEQ ID NO:2的氨基酸103、SEQ ID NO:2的氨基酸105、SEQ ID NO:2的氨基酸142、SEQ ID NO:2的氨基酸149、SEQ ID NO:2的氨基酸162、SEQID NO:2的氨基酸166、SEQ ID NO:2的氨基酸174、SEQ ID NO:2的氨基酸224、SEQ ID NO:2的氨基酸226、SEQ ID NO:2的氨基酸228、SEQ ID NO:2的氨基酸413及其任何组合，其中所述FIX融合蛋白展现出促凝血活性。在一些方面，FIX融合蛋白包含FIX多肽内的第二XTEN序列，所述第二XTEN序列在插入位点处，所述插入位点对应于选自以下的氨基酸：SEQ ID NO:2的氨基酸103、SEQ ID NO:2的氨基酸105、SEQ ID NO:2的氨基酸142、SEQ ID NO:2的氨基酸149、SEQ ID NO:2的氨基酸162、SEQ ID NO:2的氨基酸166、SEQ ID NO:2的氨基酸174、SEQ ID NO:2的氨基酸224、SEQ ID NO:2的氨基酸226、SEQ ID NO:2的氨基酸228、SEQ IDNO:2的氨基酸413及其任何组合，或者其中所述第二XTEN与FIX多肽的C端融合，其中所述FIX融合蛋白展现出促凝血活性。在一个具体方面，FIX融合蛋白包含与FIX的C端融合的一个XTEN序列，其中所述XTEN包含长度长于42个氨基酸且短于144个氨基酸的氨基酸序列。

II.B.2.Fc区或FcRn结合配偶体

在一些实施方案中，所述至少一个异源部分是Fc区(例如FcRn结合配偶体)或其片段。在某些方面，本公开文本的FIX融合蛋白包含插入FIX内、与FIX的C端融合或两者都有的至少一个Fc区(例如，FcRn结合配偶体)，其中所述FIX融合蛋白具有促凝血活性并且可以体内表达或在宿主细胞中体外表达。在一些实施方案中，所述FIX融合蛋白包含与FIX多肽的C端融合的Fc区。在某些实施方案中，所述FIX融合蛋白(例如FIX-Fc融合蛋白)不包含XTEN序列。除非另有说明，否则本文使用的“Fc”或“Fc区”可以是包含Fc结构域、其变体或片段的功能性新生儿Fc受体(FcRn)结合配偶体。FcRn结合配偶体是可以被FcRn受体特异性结合并随后被所述FcRn结合配偶体(包括但不限于白蛋白)的FcRn受体主动转运的任何分子。因此，术语Fc包括功能性的任何IgG Fc变体。已经基于X射线晶体学描述了与FcRn受体结合的IgG的Fc部分区域(Burmeister等,Nature 372:379(1994)，通过引用以其整体并入本文)。Fc与FcRn的主要接触范围接近CH2和CH3结构域的连接处。Fc-FcRn接触都在单个Ig重链内。FcRn结合配偶体包括但不限于整个IgG、IgG的Fc片段和包含FcRn的完整结合区的IgG的其他片段。Fc可包含免疫球蛋白的CH2和CH3结构域，其含有或不含有免疫球蛋白的铰链区。还包括有Fc片段、变体或衍生物，其维持融合蛋白中Fc区的所需特性，例如半衰期的增加，例如体内半衰期。无数突变体、片段、变体和衍生物描述于例如PCT公开号WO 2011/069164A2、WO2012/006623A2、WO 2012/006635A2或WO2012/006633A2中，所有这些都通过引用以其整体并入本文。

一个或多个Fc结构域可以插入所述FIX多肽内，与所述多肽的C端融合，或两者都有。在一些实施方案中，所述Fc结构域与所述FIX多肽融合。在某些实施方案中，所述FIX多肽包含具有与SEQ ID NO:229的氨基酸序列至少约70％、至少约75％、至少约80％、至少约85％、至少约90％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％或100％相同的氨基酸序列的FIXFc融合蛋白。在一些实施方案中，所述Fc结构域与另一个异源部分融合，如XTEN，其插入所述FIX内或与所述XTEN的C端融合。在一些实施方案中，所述FIX融合蛋白包含第二Fc结构域。第二Fc结构域可以，例如通过一个或多个共价键与第一Fc结构域缔合。

II.B.3.白蛋白

在一些实施方案中，所述至少一个异源部分是白蛋白、白蛋白结合结构域、或白蛋白结合小分子，或其变体、衍生物或片段。在某些方面，本公开文本的FIX融合蛋白包含至少一种插入FIX、与FIX的C端融合或两者都有的白蛋白多肽或其片段、变体或衍生物，其中所述FIX融合蛋白具有促凝血活性，并且可以体内表达或在宿主细胞中体外表达。人血清白蛋白(HSA，或HA)是一种其全长有609个氨基酸的蛋白质，负责显著比例的血清渗透压，并且还起到内源和外源配体的载体的作用。本文所用的术语“白蛋白”包括全长白蛋白或其功能性片段、变体、衍生物或类似物。美国专利公开号2008/0194481 A1、2008/0004206 A1、2008/0161243 A1、2008/0261877 A1或2008/0153751 A1或PCT申请公开号2008/033413 A2、2009/058322 A1或2007/021494 A2公开了白蛋白或其片段或变体的例子，其内容通过引用以其整体并入本文。

白蛋白结合多肽(ABP)可包含但不限于细菌白蛋白结合结构域、白蛋白结合肽或可与白蛋白结合的白蛋白结合抗体片段。如Kraulis等,FEBS Lett.378:190-194(1996)和Linhult等,Protein Sci.11:206-213(2002)公开的来自链球菌蛋白G的结构域3是细菌白蛋白结合结构域的例子。白蛋白结合肽的例子包括具有核心序列DICLPRWGCLW(SEQ ID NO:163)的一系列肽。参见，例如Dennis等,J.Biol.Chem.2002,277:35035-35043(2002)。Muller和Kontermann,Curr.Opin.Mol.Ther.9:319-326(2007)；Roovers等,CancerImmunol.Immunother.56:303-317(2007)以及Holt等,Prot.Eng.Design Sci.,21:283-288(2008)公开了白蛋白结合抗体片段的例子，其内容通过引用以其整体并入本文。

在某些方面，本公开文本的FIX融合蛋白包含至少一个非多肽小分子、变体或衍生物的附接位点，其可与插入FIX、与FIX的C端融合或两者都有的白蛋白(例如白蛋白结合小分子)结合，其中所述FIX融合蛋白具有促凝血活性并且可体内表达或在宿主细胞中体外表达。例如，本公开文本的FIX融合蛋白可包括一个或多个附接在FIX内的一个或多个插入位点中、或与FIX的C端融合、或两者都有的有机白蛋白结合部分，其中所述FIX融合蛋白具有促凝血活性并可在宿主细胞中体内表达或体外表达。这种白蛋白结合部分的一个例子是如Trussel等,Bioconjugate Chem.20:2286-2292(2009)所公开的2-(3-马来酰亚胺基丙酰胺基)-6-(4-(4-碘苯基)丁酰胺基)己酸酯(“Albu”标签)。

在一些实施方案中，所述白蛋白结合多肽序列通过Gly-Ser肽接头序列侧接C端、N端或两个末端。在一些实施方案中，所述Gly-Ser肽接头是Gly₄Ser(SEQ ID NO:161)。在其他实施方案中，所述Gly-Ser肽接头是(Gly₄Ser)₂(SEQ ID NO：162)。

II.B.4.CTP

在一些实施方案中，所述至少一个异源部分是人绒毛膜促性腺激素β亚单位的C端肽(CTP)或其片段、变体或衍生物。在某些方面，本公开文本的FIX融合蛋白包含插入FIX中、与FIX的C端融合或两者都有的至少一个CTP或其片段、变体或衍生物，其中所述FIX融合蛋白具有促凝血活性并且可以体内表达或在宿主细胞中体外表达。已知插入重组蛋白质中的一个或多个CTP肽会增加该蛋白质的半衰期。参见，例如美国专利号5,712,122，其内容通过引用以其整体并入本文。示例性CTP肽包括DPRFQDSSSSKAPPPSLPSPSRLPGPSDTPIL(SEQ IDNO:164)或SSSSKAPPPSLPSPSRLPGPSDTPILPQ(SEQ ID NO:165)。参见，例如美国专利申请公开No.US 2009/0087411A1，其通过引用并入。在一些实施方案中，所述CTP序列通过Gly-Ser肽接头序列侧接C端、N端或两个末端。在一些实施方案中，所述Gly-Ser肽接头是Gly₄Ser(SEQ ID NO:161)。在其他实施方案中，所述Gly-Ser肽接头是(Gly₄Ser)₂(SEQ ID NO：162)。

II.B.5.PAS

在一些实施方案中，所述至少一个异源部分是PAS肽。在某些方面，本公开文本的FIX融合蛋白包含插入FIX中、与FIX的C端融合或两者都有的至少一个PAS肽或其片段、变体或衍生物，其中所述FIX融合蛋白具有促凝血活性并且可以体内表达或在宿主细胞中体外表达。本文所用的“PAS肽”或“PAS序列”是指主要包含丙氨酸和丝氨酸残基或主要包含丙氨酸、丝氨酸和脯氨酸残基的氨基酸序列，所述氨基酸序列在生理条件下形成无规则卷曲构象。因此，所述PAS序列是构建单元，氨基酸聚合物或基本上由或由丙氨酸、丝氨酸和脯氨酸组成的序列盒，其可用作所述融合蛋白中异源部分的一部分。当在丙氨酸、丝氨酸和脯氨酸以外的残基作为PAS序列中的次要成分添加时，氨基酸聚合物也可以形成无规则卷曲构象。“次要成分”是指丙氨酸、丝氨酸和脯氨酸以外的氨基酸可以在PAS序列中添加到一定程度，例如，高达约12％，即PAS序列的100个氨基酸中的约12个氨基酸，高达约10％、高达约9％、高达约8％、约6％、约5％、约4％、约3％、约2％、或约1％的氨基酸。不同于丙氨酸、丝氨酸和脯氨酸的氨基酸可选自Arg、Asn、Asp、Cys、Gln、Glu、Gly、His、Ile、Leu、Lys、Met、Phe、Thr、Trp、Tyr、和Val。在生理条件下，PAS肽形成无规则卷曲构象，从而可以介导本公开文本的重组蛋白的增加的体内和/或体外稳定性，并且具有促凝血活性。

所述PAS肽的非限制性例子包括ASPAAPAPASPAAPAPSAPA(SEQ ID NO:154)、AAPASPAPAAPSAPAPAAPS(SEQ ID NO:155)、APSSPSPSAPSSPSPASPSS(SEQ ID NO:156)、APSSPSPSAPSSPSPASPS(SEQ ID NO:157)、SSPSAPSPSSPASPSPSSPA(SEQ ID NO:158)、AASPAAPSAPPAAASPAAPSAPPA(SEQ ID NO:159)、ASAAAPAAASAAASAPSAAA(SEQ ID NO:160)或其任何变体、衍生物、片段或组合。PAS序列的另外的例子可从例如，美国专利公开号2010/0292130A1和PCT申请公开号WO 2008/155134A1欧洲发布专利EP2173890中获知。

在一些实施方案中，所述PAS序列通过Gly-Ser肽接头序列在C端、N端或两个末端侧接。在一些实施方案中，所述Gly-Ser肽接头是Gly₄Ser(SEQ ID NO:161)。在其他实施方案中，所述Gly-Ser肽接头是(Gly₄Ser)₂(SEQ ID NO:162)。

II.B.6.HAP

在一些实施方案中，所述至少一个异源部分是同型氨基酸聚合物(HAP)肽或其片段、变体或衍生物。在某些方面，本公开文本的FIX融合蛋白包含插入FIX中、与FIX的C端融合或两者都有的至少一个同型氨基酸聚合物(HAP)肽或其片段、变体或衍生物，其中所述FIX融合蛋白具有促凝血活性并且可以体内表达或在宿主细胞中体外表达。HAP肽可包含重复的甘氨酸序列，其具有至少50个氨基酸、至少100个氨基酸、120个氨基酸、140个氨基酸、160个氨基酸、180个氨基酸、200个氨基酸、250个氨基酸、300个氨基酸、350个氨基酸、400个氨基酸、450个氨基酸或500个氨基酸的长度。HAP序列能够延长与HAP序列融合或连接的部分的半衰期。所述HAP序列的非限制性例子包括但不限于(Gly)_n、(Gly₄Ser)_n或S(Gly₄Ser)_n，其中n为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。在一个实施方案中，n为20、21、22、23、24、25、26、26、28、29、30、31、32、33、34、35、36、37、38、39或40。在另一个实施方案中，n为50、60、70、80、90、100、110、120、130、140、150、160、170、180、190或200。参见例如，Schlapschy M等,Protein Eng.Design Selection,20:273-284(2007)。

II.B.7.有机聚合物

在一些实施方案中，所述至少一个异源部分是有机聚合物，例如聚乙二醇、聚唾液酸或羟乙基淀粉。在某些方面，本公开文本的FIX融合蛋白包含插入FIX中、与FIX的C端融合或两者都有的至少一个非多肽异源部分或其片段、变体或衍生物的附接位点，其中所述FIX融合蛋白具有促凝血活性并且可以体内表达或在宿主细胞中体外表达。例如，本公开文本的FIX融合蛋白可包括一个或多个附接在FIX序列内的一个或多个插入位点中、与FIX的C端附接或两者都有的聚乙二醇(PEG)部分，其中所述FIX融合蛋白具有促凝血活性并且可以体内表达或在宿主细胞中体外表达。

聚乙二醇化FIX可指在FIX与至少一个聚乙二醇(PEG)分子之间形成的缀合物。各种分子量和平均分子量范围的PEG可以商购获得。PEG平均分子量范围的典型例子包括但不限于约200、约300、约400、约600、约1000、约1300-1600、约1450、约2000、约3000、约3000-3750、约3350、约3000-7000、约3500-4500、约5000-7000、约7000-9000、约8000、约10000、约8500-11500、约16000-24000、约35000、约40000、约60000及约80000道尔顿。这些平均分子量仅作为例子提供，并不意味着以任何方式进行限制。

本公开文本的FIX融合蛋白可被聚乙二醇化以包括单-或多-(例如2-4)PEG部分。聚乙二醇化可通过本领域已知的任何聚乙二醇化反应进行。制备聚乙二醇化蛋白质产物的方法通常会包括(i)使多肽与聚乙二醇(如PEG的反应性酯或醛衍生物)在本发明的肽与一个或多个PEG基团附接的条件下反应；(ii)获得一种或多种反应产物。通常，所述反应的最佳反应条件将基于已知参数和所需结果逐个确定。

本领域技术人员可使用许多PEG附接方法，例如Malik F等,Exp.Hematol.20:1028-35(1992)；Francis,Focus on Growth Factors 3(2):4-10(1992)；欧洲专利公开号EP0401384、EP0154316、和EP0401384；以及国际专利申请公开号WO92/16221和WO95/34326。作为非限制性例子，FIX变体在如本文所述的一个或多个插入位点处或附近可含有半胱氨酸取代，并且所述半胱氨酸可进一步与PEG聚合物缀合。参见Mei等,Blood 116:270-279(2010)和美国专利号7,632,921，其内容通过引用以其整体并入本文。

在其他实施方案中，所述有机聚合物是聚唾液酸(PSA)。PSA是天然存在的由某些细菌菌株和哺乳动物某些细胞产生的唾液酸的无支链聚合物。参见，例如Roth J.等(1993),Polysialic Acid:From Microbes to Man,编辑Roth J.Rutishauser U.,TroyF.A.(

Basel,Switzerland),第335-348页。PSA可通过有限的酸水解或通过用神经氨酸酶进行消化，或通过分馏天然的细菌衍生形式的聚合物，从n＝约80或更多的唾液酸残基直至n＝2，以不同的聚合度生产。本领域技术人员可使用许多PSA附接方法，例如，上述相同的PEG附接方法。在某些方面，活化的PSA也可与FIX上的半胱氨酸的氨基酸残基附接。参见，例如美国专利号5846951。

在其他实施方案中，所述有机聚合物是羟乙基淀粉(HES)聚合物。在某些方面，本公开文本的FIX融合蛋白包含至少一种HES聚合物，所述HES聚合物在FIX内的一个或多个位点缀合，与FIX的C端融合，或两者都有，其中所述FIX融合蛋白具有促凝活性并且可体内表达或在宿主细胞中体外表达。

III.多核苷酸、载体、宿主细胞和制备方法

本公开文本进一步提供了编码本文所述FIX融合蛋白的多核苷酸、包含所述多核苷酸的表达载体、包含所述多核苷酸或所述载体的宿主细胞，或制备所述FIX融合蛋白的方法。

所述编码FIX融合蛋白的多核苷酸可以是单个核苷酸序列、两个核苷酸序列、三个核苷酸序列或更多。在一个实施方案中，单核苷酸序列编码包含FIX多肽和异源部分(例如，XTEN)的FIX融合蛋白，例如包含FIX多肽和插入FIX多肽内的XTEN的FIX融合蛋白、与FIX多肽的C端融合的Fc结构域，以及通过任选的接头与FIX多肽融合的第二Fc结构域。在另一个实施方案中，所述多核苷酸包含两个核苷酸序列，编码FIX多肽和插入FIX多肽内的XTEN的第一核苷酸序列和编码异源部分(例如Fc)的第二核苷酸序列。在其他实施方案中，所述多核苷酸包含两个核苷酸序列，编码FIX多肽、插入FIX多肽内的XTEN和与FIX多肽融合的Fc结构域的第一核苷酸序列，以及编码第二Fc结构域的第二核苷酸序列。编码的Fc结构域可在表达后形成共价键。

在一些实施方案中，所述编码FIX融合蛋白的多核苷酸经过密码子优化。

如本文所用，表达载体是指任何核酸构建体，其含有用于插入的编码序列的转录和翻译的必需元件，或者在RNA病毒载体的情况下，当引入时合适的宿主细胞时用于复制和翻译的必需元件。表达载体可包括质粒、噬菌粒、病毒及其衍生物。

如本文所用的基因表达控制序列是任何调节核苷酸序列，如启动子序列或启动子-增强子组合，其可促进与其可操作地连接的编码核酸的有效转录和翻译。基因表达控制序列可以是，例如哺乳动物或病毒启动子，如组成型启动子或诱导型启动子。组成型哺乳动物启动子包括但不限于以下基因的启动子：次黄嘌呤磷酸核糖转移酶(HPRT)、腺苷脱氨酶、丙酮酸激酶、β-肌动蛋白启动子和其他组成型启动子。在真核细胞中组成型起作用的示例性病毒启动子包括，例如来自巨细胞病毒(CMV)、猿猴病毒(例如SV40)、乳头瘤病毒、腺病毒、人免疫缺陷病毒(HIV)、劳斯氏肉瘤病毒、巨细胞病毒、莫洛尼氏白血病毒的长末端重复序列(LTR)和其他逆转录病毒的启动子，以及单纯疱疹病毒的胸苷激酶启动子。其他组成型启动子是本领域普通技术人员已知的。可用作本公开文本的基因表达序列的启动子还包括诱导型启动子。诱导型启动子在诱导剂存在下表达。例如，在某些金属离子存在下诱导金属硫蛋白启动子以促进转录和翻译。其他诱导型启动子是本领域普通技术人员已知的。

出于本公开文本的目的，可以使用许多表达载体系统。这些表达载体典型地可作为附加体或作为宿主染色体DNA的组成部分在宿主生物中复制。表达载体可包括表达控制序列，包括但不限于启动子(例如天然缔合或异源启动子)、增强子、信号序列、剪接信号、增强子元件和转录终止序列。优选地，表达控制序列是能够转化或转染真核宿主细胞的载体中的真核启动子系统。表达载体还可以利用衍生自动物病毒的DNA元件，如牛乳头瘤病毒、多瘤病毒、腺病毒、痘苗病毒、杆状病毒、逆转录病毒(RSV、MMTV或MOMLV)、巨细胞病毒(CMV)或SV40病毒。其他涉及具有内部核糖体结合位点的多顺反子系统的使用。

一般来说，表达载体含有选择标记(例如氨苄青霉素抗性、潮霉素抗性、四环素抗性或新霉素抗性)以允许检测用所需DNA序列转化的那些细胞(参见例如，Itakura等,美国专利号4,704,362)。可以通过引入一种或多种标记来选择已将DNA整合至其染色体中的细胞，所述一种或多种标记允许选择经转染的宿主细胞。所述标记可以提供对营养缺陷型宿主的原营养、杀生物剂抗性(例如抗生素)或对重金属如铜的抗性。选择性标记基因可以直接与待表达的DNA序列连接，或通过共转化引入同一细胞中。

可用于表达优化的FIX序列的载体的例子是NEOSPLA(美国专利号6,159,730)。此载体含有巨细胞病毒启动子/增强子、小鼠β珠蛋白主要启动子、SV40复制起点、牛生长激素聚腺苷酸化序列、新霉素磷酸转移酶外显子1和外显子2、二氢叶酸还原酶基因和前导序列。已发现此载体在掺入可变区和恒定区基因、细胞中转染、随后在含有G418的培养基中选择和甲氨蝶呤扩增后，会导致非常高水平的抗体表达。在美国专利号5,736,137和5,658,570中也教导了载体系统，这些专利各通过引用以其整体并入本文。此系统提供高表达水平，例如>30pg/细胞/天。其他示例性载体系统在例如美国专利号6,413,777中公开。

在其他实施方案中，使用多顺反子构建体表达本公开文本的多肽。在这些表达系统中，可以从单个多顺反子构建体产生多个目的基因产物，如多聚体结合蛋白的多个多肽。这些系统有利地使用内部核糖体进入位点(IRES)以在真核宿主细胞中提供相对高水平的多肽。相容的IRES序列公开在美国专利号6,193,980中公开，所述专利也并入本文中。

更一般地，一旦制备了编码多肽的载体或DNA序列，就可以将表达载体引入合适的宿主细胞中。也就是说，所述宿主细胞可被转化。如上所述，可以通过本领域技术人员熟知的各种技术来实现将质粒引入宿主细胞中。转化的细胞在适于产生FIX多肽的条件下生长，并进行FIX多肽合成测定。示例性测定技术包括酶联免疫吸附测定(ELISA)、放射免疫测定(RIA)或荧光激活细胞分选仪分析(FACS)、免疫组织化学等。

在描述用于从重组宿主分离多肽的过程时，术语“细胞”和“细胞培养物”可互换使用以表示多肽来源，除非另有明确说明。换言之，从“细胞”中回收多肽可以意指从离心沉淀的全细胞，或从含有培养基和悬浮细胞二者的细胞培养物中回收。

用于蛋白质表达的宿主细胞系优选为哺乳动物来源；最优选地为人或小鼠来源。上文已经描述了示例性宿主细胞系。在产生具有FIX活性的多肽的方法的一个实施方案中，所述宿主细胞是HEK293细胞。在产生具有FIX活性的多肽的方法的另一个实施方案中，所述宿主细胞是CHO细胞。

编码本公开文本的多肽的基因也可以在非哺乳动物细胞中表达，如细菌或酵母或植物细胞。在这一方面，应当理解，也可以转化多种单细胞非哺乳动物微生物如细菌；即那些能够在培养或发酵中生长的那些微生物。易于转化的细菌包括肠杆菌科成员，如大肠杆菌(Escherichia coli)或沙门氏菌属的菌株；芽孢杆菌科，如枯草芽孢杆菌(Bacillussubtilis)；肺炎球菌；链球菌属和流感嗜血杆菌(Haemophilus influenzae)。还应理解，当在细菌中表达时，多肽典型情况下会成为内含体的一部分。必须分离、纯化多肽，然后降气组装成功能性分子。

可替代地，可将本公开文本的多核苷酸序列掺入转基因中以引入转基因动物的基因组中并随后在转基因动物的乳汁中表达(参见，例如Deboer等,US5,741,957，Rosen,US5,304,489，和Meade等,US 5,849,992)。合适的转基因包括与来自乳腺特异性基因的启动子和增强子可操作连接的多肽的编码序列(如酪蛋白或β乳球蛋白)。

体外生产允许按比例放大以给出大量的所需多肽。在组织培养条件下用于哺乳动物细胞培养的技术是本领域已知的并且包括同质悬浮培养(例如在气升式反应器或连续搅拌反应器中)，或在琼脂糖上微珠或陶瓷盒上的固定化或包埋的细胞培养(例如在中空纤维、微胶囊中)。如果必要和/或需要，可以通过常规色谱方法纯化多肽溶液，例如凝胶过滤，离子交换色谱，DEAE-纤维素色谱或(免疫)亲和色谱，例如，在合成铰链区多肽的优选生物合成后或在本文所述的HIC色谱步骤之前或之后。亲和标签序列(例如，His(6)标签)可任选地附接或包含在多肽序列内以促进下游纯化。

一旦表达后，所述FIX蛋白可以根据本领域的标准程序纯化，包括硫酸铵沉淀、亲和柱色谱、HPLC纯化、凝胶电泳等(一般参见Scopes，Protein Purification(Springer-Verlag,N.Y.,(1982)))。对于药物用途，优选至少约90％至95％同质性(最优选98％至99％或更高的同质性)的基本上纯的蛋白质，。

在一个实施方案中，所述宿主细胞是真核细胞。如本文所用，真核细胞是指具有定形核(definitive nucleus)的任何动物或植物细胞。动物的真核细胞包括脊椎动物(例如哺乳动物)的细胞和无脊椎动物(例如昆虫)的细胞。植物的真核细胞特别地可包括但不限于酵母细胞。真核细胞不同于原核细胞(例如细菌)。

在某些实施方案中，所述真核细胞是哺乳动物细胞。哺乳动物细胞是衍生自哺乳动物的任何细胞。哺乳动物细胞特别包括但不限于哺乳动物细胞系。在一个实施方案中，所述哺乳动物细胞是人细胞。在另一个实施方案中，所述哺乳动物细胞是HEK 293细胞，它是人胚肾细胞系。HEK 293细胞可从American Type Culture Collection,Manassas,VA以CRL-1533获得，以及从Invitrogen(Carlsbad，Calif)以293-H细胞(目录号11631-017)或者293-F细胞(目录号11625-019)获得。在一些实施方案中，所述哺乳动物细胞是

细胞，它是衍生自视网膜的人细胞系。

细胞可从Crucell(Leiden，TheNetherlands)获得。在其他实施方案中，所述哺乳动物细胞是中国仓鼠卵巢(CHO)细胞。CHO细胞可从American Type Culture Collection,Manassas,VA获得。(例如CHO-K1；CCL-61)。在仍其他实施方案中，所述哺乳动物细胞是幼仓鼠肾(BHK)细胞。BHK细胞可从AmericanType Culture Collection,Manassas,Va.获得(例如CRL-1632)。在一些实施方案中，所述哺乳动物细胞是HKB11细胞，其是HEK293细胞和人B细胞系的杂交细胞系。Mei等,Mol.Biotechnol.34(2):165-78(2006)。

在仍其他实施方案中，转染的细胞被稳定转染。可以使用本领域技术人员已知的常规技术选择和维持这些细胞作为稳定的细胞系。

含有蛋白质的DNA构建体的宿主细胞在合适的生长培养基中生长。如本文所用，术语“合适的生长培养基”是指含有细胞生长所需的营养物的培养基。细胞生长所需的营养物可包括碳源、氮源、必需氨基酸、维生素、矿物质和生长因子。任选地，所述培养基可含有一个或多个选择因子。任选地，所述培养基可含有小牛血清或胎牛血清(FCS)。在一个实施方案中，所述培养基基本上不含IgG。所述生长培养基通常通过例如药物选择或必需营养素缺乏来选择含有DNA构建体的细胞，所述必需营养素由DNA构建体上的选择性标记补充或与DNA构建体共转染。培养的哺乳动物细胞通常在市售的含血清或无血清培养基(例如MEM、DMEM、DMEM/F12)中生长。在一个实施方案中，所述培养基是CD293(Invitrogen，Carlsbad，CA)。在另一个实施方案中，所述培养基是CD17(Invitrogen，Carlsbad，CA)。适合用于所用具体细胞系的培养基的选择在本领域普通技术人员的水平内。

在一些实施方案中，所述核酸、载体或宿主细胞还包含编码蛋白质转化酶的另外的核苷酸。蛋白质转化酶可选自前蛋白转化酶枯草杆菌蛋白酶/kexin 5型(PCSK5或PC5)、前蛋白转化酶枯草杆菌蛋白酶/kexin 7型(PCSK7或PC5)、酵母Kex 2、前蛋白转化酶枯草杆菌蛋白酶/kexin 3型(PACE或PCSK3)，及其两种或更多种组合。在一些实施方案中，所述蛋白质转化酶是PACE，PC5或PC7。在一个特定实施方案中，所述蛋白质转化酶是PC5或PC7。见国际申请公开号WO 2012/006623，其通过引用并入本文。在另一个实施方案中，所述蛋白质转化酶是PACE/弗林蛋白酶。

在某些方面，本公开文本涉及通过本文描述的方法产生的FIX融合蛋白。

在某些方面，本公开文本的宿主细胞可体内或体外表达所述FIX融合蛋白。体外生产允许按比例放大以产生大量所需的改变的本公开文本的多肽。通过在表达FIX融合蛋白的条件下培养本文所述的宿主细胞，可产生FIX融合蛋白。在组织培养条件下用于哺乳动物细胞培养的技术是本领域已知的并且包括同质悬浮培养(例如在气升式反应器或连续搅拌反应器中)，或在琼脂糖上微珠或陶瓷盒上的固定化或包埋的细胞培养(例如在中空纤维、微胶囊中)。如果必要和/或需要的话，可通过常规色谱方法例如凝胶过滤、离子交换色谱法、疏水相互作用色谱(HIC，DEAE纤维素色谱或亲和色谱)来纯化多肽的溶液。在其他方面，所述宿主细胞在体内表达所述FIX融合蛋白。

在一个实施方案中，本公开文本包括制备FIX融合蛋白的方法，所述方法包括如本文所述的将异源部分插入插入位点、将异源部分与FIX的C端融合或两者都有，其中所述FIX融合蛋白展现出促凝血活性。

在另一个实施方案中，本公开文本包括增加FIX蛋白的半衰期而不消除或降低FIX蛋白的促凝血活性的方法，其包括如本文所述将异源部分插入插入位点、将异源部分与FIX的C端融合或两者都有，其中所述FIX融合蛋白与不含有异源部分的FIX蛋白相比，展现出促凝血活性和增加的半衰期。

在其他实施方案中，本公开文本提供了构建FIX融合蛋白的方法，所述方法包括设计编码FIX融合蛋白的核苷酸序列，所述FIX融合蛋白包含如本文所述的插入位点中、与FIX的C端融合或两者都有的至少一个异源部分。

在某些实施方案中，本公开文本包括增加FIX融合蛋白表达的方法，所述方法包括如本文所述的将异源部分插入插入位点、与FIX的C端融合或两者都有，其中所述FIX融合蛋白展现出促凝血活性。

在仍其他实施方案中，本公开文本提供了保留FIX融合蛋白的促凝血活性的方法，所述方法包括如本文所述的将异源部分插入插入位点、将异源部分与FIX的C端融合或两者都有，其中所述FIX融合蛋白展现出促凝血活性。

IV.药物组合物和治疗方法

本公开文本还提供了使用包含本公开文本的FIX融合蛋白的药物组合物预防、治疗、改善或管理有此需要的人类受试者的凝血疾病或病症或出血病症的方法。示例性方法包括向有需要的受试者给予治疗有效量的包含本公开文本的FIX融合蛋白的药物组合物/配制品。在其他方面，可将包含编码本公开文本的融合蛋白的DNA的组合物给予有此需要的受试者。在本公开文本的某些方面，可将表达本公开文本的FIX融合蛋白的细胞给予有此需要的受试者。在本公开的某些方面，所述药物组合物包含(i)FIX融合蛋白，(ii)编码FIX融合蛋白的分离的核酸，(iii)包含编码FIX融合蛋白的核酸的载体，(iv)包含编码FIX融合蛋白的分离的核酸的细胞和/或包含编码FIX融合蛋白的核酸的载体，或(v)其组合，并且所述药物组合物还包含可接受的赋形剂或载体。

在一个方面，本公开文本涉及给予因子IX(FIX)融合蛋白的方法，其包括向受试者给予FIX融合蛋白，其中(a)所述FIX融合蛋白包含FIX多肽和至少一个XTEN，所述至少一个XTEN在插入位点处插入所述FIX多肽内，所述插入位点对应于选自以下的氨基酸：SEQ IDNO:2的氨基酸103、SEQ ID NO:2的氨基酸105、SEQ ID NO:2的氨基酸142、SEQ ID NO:2的氨基酸149、SEQ ID NO:2的氨基酸162、SEQ ID NO:2的氨基酸166、SEQ ID NO:2的氨基酸174、SEQ ID NO:2的氨基酸224、SEQ ID NO:2的氨基酸226、SEQ ID NO:2的氨基酸228、SEQ IDNO:2的氨基酸413及其任何组合；(b)其中所述FIX融合蛋白被皮下给予；(c)其中在给予后，FIX融合蛋白展现出约1％至约30％(例如约5％至约30％)的血浆活性。

在一些实施方案中，在给予本文公开的FIX融合蛋白后，在治疗期间(例如，从第一次给予到第二次给予)FIX融合蛋白的血浆活性为约1％至约30％，例如5％至30％，例如1％至20％，例如5％至20％，例如1％至10％，例如5％至10％，例如约10％至约30％，约10％至约20％。例如，给予本文公开的FIX融合蛋白后，在治疗期间(从第一次给药到第二次、第三次、第四次、第五次、第六次、第七次、第八次、第九次或第十次(或更多)给药)血浆活性可高于1％、2％、3％、4％、5％、6％、7％、8％、9％或10％，并且低于30％、29％、28％、27％、26％、25％、24％、23％、22％、21％、20％、19％、18％、17％、16％、15％、14％、13％、12％或11％。

在一些实施方案中，所述FIX融合蛋白是以有效剂量给予。在某些实施方案中，所述FIX融合蛋白是以约1IU/kg至约500IU/kg的剂量给予。在一些实施方案中，FIX融合蛋白是以约50IU/kg至约300IU/kg、约50IU/kg至约250IU/kg、约50IU/kg至约200IU/kg、约50IU/kg至约150IU/kg、约50IU/kg至约100IU/kg、约100IU/kg至约300IU/kg、约150IU/kg至约300IU/kg、约200IU/kg至约300IU/kg、约250IU/kg至约300IU/kg、约100IU/kg至约250IU/kg、约100IU/kg至约200IU/kg、约100IU/kg kg至约150IU/kg、约150IU/kg至约250IU/kg或约150IU/kg至约200IU/kg的剂量给予。在一个实施方案中，所述FIX融合蛋白是以约50IU/kg至约300IU/kg的剂量给予。

在一些实施方案中，所述FIX融合蛋白是以约25IU/kg、约50IU/kg、约75IU/kg、约100IU/kg、约125IU/kg、约150IU/kg、约175IU/kg、约200IU/kg、约225IU/kg、约250IU/kg、约275IU/kg、约300IU/kg、约325IU/kg、约350IU/kg、约375IU/kg或约400IU/kg的剂量给予。在一个实施方案中，所述FIX融合蛋白是以约100IU/kg的剂量给予。在另一个实施方案中，所述FIX融合蛋白是以约200IU/kg的剂量给予。

在一些实施方案中，所述FIX融合蛋白展现出约1％至约50％的血浆活性峰值。在一些实施方案中，所述FIX融合蛋白展现出约5％至约50％、约10％至约50％、约15％至约50％、约20％至约50％、约25％至约50％、约30％至约50％、约35％至约50％、约40％至约50％、约10％至约45％、约15％至约40％、约20％至约40％、约20％至约35％、约25％至约40％或约25％至约35％的血浆活性峰值。在某些实施方案中，所述FIX融合蛋白展现出约10％至约30％的血浆活性峰值。

在一些实施方案中，所述FIX融合蛋白展现出约10％、约11％、约12％、约13％、约14％、约15％、约16％、约17％、约18％、约19％、约20％、约21％、约22％、约23％、约24％、约25％、约26％、约27％、约28％、约29％或约30％的血浆活性峰值。在一个具体实施方案中，所述FIX融合蛋白展现出约30％的血浆活性峰值。在另一个实施方案中，所述FIX融合蛋白展现出约15％的血浆活性峰值。

在一些实施方案中，所述FIX融合蛋白展现出约1％至约20％的血浆活性谷值。在某些实施方案中，所述FIX融合蛋白展现出约5％至约20％、约10％至约20％、约15％至约20％、约1％至约15％、约1％的至约10％、约1％至约5％、或约5％至约15％血浆活性谷值。在一个实施方案中，所述FIX融合蛋白展现出约5％至约10％的血浆活性谷值。

在一些实施方案中，所述FIX融合蛋白展现出约1％、约2％、约3％、约4％、约5％、约6％、约7％、约8％、约9％、约10％、约11％、约12％、约13％、约14％或约15％的血浆活性谷值。在一个具体实施方案中，所述FIX融合蛋白展现出约5％的血浆活性谷值。

本公开文本的FIX融合蛋白可以静脉内、皮下或口服给予患者。在某些实施方案中，所述FIX融合蛋白通过静脉内注射给予受试者。在其他实施方案中，所述FIX融合蛋白通过皮下注射给予受试者。所述注射可包括单次推注。受试者可接受多于一次注射。

本公开文本的融合蛋白可预防性使用。如本文所用，术语“预防性治疗”是指在出血事件之前给予分子。在一个实施方案中，需要一般止血剂的受试者正在进行手术或即将进行手术。本公开文本的融合蛋白可在手术之前或之后作为预防剂给予。本公开文本的融合蛋白可在手术期间或之后给予以控制急性出血事件。所述手术可包括但不限于肝移植、肝切除、牙科手术或干细胞移植。

本公开文本的融合蛋白也用于按需治疗。术语“按需治疗”是指响应出血事件的症状或在可能引起出血的活动之前给予融合蛋白。在一个方面，当开始出血时，如在受伤之后，或者在预期会出血时，如在手术之前，给予受试者按需治疗。在另一方面，在增加出血风险的活动之前给予按需治疗，如接触性运动。

在其他实施方案中，所述融合蛋白用于控制、改善或治疗急性出血事件。在其他实施方案中，与不含异源部分的相应FIX蛋白相比，所述FIX融合蛋白展现出一个或多个药代动力学参数。PK参数可以基于FIX抗原水平(在本文中通常附带表示为“抗原”)或FIX活性水平(在本文中通常附带表示为“活性”)。在文献中，PK参数通常基于FIX活性水平，这是由于在具有内源性、无活性FIX的一些受试者血浆中的存在，其干扰了使用针对FIX的抗体测量给予的(即外源的)FIX的能力。然而，当FIX作为本文提供的Fc融合蛋白的一部分给予时，给予的(即外源的)FIX抗原可以使用针对异源多肽的抗体精确测量。另外，某些PK参数可以基于模型预测的数据(在本文中通常附带表示为“模型预测”)或基于观察的数据(在本文中通常附带表示为“观察的”)，并且优选地基于观察到的数据。

所述FIX融合蛋白可以通过本领域已知的任何方法给予受试者。例如，所述FIX融合蛋白可以通过局部(例如透皮或眼部)给予、口服给予、经颊给予、鼻腔给予、阴道给予、直肠或肠胃外(例如皮下、皮内、血管内/静脉内、肌肉内，脊柱、颅内、鞘内、眼内、眼周、眶内、滑膜内和腹膜内注射)给予。在一个具体实施方案中，所述FIX融合蛋白通过皮下注射给予。所述皮下注射可包括一次或多次推注，包括，例如FIX融合蛋白的剂量的单次推注。可替代地，所述FIX融合蛋白可以通过静脉内注射给予。

所述FIX融合蛋白的剂量可以根据具体融合蛋白的性质和受试者状况的性质而变化。在一些实施方案中，所述FIX融合蛋白的剂量可包含1至1000IU/kg的FIX融合蛋白。

所述出血病症可由血液凝固障碍引起。血液凝固障碍也可称为凝血障碍。在一个实施例中，可以用本公开文本的药物组合物治疗的血液凝固障碍是血友病。在另一个实施例中，可以用本公开文本的药物组合物治疗的血液凝固障碍是血友病B。

在一些实施方案中，与出血病症有关的出血类型选自：关节积血、肌肉出血、口出血、内出血、内出血进入肌肉、口腔出血、创伤、头部床上、胃肠道出血、颅内出血、腹腔内出血、胸腔内出血、骨折、中枢神经系统出血、咽后间隙出血、腹膜后间隙出血和髂腰肌鞘出血。

在其他实施方案中，患有出血病症的受试者需要进行手术治疗，包括例如手术预防或围手术期管理。在一个实施例中，所述手术选自小手术和大手术。示例性外科手术包括拔牙、扁桃体切除术、腹股沟疝切除术、滑膜切除术、开颅术、骨缝合术、创伤手术、颅内手术、腹腔内手术、胸腔内手术、关节置换手术(例如全膝关节置换术、髋关节置换术等)、心脏手术和剖腹产。

在另一个实施例中，所述受试者同时用因子VIII治疗。因为本公开文本的化合物能够活化FIXa，所以它们可以在将FIXa给予受试者之前用于预活化FIXa多肽。

本公开文本的方法可以在需要预防性治疗或按需治疗的受试者上实施。

包含本公开文本的FIX融合蛋白的药物组合物可以配制用于任何适当的给予方式，包括例如局部(例如，透皮或眼部)给予、口服给予、经颊给予、鼻腔给予、阴道给予、直肠或肠胃外给予。

本文所用的术语肠胃外包括皮下、皮内、血管内(例如静脉内)、肌内内、脊柱、颅内、鞘内、眼内、眼周、眶内、滑膜内和腹膜内注射，以及任何类似的注射或输注技术。特别地，包含本公开文本的FIX融合蛋白的药物组合物可以配制用于皮下给予。所述组合物还可以是例如悬浮液、乳液、缓释配制品、乳膏、凝胶或粉末。所述组合物可以用传统的粘合剂和载体(如甘油三酯)配制成栓剂。

在一个实施例中，所述药物配制品是液体配制品，例如缓冲的等渗水溶液。在另一个实施例中，所述药物组合物具有生理pH或接近生理pH。在其他实施例中，所述含水配制品具有生理渗透压和盐度或接近生理渗透压和盐度。它可含有氯化钠和/或乙酸钠。在一些实施例中，本公开文本的组合物是冻干的。

本公开文本的融合蛋白可在哺乳动物(例如人类患者中)体内产生，使用基因疗法途径治疗选自以下的出血性疾病或障碍将对治疗有益：出血性凝血障碍、关节积血、肌肉出血、口出血、内出血、内出血进入肌肉、口腔出血、创伤、头部床上、胃肠道出血、颅内出血、腹腔内出血、胸腔内出血、骨折、中枢神经系统出血、咽后间隙出血、腹膜后间隙出血和髂腰肌鞘出血。在一个实施方案中，所述出血性疾病或障碍是血友病。在另一个实施方案中，所述出血性疾病或障碍是血友病B。这涉及与合适的表达控制序列可操作地连接的合适的融合蛋白编码核酸的给予。在某些实施方案中，这些序列被掺入病毒载体中。用于此类基因疗法的合适病毒载体包括腺病毒载体、慢病毒载体、杆状病毒载体、Epstein Barr病毒载体、乳多空病毒载体、痘苗病毒载体、单纯疱疹病毒载体和腺相关病毒(AAV)载体。所述病毒载体可以是复制缺陷型病毒载体。在其他实施方案中，腺病毒载体在其E1基因或E3基因中有缺失。当使用腺病毒载体时，哺乳动物可能不会暴露于编码选择性标记基因的核酸。在其他实施方案中，所述序列被掺入本领域技术人员已知的非病毒载体中。

除非另有说明，否则本公开文本的实践将采用细胞生物学、细胞培养、分子生物学、转基因生物学、微生物学、重组DNA和免疫学的修复技术，这些技术在本领域的技术范围内。此类技术在文献中得到充分解释。参见，例如Molecular Cloning A LaboratoryManual,第2版,Sambrook等编,Cold Spring Harbor Laboratory Press:(1989)；Molecular Cloning:A Laboratory Manual,Sambrook等编,Cold Springs HarborLaboratory,New York(1992),DNA Cloning,D.N.Glover编,第I卷和第II卷(1985)；Oligonucleotide Synthesis,M.J.Gait编,(1984)；Mullis等美国专利号4,683,195；Nucleic Acid Hybridization,B.D.Hames&S.J.Higgins编(1984)；Transcription AndTranslation,B.D.Hames&S.J.Higgins编(1984)；Culture Of Animal Cells,R.I.Freshney,Alan R.Liss,Inc.,(1987)；Immobilized Cells And Enzymes,IRL Press,(1986)；B.Perbal,A Practical Guide To Molecular Cloning(1984)；专著Methods InEnzymology,Academic Press,Inc.,N.Y.；Gene Transfer Vectors For MammalianCells,J.H.Miller和M.P.Calos编,Cold Spring Harbor Laboratory(1987)；Methods InEnzymology,第154卷和第155卷(Wu等编)；Immunochemical Methods In Cell AndMolecular Biology,Mayer和Walker编,Academic Press,London(1987)；Handbook OfExperimental Immunology,第I-IV卷,D.M.Weir和C.C.Blackwell编,(1986)；Manipulating the Mouse Embryo,Cold Spring Harbor Laboratory Press,Cold SpringHarbor,N.Y.,(1986)；以及Ausubel等,Current Protocols in Molecular Biology,JohnWiley and Sons,Baltimore,Maryland(1989)。

陈述阐明免疫学一般原则的标准参考文献包括Current Protocols inImmunology,John Wiley&Sons,New York；Klein,J.,Immunology:The Science of Self-Nonself Discrimination,John Wiley&Sons,New York(1982)；Roitt,I.,Brostoff,J.和Male D.,Immunology,第6版,London:Mosby(2001)；Abbas A.,Abul,A.和Lichtman,A.,Cellular and Molecular Immunology,第5版,Elsevier Health Sciences Division(2005)；以及Harlow和Lane,Antibodies:A Laboratory Manual,Cold Spring HarborPress(1988)。

虽然现已详细描述本公开文本，但参照以下实施例将更清楚地理解所述实施方案，本文所述实施例仅出于说明目的而被包括，并且不打算受本公开文本的限制。

实施例

实施例1：活性FIX-XTEN变体的鉴定

构建了包含FIX多肽的FIX融合蛋白，其具有一个或多个XTEN插入以改进FIX蛋白的特性。然而，XTEN修饰的位置、长度、组成和数量可以容易地改变，并且可以评价这些修饰对FIX活性和清除的影响。

本实施例旨在鉴定FIX中可以容纳引入XTEN而不消除FIX活性的位点，并将该途径应用于其他未修饰的FIX和重组FIX-Fc融合蛋白。

方法

在紧邻编码起始Met残基的ATG密码子的5'引入Kozak翻译起始序列(GCCGCCACC)后，将FIX多肽编码序列连接到BsiWI与PmeI位点之间的表达载体pcDNA4/myc-His C(INVITROGEN^TM，Carlsbad，CA)中。

使用聚乙烯亚胺(PEI，Polysciences Inc.，Warrington，PA)用质粒转染HEK293F细胞(INVITROGEN^TM，Carlsbad，CA)。使瞬时转染的细胞在FREESTYLE^TM 293培养基或FREESTYLE^TM 293和CD OPTICHO^TM培养基(INVITROGEN^TM，Carlsbad，CA)的混合物中生长。转染后5天收获细胞培养基，并通过显色测定或aPTT FIX活性测定分析其FIX活性。

使用来自Aniara的BIOPHEN因子IX试剂盒测量显色FIX活性，并且在37℃板加热器上振荡进行所有温育。使用Tris-BSA稀释缓冲液(R4)将来自6孔板的FIX-XTEN变体的瞬时转染培养基的细胞培养物收获物稀释至所需的FIX活性范围。并在Tris-BSA稀释缓冲液中制备FIX标准品。将标准品、稀释的细胞培养物样品和合并的正常人血浆测定对照(50μL/孔)一式两份添加到2HB 96孔板中。将人因子X、FVIII:C和纤维蛋白聚合抑制剂(50μL)，因子XIa、凝血酶、磷脂和钙的50μL混合物，以及50μL因子Xa特异性显色底物(SXa-11)依次添加到各孔中，每次添加前后温育2分钟。在与底物一起温育后，添加50μL的20％乙酸以终止显色反应，并用

plus(MOLECULAR

)仪器测量405nm处的吸光度。使用

Pro软件(5.2版)进行数据分析。

使用一步活化部分凝血活酶时间(aPTT)凝血测定来评估FIX活性。使用

CA-1500仪器(Siemens Healthcare Diagnostics Inc.,Tarrytown,NY)测量FIX-XTEN aPTT活性。为了产生测定的标准曲线，用匹配的培养基浓度的模拟转染培养基稀释WHO因子IX标准品作为测试样品。使用模拟转染培养基将来自6孔板的FIX-XTEN变体的瞬时转染培养基的细胞培养物收获物稀释至所需的FIX活性范围。稀释后，使用Sysmex仪器按如下进行aPTT测定：将50μl稀释的标准品和样品与50μl Siemens人FIX耗尽的血浆混合，然后与50μl Siemens Actin FSL(鞣花酸)活化剂混合。将混合物温育1分钟。随后，将50μlSiemens CaCl₂添加到混合物中，并将混合物温育240秒。在此温育后立即测量凝固时间。为了确定测试样品FIX活性，使用对数标度绘制标准品的凝固时间，以推断凝固时间与FIX活性之间的等式，然后对照标准曲线计算FIX-XTEN活性。

插入位点的选择

分析来自Protein Data Bank、1PFX、1IXA、1CFI、1CFH、1EDM、3LC3、3LC5、1RFN、1X7A和3KCG的FIX结构，以选择FIX中用于插入XTEN的位点。由于GLA结构域在将FIX锚定到磷脂表面和内皮下IV型胶原上的重要作用，因此避免在GLA结构域内插入XTEN。通过分析蛋白质数据库中的可用FIX结构并结合以下标准选择XTEN插入位点：1)通过算法软件ASAView(http://www.abren.net/asaview/)和Get Area(http://curie.utmb.edu/getarea.html)计算的可达到的表面积，2)通过氢/氘交换质谱(H/DX-MS)评估的溶剂可及性，3)限定的二级结构元件内位点的排除，4)对具有显著种间蛋白质序列可变性的位置的偏好，以及5)已知血友病B突变近端的位点的排除。

选择EGF1结构域中的4个位点、EGF2结构域中的5个位点、AP结构域与EGF2结构域之间的接头区域中的2个位点、AP(活化肽)结构域中的4个位点和催化结构域中的18个位点用于XTEN的插入(表6)。

表6：用于将XTEN插入FIX中的潜在位点(在指定残基的C端插入)

42-氨基酸XTEN插入和C端融合的活性筛选

高活性FIX Padua变体(R338L)用作支架，以抵消由于引入XTEN引起的活性降低导致的潜在FIX活性丧失。将42残基XTEN元件(AE42)在通过使用上述标准选择的位点处插入或与FIX的C端融合。如上所述，在转染的HEK293细胞的条件培养基中评价这些变体的FIX活性。FIX-AE42的FIX活性显示为不含XTEN的碱基构建体FIX-R338L的百分比(图1)。

如通过FIX显色测定所确定的，XTEN插入在有限的位点是耐受的(图1和表7)。通过插入AE-42选择并评价FIX中的总共33个位点。其中，EGF2结构域中两个、EGF2结构域与AP结构域之间的接头区域中一个、AP结构域中四个、催化结构域中四个(包括C端)通过FIX活性分析被鉴定为允许插入的位点(图1和表7)。

表7：示例FIX插入位点

注意：ND＝未检测到活性；(+)＝检测到小于30％的活性；(++)＝检测到30％与70％之间的活性；及(+++)＝检测到大于70％的活性，通过显色测定依照碱基构建体的百分比(参见图5A-5C和6A-6B)。

更长的XTEN插入和C端融合的活性

然后在显示允许AE42插入的位点处类似地测试更长的XTEN(AE-72、-144和-288)。如前所述测定FIX活性，并显示为不含XTEN的碱基构建体FIX-R338L的百分比(图2)。

只有AP中的位点和FIX的C端或附近的位点才能耐受更长的XTEN(AE144、AE288或AE864)(图2)。在条件培养基中检测到的FIX活性与引入的XTEN的长度呈负相关(图2，表7)。选择FIX的不同结构域中的四个允许插入位点以生成组合文库。

多重XTEN插入

基于使用单个XTEN变体获得的结果，通过aPTT测定评价进行了不同长度和在四个不同位置的多重XTEN插入的FIX变体(参见图4和表8)在经转染的HEK293细胞的条件培养基中的FIX活性(表8-10)。FIX活性显示为不含XTEN的碱基构建体FIX-R338L的百分比(图4)。

表8：示例FIX双重插入

注意：ND＝未检测到活性；(+)＝检测到小于30％的活性；(++)＝检测到30％至70％的活性；及(+++)＝检测到大于70％的活性，通过显色测定依照碱基构建体的百分比(参见图8A-8C)。

表9：插入每个结构域的XTEN元件

<u>位置</u>	<u>元件</u>
		EGF2	AE42
AP	AE42,AE72,AE144
		催化60-环	AE42
C端	AE72,AE144,AE288,Fc

表10：作为单个、双重、三重和四重组合插入的构建体的总数

组合	构建体数量
		单个	9
双重	27
		三重	31
四重	12
			总计79

三个组(具有单个XTEN的FIX、具有双重XTEN插入的FIX和具有单个XTEN插入的FIX-Fc)显示出可检测的活性，而在三个或更多个位点处插入/融合的组合消除了FIX活性(图4)。

总之，FIX中存在若干个允许XTEN插入的位点，并且XTEN插入变体的选择组合保留了FIX活性。本文鉴定的活性FIX-XTEN变体是血友病B小鼠中药代动力学表征的候选者。

实施例2：FIX融合蛋白及其血浆回收率和AUC/D

因子IX缺陷(HemB,B6.129P2-F9tm1Dws/J,MGI:1932297)小鼠(Lin等，1997)最初从Darrel Stafford博士(北卡罗来纳大学(University of North Carolina)，ChapelHill)获得。对每只雄性/雌性HemB小鼠按单次静脉内推注静脉内注射50或200IU/kg的FIX融合蛋白(例如FIX-CT.288(与FIX多肽C端融合的AE288 XTEN)、FIX-CT.864(与FIX多肽的C端融合的AE864 XTEN)、FIX-AP.144(在FIX多肽的AP结构域内的D166后插入的AE144XTEN)、FIX-AP.72(在FIX多肽的AP结构域内的D166之后插入的AE72 XTEN)、FIX-AP.42(在FIX多肽的AP结构域内的D166之后插入的AE42 XTEN)、FIXFc和FIX)，给药量为10mL/kg，t＝0小时。在给药后5分钟至给药后168小时(7天)收集血液。对于每个指定的时间点，通过每个时间点3-4只小鼠的眶后或终末腔静脉出血收集约100μl柠檬酸化血液。每只小鼠最多产生3个时间点。通过以5000rpm离心8分钟分离血浆，并将血浆样品在干冰乙醇浴中快速冷冻且储存在-80℃直至用一步活化凝血活酶时间(aPTT)测定在Sysmex-CA1500凝血分析仪上分析，使用Dade Behring试剂和肌动蛋白FSL作为活化剂和给药材料作为活性标准。在图5A-5B中，血浆活性被绘制为注射剂量的％。使用Phoenix WinNonlin 6.2.1(Pharsight，Certera，NCA分析)采用非房室建模计算平均停留时间(MRT)和其他药代动力学(PK)参数。图5C描绘了相对血浆回收率(Y轴)对比MRT(X轴)。点的面积表示每剂量曲线下的面积(AUC/D，单位为h/kg/mL)，并且显示FIX血浆活性回收率和AUC/D随着XTEN长度的增加而增加(图5C)。这些图显示，XTEN长度增加(C端的288和864或AP结构域中的144、72和42)的FIX融合蛋白在静脉推注给药后在血浆回收率上展现出高达60％的尺寸依赖性增加和AUC/D增加。

实施例3：FIX融合蛋白及其半衰期

对FIX缺陷型小鼠静脉内给药50或200IU/kg的FIX融合蛋白：与具有288个氨基酸的XTEN融合的FIX(例如AE288)；FIX-Fc，其中具有72个氨基酸的XTEN(例如AE72)在D166后插入AP结构域；FIX-Fc，其中具有42个氨基酸的XTEN(例如AE42)在D166后插入AP结构域；和对照(例如FIXFc和FIX)。收集血浆并用与实施例5中描述的方法同一地进行FIX活性和PK分析。图6A将血浆活性绘制为注射剂量的％。使用WinNonlin 6.2.1(Pharsight，Certera)通过NCA分析计算药代动力学(PK)参数，并且图6B描绘相对血浆回收率(Y轴)对比MRT(X-轴)。点的面积表示每剂量的曲线下面积(AUC/D，单位为h/kg/mL)，并显示将XTEN序列插入FIXFc的活化肽(AP)结构域中使单独rFIXFc的平均停留时间与FIX相比延长更长(图6B)。此外，随着XTEN长度的增加，血浆活性回收率和AUC/D得到改进(图6A-6B)。与rFIXFc相比，rFIX-CT.288(SEQ ID NO:226)和rFIXFc-AP.72(SEQ ID NO:151)的AUC/D分别改进了3.4倍和4.5倍(图6A-6B)。与静脉内给药的rFIX相比，这分别相当于AUC/D的8.5和14.5倍改进(图6A-6B)。因此，与rFIX和rFIXFc相比，AP结构域中XTEN的插入与rFIXFc-R338L中Fc介导的半衰期延长的组合既延长了半衰期，又增加了血浆回收率和AUC/剂量。

实施例4：通过皮下递送改进的FIX融合蛋白的药代动力学

在t＝0时向FIX缺陷型小鼠皮下给药50或200IU/kg FIX融合蛋白：在C端与具有288个氨基酸的XTEN(例如AE288)融合的FIX(FIX-CT.288)；AP结构域中具有72个氨基酸的XTEN(例如AE72)的FIXFc(FIXFc-AP.72)；EGF2结构域中具有42个氨基酸的XTEN(例如AE42)的FIXFc(例如FIXFc-EGF.42)；和对照(FIXFc和FIX)。收集血浆并用与实施例1中描述的方法同一地进行FIX活性和PK分析。图7A将血浆活性绘制为注射剂量的％。使用WinNonlin6.2.1(Pharsight，Certera)通过NCA分析计算药代动力学(PK)参数，并且图7B描绘相对生物利用度(Y轴)对比MRT(X-轴)。点的面积代表每剂量曲线下的面积(AUC/D，单位为h/kg/mL)，并显示XTEN多肽序列在rFIX的羧基端的融合或活化肽(AP)结构域或FIXFc的EGF2结构域中XTEN序列的插入极大地改进了FIX融合蛋白的皮下给药图谱(图7B)。与HemB小鼠中的rFIXFc相比，皮下给药的rFIXFc-AP.72和rFIX-CT.288将AUC/D改进6至9倍，生物利用度改进1.5至2倍，C_max/D改进3至10倍。。当与rFIX相比，FIXFc-AP.72和rFIX-CT.288与rFIX相比的药代动力学参数的改进分别是AUC/D改进28至40倍，生物利用度增加3倍，C_max/D改进15至30倍(图7A-7B)。

总之，所述FIX融合蛋白(例如rFIX-CT.288和rFIXFc-AP.72)显示与rFIXFc的静脉内给药相比，皮下给药的AUC/D改进了2.6倍和1.9倍，后者支持人体中用于预防的每周一次或更少频次的静脉内给药。

实施例5：FIX融合蛋白的体外功效

将人血友病B血液掺入指定剂量的3 10和30IU/dL的rFIXFc(空心圆圈，虚线)或FIX融合蛋白(例如rFIXFc-AP.72)(实心点，实线)或媒介物(空心三角形)(图8A-8C)。使用旋转血栓弹力测定法(ROTEM)确定全血凝固特征，并通过血液再钙化(NATEM)引发凝血。与rFIXFc相比，在血友病B血液中rFIXFc-AP.72在凝血时间(CT，以秒计)、α角(以度计)和最大凝块硬度(MCF以mm计)方面显示出相似的活性(图8A-8C)。每个时间点的数据是4至5个重复样品的平均值+/-标准偏差(图8A-8C)。

与rFIX和rFIXFc相比，rFIXFc-AP.72和rFIX-CT.288在HemB小鼠中显示出显著改进的皮下药代动力学。正在进行进一步的研究以解决临床前动物模型中的功效和异速类推。

实施例6：rFIXFc-AP.72在急性鼠类尾夹出血模型中的体内功效

在盲法鼠类尾夹出血模型中研究急性功效，其中在切断尾尖后测量给药小鼠的总失血量，如前所述(Dumont等,Blood,119(13):3024-3030,2012)。简而言之，用50mg/kg氯胺酮和0.5mg/kg右美托咪定的混合物麻醉8-15周龄雄性血友病B小鼠(Lin等,Blood(1997)90:3962-3966)。将尾部浸入37℃盐水中10分钟，以使侧静脉扩张，随后在尾静脉静脉内以50、100和200IU/kg剂量注射媒介物(3.88g/L L-组氨酸，23.8g/L甘露醇，11.9g/L蔗糖，3.25g/L氯化钠，0.01％(w/v)聚山梨醇酯20(pH 7.1)，3％人血清白蛋白)、rFIXFc-AP.72或rFIXFc。给药后5分钟，将尾部的5mm远侧尖端夹住并浸没在含有13mL盐水的预称重试管中30分钟。按重量量化失血量。在GraphPad Prism 6中使用非配对双尾t检验计算统计学显著性。这些双尾t检验显示，50、100和200IU/kg剂量的rFIXFc-AP.72与媒介物显著不同(p值<0.0001)。此外，数据显示，与相同的低剂量(即50IU/kg)的rFIXFc相比，低剂量(例如50IU/kg)的rFIXFc-AP.72导致显著更低的失血量。这些结果表明，在此出血模型中，与rFIXFc相比，rFIXFc-AP.72具有相等或改进的急性功效。

实施例7：FIXFc-AP.72在预防性鼠类尾静脉横切出血模型中的体内功效在盲法鼠类尾静脉横切(TVT)出血模型中研究延长的功效，其中如前所述(Toby等,PLOS One,DOI:10.1371/journal.pone.0148255,2016；Pan等,Blood 114:2802-2822(2009))，在横切一个侧尾静脉后测量给药的血友病B小鼠的存活时间。简而言之，向8-15周龄的雄性血友病B小鼠(Lin等,Blood 90:3962-3966(1997))预先静脉内给予15、50、100IU/kg FIX活性的rFIXFc或匹配的皮下注射剂量的FIXFc-AP.72并与接受推注剂量媒介物的小鼠相比较。在给药后72小时，将所有小鼠麻醉并在尾部直径为2.7mm处横切一个侧尾静脉。在紧临TVT之后的9至11小时期间，并且然后在24小时的过夜时间点，每小时监测并记录定性终点，包括再出血和至死亡时间(定义为至安乐死的时间，按当动物濒死时确定)。所有小鼠在24小时研究结束时接受安乐死，而未死亡或垂死的动物被确定为在24小时处于存活状态。

使用GraphPad Prism 6将数据绘制为TVT后的存活百分比。小鼠皮下给药媒介物(虚线)、皮下给药FIXFc-AP.72(实线，闭合符号)或静脉内给药FIXFc(虚线，空心符号)(15IU/kg、50IU/kg、100IU/kg n＝20/剂量，媒介物剂量除外；n＝30)(图10)。用匹配IU/kg剂量的皮下给药的FIXFc-AP.72对比静脉内给药的rFIXFc进行治疗的小鼠的存活曲线显示，与在所有测试剂量下的等效静脉内给药的rFIXFc相比，用FIXFc-AP.72皮下给药的HemB小鼠的存活率得到改进(图10)。

实施例8：在HemB小鼠中与rFIX相比，FIXFc-AP.72(FIX-216，双链Fc)的静脉内和皮下药代动力学参数得到改进

对血友病B小鼠给予200IU/kg的FIXFc-AP.72(FIX-216，双链Fc)或rFIX。在指定时间通过眼眶后出血收集血液。使用给药材料作为活性标准，通过一步凝血测定活性来确定FIX的血浆水平。在图11A中血浆活性被绘制为注射剂量的百分比％。图11B显示了使用Phoenix WinNonLin 6.2.1(Pharsight，Certara)通过NCA(非房室)分析计算的药代动力学参数表。FIX-216对比rFIX显示出的改进的药代动力学参数包括平均停留时间(MRT)、AUC/剂量和其他参数。

在小鼠中给药后约20小时，FIXFc-AP.72的皮下给药显示出t_max，并且显示出与类似(IU/kg)静脉内给药的rFIX或rFIXFc相比改进的血浆活性水平。使用HemB小鼠中的TVT出血模型，我们显示在给药后72小时，与在所有测试剂量下静脉内给药的rFIXFc相比，皮下给药的FIXFc-AP.72具有改进的体内功效。类似地，与rFIXFc相比，HemB小鼠尾夹出血模型中的急性功效测试显示出静脉内给药FIXFc-AP.72的改进的功效。这些数据支持FIXFc-AP.72在人体中每周一次或更频次的皮下预防性给药的潜力。

实施例9：SQ rFIXFc-XTEN的PK剂量线性

在HemB小鼠中评价皮下给药的rFIXFc-AP.72(pJH84；SEQ ID NO:151)的PK剂量线性。三组的四只小鼠各给药50、100、200或400IU/kg的rFIXFc-AP.72。通过眶后出血在三个连续时间点于10％w/v柠檬酸盐中从每只小鼠收集血液(即给药后1、6、24、48、72、96、144、168和192小时)。通过一步活性测定测量FIX活性以达到自我标准。对照FIX WHO标准确认给药溶液。使用Phoenix程序(Pharsight Corp，Mountainview，CA)进行药代动力学分析。血浆FIX活性和计算回收率分别如图14A和图14B所示。FIX活性曲线对于增加的剂量而言平行运行(图14A)，并且当作为注射剂量的回收率百分位数(％)绘制时重叠(图14B)，表明在HemB小鼠中50-400IU/kg的剂量范围内呈剂量线性。剂量线性通过每个测试剂量的PK参数得到确认，如通过Phoenix WinNonLin软件使用实际测量剂量的非房室分析和匹配的血浆活性水平数据所计算的(图14C)。

实施例10：rFIXFc-XTEN在食蟹猴中的药代动力学

通过静脉内或皮下给药途径，向每个队列中的三只幼稚雄性食蟹猴各给予100IU/kg的rFIXFc-XTEN(pJH84；SEQ ID NO:151)。在给药前后的指定时间点收集血液(图15A)。通过rFIXFc-XTEN特异性ELISA(XTEN-捕获和人FIX检测)以及测量rFIXFc-XTEN特异性血浆活性的改良(XTEN-捕获)FIX显色活性测定来确定FIX的血浆水平。对照FIX WHO标准确认给药，并使用rFIXFc-XTEN作为标准测定rFIXFc-XTEN血浆水平。在图15A中，将血浆抗原水平(虚线)和血浆活性(实线n＝3)的平均值±标准偏差绘制为从注射剂量回收的百分位数。图15B显示了使用Phoenix WinNonLin 6.2.1(Pharsight，Certara)通过NCA分析计算的PK参数表，包括平均停留时间(MRT)、AUC/剂量和其他参数。

实施例11：静脉内给药和皮下给药的比较

将HemB小鼠静脉内给予50IU/kg(实线)、100(大虚线)或200IU/kg(小虚线)的rFIXFc，并且在给药后直至7天的不同时间测量FIX血浆活性水平(图16)。阴影区域代表100和200IU/kg皮下给药rFIXFc-AP.72(pJH84；SEQ ID NO:151)的模拟FIX血浆活性水平，所述FIX血浆活性水平使用拟合图14A-14C所述的所有测量血浆活性数据的一室PK模型来计算。皮下给药的rFIXFc-AP.72在给药后大约1天达到其预测的血浆峰值。100IU/kg和200IU/kg皮下给药的rFIXFc-AP.72分别大约15IU/dL和30IU/dL的峰值说明通过皮下给药途径减小了给药过量的可能性。大于150IU/kg峰值时预计存在血栓形成的潜在风险，超过150IU/kg的静脉内rFIX剂量很容易达到。值得注意的是，与等效剂量静脉给予的rFIXFc相比，皮下给药的rFIXFc-AP.72在给药后一天提供更高的血浆水平并在每周给药间隔期间提供谷值水平。这表明，与在7天周期的第1天静脉内给予的等效量的rFIXFc相比，皮下给予的rFIXFc-AP.72可以在给予后7天中的6天提供更好的出血防护。

特定实施方案的前述描述将如此充分地揭示本公开文本的一般性质，其他人可通过应用本领域技术范围内的知识，容易地修改和/或调整此类特定实施方案用于各种应用，而无需过度实验，不会背离本公开文本的一般概念。因此，基于本文给出的教导和指导，这些调整和修改旨在包含在所公开的实施方案的等效方案的含义和范围内。应理解，本文中的措辞或术语是出于描述而非限制的目的，因此本说明书的术语或措辞将由本领域技术人员根据教导和指导来解释。

考虑到本文公开的说明书和实践，本公开文本的其他实施方案对于本领域技术人员而言是显而易见的。所述说明书和实施例旨在仅被视为示例性的，所附权利要求书指示了本公开文本的真实范围和精神。

本申请要求于2017年1月31日提交的美国临时申请号62/452,826的权益，其通过引用以全文并入本文。

实施方案

E1.一种在有需要的受试者中给予因子IX(FIX)融合蛋白的方法，其包括向受试者皮下给予FIX融合蛋白，其中

E2.E1的方法，其中所述FIX融合蛋白是以约50IU/kg至约400IU/kg的剂量给予。

E3.E1或E2的方法，其中所述FIX融合蛋白是以约50IU/kg、约100IU/kg、约200IU/kg或约400IU/kg的剂量给予。

E4.E1至E3中任一项的方法，其中所述FIX融合蛋白展现出约10％至约30％的血浆活性峰值。

E5.E1至E4中任一项的方法，其中所述FIX融合蛋白展现出约10％、约11％、约12％、约13％、约14％、约15％、约16％、约17％、约18％、约19％、约20％、约21％、约22％、约23％、约24％、约25％、约26％、约27％、约28％、约29％或约30％的血浆活性峰值。

E6.E1至E5中任一项的方法，其中所述FIX融合蛋白展现出约30％的血浆活性峰值。

E7.E1至E6中任一项的方法，其中所述FIX融合蛋白展现出约5％至约10％的血浆活性谷值。

E8.E1至E7中任一项的方法，其中所述FIX融合蛋白展现出约5％、约6％、约7％、约8％、约9％或约10％的血浆活性谷值。

E9.E1至E8中任一项的方法，其中所述FIX融合蛋白展现出约5％的血浆活性谷值。

E10.E1至E9中任一项的方法，其中所述FIX融合蛋白展现出约30％的血浆活性峰峰值，并且所述FIX蛋白展现出约5％的血浆活性谷值。

E11.E1至E10中任一项的方法，其中所述插入位点对应于选自以下的氨基酸：SEQID NO:2的氨基酸149、SEQ ID NO:2的氨基酸162、SEQ ID NO:2的氨基酸166、SEQ ID NO:2的氨基酸174及其任何组合。

E12.E1至E11中任一项的方法，其中所述插入位点对应于选自以下的氨基酸：SEQID NO:2的氨基酸224、SEQ ID NO:2的氨基酸226、SEQ ID NO:2的氨基酸228、SEQ ID NO:2的氨基酸413及其任何组合。

E13.E1至E12中任一项的方法，其中所述插入位点对应于选自以下的氨基酸：SEQID NO:2的氨基酸103、SEQ ID NO:2的氨基酸105和两者。

E14.E1至E13中任一项的方法，其中所述插入位点对应于SEQ ID NO:2的氨基酸142。

E15.E1至E14中任一项的方法，其中所述XTEN包含至少约6个氨基酸、至少约12个氨基酸、至少约36个氨基酸、至少约42个氨基酸、至少约72个氨基酸、至少约144个氨基酸或至少约288个氨基酸。

E16.E1至E15中任一项的方法，其中所述XTEN包含A42、A72、A864、A576、A288、AE144、AG864、AG576、AG288、AG144或其任何组合。

E17.E1至E16中任一项的方法，其中所述XTEN包含与选自SEQ ID NO:34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53或其任何组合的氨基酸序列至少约80％、至少约85％、至少约90％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％或约100％相同的氨基酸序列。

E18.E16或E17的方法，其中所述XTEN包含AE72或AE144。

E19.E16至E18中任一项的方法，其中所述XTEN包含AE72。

E20.E1至E19中任一项的方法，其还包含第二XTEN。

E21.E20的方法，其中所述第二XTEN在插入位点处插入所述FIX多肽内，所述插入位点对应于选自以下的氨基酸：SEQ ID NO:2的氨基酸103、SEQ ID NO:2的氨基酸105、SEQID NO:2的氨基酸142、SEQ ID NO:2的氨基酸149、SEQ ID NO:2的氨基酸162、SEQ ID NO:2的氨基酸166、SEQ ID NO:2的氨基酸174、SEQ ID NO:2的氨基酸224、SEQ ID NO:2的氨基酸226、SEQ ID NO:2的氨基酸228、SEQ ID NO:2的氨基酸413及其任何组合，或者其中所述第二XTEN与FIX多肽的C端融合或与融合到FIX多肽的C端的接头融合。

E22.E20或E21的方法，其中所述XTEN和所述第二XTEN分别在插入位点处插入所述FIX多肽内和/或与所述FIX多肽的C端融合，所述插入位点对应于选自以下的氨基酸：

i.SEQ ID NO:2的氨基酸105和SEQ ID NO:2的氨基酸166；

ii.SEQ ID NO:2的氨基酸105和SEQ ID NO:2的氨基酸224；

iii.SEQ ID NO:2的氨基酸105，并与所述C端融合；

iv.SEQ ID NO:2的氨基酸166和SEQ ID NO:2的氨基酸224；

v.SEQ ID NO:2的氨基酸166，并与所述C端融合；和

vi.SEQ ID NO:2的氨基酸224，并与所述C端融合。

E23.E20或E21的方法，其中所述XTEN在对应于SEQ ID NO:2的氨基酸166的插入位点处插入所述FIX多肽内，并且其中所述第二XTEN与所述FIX多肽的C端融合。

E24.E20至E23中任一项的方法，其中所述第二XTEN包含至少约6个氨基酸、至少约12个氨基酸、至少约36个氨基酸、至少约42个氨基酸、至少约72个氨基酸、至少约144个氨基酸或至少约288个氨基酸。

E25.E20至E24中任一项的方法，其中所述第二XTEN选自A42、A72、A864、A576、A288、AE144、AG864、AG576、AG288、AG144及其任何组合。

E26.E25的方法，其中所述第二XTEN是A72或AE144。

E27.E20至E26中任一项的方法，其中所述第二XTEN包含与选自SEQ ID NO:34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53或其任何组合的氨基酸序列至少约80％、至少约85％、至少约90％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％或约100％相同的氨基酸序列。

E28.E20至E27中任一项的方法，其还包含第三、第四、第五或第六XTEN。

E29.一种包含FIX多肽和含有XTEN的异源部分的方法，其中所述XTEN与所述FIX多肽的C端融合，并且包含长度长于42个氨基酸且短于144个氨基酸的氨基酸序列。

E30.E29的方法，其中所述XTEN包含长于50、55、60、65或70个氨基酸且短于140、130、120、110、100、90或80个氨基酸或其任何组合的氨基酸序列。

E31.E30的方法，其中所述XTEN的长度为72个氨基酸。

E32.E31的方法，其中所述XTEN是A72。

E33.E29的方法，其中所述XTEN包含与SEQ ID NO:35至少约80％、至少约85％、至少约90％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％或100％相同的氨基酸序列。

E34.E1至E33中任一项的方法，其还包含Fc结构域。

E35.E34的方法，其中所述Fc结构域与FIX多肽或XTEN融合。

E36.E34或E35的方法，其包含第二Fc结构域。

E37.E36的方法，其中所述第二Fc结构域与所述第一Fc结构域缔合。

E38.E36或E37的方法，其包含两条多肽链，其中第一多肽链包含与所述Fc结构域融合的FIX多肽，并且第二多肽链包含第二Fc结构域，其中所述第一Fc结构域和所述第二Fc结构域通过共价键缔合。

E39.E36或E37的方法，其是包含所述FIX多肽、所述Fc结构域、所述第二Fc结构域和连接Fc结构域与第二Fc结构域的接头的单一多肽链。

E40.E39的方法，其中所述接头还包含一个或多个细胞内加工位点。

E41.E39或E40的方法，其中所述接头包含(Gly4Ser)n，其中n是选自1至100的整数。

E42.E1至E41中任一项的方法，其包含与选自SEQ ID NO:54至SEQ ID NO:153的序列至少约80％、至少约85％、至少约90％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％或约100％相同的氨基酸序列，不含信号肽和前肽序列。

E43.E1至E42中任一项的方法，其具有原生FIX的促凝血活性的至少约10％、至少约20％、至少约30％、至少约40％、至少约50％、至少约60％、至少约70％、至少约80％、至少约90％或100％。

E44.E43的方法，其中通过显色底物测定、一步凝血测定或两者来测量促凝血活性。

E45.E1至E44中任一项的方法，其中所述FIX多肽是R338L FIX变体。

E46.E45的方法，其中所述R338L FIX变体包含与SEQ ID NO:2至少约80％、至少约85％、至少约90％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％或100％相同的氨基酸序列。

E47.E1至E10中任一项的方法，其中所述FIX融合蛋白包含第一链和第二链，其中：

(a)所述第一链包含：

(i)FIX多肽；

(ii)至少一个XTEN，其中所述至少一个XTEN在对应于SEQ ID NO:2的氨基酸166的插入位点处插入所述FIX多肽内，并且其中所述至少一个XTEN包含具有至少约72个氨基酸的氨基酸序列；和

(iii)第一Fc结构域，其中所述第一Fc结构域与所述至少一个XTEN的FIX多肽融合；和

(b)所述第二链包含第二Fc结构域；

其中所述第一Fc结构域和所述第二Fc结构域通过共价键缔合。

E48.E47的方法，其中所述至少一个XTEN包含与SEQ ID NO:35的氨基酸序列至少约80％、至少约85％、至少约90％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％或100％相同的氨基酸序列。

E49.E47或E48的方法，其中所述FIX融合蛋白的第一条链包含与SEQ ID NO:227的氨基酸序列至少约80％、至少约85％、至少约90％、至少约95％、至少约96％、至少约97％、至少约98％或至少约99％相同的氨基酸序列；并且其中所述FIX融合蛋白的第二链包含与SEQ ID NO:228的氨基酸序列至少约80％、至少约85％、至少约90％、至少约95％、至少约96％、至少约97％、至少约98％或至少约99％相同的氨基酸序列。

E50.E47至E49中任一项的FIX融合蛋白，其中所述FIX融合蛋白的第一链包含SEQID NO:227的氨基酸序列；并且其中所述FIX融合蛋白的第二链包含SEQ ID NO:228的氨基酸序列。

在前述实施例和本申请的其他地方引用了以下载体序列。以下关键词有助于理解信息：

关键词：

信号肽(肽前体(pre-peptide))

前肽(pro-peptide)

XTEN和/或Fc的插入或融合

SEQ ID NO:54 E0113_AE42；PNL118

SEQ ID NO:55 N0089_AE42 pNL116

SEQ ID NO:56 A0103_AE42 pNL117

SEQ ID NO:57 P0129_AE42 pNL119

SEQ ID NO:58 K0142_AE42 pNL120

SEQ ID NO:59 V0149_AE42 pNL121

SEQ ID NO:60 E0162_AE42 pNL122

SEQ ID NO:61 D0166_AE42 pNL123

SEQ ID NO:62 S0174_AE42 pNL124

SEQ ID NO:63 K0188_AE42 pNL125

SEQ ID NO:64 V0202_AE42 pNL126

SEQ ID NO:65 E0224_AE42 pNL127

SEQ ID NO:66 E0240_AE42 pNL128

SEQ ID NO:67 H0257_AE42 pNL129

SEQ ID NO:68 K0265_AE42 pNL130

SEQ ID NO:69 E0277_AE42 pNL131

SEQ ID NO:70 D0292_AE42 pNL132

SEQ ID NO:71 K0316_AE42 pNL133

SEQ ID NO:72 K0341_AE42 pNL134

SEQ ID NO:73 H0354_AE42 pNL135

SEQ ID NO:74 K0392_AE42 pNL136

SEQ ID NO:75 R0403_AE42 pNL137

SEQ ID NO:76 K0413_AE42 pNL138

SEQ ID NO:77 CT_AE42 pNL140

SEQ ID NO:78 E0052_AE42 pNL141

SEQ ID NO:79 G0059_AE42 pNL142

SEQ ID NO:80 I0066_AE42 pNL143

SEQ ID NO:81 K0080_AE42 pNL144

SEQ ID NO:82 D0085_AE42 pNL145

SEQ ID NO:83 CT_AE144 pNL164

SEQ ID NO:84 CT_AE288 pNL165

SEQ ID NO:85 CT_AE864 pNL166

SEQ ID NO:86 K0142_AE72 pNL167

SEQ ID NO:87 K0142_AE144 pNL168

SEQ ID NO:88 K0142_AE288 pNL169

SEQ ID NO:89 V0149_AE72 pNL170

SEQ ID NO:90 V0149_AE144 pNL171

SEQ ID NO:91 V0149_AE288 pNL172

SEQ ID NO:92 E0162_AE72 pNL173

SEQ ID NO:93 E0162_AE144 pNL174

SEQ ID NO:94 E0162_AE288 pNL175

SEQ ID NO:95 D0166_AE72 pNL176

SEQ ID NO:96 D0166_AE144 pNL177

SEQ ID NO:97 D0166_AE288 pNL178

SEQ ID NO:98 S0174_AE72 pNL179

SEQ ID NO:99 S0174_AE144 pNL180

SEQ ID NO:100 S0174_AE288 pNL181

SEQ ID NO:101 E0224_AE72 pNL182

SEQ ID NO:102 E0224_AE144 pNL183

SEQ ID NO:103 E0224_AE288 pNL184

SEQ ID NO:104 K0413_AE72 pNL185

SEQ ID NO:105 K0413_AE144 pNL186

SEQ ID NO:106 K0413_AE288 pNL187

SEQ ID NO:107 A0103_AE72 pNL188

SEQ ID NO:108 A0103_AE144 pNL189

SEQ ID NO:109 A0103_AE288 pNL190

SEQ ID NO:110 G0226_AE42 pNL195

SEQ ID NO:111 K0228_AE42 pNL196

SEQ ID NO:112 T0230_AE42 pNL197

SEQ ID NO:113 N0105_AE42 pNL198

SEQ ID NO:114 S0283_AE42 pNL199

SEQ ID NO:115 CT_AE72 pNL202

SEQ ID NO:116 C端-AE864 FIX-092

SEQ ID NO:117 C端-AE144 pJH0131

SEQ ID NO:118 N105-AE42 pJH44

MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNGAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPASSKVVCSCTEGYRLAENQKSCEPAVPFPCGRVSVSQTSKLTRAETVFPDVDYVNSTEAETILDNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLLSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT

SEQ ID NO:119 D166-AE72 pJH46

MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGYRLAENQKSCEPAVPFPCGRVSVSQTSKLTRAETVFPDVDYVNSTEAETILDGAPSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGASSNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLLSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT

SEQ ID NO:120 D166-AE144 pJH47

MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGYRLAENQKSCEPAVPFPCGRVSVSQTSKLTRAETVFPDVDYVNSTEAETILDGAPSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGASSNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLLSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT

SEQ ID NO:121 C端-AE144 pJH50

SEQ ID NO:122 C端-AE288 pJH51

SEQ ID NO:123 C端-AE72 pJH52

SEQ ID NO:124 E224-AE42 pJH54

MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGYRLAENQKSCEPAVPFPCGRVSVSQTSKLTRAETVFPDVDYVNSTEAETILDNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVEGAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPASSTGVKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLLSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT

SEQ ID NO:125 D166-AE42 pJH55

MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGYRLAENQKSCEPAVPFPCGRVSVSQTSKLTRAETVFPDVDYVNSTEAETILDGAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPASSNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNI FLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLLSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKL

SEQ ID NO:126 D166-AE42，C端-AE72 pJH59

SEQ ID NO:127 D166-AE42，C端-AE144 pJH60

SEQ ID NO:128 D166-AE42，C端-AE288 pJH61

SEQ ID NO:129 D166-AE72，C端-AE72 pJH62

SEQ ID NO:130 D166-AE72，C端-AE144 pJH63

SEQ ID NO:131 D166-AE72，C端-AE288 pJH64

SEQ ID NO:132 D166-AE144，C端-AE72 pJH65

SEQ ID NO:133 D166-AE144，C端-AE144 pJH66

SEQ ID NO:134 D166-AE144，C端-AE288 pJH67

SEQ ID NO:135 N105-AE42,D166-AE42 pJH68

MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNGAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPASSKVVCSCTEGYRLAENQKSCEPAVPFPCGRVSVSQTSKLTRAETVFPDVDYVNSTEAETILDGAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPASSNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLLSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT

SEQ ID NO:136 N105-AE42,D166-AE72 pJH69

MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNGAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPASSKVVCSCTEGYRLAENQKSCEPAVPFPCGRVSVSQTSKLTRAETVFPDVDYVNSTEAETILDGAPSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGASSNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLLSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT

SEQ ID NO:137 N105-AE42,D166-AE144 pJH70

MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNGAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPASSKVVCSCTEGYRLAENQKSCEPAVPFPCGRVSVSQTSKLTRAETVFPDVDYVNSTEAETILDGAPSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGASSNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLLSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT

SEQ ID NO:138 N105-AE42，C端-AE72 pJH71

SEQ ID NO:139 N105-AE42，C端-AE144 pJH72

SEQ ID NO:140 N105-AE42，C端-AE288 pJH73

SEQ ID NO:141 N105-AE42,E224-AE42 pJH74

MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNGAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPASSKVVCSCTEGYRLAENQKSCEPAVPFPCGRVSVSQTSKLTRAETVFPDVDYVNSTEAETILDNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVEGAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPASSTGVKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLLSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT

SEQ ID NO:142 D166-AE42,E224-AE42 pJH75

MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGYRLAENQKSCEPAVPFPCGRVSVSQTSKLTRAETVFPDVDYVNSTEAETILDGAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPASSNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVEGAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPASSTGVKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLLSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT

SEQ ID NO:143 D166-AE72,E224-AE42 pJH76

MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGYRLAENQKSCEPAVPFPCGRVSVSQTSKLTRAETVFPDVDYVNSTEAETILDGAPSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGASSNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVEGAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPASSTGVKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLLSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT

SEQ ID NO:144 D166-AE144,E224-AE42 pJH77

MEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGYRLAENQKSCEPAVPFPCGRVSVSQTSKLTRAETVFPDVDYVNSTEAETILDGAPSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPGASSNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVEGAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPASSTGVKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLLSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT

SEQ ID NO:145 E224-AE42，C端-AE72 pJH78

SEQ ID NO:146 E224-AE42，C端-AE144 pJH79

SEQ ID NO:147 E224-AE42，C端-AE288 pJH80

SEQ ID NO:148 N105-AE42，C端-Fc pJH81

SEQ ID NO:149 E224-AE42，C端-Fc pJH82

SEQ ID NO:150 D166-AE42，C端-Fc pJH83

SEQ ID NO:151 D166-AE72，C端-Fc pJH84

SEQ ID NO:152 D166-AE144，C端-Fc pJH85

SEQ ID NO:153 C端-Fc pJH56

SEQ ID NO:226 C端-AE288 pSYN-FIX-102

SEQ ID NO:227双链D166-AE72，C端-Fc pSYN-FIX-216

SEQ ID NO:228双链D166-AE72，C端-Fc pSYN-FIX-216-Fc链部分DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

SEQ ID NO:229 rFIXFc-R338L，C端FcYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGYRLAENQKSCEPAVPFPCGRVSVSQTSKLTRAETVFPDVDYVNSTEAETILDNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLLSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLTDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

序列表

<110> 比奥维拉迪维治疗股份有限公司(BIOVERATIV THERAPEUTICS INC.)

A·范德弗莱尔(VAN DER FLIER, Arjan)

刘钱智(LIU, Zhiqian)

D·R·莱特(LIGHT, David R.)

E·S·恰布拉(CHHABRA, Ekta Seth)

刘童瑶(LIU, Tongyao)

R·T·彼得斯(PETERS, Robert T.)

J·库尔曼(KULMAN, John)

A·伊斯梅尔(ISMAIL, Ayman)

<120> 因子IX融合蛋白及其制备和使用方法

<130> 4159.487PC01/C-K/BMD

<150> 62/452,826

<151> 2017-01-31

<160> 230

<170> PatentIn 3.5版

<210> 1

<211> 415

<212> PRT

<213> 人工序列

<220>

<223> 人FIX多肽

<400> 1

Tyr Asn Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg

1 5 10 15

Glu Cys Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe

20 25 30

Glu Asn Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly

35 40 45

Asp Gln Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp

50 55 60

Asp Ile Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys

65 70 75 80

Asn Cys Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu

85 90 95

Gln Phe Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr

100 105 110

Glu Gly Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val

115 120 125

Pro Phe Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr

130 135 140

Arg Ala Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu

145 150 155 160

Ala Glu Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn

165 170 175

Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe

180 185 190

Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly

195 200 205

Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu

210 215 220

Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu

225 230 235 240

Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His

245 250 255

His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu

260 265 270

Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile

275 280 285

Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser

290 295 300

Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala

305 310 315 320

Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys

325 330 335

Leu Arg Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly

340 345 350

Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro

355 360 365

His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser

370 375 380

Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys

385 390 395 400

Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr

405 410 415

<210> 2

<211> 415

<212> PRT

<213> 人工序列

<220>

<223> Padua FIX多肽

<400> 2

Tyr Asn Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg

1 5 10 15

Glu Cys Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe

20 25 30

Glu Asn Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly

35 40 45

Asp Gln Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp

50 55 60

Asp Ile Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys

65 70 75 80

Asn Cys Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu

85 90 95

Gln Phe Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr

100 105 110

Glu Gly Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val

115 120 125

Pro Phe Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr

130 135 140

Arg Ala Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu

145 150 155 160

Ala Glu Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn

165 170 175

Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe

180 185 190

Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly

195 200 205

Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu

210 215 220

Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu

225 230 235 240

Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His

245 250 255

His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu

260 265 270

Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile

275 280 285

Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser

290 295 300

Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala

305 310 315 320

Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys

325 330 335

Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly

340 345 350

Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro

355 360 365

His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser

370 375 380

Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys

385 390 395 400

Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr

405 410 415

<210> 3

<211> 46

<212> PRT

<213> 人工序列

<220>

<223> 人FIX信号多肽和前肽

<400> 3

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg

35 40 45

<210> 4

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AD

<400> 4

Gly Glu Ser Pro Gly Gly Ser Ser Gly Ser Glu Ser

1 5 10

<210> 5

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AD

<400> 5

Gly Ser Glu Gly Ser Ser Gly Pro Gly Glu Ser Ser

1 5 10

<210> 6

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AD

<400> 6

Gly Ser Ser Glu Ser Gly Ser Ser Glu Gly Gly Pro

1 5 10

<210> 7

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AD

<400> 7

Gly Ser Gly Gly Glu Pro Ser Glu Ser Gly Ser Ser

1 5 10

<210> 8

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AE, AM

<400> 8

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

1 5 10

<210> 9

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AE, AM, AQ

<400> 9

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

1 5 10

<210> 10

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AE, AM, AQ

<400> 10

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

1 5 10

<210> 11

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AE, AM, AQ

<400> 11

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

1 5 10

<210> 12

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AF, AM

<400> 12

Gly Ser Thr Ser Glu Ser Pro Ser Gly Thr Ala Pro

1 5 10

<210> 13

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AF, AM

<400> 13

Gly Thr Ser Thr Pro Glu Ser Gly Ser Ala Ser Pro

1 5 10

<210> 14

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AF, AM

<400> 14

Gly Thr Ser Pro Ser Gly Glu Ser Ser Thr Ala Pro

1 5 10

<210> 15

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AF, AM

<400> 15

Gly Ser Thr Ser Ser Thr Ala Glu Ser Pro Gly Pro

1 5 10

<210> 16

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AG, AM

<400> 16

Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro

1 5 10

<210> 17

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AG, AM

<400> 17

Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro

1 5 10

<210> 18

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AG, AM

<400> 18

Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro

1 5 10

<210> 19

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AG, AM

<400> 19

Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

1 5 10

<210> 20

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AQ

<400> 20

Gly Glu Pro Ala Gly Ser Pro Thr Ser Thr Ser Glu

1 5 10

<210> 21

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AQ

<400> 21

Gly Thr Gly Glu Pro Ser Ser Thr Pro Ala Ser Glu

1 5 10

<210> 22

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AQ

<400> 22

Gly Ser Gly Pro Ser Thr Glu Ser Ala Pro Thr Glu

1 5 10

<210> 23

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AQ

<400> 23

Gly Ser Glu Thr Pro Ser Gly Pro Ser Glu Thr Ala

1 5 10

<210> 24

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AQ

<400> 24

Gly Pro Ser Glu Thr Ser Thr Ser Glu Pro Gly Ala

1 5 10

<210> 25

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> AQ

<400> 25

Gly Ser Pro Ser Glu Pro Thr Glu Gly Thr Ser Ala

1 5 10

<210> 26

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> BC

<400> 26

Gly Ser Gly Ala Ser Glu Pro Thr Ser Thr Glu Pro

1 5 10

<210> 27

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> BC

<400> 27

Gly Ser Glu Pro Ala Thr Ser Gly Thr Glu Pro Ser

1 5 10

<210> 28

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> BC

<400> 28

Gly Thr Ser Glu Pro Ser Thr Ser Glu Pro Gly Ala

1 5 10

<210> 29

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> BC

<400> 29

Gly Thr Ser Thr Glu Pro Ser Glu Pro Gly Ser Ala

1 5 10

<210> 30

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> BD

<400> 30

Gly Ser Thr Ala Gly Ser Glu Thr Ser Thr Glu Ala

1 5 10

<210> 31

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> BD

<400> 31

Gly Ser Glu Thr Ala Thr Ser Gly Ser Glu Thr Ala

1 5 10

<210> 32

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> BD

<400> 32

Gly Thr Ser Glu Ser Ala Thr Ser Glu Ser Gly Ala

1 5 10

<210> 33

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> BD

<400> 33

Gly Thr Ser Thr Glu Ala Ser Glu Gly Ser Ala Ser

1 5 10

<210> 34

<211> 42

<212> PRT

<213> 人工序列

<220>

<223> AE42

<400> 34

Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

1 5 10 15

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

20 25 30

Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser

35 40

<210> 35

<211> 78

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<213> 人工序列

<220>

<223> AE72

<400> 35

Gly Ala Pro Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

1 5 10 15

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

20 25 30

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

35 40 45

Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr

50 55 60

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser

65 70 75

<210> 36

<211> 144

<212> PRT

<213> 人工序列

<220>

<223> AE144

<400> 36

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu

1 5 10 15

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

20 25 30

Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

35 40 45

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Glu Pro

50 55 60

Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly

65 70 75 80

Ser Glu Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

85 90 95

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu

100 105 110

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

115 120 125

Ser Glu Thr Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

130 135 140

<210> 37

<211> 144

<212> PRT

<213> 人工序列

<220>

<223> AE144_2A

<400> 37

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly

1 5 10 15

Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly

20 25 30

Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

35 40 45

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu

50 55 60

Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

65 70 75 80

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

85 90 95

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu

100 105 110

Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

115 120 125

Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

130 135 140

<210> 38

<211> 144

<212> PRT

<213> 人工序列

<220>

<223> AE144_3B

<400> 38

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser

1 5 10 15

Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

20 25 30

Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

35 40 45

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu

50 55 60

Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

65 70 75 80

Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

85 90 95

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu

100 105 110

Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

115 120 125

Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

130 135 140

<210> 39

<211> 144

<212> PRT

<213> 人工序列

<220>

<223> AE144_4A

<400> 39

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

1 5 10 15

Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

20 25 30

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

35 40 45

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu

50 55 60

Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

65 70 75 80

Ser Gly Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

85 90 95

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly

100 105 110

Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu

115 120 125

Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

130 135 140

<210> 40

<211> 144

<212> PRT

<213> 人工序列

<220>

<223> AE144_5A

<400> 40

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

1 5 10 15

Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

20 25 30

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

35 40 45

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu

50 55 60

Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

65 70 75 80

Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

85 90 95

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser

100 105 110

Ala Thr Pro Glu Ser Gly Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

115 120 125

Thr Glu Glu Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

130 135 140

<210> 41

<211> 144

<212> PRT

<213> 人工序列

<220>

<223> AE144_6B

<400> 41

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser

1 5 10 15

Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

20 25 30

Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

35 40 45

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala

50 55 60

Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

65 70 75 80

Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

85 90 95

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Glu Pro Ala

100 105 110

Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

115 120 125

Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

130 135 140

<210> 42

<211> 144

<212> PRT

<213> 人工序列

<220>

<223> AG144

<400> 42

Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser Thr

1 5 10 15

Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Pro Ser Ala Ser Thr

20 25 30

Gly Thr Gly Pro Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro

35 40 45

Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ala Ser Pro

50 55 60

Gly Thr Ser Ser Thr Gly Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala

65 70 75 80

Thr Gly Ser Pro Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro

85 90 95

Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ser Ser Pro

100 105 110

Ser Ala Ser Thr Gly Thr Gly Pro Gly Thr Pro Gly Ser Gly Thr Ala

115 120 125

Ser Ser Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro

130 135 140

<210> 43

<211> 144

<212> PRT

<213> 人工序列

<220>

<223> AG144_A

<400> 43

Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ser Ser Pro

1 5 10 15

Ser Ala Ser Thr Gly Thr Gly Pro Gly Ser Ser Pro Ser Ala Ser Thr

20 25 30

Gly Thr Gly Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro

35 40 45

Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Pro

50 55 60

Ser Ala Ser Thr Gly Thr Gly Pro Gly Ala Ser Pro Gly Thr Ser Ser

65 70 75 80

Thr Gly Ser Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro

85 90 95

Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Thr Pro Gly

100 105 110

Ser Gly Thr Ala Ser Ser Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser

115 120 125

Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

130 135 140

<210> 44

<211> 144

<212> PRT

<213> 人工序列

<220>

<223> AG144_B

<400> 44

Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser Thr

1 5 10 15

Pro Ser Gly Ala Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser

20 25 30

Thr Gly Ser Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro

35 40 45

Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Pro

50 55 60

Ser Ala Ser Thr Gly Thr Gly Pro Gly Ser Ser Pro Ser Ala Ser Thr

65 70 75 80

Gly Thr Gly Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro

85 90 95

Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ala Ser Pro

100 105 110

Gly Thr Ser Ser Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser

115 120 125

Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

130 135 140

<210> 45

<211> 144

<212> PRT

<213> 人工序列

<220>

<223> AG144_C

<400> 45

Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ala Ser Pro

1 5 10 15

Gly Thr Ser Ser Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser

20 25 30

Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

35 40 45

Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Thr Pro Gly

50 55 60

Ser Gly Thr Ala Ser Ser Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser

65 70 75 80

Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

85 90 95

Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ser Ser Thr

100 105 110

Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala

115 120 125

Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

130 135 140

<210> 46

<211> 144

<212> PRT

<213> 人工序列

<220>

<223> AG144_F

<400> 46

Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Ser Ser Pro

1 5 10 15

Ser Ala Ser Thr Gly Thr Gly Pro Gly Ala Ser Pro Gly Thr Ser Ser

20 25 30

Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

35 40 45

Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Pro

50 55 60

Ser Ala Ser Thr Gly Thr Gly Pro Gly Ala Ser Pro Gly Thr Ser Ser

65 70 75 80

Thr Gly Ser Pro Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro

85 90 95

Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser Thr

100 105 110

Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala

115 120 125

Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

130 135 140

<210> 47

<211> 288

<212> PRT

<213> 人工序列

<220>

<223> AE288

<400> 47

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro

1 5 10 15

Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro

20 25 30

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

35 40 45

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr

50 55 60

Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr

65 70 75 80

Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

85 90 95

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu

100 105 110

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Pro Ala Gly Ser Pro Thr

115 120 125

Ser Thr Glu Glu Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

130 135 140

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu

145 150 155 160

Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro

165 170 175

Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

180 185 190

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro

195 200 205

Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr

210 215 220

Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

225 230 235 240

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Glu Pro

245 250 255

Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro

260 265 270

Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

275 280 285

<210> 48

<211> 288

<212> PRT

<213> 人工序列

<220>

<223> AE288_2

<400> 48

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu

1 5 10 15

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

20 25 30

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

35 40 45

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

50 55 60

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu

65 70 75 80

Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

85 90 95

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

100 105 110

Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr

115 120 125

Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

130 135 140

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro

145 150 155 160

Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro

165 170 175

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

180 185 190

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr

195 200 205

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro

210 215 220

Glu Ser Gly Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

225 230 235 240

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala

245 250 255

Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro

260 265 270

Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

275 280 285

<210> 49

<211> 288

<212> PRT

<213> 人工序列

<220>

<223> AG288

<400> 49

Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ala Ser

1 5 10 15

Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Thr Pro Gly Ser Gly Thr

20 25 30

Ala Ser Ser Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser

35 40 45

Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser

50 55 60

Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Thr Pro Gly Ser Gly Thr

65 70 75 80

Ala Ser Ser Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser

85 90 95

Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser

100 105 110

Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Ser Ser Pro Ser Ala Ser

115 120 125

Thr Gly Thr Gly Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser

130 135 140

Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser

145 150 155 160

Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Pro Ser Ala Ser

165 170 175

Thr Gly Thr Gly Pro Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly

180 185 190

Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ala Ser

195 200 205

Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ser Ser Thr Pro Ser Gly

210 215 220

Ala Thr Gly Ser Pro Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly

225 230 235 240

Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ser Ser

245 250 255

Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Thr Pro Gly Ser Gly Thr

260 265 270

Ala Ser Ser Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser

275 280 285

<210> 50

<211> 576

<212> PRT

<213> 人工序列

<220>

<223> AE576

<400> 50

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu

1 5 10 15

Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu

20 25 30

Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

35 40 45

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

50 55 60

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro

65 70 75 80

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

85 90 95

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala

100 105 110

Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro

115 120 125

Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

130 135 140

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala

145 150 155 160

Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu

165 170 175

Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

180 185 190

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr

195 200 205

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro

210 215 220

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

225 230 235 240

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

245 250 255

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro

260 265 270

Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

275 280 285

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu

290 295 300

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

305 310 315 320

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

325 330 335

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

340 345 350

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu

355 360 365

Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

370 375 380

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

385 390 395 400

Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr

405 410 415

Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

420 425 430

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro

435 440 445

Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro

450 455 460

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

465 470 475 480

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr

485 490 495

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro

500 505 510

Glu Ser Gly Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

515 520 525

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala

530 535 540

Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro

545 550 555 560

Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

565 570 575

<210> 51

<211> 576

<212> PRT

<213> 人工序列

<220>

<223> AG576

<400> 51

Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser

1 5 10 15

Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Pro Ser Ala Ser

20 25 30

Thr Gly Thr Gly Pro Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly

35 40 45

Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser

50 55 60

Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser

65 70 75 80

Ser Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser

85 90 95

Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Thr Pro

100 105 110

Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ala Ser Pro Gly Thr Ser

115 120 125

Ser Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser

130 135 140

Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ser Ser

145 150 155 160

Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Thr Pro Gly Ser Gly Thr

165 170 175

Ala Ser Ser Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser

180 185 190

Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ala Ser

195 200 205

Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ser Ser Thr Pro Ser Gly

210 215 220

Ala Thr Gly Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser

225 230 235 240

Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Thr Pro

245 250 255

Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser Thr Pro Ser Gly

260 265 270

Ala Thr Gly Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser

275 280 285

Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser

290 295 300

Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Ala Ser Pro Gly Thr Ser

305 310 315 320

Ser Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser

325 330 335

Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ala Ser

340 345 350

Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser

355 360 365

Ser Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser

370 375 380

Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Thr Pro

385 390 395 400

Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser Thr Pro Ser Gly

405 410 415

Ala Thr Gly Ser Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser

420 425 430

Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Thr Pro

435 440 445

Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser Thr Pro Ser Gly

450 455 460

Ala Thr Gly Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser

465 470 475 480

Pro Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Ser Ser

485 490 495

Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Ala Ser Pro Gly Thr Ser

500 505 510

Ser Thr Gly Ser Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser

515 520 525

Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser

530 535 540

Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Ser Ser Pro Ser Ala Ser

545 550 555 560

Thr Gly Thr Gly Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser

565 570 575

<210> 52

<211> 864

<212> PRT

<213> 人工序列

<220>

<223> AE864

<400> 52

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu

1 5 10 15

Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu

20 25 30

Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

35 40 45

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

50 55 60

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro

65 70 75 80

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

85 90 95

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala

100 105 110

Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro

115 120 125

Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

130 135 140

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala

145 150 155 160

Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu

165 170 175

Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

180 185 190

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr

195 200 205

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro

210 215 220

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

225 230 235 240

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

245 250 255

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro

260 265 270

Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

275 280 285

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu

290 295 300

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

305 310 315 320

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

325 330 335

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

340 345 350

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu

355 360 365

Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

370 375 380

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

385 390 395 400

Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr

405 410 415

Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

420 425 430

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro

435 440 445

Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro

450 455 460

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

465 470 475 480

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr

485 490 495

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro

500 505 510

Glu Ser Gly Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

515 520 525

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala

530 535 540

Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro

545 550 555 560

Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

565 570 575

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro

580 585 590

Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro

595 600 605

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

610 615 620

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr

625 630 635 640

Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr

645 650 655

Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

660 665 670

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu

675 680 685

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Pro Ala Gly Ser Pro Thr

690 695 700

Ser Thr Glu Glu Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

705 710 715 720

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu

725 730 735

Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro

740 745 750

Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

755 760 765

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro

770 775 780

Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr

785 790 795 800

Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

805 810 815

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Glu Pro

820 825 830

Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro

835 840 845

Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

850 855 860

<210> 53

<211> 864

<212> PRT

<213> 人工序列

<220>

<223> AG864

<400> 53

Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ser Ser Pro

1 5 10 15

Ser Ala Ser Thr Gly Thr Gly Pro Gly Ser Ser Pro Ser Ala Ser Thr

20 25 30

Gly Thr Gly Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro

35 40 45

Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Pro

50 55 60

Ser Ala Ser Thr Gly Thr Gly Pro Gly Ala Ser Pro Gly Thr Ser Ser

65 70 75 80

Thr Gly Ser Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro

85 90 95

Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Thr Pro Gly

100 105 110

Ser Gly Thr Ala Ser Ser Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser

115 120 125

Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

130 135 140

Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser Thr

145 150 155 160

Pro Ser Gly Ala Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser

165 170 175

Thr Gly Ser Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro

180 185 190

Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Pro

195 200 205

Ser Ala Ser Thr Gly Thr Gly Pro Gly Ser Ser Pro Ser Ala Ser Thr

210 215 220

Gly Thr Gly Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro

225 230 235 240

Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ala Ser Pro

245 250 255

Gly Thr Ser Ser Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser

260 265 270

Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

275 280 285

Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ala Ser Pro

290 295 300

Gly Thr Ser Ser Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser

305 310 315 320

Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

325 330 335

Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Thr Pro Gly

340 345 350

Ser Gly Thr Ala Ser Ser Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser

355 360 365

Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

370 375 380

Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ser Ser Thr

385 390 395 400

Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala

405 410 415

Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

420 425 430

Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser Thr

435 440 445

Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala

450 455 460

Thr Gly Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro

465 470 475 480

Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Ala Ser Pro

485 490 495

Gly Thr Ser Ser Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser

500 505 510

Thr Gly Ser Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro

515 520 525

Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ala Ser Pro

530 535 540

Gly Thr Ser Ser Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser

545 550 555 560

Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

565 570 575

Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser Thr

580 585 590

Pro Ser Gly Ala Thr Gly Ser Pro Gly Thr Pro Gly Ser Gly Thr Ala

595 600 605

Ser Ser Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro

610 615 620

Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser Thr

625 630 635 640

Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala

645 650 655

Thr Gly Ser Pro Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro

660 665 670

Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Ala Ser Pro

675 680 685

Gly Thr Ser Ser Thr Gly Ser Pro Gly Thr Pro Gly Ser Gly Thr Ala

690 695 700

Ser Ser Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro

705 710 715 720

Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Ser Ser Pro

725 730 735

Ser Ala Ser Thr Gly Thr Gly Pro Gly Ala Ser Pro Gly Thr Ser Ser

740 745 750

Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

755 760 765

Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Pro

770 775 780

Ser Ala Ser Thr Gly Thr Gly Pro Gly Ala Ser Pro Gly Thr Ser Ser

785 790 795 800

Thr Gly Ser Pro Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro

805 810 815

Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser Thr

820 825 830

Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala

835 840 845

Thr Gly Ser Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

850 855 860

<210> 54

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL118

<400> 54

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr

165 170 175

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr

180 185 190

Ser Gly Ser Glu Thr Pro Ala Ser Ser Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 55

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL116

<400> 55

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Gly Ala Pro Gly Ser Pro Ala Gly Ser

130 135 140

Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

145 150 155 160

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser

165 170 175

Ser Ile Lys Asn Gly Arg Cys Glu Gln Phe Cys Lys Asn Ser Ala Asp

180 185 190

Asn Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 56

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL117

<400> 56

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr

145 150 155 160

Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

165 170 175

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Asp

180 185 190

Asn Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 57

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL119

<400> 57

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Gly

165 170 175

Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr

180 185 190

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr

195 200 205

Ser Gly Ser Glu Thr Pro Ala Ser Ser Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 58

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL120

<400> 58

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Gly Ala Pro Gly

180 185 190

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser

195 200 205

Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

210 215 220

Glu Thr Pro Ala Ser Ser Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 59

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL121

<400> 59

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr

195 200 205

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

210 215 220

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 60

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL122

<400> 60

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

210 215 220

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

225 230 235 240

Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 61

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL123

<400> 61

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

210 215 220

Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

225 230 235 240

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 62

<211> 549

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<213> 人工序列

<220>

<223> pNL124

<400> 62

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Gly Ala Pro Gly

210 215 220

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser

225 230 235 240

Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

245 250 255

Glu Thr Pro Ala Ser Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 63

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL125

<400> 63

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Gly Ala Pro Gly Ser Pro

225 230 235 240

Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr

245 250 255

Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr

260 265 270

Pro Ala Ser Ser Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 64

<211> 549

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<213> 人工序列

<220>

<223> pNL126

<400> 64

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Gly Ala Pro Gly Ser Pro Ala Gly

245 250 255

Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu

260 265 270

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala

275 280 285

Ser Ser Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 65

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL127

<400> 65

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Gly Ala

260 265 270

Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser

275 280 285

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser

290 295 300

Gly Ser Glu Thr Pro Ala Ser Ser Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 66

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL128

<400> 66

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Gly Ala

275 280 285

Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser

290 295 300

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser

305 310 315 320

Gly Ser Glu Thr Pro Ala Ser Ser Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 67

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL129

<400> 67

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Gly

290 295 300

Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr

305 310 315 320

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr

325 330 335

Ser Gly Ser Glu Thr Pro Ala Ser Ser Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 68

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL130

<400> 68

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Gly Ala Pro Gly Ser Pro Ala Gly Ser

305 310 315 320

Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

325 330 335

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser

340 345 350

Ser Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 69

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL131

<400> 69

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr

325 330 335

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

340 345 350

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 70

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL132

<400> 70

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu

340 345 350

Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu

355 360 365

Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 71

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL133

<400> 71

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Ala Pro Gly Ser Pro

355 360 365

Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr

370 375 380

Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr

385 390 395 400

Pro Ala Ser Ser Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 72

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL134

<400> 72

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr

385 390 395 400

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

405 410 415

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 73

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL135

<400> 73

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

405 410 415

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

420 425 430

Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 74

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL136

<400> 74

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro

435 440 445

Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

450 455 460

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 75

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL137

<400> 75

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

450 455 460

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro

465 470 475 480

Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 76

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL138

<400> 76

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Gly Ala Pro Gly Ser

450 455 460

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala

465 470 475 480

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

485 490 495

Thr Pro Ala Ser Ser Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 77

<211> 575

<212> PRT

<213> 人工序列

<220>

<223> pNL140

<400> 77

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly

450 455 460

Ser Pro Gly Ala Glu Thr Ala Leu Val Pro Arg Ser Phe Leu Leu Arg

465 470 475 480

Asn Pro Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly

485 490 495

Ala Gly Ser Pro Gly Ala Glu Thr Ala Gly Ala Pro Gly Ser Pro Ala

500 505 510

Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro

515 520 525

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

530 535 540

Ala Ser Ser Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser Glu Glu

545 550 555 560

Asp Leu Ser Pro Ala Thr Gly His His His His His His His His

565 570 575

<210> 78

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL141

<400> 78

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu

100 105 110

Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu

115 120 125

Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Ser Asn Pro Cys

130 135 140

Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile Asn Ser Tyr Glu Cys Trp

145 150 155 160

Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys Glu Leu Asp Val Thr Cys

165 170 175

Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe Cys Lys Asn Ser Ala Asp

180 185 190

Asn Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 79

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL142

<400> 79

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ala Pro Gly Ser Pro Ala

100 105 110

Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro

115 120 125

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

130 135 140

Ala Ser Ser Gly Ser Cys Lys Asp Asp Ile Asn Ser Tyr Glu Cys Trp

145 150 155 160

Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys Glu Leu Asp Val Thr Cys

165 170 175

Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe Cys Lys Asn Ser Ala Asp

180 185 190

Asn Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 80

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL143

<400> 80

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

115 120 125

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

130 135 140

Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Asn Ser Tyr Glu Cys Trp

145 150 155 160

Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys Glu Leu Asp Val Thr Cys

165 170 175

Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe Cys Lys Asn Ser Ala Asp

180 185 190

Asn Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 81

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL144

<400> 81

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Gly Ala

115 120 125

Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser

130 135 140

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser

145 150 155 160

Gly Ser Glu Thr Pro Ala Ser Ser Asn Cys Glu Leu Asp Val Thr Cys

165 170 175

Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe Cys Lys Asn Ser Ala Asp

180 185 190

Asn Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 82

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL145

<400> 82

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr

130 135 140

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

145 150 155 160

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Val Thr Cys

165 170 175

Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe Cys Lys Asn Ser Ala Asp

180 185 190

Asn Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 83

<211> 683

<212> PRT

<213> 人工序列

<220>

<223> pNL164

<400> 83

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly

450 455 460

Ser Pro Gly Ala Glu Thr Ala Leu Val Pro Arg Ser Phe Leu Leu Arg

465 470 475 480

Asn Pro Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly

485 490 495

Ala Gly Ser Pro Gly Ala Glu Thr Ala Gly Ala Pro Thr Ser Thr Glu

500 505 510

Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

515 520 525

Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

530 535 540

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

545 550 555 560

Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

565 570 575

Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

580 585 590

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu

595 600 605

Pro Ser Glu Gly Ser Ala Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

610 615 620

Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

625 630 635 640

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser Gly

645 650 655

Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro

660 665 670

Ala Thr Gly His His His His His His His His

675 680

<210> 84

<211> 827

<212> PRT

<213> 人工序列

<220>

<223> pNL165

<400> 84

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly

450 455 460

Ser Pro Gly Ala Glu Thr Ala Leu Val Pro Arg Ser Phe Leu Leu Arg

465 470 475 480

Asn Pro Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly

485 490 495

Ala Gly Ser Pro Gly Ala Glu Thr Ala Gly Ala Pro Gly Thr Ser Glu

500 505 510

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

515 520 525

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

530 535 540

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu

545 550 555 560

Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu

565 570 575

Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

580 585 590

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro

595 600 605

Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro

610 615 620

Glu Ser Gly Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

625 630 635 640

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr

645 650 655

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro

660 665 670

Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

675 680 685

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro

690 695 700

Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly

705 710 715 720

Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

725 730 735

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

740 745 750

Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Glu Pro Ala Thr Ser Gly

755 760 765

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

770 775 780

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Ala Ser Ser Gly

785 790 795 800

Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro

805 810 815

Ala Thr Gly His His His His His His His His

820 825

<210> 85

<211> 1403

<212> PRT

<213> 人工序列

<220>

<223> pNL166

<400> 85

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly

450 455 460

Ser Pro Gly Ala Glu Thr Ala Leu Val Pro Arg Ser Phe Leu Leu Arg

465 470 475 480

Asn Pro Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly

485 490 495

Ala Gly Ser Pro Gly Ala Glu Thr Ala Gly Ala Pro Gly Ser Pro Ala

500 505 510

Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro

515 520 525

Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

530 535 540

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr

545 550 555 560

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu

565 570 575

Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

580 585 590

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro

595 600 605

Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr

610 615 620

Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

625 630 635 640

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

645 650 655

Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr

660 665 670

Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

675 680 685

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu

690 695 700

Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu

705 710 715 720

Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

725 730 735

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Thr

740 745 750

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu

755 760 765

Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

770 775 780

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Pro Ala

785 790 795 800

Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro

805 810 815

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

820 825 830

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr

835 840 845

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu

850 855 860

Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

865 870 875 880

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

885 890 895

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu

900 905 910

Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

915 920 925

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu

930 935 940

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

945 950 955 960

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

965 970 975

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu

980 985 990

Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu

995 1000 1005

Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

1010 1015 1020

Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser

1025 1030 1035

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly

1040 1045 1050

Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro

1055 1060 1065

Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

1070 1075 1080

Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

1085 1090 1095

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser

1100 1105 1110

Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

1115 1120 1125

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

1130 1135 1140

Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser

1145 1150 1155

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser

1160 1165 1170

Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

1175 1180 1185

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

1190 1195 1200

Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser

1205 1210 1215

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu

1220 1225 1230

Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro

1235 1240 1245

Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

1250 1255 1260

Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

1265 1270 1275

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala

1280 1285 1290

Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr

1295 1300 1305

Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

1310 1315 1320

Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser

1325 1330 1335

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser

1340 1345 1350

Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu

1355 1360 1365

Gly Ser Ala Pro Ala Ser Ser Gly Ala Glu Thr Ala Glu Gln Lys

1370 1375 1380

Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

1385 1390 1395

His His His His His

1400

<210> 86

<211> 585

<212> PRT

<213> 人工序列

<220>

<223> pNL167

<400> 86

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Gly Ala Pro Ser

180 185 190

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala

195 200 205

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

210 215 220

Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr

225 230 235 240

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro

245 250 255

Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser Leu Thr Arg Ala Glu Thr

260 265 270

Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile

275 280 285

Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg

290 295 300

Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val

305 310 315 320

Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn

325 330 335

Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys

340 345 350

Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr

355 360 365

Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn

370 375 380

Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp

385 390 395 400

Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp

405 410 415

Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser

420 425 430

Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln

435 440 445

Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr

450 455 460

Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly

465 470 475 480

Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu

485 490 495

Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu

500 505 510

Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr

515 520 525

Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro

530 535 540

Ser Lys Leu Thr Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu

545 550 555 560

Thr Ala Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr

565 570 575

Gly His His His His His His His His

580 585

<210> 87

<211> 657

<212> PRT

<213> 人工序列

<220>

<223> pNL168

<400> 87

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Gly Ala Pro Ser

180 185 190

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala

195 200 205

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

210 215 220

Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr

225 230 235 240

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro

245 250 255

Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

260 265 270

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr

275 280 285

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro

290 295 300

Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr

305 310 315 320

Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala

325 330 335

Ser Ser Leu Thr Arg Ala Glu Thr Val Phe Pro Asp Val Asp Tyr Val

340 345 350

Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr

355 360 365

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

370 375 380

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

385 390 395 400

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

405 410 415

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

420 425 430

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

435 440 445

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

450 455 460

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

465 470 475 480

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

485 490 495

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

500 505 510

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

515 520 525

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

530 535 540

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

545 550 555 560

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

565 570 575

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

580 585 590

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

595 600 605

Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

610 615 620

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

625 630 635 640

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

645 650 655

His

<210> 88

<211> 801

<212> PRT

<213> 人工序列

<220>

<223> pNL169

<400> 88

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Gly Ala Pro Gly

180 185 190

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

195 200 205

Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

210 215 220

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

225 230 235 240

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu

245 250 255

Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

260 265 270

Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

275 280 285

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser

290 295 300

Ala Thr Pro Glu Ser Gly Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

305 310 315 320

Thr Glu Glu Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

325 330 335

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser

340 345 350

Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

355 360 365

Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

370 375 380

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala

385 390 395 400

Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

405 410 415

Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

420 425 430

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Glu Pro Ala

435 440 445

Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

450 455 460

Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Ala

465 470 475 480

Ser Ser Leu Thr Arg Ala Glu Thr Val Phe Pro Asp Val Asp Tyr Val

485 490 495

Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr

500 505 510

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

515 520 525

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

530 535 540

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

545 550 555 560

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

565 570 575

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

580 585 590

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

595 600 605

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

610 615 620

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

625 630 635 640

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

645 650 655

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

660 665 670

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

675 680 685

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

690 695 700

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

705 710 715 720

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

725 730 735

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

740 745 750

Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

755 760 765

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

770 775 780

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

785 790 795 800

His

<210> 89

<211> 585

<212> PRT

<213> 人工序列

<220>

<223> pNL170

<400> 89

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu

195 200 205

Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu

210 215 220

Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr

225 230 235 240

Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

245 250 255

Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser

260 265 270

Ser Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile

275 280 285

Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg

290 295 300

Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val

305 310 315 320

Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn

325 330 335

Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys

340 345 350

Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr

355 360 365

Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn

370 375 380

Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp

385 390 395 400

Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp

405 410 415

Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser

420 425 430

Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln

435 440 445

Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr

450 455 460

Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly

465 470 475 480

Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu

485 490 495

Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu

500 505 510

Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr

515 520 525

Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro

530 535 540

Ser Lys Leu Thr Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu

545 550 555 560

Thr Ala Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr

565 570 575

Gly His His His His His His His His

580 585

<210> 90

<211> 657

<212> PRT

<213> 人工序列

<220>

<223> pNL171

<400> 90

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu

195 200 205

Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu

210 215 220

Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr

225 230 235 240

Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

245 250 255

Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser

260 265 270

Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser

275 280 285

Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

290 295 300

Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro

305 310 315 320

Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser

325 330 335

Glu Gly Ser Ala Pro Gly Ala Ser Ser Phe Pro Asp Val Asp Tyr Val

340 345 350

Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr

355 360 365

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

370 375 380

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

385 390 395 400

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

405 410 415

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

420 425 430

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

435 440 445

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

450 455 460

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

465 470 475 480

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

485 490 495

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

500 505 510

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

515 520 525

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

530 535 540

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

545 550 555 560

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

565 570 575

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

580 585 590

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

595 600 605

Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

610 615 620

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

625 630 635 640

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

645 650 655

His

<210> 91

<211> 801

<212> PRT

<213> 人工序列

<220>

<223> pNL172

<400> 91

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Gly Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

195 200 205

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr

210 215 220

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr

225 230 235 240

Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

245 250 255

Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser

260 265 270

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala

275 280 285

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

290 295 300

Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

305 310 315 320

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly Ser

325 330 335

Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

340 345 350

Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr

355 360 365

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala

370 375 380

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

385 390 395 400

Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser

405 410 415

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro

420 425 430

Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

435 440 445

Ala Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr

450 455 460

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro

465 470 475 480

Ser Glu Gly Ser Ala Pro Ala Ser Ser Phe Pro Asp Val Asp Tyr Val

485 490 495

Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr

500 505 510

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

515 520 525

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

530 535 540

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

545 550 555 560

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

565 570 575

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

580 585 590

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

595 600 605

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

610 615 620

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

625 630 635 640

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

645 650 655

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

660 665 670

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

675 680 685

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

690 695 700

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

705 710 715 720

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

725 730 735

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

740 745 750

Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

755 760 765

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

770 775 780

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

785 790 795 800

His

<210> 92

<211> 585

<212> PRT

<213> 人工序列

<220>

<223> pNL173

<400> 92

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr

210 215 220

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr

225 230 235 240

Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

245 250 255

Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr

260 265 270

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser Thr Ile

275 280 285

Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg

290 295 300

Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val

305 310 315 320

Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn

325 330 335

Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys

340 345 350

Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr

355 360 365

Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn

370 375 380

Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp

385 390 395 400

Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp

405 410 415

Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser

420 425 430

Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln

435 440 445

Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr

450 455 460

Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly

465 470 475 480

Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu

485 490 495

Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu

500 505 510

Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr

515 520 525

Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro

530 535 540

Ser Lys Leu Thr Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu

545 550 555 560

Thr Ala Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr

565 570 575

Gly His His His His His His His His

580 585

<210> 93

<211> 657

<212> PRT

<213> 人工序列

<220>

<223> pNL174

<400> 93

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr

210 215 220

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr

225 230 235 240

Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

245 250 255

Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr

260 265 270

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro

275 280 285

Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

290 295 300

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr

305 310 315 320

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser

325 330 335

Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

340 345 350

Ala Pro Gly Ala Ser Ser Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr

355 360 365

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

370 375 380

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

385 390 395 400

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

405 410 415

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

420 425 430

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

435 440 445

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

450 455 460

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

465 470 475 480

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

485 490 495

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

500 505 510

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

515 520 525

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

530 535 540

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

545 550 555 560

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

565 570 575

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

580 585 590

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

595 600 605

Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

610 615 620

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

625 630 635 640

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

645 650 655

His

<210> 94

<211> 801

<212> PRT

<213> 人工序列

<220>

<223> pNL175

<400> 94

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Gly Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

210 215 220

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser

225 230 235 240

Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

245 250 255

Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

260 265 270

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly

275 280 285

Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu

290 295 300

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

305 310 315 320

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Pro Ala Gly

325 330 335

Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly Ser Pro Thr Ser

340 345 350

Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

355 360 365

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser

370 375 380

Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

385 390 395 400

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

405 410 415

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly

420 425 430

Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly

435 440 445

Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

450 455 460

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser

465 470 475 480

Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

485 490 495

Ser Ala Pro Ala Ser Ser Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr

500 505 510

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

515 520 525

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

530 535 540

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

545 550 555 560

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

565 570 575

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

580 585 590

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

595 600 605

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

610 615 620

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

625 630 635 640

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

645 650 655

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

660 665 670

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

675 680 685

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

690 695 700

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

705 710 715 720

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

725 730 735

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

740 745 750

Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

755 760 765

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

770 775 780

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

785 790 795 800

His

<210> 95

<211> 585

<212> PRT

<213> 人工序列

<220>

<223> pNL176

<400> 95

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr

210 215 220

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

225 230 235 240

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

245 250 255

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

260 265 270

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala

275 280 285

Ser Ser Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg

290 295 300

Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val

305 310 315 320

Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn

325 330 335

Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys

340 345 350

Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr

355 360 365

Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn

370 375 380

Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp

385 390 395 400

Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp

405 410 415

Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser

420 425 430

Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln

435 440 445

Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr

450 455 460

Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly

465 470 475 480

Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu

485 490 495

Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu

500 505 510

Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr

515 520 525

Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro

530 535 540

Ser Lys Leu Thr Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu

545 550 555 560

Thr Ala Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr

565 570 575

Gly His His His His His His His His

580 585

<210> 96

<211> 657

<212> PRT

<213> 人工序列

<220>

<223> pNL177

<400> 96

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr

210 215 220

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

225 230 235 240

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

245 250 255

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

260 265 270

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr

275 280 285

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro

290 295 300

Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

305 310 315 320

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser

325 330 335

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro

340 345 350

Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser Asn Ile Thr Gln Ser Thr

355 360 365

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

370 375 380

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

385 390 395 400

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

405 410 415

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

420 425 430

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

435 440 445

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

450 455 460

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

465 470 475 480

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

485 490 495

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

500 505 510

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

515 520 525

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

530 535 540

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

545 550 555 560

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

565 570 575

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

580 585 590

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

595 600 605

Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

610 615 620

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

625 630 635 640

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

645 650 655

His

<210> 97

<211> 801

<212> PRT

<213> 人工序列

<220>

<223> pNL178

<400> 97

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

210 215 220

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

225 230 235 240

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

245 250 255

Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

260 265 270

Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

275 280 285

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser

290 295 300

Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

305 310 315 320

Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

325 330 335

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly

340 345 350

Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly

355 360 365

Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

370 375 380

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser

385 390 395 400

Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

405 410 415

Glu Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

420 425 430

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu

435 440 445

Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

450 455 460

Ser Ala Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

465 470 475 480

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu

485 490 495

Pro Ser Glu Gly Ser Ala Pro Ala Ser Ser Asn Ile Thr Gln Ser Thr

500 505 510

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

515 520 525

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

530 535 540

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

545 550 555 560

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

565 570 575

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

580 585 590

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

595 600 605

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

610 615 620

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

625 630 635 640

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

645 650 655

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

660 665 670

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

675 680 685

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

690 695 700

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

705 710 715 720

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

725 730 735

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

740 745 750

Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

755 760 765

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

770 775 780

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

785 790 795 800

His

<210> 98

<211> 585

<212> PRT

<213> 人工序列

<220>

<223> pNL179

<400> 98

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Gly Ala Pro Ser

210 215 220

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala

225 230 235 240

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

245 250 255

Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr

260 265 270

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro

275 280 285

Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser Phe Asn Asp Phe Thr Arg

290 295 300

Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val

305 310 315 320

Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn

325 330 335

Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys

340 345 350

Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr

355 360 365

Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn

370 375 380

Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp

385 390 395 400

Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp

405 410 415

Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser

420 425 430

Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln

435 440 445

Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr

450 455 460

Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly

465 470 475 480

Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu

485 490 495

Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu

500 505 510

Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr

515 520 525

Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro

530 535 540

Ser Lys Leu Thr Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu

545 550 555 560

Thr Ala Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr

565 570 575

Gly His His His His His His His His

580 585

<210> 99

<211> 657

<212> PRT

<213> 人工序列

<220>

<223> pNL180

<400> 99

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Gly Ala Pro Ser

210 215 220

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala

225 230 235 240

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

245 250 255

Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr

260 265 270

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro

275 280 285

Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

290 295 300

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr

305 310 315 320

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro

325 330 335

Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr

340 345 350

Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala

355 360 365

Ser Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

370 375 380

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

385 390 395 400

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

405 410 415

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

420 425 430

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

435 440 445

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

450 455 460

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

465 470 475 480

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

485 490 495

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

500 505 510

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

515 520 525

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

530 535 540

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

545 550 555 560

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

565 570 575

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

580 585 590

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

595 600 605

Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

610 615 620

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

625 630 635 640

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

645 650 655

His

<210> 100

<211> 801

<212> PRT

<213> 人工序列

<220>

<223> pNL181

<400> 100

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Gly Ala Pro Gly

210 215 220

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

225 230 235 240

Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

245 250 255

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

260 265 270

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu

275 280 285

Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

290 295 300

Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

305 310 315 320

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser

325 330 335

Ala Thr Pro Glu Ser Gly Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

340 345 350

Thr Glu Glu Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

355 360 365

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser

370 375 380

Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

385 390 395 400

Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

405 410 415

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala

420 425 430

Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

435 440 445

Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

450 455 460

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Glu Pro Ala

465 470 475 480

Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

485 490 495

Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Ala

500 505 510

Ser Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

515 520 525

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

530 535 540

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

545 550 555 560

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

565 570 575

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

580 585 590

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

595 600 605

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

610 615 620

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

625 630 635 640

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

645 650 655

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

660 665 670

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

675 680 685

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

690 695 700

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

705 710 715 720

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

725 730 735

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

740 745 750

Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

755 760 765

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

770 775 780

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

785 790 795 800

His

<210> 101

<211> 585

<212> PRT

<213> 人工序列

<220>

<223> pNL182

<400> 101

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Gly Ala

260 265 270

Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu

275 280 285

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

290 295 300

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

305 310 315 320

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

325 330 335

Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser Thr Gly Val Lys

340 345 350

Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr

355 360 365

Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn

370 375 380

Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp

385 390 395 400

Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp

405 410 415

Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser

420 425 430

Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln

435 440 445

Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr

450 455 460

Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly

465 470 475 480

Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu

485 490 495

Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu

500 505 510

Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr

515 520 525

Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro

530 535 540

Ser Lys Leu Thr Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu

545 550 555 560

Thr Ala Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr

565 570 575

Gly His His His His His His His His

580 585

<210> 102

<211> 657

<212> PRT

<213> 人工序列

<220>

<223> pNL183

<400> 102

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Gly Ala

260 265 270

Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu

275 280 285

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

290 295 300

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

305 310 315 320

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

325 330 335

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu

340 345 350

Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

355 360 365

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

370 375 380

Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr

385 390 395 400

Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

405 410 415

Gly Ala Ser Ser Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

420 425 430

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

435 440 445

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

450 455 460

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

465 470 475 480

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

485 490 495

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

500 505 510

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

515 520 525

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

530 535 540

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

545 550 555 560

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

565 570 575

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

580 585 590

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

595 600 605

Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

610 615 620

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

625 630 635 640

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

645 650 655

His

<210> 103

<211> 801

<212> PRT

<213> 人工序列

<220>

<223> pNL184

<400> 103

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Gly Ala

260 265 270

Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu

275 280 285

Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr

290 295 300

Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr

305 310 315 320

Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser

325 330 335

Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro

340 345 350

Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

355 360 365

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser

370 375 380

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Pro Ala Gly Ser Pro

385 390 395 400

Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu

405 410 415

Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser

420 425 430

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr

435 440 445

Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

450 455 460

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu

465 470 475 480

Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro

485 490 495

Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

500 505 510

Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Glu

515 520 525

Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr

530 535 540

Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

545 550 555 560

Pro Ala Ser Ser Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

565 570 575

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

580 585 590

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

595 600 605

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

610 615 620

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

625 630 635 640

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

645 650 655

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

660 665 670

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

675 680 685

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

690 695 700

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

705 710 715 720

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

725 730 735

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

740 745 750

Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

755 760 765

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

770 775 780

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

785 790 795 800

His

<210> 104

<211> 585

<212> PRT

<213> 人工序列

<220>

<223> pNL185

<400> 104

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Gly Ala Pro Ser Pro

450 455 460

Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr

465 470 475 480

Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr

485 490 495

Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser

500 505 510

Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser

515 520 525

Glu Gly Ser Ala Pro Gly Ala Ser Ser Leu Thr Gly Pro Glu Gly Pro

530 535 540

Ser Lys Leu Thr Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu

545 550 555 560

Thr Ala Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr

565 570 575

Gly His His His His His His His His

580 585

<210> 105

<211> 657

<212> PRT

<213> 人工序列

<220>

<223> pNL186

<400> 105

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Gly Ala Pro Ser Pro

450 455 460

Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr

465 470 475 480

Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr

485 490 495

Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser

500 505 510

Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser

515 520 525

Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

530 535 540

Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser

545 550 555 560

Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser

565 570 575

Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu

580 585 590

Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser

595 600 605

Ser Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

610 615 620

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

625 630 635 640

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

645 650 655

His

<210> 106

<211> 801

<212> PRT

<213> 人工序列

<220>

<223> pNL187

<400> 106

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Gly Ala Pro Gly Thr

450 455 460

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr

465 470 475 480

Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

485 490 495

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr

500 505 510

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro

515 520 525

Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr

530 535 540

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

545 550 555 560

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

565 570 575

Thr Pro Glu Ser Gly Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr

580 585 590

Glu Glu Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr

595 600 605

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala

610 615 620

Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

625 630 635 640

Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

645 650 655

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala Thr

660 665 670

Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr

675 680 685

Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr

690 695 700

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Glu Pro Ala Thr

705 710 715 720

Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

725 730 735

Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Ala Ser

740 745 750

Ser Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

755 760 765

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

770 775 780

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

785 790 795 800

His

<210> 107

<211> 585

<212> PRT

<213> 人工序列

<220>

<223> pNL188

<400> 107

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser

145 150 155 160

Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

165 170 175

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser

180 185 190

Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

195 200 205

Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

210 215 220

Ala Ser Ser Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg

225 230 235 240

Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys

245 250 255

Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr

260 265 270

Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile

275 280 285

Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg

290 295 300

Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val

305 310 315 320

Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn

325 330 335

Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys

340 345 350

Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr

355 360 365

Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn

370 375 380

Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp

385 390 395 400

Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp

405 410 415

Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser

420 425 430

Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln

435 440 445

Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr

450 455 460

Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly

465 470 475 480

Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu

485 490 495

Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu

500 505 510

Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr

515 520 525

Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro

530 535 540

Ser Lys Leu Thr Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu

545 550 555 560

Thr Ala Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr

565 570 575

Gly His His His His His His His His

580 585

<210> 108

<211> 657

<212> PRT

<213> 人工序列

<220>

<223> pNL189

<400> 108

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser

145 150 155 160

Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

165 170 175

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser

180 185 190

Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

195 200 205

Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

210 215 220

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu

225 230 235 240

Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

245 250 255

Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

260 265 270

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu

275 280 285

Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser Asp Asn Lys Val Val

290 295 300

Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys

305 310 315 320

Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser Val Ser Gln Thr

325 330 335

Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp Val Asp Tyr Val

340 345 350

Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr

355 360 365

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

370 375 380

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

385 390 395 400

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

405 410 415

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

420 425 430

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

435 440 445

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

450 455 460

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

465 470 475 480

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

485 490 495

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

500 505 510

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

515 520 525

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

530 535 540

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

545 550 555 560

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

565 570 575

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

580 585 590

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

595 600 605

Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

610 615 620

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

625 630 635 640

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

645 650 655

His

<210> 109

<211> 801

<212> PRT

<213> 人工序列

<220>

<223> pNL190

<400> 109

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Gly Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro

145 150 155 160

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

165 170 175

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro

180 185 190

Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro

195 200 205

Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

210 215 220

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu

225 230 235 240

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

245 250 255

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

260 265 270

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala

275 280 285

Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu

290 295 300

Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

305 310 315 320

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu

325 330 335

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

340 345 350

Ser Glu Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

355 360 365

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr

370 375 380

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu

385 390 395 400

Gly Ser Ala Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

405 410 415

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr

420 425 430

Glu Pro Ser Glu Gly Ser Ala Pro Ala Ser Ser Asp Asn Lys Val Val

435 440 445

Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys

450 455 460

Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser Val Ser Gln Thr

465 470 475 480

Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp Val Asp Tyr Val

485 490 495

Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr

500 505 510

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

515 520 525

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

530 535 540

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

545 550 555 560

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

565 570 575

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

580 585 590

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

595 600 605

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

610 615 620

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

625 630 635 640

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

645 650 655

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

660 665 670

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

675 680 685

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

690 695 700

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

705 710 715 720

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

725 730 735

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

740 745 750

Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr

755 760 765

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser

770 775 780

Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His His

785 790 795 800

His

<210> 110

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL195

<400> 110

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

275 280 285

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

290 295 300

Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 111

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL196

<400> 111

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu

275 280 285

Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu

290 295 300

Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 112

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL197

<400> 112

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

275 280 285

Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

290 295 300

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 113

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL198

<400> 113

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Gly Ala Pro Gly Ser Pro Ala Gly Ser

145 150 155 160

Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

165 170 175

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser

180 185 190

Ser Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 114

<211> 549

<212> PRT

<213> 人工序列

<220>

<223> pNL199

<400> 114

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Gly Ala Pro Gly Ser Pro Ala

325 330 335

Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro

340 345 350

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

355 360 365

Ala Ser Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu Gly Pro Ser Lys Leu Thr

500 505 510

Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Glu Gln

515 520 525

Lys Leu Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His

530 535 540

His His His His His

545

<210> 115

<211> 611

<212> PRT

<213> 人工序列

<220>

<223> pNL202

<400> 115

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly

450 455 460

Ser Pro Gly Ala Glu Thr Ala Leu Val Pro Arg Ser Phe Leu Leu Arg

465 470 475 480

Asn Pro Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly

485 490 495

Ala Gly Ser Pro Gly Ala Glu Thr Ala Gly Ala Pro Ser Pro Ala Gly

500 505 510

Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu

515 520 525

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

530 535 540

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu

545 550 555 560

Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

565 570 575

Ser Ala Pro Gly Ala Ser Ser Gly Ala Glu Thr Ala Glu Gln Lys Leu

580 585 590

Ile Ser Glu Glu Asp Leu Ser Pro Ala Thr Gly His His His His His

595 600 605

His His His

610

<210> 116

<211> 1345

<212> PRT

<213> 人工序列

<220>

<223> FIX-092

<400> 116

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Arg

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu

450 455 460

Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr Gly Ser Pro Gly Ser Pro

465 470 475 480

Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr

485 490 495

Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

500 505 510

Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser

515 520 525

Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser

530 535 540

Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

545 550 555 560

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu

565 570 575

Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro

580 585 590

Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

595 600 605

Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser

610 615 620

Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro

625 630 635 640

Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

645 650 655

Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser

660 665 670

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser

675 680 685

Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

690 695 700

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser

705 710 715 720

Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser

725 730 735

Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

740 745 750

Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Pro

755 760 765

Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr

770 775 780

Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr

785 790 795 800

Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser

805 810 815

Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser

820 825 830

Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

835 840 845

Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser

850 855 860

Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser

865 870 875 880

Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu

885 890 895

Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser

900 905 910

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser

915 920 925

Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

930 935 940

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser

945 950 955 960

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser

965 970 975

Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

980 985 990

Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro

995 1000 1005

Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly Ser

1010 1015 1020

Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu

1025 1030 1035

Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

1040 1045 1050

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu

1055 1060 1065

Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

1070 1075 1080

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

1085 1090 1095

Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

1100 1105 1110

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro

1115 1120 1125

Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala

1130 1135 1140

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

1145 1150 1155

Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

1160 1165 1170

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro

1175 1180 1185

Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro

1190 1195 1200

Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

1205 1210 1215

Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

1220 1225 1230

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu

1235 1240 1245

Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala Thr

1250 1255 1260

Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

1265 1270 1275

Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

1280 1285 1290

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Glu

1295 1300 1305

Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

1310 1315 1320

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

1325 1330 1335

Ser Ala Pro Gly Ser Ser Ser

1340 1345

<210> 117

<211> 655

<212> PRT

<213> 人工序列

<220>

<223> pJH0131

<400> 117

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly

450 455 460

Ser Pro Gly Ala Glu Thr Ala Leu Val Pro Arg Ser Phe Leu Leu Arg

465 470 475 480

Asn Pro Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly

485 490 495

Ala Gly Ser Pro Gly Ala Glu Thr Ala Gly Ala Pro Ser Pro Ala Gly

500 505 510

Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu

515 520 525

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

530 535 540

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu

545 550 555 560

Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

565 570 575

Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

580 585 590

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu

595 600 605

Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

610 615 620

Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

625 630 635 640

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser

645 650 655

<210> 118

<211> 503

<212> PRT

<213> 人工序列

<220>

<223> pJH44

<400> 118

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Gly Ala Pro Gly Ser Pro Ala Gly Ser

145 150 155 160

Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

165 170 175

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser

180 185 190

Ser Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr

500

<210> 119

<211> 539

<212> PRT

<213> 人工序列

<220>

<223> pJH46

<400> 119

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr

210 215 220

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

225 230 235 240

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

245 250 255

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

260 265 270

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala

275 280 285

Ser Ser Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg

290 295 300

Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val

305 310 315 320

Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn

325 330 335

Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys

340 345 350

Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr

355 360 365

Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn

370 375 380

Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp

385 390 395 400

Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp

405 410 415

Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser

420 425 430

Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln

435 440 445

Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr

450 455 460

Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly

465 470 475 480

Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu

485 490 495

Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu

500 505 510

Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr

515 520 525

Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr

530 535

<210> 120

<211> 611

<212> PRT

<213> 人工序列

<220>

<223> pJH47

<400> 120

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr

210 215 220

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

225 230 235 240

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

245 250 255

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

260 265 270

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr

275 280 285

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro

290 295 300

Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

305 310 315 320

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser

325 330 335

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro

340 345 350

Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser Asn Ile Thr Gln Ser Thr

355 360 365

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

370 375 380

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

385 390 395 400

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

405 410 415

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

420 425 430

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

435 440 445

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

450 455 460

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

465 470 475 480

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

485 490 495

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

500 505 510

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

515 520 525

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

530 535 540

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

545 550 555 560

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

565 570 575

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

580 585 590

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

595 600 605

Lys Leu Thr

610

<210> 121

<211> 655

<212> PRT

<213> 人工序列

<220>

<223> pJH50

<400> 121

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly

450 455 460

Ser Pro Gly Ala Glu Thr Ala Leu Val Pro Arg Ser Phe Leu Leu Arg

465 470 475 480

Asn Pro Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly

485 490 495

Ala Gly Ser Pro Gly Ala Glu Thr Ala Gly Ala Pro Thr Ser Thr Glu

500 505 510

Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

515 520 525

Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

530 535 540

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

545 550 555 560

Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

565 570 575

Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

580 585 590

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu

595 600 605

Pro Ser Glu Gly Ser Ala Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

610 615 620

Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

625 630 635 640

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser

645 650 655

<210> 122

<211> 799

<212> PRT

<213> 人工序列

<220>

<223> pJH51

<400> 122

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly

450 455 460

Ser Pro Gly Ala Glu Thr Ala Leu Val Pro Arg Ser Phe Leu Leu Arg

465 470 475 480

Asn Pro Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly

485 490 495

Ala Gly Ser Pro Gly Ala Glu Thr Ala Gly Ala Pro Gly Thr Ser Glu

500 505 510

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

515 520 525

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

530 535 540

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu

545 550 555 560

Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu

565 570 575

Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

580 585 590

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro

595 600 605

Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro

610 615 620

Glu Ser Gly Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

625 630 635 640

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr

645 650 655

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro

660 665 670

Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

675 680 685

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro

690 695 700

Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly

705 710 715 720

Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu

725 730 735

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

740 745 750

Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Glu Pro Ala Thr Ser Gly

755 760 765

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

770 775 780

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Ala Ser Ser

785 790 795

<210> 123

<211> 583

<212> PRT

<213> 人工序列

<220>

<223> pJH52

<400> 123

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly

450 455 460

Ser Pro Gly Ala Glu Thr Ala Leu Val Pro Arg Ser Phe Leu Leu Arg

465 470 475 480

Asn Pro Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly

485 490 495

Ala Gly Ser Pro Gly Ala Glu Thr Ala Gly Ala Pro Thr Ser Glu Ser

500 505 510

Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

515 520 525

Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

530 535 540

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser

545 550 555 560

Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

565 570 575

Ser Ala Pro Gly Ala Ser Ser

580

<210> 124

<211> 503

<212> PRT

<213> 人工序列

<220>

<223> pJH54

<400> 124

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Gly Ala

260 265 270

Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser

275 280 285

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser

290 295 300

Gly Ser Glu Thr Pro Ala Ser Ser Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr

500

<210> 125

<211> 503

<212> PRT

<213> 人工序列

<220>

<223> pJH55

<400> 125

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

210 215 220

Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

225 230 235 240

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr

500

<210> 126

<211> 625

<212> PRT

<213> 人工序列

<220>

<223> pJH59

<400> 126

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

210 215 220

Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

225 230 235 240

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr

500 505 510

Ala Leu Val Pro Arg Ser Phe Leu Leu Arg Asn Pro Asn Asp Lys Tyr

515 520 525

Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly Ala Gly Ser Pro Gly Ala

530 535 540

Glu Thr Ala Gly Ala Pro Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

545 550 555 560

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser

565 570 575

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser

580 585 590

Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

595 600 605

Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser

610 615 620

Ser

625

<210> 127

<211> 697

<212> PRT

<213> 人工序列

<220>

<223> pJH60

<400> 127

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

210 215 220

Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

225 230 235 240

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr

500 505 510

Ala Leu Val Pro Arg Ser Phe Leu Leu Arg Asn Pro Asn Asp Lys Tyr

515 520 525

Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly Ala Gly Ser Pro Gly Ala

530 535 540

Glu Thr Ala Gly Ala Pro Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

545 550 555 560

Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser

565 570 575

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr

580 585 590

Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr

595 600 605

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro

610 615 620

Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser

625 630 635 640

Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

645 650 655

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser

660 665 670

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser

675 680 685

Glu Gly Ser Ala Pro Gly Ala Ser Ser

690 695

<210> 128

<211> 841

<212> PRT

<213> 人工序列

<220>

<223> pJH61

<400> 128

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

210 215 220

Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

225 230 235 240

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr

500 505 510

Ala Leu Val Pro Arg Ser Phe Leu Leu Arg Asn Pro Asn Asp Lys Tyr

515 520 525

Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly Ala Gly Ser Pro Gly Ala

530 535 540

Glu Thr Ala Gly Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

545 550 555 560

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr

565 570 575

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr

580 585 590

Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

595 600 605

Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser

610 615 620

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala

625 630 635 640

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

645 650 655

Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

660 665 670

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly Ser

675 680 685

Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

690 695 700

Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr

705 710 715 720

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala

725 730 735

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

740 745 750

Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser

755 760 765

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro

770 775 780

Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

785 790 795 800

Ala Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr

805 810 815

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro

820 825 830

Ser Glu Gly Ser Ala Pro Ala Ser Ser

835 840

<210> 129

<211> 661

<212> PRT

<213> 人工序列

<220>

<223> pJH62

<400> 129

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr

210 215 220

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

225 230 235 240

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

245 250 255

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

260 265 270

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala

275 280 285

Ser Ser Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg

290 295 300

Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val

305 310 315 320

Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn

325 330 335

Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys

340 345 350

Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr

355 360 365

Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn

370 375 380

Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp

385 390 395 400

Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp

405 410 415

Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser

420 425 430

Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln

435 440 445

Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr

450 455 460

Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly

465 470 475 480

Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu

485 490 495

Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu

500 505 510

Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr

515 520 525

Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly Ser Pro

530 535 540

Gly Ala Glu Thr Ala Leu Val Pro Arg Ser Phe Leu Leu Arg Asn Pro

545 550 555 560

Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly Ala Gly

565 570 575

Ser Pro Gly Ala Glu Thr Ala Gly Ala Pro Thr Ser Glu Ser Ala Thr

580 585 590

Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr

595 600 605

Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu

610 615 620

Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr

625 630 635 640

Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

645 650 655

Pro Gly Ala Ser Ser

660

<210> 130

<211> 733

<212> PRT

<213> 人工序列

<220>

<223> pJH63

<400> 130

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr

210 215 220

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

225 230 235 240

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

245 250 255

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

260 265 270

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala

275 280 285

Ser Ser Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg

290 295 300

Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val

305 310 315 320

Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn

325 330 335

Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys

340 345 350

Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr

355 360 365

Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn

370 375 380

Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp

385 390 395 400

Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp

405 410 415

Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser

420 425 430

Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln

435 440 445

Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr

450 455 460

Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly

465 470 475 480

Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu

485 490 495

Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu

500 505 510

Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr

515 520 525

Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly Ser Pro

530 535 540

Gly Ala Glu Thr Ala Leu Val Pro Arg Ser Phe Leu Leu Arg Asn Pro

545 550 555 560

Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly Ala Gly

565 570 575

Ser Pro Gly Ala Glu Thr Ala Gly Ala Pro Thr Ser Thr Glu Pro Ser

580 585 590

Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

595 600 605

Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser

610 615 620

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser

625 630 635 640

Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr

645 650 655

Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser

660 665 670

Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser

675 680 685

Glu Gly Ser Ala Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr

690 695 700

Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser

705 710 715 720

Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser

725 730

<210> 131

<211> 877

<212> PRT

<213> 人工序列

<220>

<223> pJH64

<400> 131

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr

210 215 220

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

225 230 235 240

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

245 250 255

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

260 265 270

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala

275 280 285

Ser Ser Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg

290 295 300

Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val

305 310 315 320

Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn

325 330 335

Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys

340 345 350

Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr

355 360 365

Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn

370 375 380

Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp

385 390 395 400

Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp

405 410 415

Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser

420 425 430

Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln

435 440 445

Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr

450 455 460

Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly

465 470 475 480

Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu

485 490 495

Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu

500 505 510

Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr

515 520 525

Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly Ser Pro

530 535 540

Gly Ala Glu Thr Ala Leu Val Pro Arg Ser Phe Leu Leu Arg Asn Pro

545 550 555 560

Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly Ala Gly

565 570 575

Ser Pro Gly Ala Glu Thr Ala Gly Ala Pro Gly Thr Ser Glu Ser Ala

580 585 590

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

595 600 605

Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

610 615 620

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

625 630 635 640

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

645 650 655

Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr

660 665 670

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr

675 680 685

Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

690 695 700

Gly Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser

705 710 715 720

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro

725 730 735

Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

740 745 750

Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr

755 760 765

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr

770 775 780

Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

785 790 795 800

Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr

805 810 815

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro

820 825 830

Ser Glu Gly Ser Ala Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

835 840 845

Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr

850 855 860

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Ala Ser Ser

865 870 875

<210> 132

<211> 733

<212> PRT

<213> 人工序列

<220>

<223> pJH65

<400> 132

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr

210 215 220

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

225 230 235 240

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

245 250 255

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

260 265 270

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr

275 280 285

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro

290 295 300

Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

305 310 315 320

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser

325 330 335

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro

340 345 350

Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser Asn Ile Thr Gln Ser Thr

355 360 365

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

370 375 380

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

385 390 395 400

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

405 410 415

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

420 425 430

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

435 440 445

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

450 455 460

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

465 470 475 480

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

485 490 495

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

500 505 510

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

515 520 525

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

530 535 540

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

545 550 555 560

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

565 570 575

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

580 585 590

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

595 600 605

Lys Leu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Leu Val Pro

610 615 620

Arg Ser Phe Leu Leu Arg Asn Pro Asn Asp Lys Tyr Glu Pro Phe Trp

625 630 635 640

Glu Asp Glu Glu Ser Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Gly

645 650 655

Ala Pro Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu

660 665 670

Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr

675 680 685

Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr

690 695 700

Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser

705 710 715 720

Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser

725 730

<210> 133

<211> 805

<212> PRT

<213> 人工序列

<220>

<223> pJH66

<400> 133

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr

210 215 220

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

225 230 235 240

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

245 250 255

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

260 265 270

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr

275 280 285

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro

290 295 300

Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

305 310 315 320

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser

325 330 335

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro

340 345 350

Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser Asn Ile Thr Gln Ser Thr

355 360 365

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

370 375 380

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

385 390 395 400

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

405 410 415

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

420 425 430

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

435 440 445

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

450 455 460

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

465 470 475 480

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

485 490 495

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

500 505 510

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

515 520 525

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

530 535 540

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

545 550 555 560

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

565 570 575

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

580 585 590

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

595 600 605

Lys Leu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Leu Val Pro

610 615 620

Arg Ser Phe Leu Leu Arg Asn Pro Asn Asp Lys Tyr Glu Pro Phe Trp

625 630 635 640

Glu Asp Glu Glu Ser Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Gly

645 650 655

Ala Pro Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser

660 665 670

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr

675 680 685

Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

690 695 700

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu

705 710 715 720

Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro

725 730 735

Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

740 745 750

Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Glu

755 760 765

Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr

770 775 780

Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

785 790 795 800

Pro Gly Ala Ser Ser

805

<210> 134

<211> 949

<212> PRT

<213> 人工序列

<220>

<223> pJH67

<400> 134

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr

210 215 220

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

225 230 235 240

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

245 250 255

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

260 265 270

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr

275 280 285

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro

290 295 300

Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

305 310 315 320

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser

325 330 335

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro

340 345 350

Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser Asn Ile Thr Gln Ser Thr

355 360 365

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

370 375 380

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

385 390 395 400

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

405 410 415

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

420 425 430

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

435 440 445

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

450 455 460

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

465 470 475 480

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

485 490 495

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

500 505 510

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

515 520 525

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

530 535 540

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

545 550 555 560

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

565 570 575

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

580 585 590

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

595 600 605

Lys Leu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Leu Val Pro

610 615 620

Arg Ser Phe Leu Leu Arg Asn Pro Asn Asp Lys Tyr Glu Pro Phe Trp

625 630 635 640

Glu Asp Glu Glu Ser Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Gly

645 650 655

Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

660 665 670

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

675 680 685

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

690 695 700

Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr

705 710 715 720

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser

725 730 735

Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

740 745 750

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr

755 760 765

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Pro Ala Gly Ser

770 775 780

Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr

785 790 795 800

Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr

805 810 815

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala

820 825 830

Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

835 840 845

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser

850 855 860

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser

865 870 875 880

Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

885 890 895

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser

900 905 910

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

915 920 925

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

930 935 940

Ala Pro Ala Ser Ser

945

<210> 135

<211> 545

<212> PRT

<213> 人工序列

<220>

<223> pJH68

<400> 135

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Gly Ala Pro Gly Ser Pro Ala Gly Ser

145 150 155 160

Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

165 170 175

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser

180 185 190

Ser Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Gly Ala

245 250 255

Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser

260 265 270

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser

275 280 285

Gly Ser Glu Thr Pro Ala Ser Ser Asn Ile Thr Gln Ser Thr Gln Ser

290 295 300

Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly

305 310 315 320

Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys

325 330 335

Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys

340 345 350

Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile

355 360 365

Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile

370 375 380

Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile

385 390 395 400

Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr

405 410 415

Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe

420 425 430

Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg

435 440 445

Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala

450 455 460

Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys

465 470 475 480

Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly

485 490 495

Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile

500 505 510

Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr

515 520 525

Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu

530 535 540

Thr

545

<210> 136

<211> 581

<212> PRT

<213> 人工序列

<220>

<223> pJH69

<400> 136

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Gly Ala Pro Gly Ser Pro Ala Gly Ser

145 150 155 160

Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

165 170 175

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser

180 185 190

Ser Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Gly Ala

245 250 255

Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu

260 265 270

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

275 280 285

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

290 295 300

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

305 310 315 320

Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser Asn Ile Thr Gln

325 330 335

Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp

340 345 350

Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val

355 360 365

Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr

370 375 380

Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly

385 390 395 400

Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val

405 410 415

Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr

420 425 430

Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn

435 440 445

Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile

450 455 460

Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe

465 470 475 480

His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu

485 490 495

Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn

500 505 510

Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln

515 520 525

Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe

530 535 540

Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys

545 550 555 560

Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu

565 570 575

Lys Thr Lys Leu Thr

580

<210> 137

<211> 653

<212> PRT

<213> 人工序列

<220>

<223> pJH70

<400> 137

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Gly Ala Pro Gly Ser Pro Ala Gly Ser

145 150 155 160

Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

165 170 175

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser

180 185 190

Ser Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Gly Ala

245 250 255

Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu

260 265 270

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

275 280 285

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

290 295 300

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

305 310 315 320

Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu

325 330 335

Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

340 345 350

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr

355 360 365

Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr

370 375 380

Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

385 390 395 400

Gly Ala Ser Ser Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

405 410 415

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

420 425 430

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

435 440 445

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

450 455 460

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

465 470 475 480

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

485 490 495

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

500 505 510

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

515 520 525

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

530 535 540

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

545 550 555 560

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

565 570 575

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

580 585 590

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

595 600 605

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

610 615 620

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

625 630 635 640

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr

645 650

<210> 138

<211> 625

<212> PRT

<213> 人工序列

<220>

<223> pJH71

<400> 138

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Gly Ala Pro Gly Ser Pro Ala Gly Ser

145 150 155 160

Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

165 170 175

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser

180 185 190

Ser Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr

500 505 510

Ala Leu Val Pro Arg Ser Phe Leu Leu Arg Asn Pro Asn Asp Lys Tyr

515 520 525

Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly Ala Gly Ser Pro Gly Ala

530 535 540

Glu Thr Ala Gly Ala Pro Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

545 550 555 560

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser

565 570 575

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser

580 585 590

Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

595 600 605

Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser

610 615 620

Ser

625

<210> 139

<211> 697

<212> PRT

<213> 人工序列

<220>

<223> pJH72

<400> 139

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Gly Ala Pro Gly Ser Pro Ala Gly Ser

145 150 155 160

Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

165 170 175

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser

180 185 190

Ser Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr

500 505 510

Ala Leu Val Pro Arg Ser Phe Leu Leu Arg Asn Pro Asn Asp Lys Tyr

515 520 525

Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly Ala Gly Ser Pro Gly Ala

530 535 540

Glu Thr Ala Gly Ala Pro Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

545 550 555 560

Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser

565 570 575

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr

580 585 590

Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr

595 600 605

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro

610 615 620

Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser

625 630 635 640

Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

645 650 655

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser

660 665 670

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser

675 680 685

Glu Gly Ser Ala Pro Gly Ala Ser Ser

690 695

<210> 140

<211> 841

<212> PRT

<213> 人工序列

<220>

<223> pJH73

<400> 140

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Gly Ala Pro Gly Ser Pro Ala Gly Ser

145 150 155 160

Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

165 170 175

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser

180 185 190

Ser Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr

500 505 510

Ala Leu Val Pro Arg Ser Phe Leu Leu Arg Asn Pro Asn Asp Lys Tyr

515 520 525

Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly Ala Gly Ser Pro Gly Ala

530 535 540

Glu Thr Ala Gly Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

545 550 555 560

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr

565 570 575

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr

580 585 590

Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

595 600 605

Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser

610 615 620

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala

625 630 635 640

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

645 650 655

Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

660 665 670

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly Ser

675 680 685

Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

690 695 700

Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr

705 710 715 720

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala

725 730 735

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

740 745 750

Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser

755 760 765

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro

770 775 780

Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

785 790 795 800

Ala Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr

805 810 815

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro

820 825 830

Ser Glu Gly Ser Ala Pro Ala Ser Ser

835 840

<210> 141

<211> 545

<212> PRT

<213> 人工序列

<220>

<223> pJH74

<400> 141

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Gly Ala Pro Gly Ser Pro Ala Gly Ser

145 150 155 160

Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

165 170 175

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser

180 185 190

Ser Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Gly Ala Pro Gly Ser Pro Ala Gly

305 310 315 320

Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu

325 330 335

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala

340 345 350

Ser Ser Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile

355 360 365

Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile

370 375 380

Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile

385 390 395 400

Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr

405 410 415

Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe

420 425 430

Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg

435 440 445

Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala

450 455 460

Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys

465 470 475 480

Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly

485 490 495

Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile

500 505 510

Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr

515 520 525

Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu

530 535 540

Thr

545

<210> 142

<211> 545

<212> PRT

<213> 人工序列

<220>

<223> pJH75

<400> 142

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

210 215 220

Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

225 230 235 240

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Gly Ala Pro Gly Ser Pro Ala Gly

305 310 315 320

Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu

325 330 335

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala

340 345 350

Ser Ser Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile

355 360 365

Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile

370 375 380

Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile

385 390 395 400

Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr

405 410 415

Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe

420 425 430

Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg

435 440 445

Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala

450 455 460

Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys

465 470 475 480

Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly

485 490 495

Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile

500 505 510

Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr

515 520 525

Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu

530 535 540

Thr

545

<210> 143

<211> 581

<212> PRT

<213> 人工序列

<220>

<223> pJH76

<400> 143

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr

210 215 220

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

225 230 235 240

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

245 250 255

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

260 265 270

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala

275 280 285

Ser Ser Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg

290 295 300

Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val

305 310 315 320

Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn

325 330 335

Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Gly Ala Pro Gly

340 345 350

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser

355 360 365

Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

370 375 380

Glu Thr Pro Ala Ser Ser Thr Gly Val Lys Ile Thr Val Val Ala Gly

385 390 395 400

Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val

405 410 415

Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr

420 425 430

Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn

435 440 445

Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile

450 455 460

Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe

465 470 475 480

His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu

485 490 495

Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn

500 505 510

Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln

515 520 525

Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe

530 535 540

Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys

545 550 555 560

Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu

565 570 575

Lys Thr Lys Leu Thr

580

<210> 144

<211> 653

<212> PRT

<213> 人工序列

<220>

<223> pJH77

<400> 144

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr

210 215 220

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

225 230 235 240

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

245 250 255

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

260 265 270

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr

275 280 285

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro

290 295 300

Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

305 310 315 320

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser

325 330 335

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro

340 345 350

Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser Asn Ile Thr Gln Ser Thr

355 360 365

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

370 375 380

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

385 390 395 400

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

405 410 415

His Cys Val Glu Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

420 425 430

Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

435 440 445

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Thr Gly

450 455 460

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

465 470 475 480

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

485 490 495

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

500 505 510

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

515 520 525

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

530 535 540

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

545 550 555 560

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

565 570 575

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

580 585 590

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

595 600 605

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

610 615 620

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

625 630 635 640

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr

645 650

<210> 145

<211> 625

<212> PRT

<213> 人工序列

<220>

<223> pJH78

<400> 145

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Gly Ala

260 265 270

Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser

275 280 285

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser

290 295 300

Gly Ser Glu Thr Pro Ala Ser Ser Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr

500 505 510

Ala Leu Val Pro Arg Ser Phe Leu Leu Arg Asn Pro Asn Asp Lys Tyr

515 520 525

Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly Ala Gly Ser Pro Gly Ala

530 535 540

Glu Thr Ala Gly Ala Pro Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

545 550 555 560

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser

565 570 575

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser

580 585 590

Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly

595 600 605

Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser

610 615 620

Ser

625

<210> 146

<211> 697

<212> PRT

<213> 人工序列

<220>

<223> pJH79

<400> 146

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Gly Ala

260 265 270

Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser

275 280 285

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser

290 295 300

Gly Ser Glu Thr Pro Ala Ser Ser Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr

500 505 510

Ala Leu Val Pro Arg Ser Phe Leu Leu Arg Asn Pro Asn Asp Lys Tyr

515 520 525

Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly Ala Gly Ser Pro Gly Ala

530 535 540

Glu Thr Ala Gly Ala Pro Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

545 550 555 560

Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser

565 570 575

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr

580 585 590

Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr

595 600 605

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro

610 615 620

Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser

625 630 635 640

Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala

645 650 655

Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser

660 665 670

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser

675 680 685

Glu Gly Ser Ala Pro Gly Ala Ser Ser

690 695

<210> 147

<211> 841

<212> PRT

<213> 人工序列

<220>

<223> pJH80

<400> 147

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Gly Ala

260 265 270

Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser

275 280 285

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser

290 295 300

Gly Ser Glu Thr Pro Ala Ser Ser Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Gly Ala Gly Ser Pro Gly Ala Glu Thr

500 505 510

Ala Leu Val Pro Arg Ser Phe Leu Leu Arg Asn Pro Asn Asp Lys Tyr

515 520 525

Glu Pro Phe Trp Glu Asp Glu Glu Ser Gly Ala Gly Ser Pro Gly Ala

530 535 540

Glu Thr Ala Gly Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

545 550 555 560

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr

565 570 575

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr

580 585 590

Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

595 600 605

Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser

610 615 620

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala

625 630 635 640

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

645 650 655

Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

660 665 670

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly Ser

675 680 685

Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

690 695 700

Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr

705 710 715 720

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala

725 730 735

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

740 745 750

Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser

755 760 765

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro

770 775 780

Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

785 790 795 800

Ala Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr

805 810 815

Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro

820 825 830

Ser Glu Gly Ser Ala Pro Ala Ser Ser

835 840

<210> 148

<211> 977

<212> PRT

<213> 人工序列

<220>

<223> pJH81

<400> 148

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Gly Ala Pro Gly Ser Pro Ala Gly Ser

145 150 155 160

Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser

165 170 175

Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser

180 185 190

Ser Lys Val Val Cys Ser Cys Thr Glu Gly Tyr Arg Leu Ala Glu Asn

195 200 205

Gln Lys Ser Cys Glu Pro Ala Val Pro Phe Pro Cys Gly Arg Val Ser

210 215 220

Val Ser Gln Thr Ser Lys Leu Thr Arg Ala Glu Thr Val Phe Pro Asp

225 230 235 240

Val Asp Tyr Val Asn Ser Thr Glu Ala Glu Thr Ile Leu Asp Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Asp Lys Thr His Thr Cys Pro Pro Cys

500 505 510

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

515 520 525

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

530 535 540

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

545 550 555 560

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

565 570 575

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

580 585 590

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

595 600 605

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

610 615 620

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

625 630 635 640

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

645 650 655

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

660 665 670

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

675 680 685

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

690 695 700

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

705 710 715 720

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly

725 730 735

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys

740 745 750

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

755 760 765

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

770 775 780

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

785 790 795 800

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

805 810 815

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

820 825 830

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

835 840 845

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

850 855 860

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

865 870 875 880

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

885 890 895

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

900 905 910

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

915 920 925

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

930 935 940

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

945 950 955 960

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

965 970 975

Lys

<210> 149

<211> 977

<212> PRT

<213> 人工序列

<220>

<223> pJH81

<400> 149

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Gly Ala

260 265 270

Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser

275 280 285

Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser

290 295 300

Gly Ser Glu Thr Pro Ala Ser Ser Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Asp Lys Thr His Thr Cys Pro Pro Cys

500 505 510

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

515 520 525

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

530 535 540

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

545 550 555 560

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

565 570 575

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

580 585 590

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

595 600 605

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

610 615 620

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

625 630 635 640

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

645 650 655

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

660 665 670

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

675 680 685

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

690 695 700

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

705 710 715 720

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly

725 730 735

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys

740 745 750

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

755 760 765

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

770 775 780

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

785 790 795 800

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

805 810 815

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

820 825 830

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

835 840 845

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

850 855 860

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

865 870 875 880

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

885 890 895

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

900 905 910

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

915 920 925

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

930 935 940

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

945 950 955 960

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

965 970 975

Lys

<210> 150

<211> 977

<212> PRT

<213> 人工序列

<220>

<223> pJH82

<400> 150

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

210 215 220

Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

225 230 235 240

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Ala Ser Ser Asn Ile

245 250 255

Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly

260 265 270

Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly

275 280 285

Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile

290 295 300

Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val

305 310 315 320

Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg

325 330 335

Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn

340 345 350

Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val

355 360 365

Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr

370 375 380

Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg

385 390 395 400

Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val

405 410 415

Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile

420 425 430

Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser

435 440 445

Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr

450 455 460

Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys

465 470 475 480

Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile

485 490 495

Lys Glu Lys Thr Lys Leu Thr Asp Lys Thr His Thr Cys Pro Pro Cys

500 505 510

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

515 520 525

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

530 535 540

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

545 550 555 560

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

565 570 575

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

580 585 590

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

595 600 605

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

610 615 620

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

625 630 635 640

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

645 650 655

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

660 665 670

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

675 680 685

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

690 695 700

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

705 710 715 720

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly

725 730 735

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys

740 745 750

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

755 760 765

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

770 775 780

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

785 790 795 800

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

805 810 815

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

820 825 830

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

835 840 845

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

850 855 860

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

865 870 875 880

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

885 890 895

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

900 905 910

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

915 920 925

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

930 935 940

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

945 950 955 960

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

965 970 975

Lys

<210> 151

<211> 1013

<212> PRT

<213> 人工序列

<220>

<223> pJH84

<400> 151

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr

210 215 220

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

225 230 235 240

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

245 250 255

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

260 265 270

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala

275 280 285

Ser Ser Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg

290 295 300

Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val

305 310 315 320

Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn

325 330 335

Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys

340 345 350

Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr

355 360 365

Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn

370 375 380

Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp

385 390 395 400

Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp

405 410 415

Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser

420 425 430

Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln

435 440 445

Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr

450 455 460

Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly

465 470 475 480

Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu

485 490 495

Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu

500 505 510

Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr

515 520 525

Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Asp Lys Thr His Thr

530 535 540

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

545 550 555 560

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

565 570 575

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

580 585 590

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

595 600 605

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

610 615 620

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

625 630 635 640

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

645 650 655

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

660 665 670

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

675 680 685

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

690 695 700

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

705 710 715 720

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

725 730 735

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

740 745 750

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly

755 760 765

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

770 775 780

Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

785 790 795 800

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

805 810 815

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

820 825 830

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

835 840 845

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

850 855 860

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

865 870 875 880

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

885 890 895

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

900 905 910

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

915 920 925

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

930 935 940

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

945 950 955 960

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

965 970 975

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

980 985 990

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

995 1000 1005

Leu Ser Pro Gly Lys

1010

<210> 152

<211> 1085

<212> PRT

<213> 人工序列

<220>

<223> pJH85

<400> 152

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Ala Pro Ser Pro Ala Gly Ser Pro Thr Ser Thr

210 215 220

Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

225 230 235 240

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

245 250 255

Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

260 265 270

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr

275 280 285

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro

290 295 300

Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser

305 310 315 320

Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser

325 330 335

Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro

340 345 350

Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser Asn Ile Thr Gln Ser Thr

355 360 365

Gln Ser Phe Asn Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys

370 375 380

Pro Gly Gln Phe Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala

385 390 395 400

Phe Cys Gly Gly Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala

405 410 415

His Cys Val Glu Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His

420 425 430

Asn Ile Glu Glu Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg

435 440 445

Ile Ile Pro His His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His

450 455 460

Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr

465 470 475 480

Val Thr Pro Ile Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu

485 490 495

Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys

500 505 510

Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp

515 520 525

Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met

530 535 540

Phe Cys Ala Gly Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp

545 550 555 560

Ser Gly Gly Pro His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr

565 570 575

Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly

580 585 590

Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr

595 600 605

Lys Leu Thr Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

610 615 620

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

625 630 635 640

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

645 650 655

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

660 665 670

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

675 680 685

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

690 695 700

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

705 710 715 720

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

725 730 735

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn

740 745 750

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

755 760 765

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

770 775 780

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

785 790 795 800

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

805 810 815

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

820 825 830

Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

835 840 845

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys

850 855 860

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

865 870 875 880

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

885 890 895

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

900 905 910

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

915 920 925

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

930 935 940

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

945 950 955 960

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys

965 970 975

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

980 985 990

Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

995 1000 1005

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

1010 1015 1020

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

1025 1030 1035

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser

1040 1045 1050

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

1055 1060 1065

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

1070 1075 1080

Gly Lys

1085

<210> 153

<211> 935

<212> PRT

<213> 人工序列

<220>

<223> pJH56

<400> 153

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Asp Lys Thr

450 455 460

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

465 470 475 480

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

485 490 495

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

500 505 510

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

515 520 525

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val

530 535 540

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

545 550 555 560

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

565 570 575

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

580 585 590

Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys

595 600 605

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

610 615 620

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

625 630 635 640

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser

645 650 655

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

660 665 670

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

675 680 685

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

690 695 700

Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

705 710 715 720

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

725 730 735

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

740 745 750

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

755 760 765

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

770 775 780

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

785 790 795 800

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

805 810 815

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

820 825 830

Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys

835 840 845

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

850 855 860

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

865 870 875 880

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

885 890 895

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

900 905 910

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

915 920 925

Leu Ser Leu Ser Pro Gly Lys

930 935

<210> 154

<211> 20

<212> PRT

<213> 人工序列

<220>

<223> PAS肽

<400> 154

Ala Ser Pro Ala Ala Pro Ala Pro Ala Ser Pro Ala Ala Pro Ala Pro

1 5 10 15

Ser Ala Pro Ala

20

<210> 155

<211> 20

<212> PRT

<213> 人工序列

<220>

<223> PAS肽

<400> 155

Ala Ala Pro Ala Ser Pro Ala Pro Ala Ala Pro Ser Ala Pro Ala Pro

1 5 10 15

Ala Ala Pro Ser

20

<210> 156

<211> 20

<212> PRT

<213> 人工序列

<220>

<223> PAS肽

<400> 156

Ala Pro Ser Ser Pro Ser Pro Ser Ala Pro Ser Ser Pro Ser Pro Ala

1 5 10 15

Ser Pro Ser Ser

20

<210> 157

<211> 19

<212> PRT

<213> 人工序列

<220>

<223> PAS肽

<400> 157

Ala Pro Ser Ser Pro Ser Pro Ser Ala Pro Ser Ser Pro Ser Pro Ala

1 5 10 15

Ser Pro Ser

<210> 158

<211> 20

<212> PRT

<213> 人工序列

<220>

<223> PAS肽

<400> 158

Ser Ser Pro Ser Ala Pro Ser Pro Ser Ser Pro Ala Ser Pro Ser Pro

1 5 10 15

Ser Ser Pro Ala

20

<210> 159

<211> 24

<212> PRT

<213> 人工序列

<220>

<223> PAS肽

<400> 159

Ala Ala Ser Pro Ala Ala Pro Ser Ala Pro Pro Ala Ala Ala Ser Pro

1 5 10 15

Ala Ala Pro Ser Ala Pro Pro Ala

20

<210> 160

<211> 20

<212> PRT

<213> 人工序列

<220>

<223> PAS肽

<400> 160

Ala Ser Ala Ala Ala Pro Ala Ala Ala Ser Ala Ala Ala Ser Ala Pro

1 5 10 15

Ser Ala Ala Ala

20

<210> 161

<211> 4

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 161

Gly Gly Gly Ser

1

<210> 162

<211> 8

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 162

Gly Gly Gly Ser Gly Gly Gly Ser

1 5

<210> 163

<211> 11

<212> PRT

<213> 人工序列

<220>

<223> 白蛋白结合肽核心序列

<400> 163

Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp

1 5 10

<210> 164

<211> 32

<212> PRT

<213> 人工序列

<220>

<223> CTP肽

<400> 164

Asp Pro Arg Phe Gln Asp Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser

1 5 10 15

Leu Pro Ser Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu

20 25 30

<210> 165

<211> 28

<212> PRT

<213> 人工序列

<220>

<223> CTP肽

<400> 165

Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser Pro Ser Arg

1 5 10 15

Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro Gln

20 25

<210> 166

<211> 9

<212> PRT

<213> 人工序列

<220>

<223> FXIa切割位点

<400> 166

Thr Gln Ser Phe Asn Asp Phe Thr Arg

1 5

<210> 167

<211> 10

<212> PRT

<213> 人工序列

<220>

<223> FXIa切割位点

<400> 167

Ser Val Ser Gln Thr Ser Lys Leu Thr Arg

1 5 10

<210> 168

<211> 10

<212> PRT

<213> 人工序列

<220>

<223> 凝血酶切割位点

<400> 168

Asp Phe Leu Ala Glu Gly Gly Gly Val Arg

1 5 10

<210> 169

<211> 7

<212> PRT

<213> 人工序列

<220>

<223> 凝血酶切割位点

<400> 169

Thr Thr Lys Ile Lys Pro Arg

1 5

<210> 170

<211> 5

<212> PRT

<213> 人工序列

<220>

<223> 凝血酶切割位点

<400> 170

Leu Val Pro Arg Gly

1 5

<210> 171

<211> 5

<212> PRT

<213> 人工序列

<220>

<223> 凝血酶切割位点

<400> 171

Ala Leu Arg Pro Arg

1 5

<210> 172

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 172

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10

<210> 173

<211> 16

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 173

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10 15

<210> 174

<211> 20

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 174

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10 15

Gly Gly Gly Ser

20

<210> 175

<211> 24

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 175

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Ser

20

<210> 176

<211> 28

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 176

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

20 25

<210> 177

<211> 32

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 177

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

20 25 30

<210> 178

<211> 36

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 178

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

20 25 30

Gly Gly Gly Ser

35

<210> 179

<211> 40

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 179

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

20 25 30

Gly Gly Gly Ser Gly Gly Gly Ser

35 40

<210> 180

<211> 5

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 180

Ser Gly Gly Gly Ser

1 5

<210> 181

<211> 9

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 181

Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5

<210> 182

<211> 13

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 182

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10

<210> 183

<211> 17

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 183

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly

1 5 10 15

Ser

<210> 184

<211> 21

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 184

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly

1 5 10 15

Ser Gly Gly Gly Ser

20

<210> 185

<211> 25

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 185

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly

1 5 10 15

Ser Gly Gly Gly Ser Gly Gly Gly Ser

20 25

<210> 186

<211> 29

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 186

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly

1 5 10 15

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

20 25

<210> 187

<211> 33

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 187

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly

1 5 10 15

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly

20 25 30

Ser

<210> 188

<211> 37

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 188

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly

1 5 10 15

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly

20 25 30

Ser Gly Gly Gly Ser

35

<210> 189

<211> 41

<212> PRT

<213> 人工序列

<220>

<223> Gly-Ser肽接头

<400> 189

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly

1 5 10 15

Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly

20 25 30

Ser Gly Gly Gly Ser Gly Gly Gly Ser

35 40

<210> 190

<211> 6

<212> PRT

<213> 人工序列

<220>

<223> PAR1接头基序

<400> 190

Ser Phe Leu Leu Arg Asn

1 5

<210> 191

<211> 4

<212> PRT

<213> 人工序列

<220>

<223> PAR1接头基序

<400> 191

Pro Asn Asp Lys

1

<210> 192

<211> 5

<212> PRT

<213> 人工序列

<220>

<223> PAR1接头基序

<400> 192

Pro Asn Asp Lys Tyr

1 5

<210> 193

<211> 6

<212> PRT

<213> 人工序列

<220>

<223> PAR1接头基序

<400> 193

Pro Asn Asp Lys Tyr Glu

1 5

<210> 194

<211> 7

<212> PRT

<213> 人工序列

<220>

<223> PAR1接头基序

<400> 194

Pro Asn Asp Lys Tyr Glu Pro

1 5

<210> 195

<211> 8

<212> PRT

<213> 人工序列

<220>

<223> PAR1接头基序

<400> 195

Pro Asn Asp Lys Tyr Glu Pro Phe

1 5

<210> 196

<211> 9

<212> PRT

<213> 人工序列

<220>

<223> PAR1接头基序

<400> 196

Pro Asn Asp Lys Tyr Glu Pro Phe Trp

1 5

<210> 197

<211> 10

<212> PRT

<213> 人工序列

<220>

<223> PAR1接头基序

<400> 197

Pro Asn Asp Lys Tyr Glu Pro Phe Trp Glu

1 5 10

<210> 198

<211> 11

<212> PRT

<213> 人工序列

<220>

<223> PAR1接头基序

<400> 198

Pro Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp

1 5 10

<210> 199

<211> 12

<212> PRT

<213> 人工序列

<220>

<223> PAR1接头基序

<400> 199

Pro Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu

1 5 10

<210> 200

<211> 13

<212> PRT

<213> 人工序列

<220>

<223> PAR1接头基序

<400> 200

Pro Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu Glu

1 5 10

<210> 201

<211> 14

<212> PRT

<213> 人工序列

<220>

<223> PAR1接头基序

<400> 201

Pro Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu Glu Ser

1 5 10

<210> 202

<211> 72

<212> PRT

<213> 人工序列

<220>

<223> XTEN_AE72_2A_1

<400> 202

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly

1 5 10 15

Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly

20 25 30

Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

35 40 45

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu

50 55 60

Pro Ser Glu Gly Ser Ala Pro Gly

65 70

<210> 203

<211> 72

<212> PRT

<213> 人工序列

<220>

<223> XTEN_AE72_2A_2

<400> 203

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

1 5 10 15

Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

20 25 30

Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

35 40 45

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser

50 55 60

Ala Thr Pro Glu Ser Gly Pro Gly

65 70

<210> 204

<211> 72

<212> PRT

<213> 人工序列

<220>

<223> XTEN_AE72_3B_1

<400> 204

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser

1 5 10 15

Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

20 25 30

Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

35 40 45

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu

50 55 60

Pro Ser Glu Gly Ser Ala Pro Gly

65 70

<210> 205

<211> 72

<212> PRT

<213> 人工序列

<220>

<223> XTEN_AE72_3B_2

<400> 205

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu

1 5 10 15

Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

20 25 30

Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

35 40 45

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu

50 55 60

Pro Ser Glu Gly Ser Ala Pro Gly

65 70

<210> 206

<211> 72

<212> PRT

<213> 人工序列

<220>

<223> XTEN_AE72_4A_2

<400> 206

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Pro Ala Gly

1 5 10 15

Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly Ser Pro Thr Ser

20 25 30

Thr Glu Glu Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

35 40 45

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu

50 55 60

Pro Ser Glu Gly Ser Ala Pro Gly

65 70

<210> 207

<211> 72

<212> PRT

<213> 人工序列

<220>

<223> XTEN_AE72_5A_2

<400> 207

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser

1 5 10 15

Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

20 25 30

Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

35 40 45

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly

50 55 60

Ser Pro Thr Ser Thr Glu Glu Gly

65 70

<210> 208

<211> 72

<212> PRT

<213> 人工序列

<220>

<223> XTEN_AE72_6B_1

<400> 208

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser

1 5 10 15

Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

20 25 30

Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

35 40 45

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala

50 55 60

Thr Ser Gly Ser Glu Thr Pro Gly

65 70

<210> 209

<211> 72

<212> PRT

<213> 人工序列

<220>

<223> XTEN_AE72_6B_2

<400> 209

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu

1 5 10 15

Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

20 25 30

Ser Ala Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

35 40 45

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu

50 55 60

Pro Ser Glu Gly Ser Ala Pro Gly

65 70

<210> 210

<211> 72

<212> PRT

<213> 人工序列

<220>

<223> XTEN_AE72_1A_1

<400> 210

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser

1 5 10 15

Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

20 25 30

Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

35 40 45

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu

50 55 60

Pro Ser Glu Gly Ser Ala Pro Gly

65 70

<210> 211

<211> 72

<212> PRT

<213> 人工序列

<220>

<223> XTEN_AE72_1A_2

<400> 211

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

1 5 10 15

Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

20 25 30

Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

35 40 45

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu

50 55 60

Pro Ser Glu Gly Ser Ala Pro Gly

65 70

<210> 212

<211> 144

<212> PRT

<213> 人工序列

<220>

<223> XTEN_AE144_1A

<400> 212

Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser

1 5 10 15

Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

20 25 30

Ser Ala Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly

35 40 45

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu

50 55 60

Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

65 70 75 80

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

85 90 95

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly

100 105 110

Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu

115 120 125

Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

130 135 140

<210> 213

<211> 150

<212> PRT

<213> 人工序列

<220>

<223> AE150

<400> 213

Gly Ala Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

1 5 10 15

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

20 25 30

Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly Ser Pro Thr Ser

35 40 45

Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

50 55 60

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala

65 70 75 80

Thr Ser Gly Ser Glu Thr Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

85 90 95

Glu Thr Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

100 105 110

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala

115 120 125

Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

130 135 140

Ser Ala Pro Ala Ser Ser

145 150

<210> 214

<211> 150

<212> PRT

<213> 人工序列

<220>

<223> AG150

<400> 214

Gly Ala Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro Gly

1 5 10 15

Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Pro Ser

20 25 30

Ala Ser Thr Gly Thr Gly Pro Gly Ser Ser Pro Ser Ala Ser Thr Gly

35 40 45

Thr Gly Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly

50 55 60

Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ser Ser Thr Pro

65 70 75 80

Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Pro Ser Ala Ser Thr Gly

85 90 95

Thr Gly Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly

100 105 110

Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Thr Pro Gly Ser

115 120 125

Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr

130 135 140

Gly Ser Pro Ala Ser Ser

145 150

<210> 215

<211> 294

<212> PRT

<213> 人工序列

<220>

<223> AE294

<400> 215

Gly Ala Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

1 5 10 15

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser

20 25 30

Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

35 40 45

Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

50 55 60

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala Gly

65 70 75 80

Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro Glu

85 90 95

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

100 105 110

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Pro Ala Gly

115 120 125

Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly Ser Pro Thr Ser

130 135 140

Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

145 150 155 160

Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser

165 170 175

Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu

180 185 190

Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly

195 200 205

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala Gly

210 215 220

Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly

225 230 235 240

Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly

245 250 255

Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser

260 265 270

Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly

275 280 285

Ser Ala Pro Ala Ser Ser

290

<210> 216

<211> 294

<212> PRT

<213> 人工序列

<220>

<223> AG294

<400> 216

Gly Ala Pro Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

1 5 10 15

Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Thr Pro Gly

20 25 30

Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala

35 40 45

Thr Gly Ser Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro

50 55 60

Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Thr Pro Gly

65 70 75 80

Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala

85 90 95

Thr Gly Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro

100 105 110

Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Ser Ser Pro

115 120 125

Ser Ala Ser Thr Gly Thr Gly Pro Gly Ala Ser Pro Gly Thr Ser Ser

130 135 140

Thr Gly Ser Pro Gly Thr Pro Gly Ser Gly Thr Ala Ser Ser Ser Pro

145 150 155 160

Gly Ser Ser Thr Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Pro

165 170 175

Ser Ala Ser Thr Gly Thr Gly Pro Gly Ser Ser Pro Ser Ala Ser Thr

180 185 190

Gly Thr Gly Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

195 200 205

Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro Gly Ser Ser Thr

210 215 220

Pro Ser Gly Ala Thr Gly Ser Pro Gly Ser Ser Pro Ser Ala Ser Thr

225 230 235 240

Gly Thr Gly Pro Gly Ala Ser Pro Gly Thr Ser Ser Thr Gly Ser Pro

245 250 255

Gly Ser Ser Pro Ser Ala Ser Thr Gly Thr Gly Pro Gly Thr Pro Gly

260 265 270

Ser Gly Thr Ala Ser Ser Ser Pro Gly Ser Ser Thr Pro Ser Gly Ala

275 280 285

Thr Gly Ser Ala Ser Ser

290

<210> 217

<211> 36

<212> PRT

<213> 人工序列

<220>

<223> AE36

<400> 217

Gly Ser Pro Ala Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu

1 5 10 15

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

20 25 30

Ser Glu Thr Pro

35

<210> 218

<211> 78

<212> PRT

<213> 人工序列

<220>

<223> AE78

<400> 218

Gly Ala Pro Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser

1 5 10 15

Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala

20 25 30

Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu

35 40 45

Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr

50 55 60

Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser

65 70 75

<210> 219

<211> 46

<212> PRT

<213> 人工序列

<220>

<223> 接头

<400> 219

Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr Gly Ala Gly

1 5 10 15

Ser Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser Glu Glu Asp

20 25 30

Leu Ser Pro Ala Thr Gly His His His His His His His His

35 40 45

<210> 220

<211> 25

<212> PRT

<213> 人工序列

<220>

<223> 接头

<400> 220

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Leu Val Pro Arg Gly Ala

1 5 10 15

Gly Ser Pro Gly Ala Glu Thr Ala Gly

20 25

<210> 221

<211> 44

<212> PRT

<213> 人工序列

<220>

<223> 接头

<400> 221

Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala Leu Val Pro Arg Ser Phe

1 5 10 15

Leu Leu Arg Asn Pro Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu

20 25 30

Glu Ser Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala

35 40

<210> 222

<211> 23

<212> PRT

<213> 人工序列

<220>

<223> 接头

<400> 222

Gly Pro Glu Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr Gly Ala Gly

1 5 10 15

Ser Pro Gly Ala Glu Thr Ala

20

<210> 223

<211> 22

<212> PRT

<213> 人工序列

<220>

<223> 接头

<400> 223

Gly Gly Gly Gly Ala Leu Arg Pro Arg Val Val Gly Gly Ala Gly Ser

1 5 10 15

Pro Gly Ala Glu Thr Ala

20

<210> 224

<211> 40

<212> PRT

<213> 人工序列

<220>

<223> 接头

<400> 224

Gly Gly Gly Gly Thr Leu Asp Pro Arg Ser Phe Leu Leu Arg Asn Pro

1 5 10 15

Asn Asp Lys Tyr Glu Pro Phe Trp Glu Asp Glu Glu Lys Gly Gly Ala

20 25 30

Gly Ser Pro Gly Ala Glu Thr Ala

35 40

<210> 225

<211> 11

<212> PRT

<213> 人工序列

<220>

<223> 接头

<400> 225

Gly Gly Ala Gly Ser Pro Gly Ala Glu Thr Ala

1 5 10

<210> 226

<211> 798

<212> PRT

<213> 人工序列

<220>

<223> pSYN-FIX-102

<400> 226

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe

210 215 220

Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp

225 230 235 240

Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile

245 250 255

Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly

260 265 270

Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu

275 280 285

His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn

290 295 300

Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu

305 310 315 320

Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile

325 330 335

Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr

340 345 350

Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val

355 360 365

Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu

370 375 380

Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His

385 390 395 400

Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val

405 410 415

Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly

420 425 430

Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser

435 440 445

Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Gly Pro Glu

450 455 460

Gly Pro Ser Lys Leu Thr Arg Ala Glu Thr Gly Ala Gly Ser Pro Gly

465 470 475 480

Ala Glu Thr Ala Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

485 490 495

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu

500 505 510

Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly

515 520 525

Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro

530 535 540

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ser Pro Ala

545 550 555 560

Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser Ala Thr Pro

565 570 575

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

580 585 590

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Pro Ala

595 600 605

Gly Ser Pro Thr Ser Thr Glu Glu Gly Ser Pro Ala Gly Ser Pro Thr

610 615 620

Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

625 630 635 640

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu

645 650 655

Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Glu Ser Ala Thr Pro

660 665 670

Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro

675 680 685

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Ser Pro Ala

690 695 700

Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Thr Glu Pro Ser Glu

705 710 715 720

Gly Ser Ala Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

725 730 735

Gly Ser Glu Pro Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu

740 745 750

Ser Ala Thr Pro Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu

755 760 765

Gly Ser Ala Pro Gly Ala Glu Thr Ala Glu Gln Lys Leu Ile Ser Glu

770 775 780

Glu Asp Leu Ser Pro Ala Thr Gly His His His His His His

785 790 795

<210> 227

<211> 763

<212> PRT

<213> 人工序列

<220>

<223> pSYN-FIX-216

<400> 227

Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr

1 5 10 15

Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu

20 25 30

Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn

35 40 45

Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys

50 55 60

Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn

65 70 75 80

Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln

85 90 95

Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile

100 105 110

Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys

115 120 125

Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe

130 135 140

Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly

145 150 155 160

Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe

165 170 175

Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala

180 185 190

Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu

195 200 205

Thr Ile Leu Asp Gly Pro Ser Pro Gly Ser Pro Thr Ser Thr Glu Glu

210 215 220

Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro

225 230 235 240

Ala Thr Ser Gly Ser Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro

245 250 255

Glu Ser Gly Pro Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro

260 265 270

Gly Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Ala Ser Ser

275 280 285

Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe Thr Arg Val Val

290 295 300

Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp Gln Val Val Leu

305 310 315 320

Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile Val Asn Glu Lys

325 330 335

Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly Val Lys Ile Thr

340 345 350

Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu His Thr Glu Gln

355 360 365

Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn Tyr Asn Ala Ala

370 375 380

Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu Leu Asp Glu Pro

385 390 395 400

Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile Ala Asp Lys Glu

405 410 415

Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr Val Ser Gly Trp

420 425 430

Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val Leu Gln Tyr Leu

435 440 445

Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Leu Ser Thr Lys Phe

450 455 460

Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His Glu Gly Gly Arg

465 470 475 480

Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val Thr Glu Val Glu

485 490 495

Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly Glu Glu Cys Ala

500 505 510

Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser Arg Tyr Val Asn

515 520 525

Trp Ile Lys Glu Lys Thr Lys Leu Thr Asp Lys Thr His Thr Cys Pro

530 535 540

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe

545 550 555 560

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

565 570 575

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe

580 585 590

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

595 600 605

Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

610 615 620

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

625 630 635 640

Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala

645 650 655

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg

660 665 670

Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

675 680 685

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

690 695 700

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

705 710 715 720

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln

725 730 735

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

740 745 750

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

755 760

<210> 228

<211> 226

<212> PRT

<213> 人工序列

<220>

<223> pSYN-FIX-216-Fc

<400> 228

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

1 5 10 15

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly

225

<210> 229

<211> 642

<212> PRT

<213> 人工序列

<220>

<223> FIXFc

<400> 229

Tyr Asn Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg

1 5 10 15

Glu Cys Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe

20 25 30

Glu Asn Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly

35 40 45

Asp Gln Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp

50 55 60

Asp Ile Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys

65 70 75 80

Asn Cys Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu

85 90 95

Gln Phe Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr

100 105 110

Glu Gly Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val

115 120 125

Pro Phe Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr

130 135 140

Arg Ala Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu

145 150 155 160

Ala Glu Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn

165 170 175

Asp Phe Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe

180 185 190

Pro Trp Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly

195 200 205

Ser Ile Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu

210 215 220

Thr Gly Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu

225 230 235 240

Thr Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His

245 250 255

His Asn Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu

260 265 270

Leu Glu Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile

275 280 285

Cys Ile Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser

290 295 300

Gly Tyr Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala

305 310 315 320

Leu Val Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys

325 330 335

Leu Leu Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly

340 345 350

Phe His Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro

355 360 365

His Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser

370 375 380

Trp Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys

385 390 395 400

Val Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr Asp

405 410 415

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

420 425 430

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

435 440 445

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

450 455 460

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

465 470 475 480

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

485 490 495

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

500 505 510

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

515 520 525

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

530 535 540

Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu

545 550 555 560

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

565 570 575

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

580 585 590

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

595 600 605

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

610 615 620

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

625 630 635 640

Gly Lys

<210> 230

<211> 72

<212> PRT

<213> 人工序列

<220>

<223> XTEN_AE72_1A_3

<400> 230

Pro Ser Pro Gly Ser Pro Thr Ser Thr Glu Glu Gly Thr Ser Glu Ser

1 5 10 15

Ala Thr Pro Glu Ser Gly Pro Gly Ser Glu Pro Ala Thr Ser Gly Ser

20 25 30

Glu Thr Pro Gly Thr Ser Glu Ser Ala Thr Pro Glu Ser Gly Pro Gly

35 40 45

Thr Ser Thr Glu Pro Ser Glu Gly Ser Ala Pro Gly Thr Ser Thr Glu

50 55 60

Pro Ser Glu Gly Ser Ala Pro Gly

65 70

Claims

1.一种将因子IX(FIX)融合蛋白给予有此需要的受试者的方法，其包括向受试者皮下给予FIX融合蛋白，其中

(a)所述FIX融合蛋白包含FIX多肽和至少一个XTEN，所述至少一个XTEN在插入位点处插入所述FIX多肽内，所述插入位点对应于选自以下的氨基酸：SEQ ID NO:2的氨基酸103、SEQ ID NO:2的氨基酸105、SEQ ID NO:2的氨基酸142、SEQ ID NO:2的氨基酸149、SEQ IDNO:2的氨基酸162、SEQ ID NO:2的氨基酸166、SEQ ID NO:2的氨基酸174、SEQ ID NO:2的氨基酸224、SEQ ID NO:2的氨基酸226、SEQ ID NO:2的氨基酸228、SEQ ID NO:2的氨基酸413及其任何组合，并且

2.一种将因子IX(FIX)融合蛋白给予有此需要的受试者的方法，其包括向受试者皮下给予包含FIX多肽和Fc结构域的FIX融合蛋白，其中所述FIX融合蛋白包含与SEQ ID NO:229具有至少约80％序列同一性的氨基酸序列，其中在给予后，所述FIX融合蛋白在所述受试者中展现出约5％至约30％的血浆活性。

3.根据权利要求1或2的方法，其中所述FIX融合蛋白是以约50IU/kg至约400IU/kg的剂量给予。

4.根据权利要求1至3中任一项的方法，其中所述FIX融合蛋白展现出约10％至约30％的血浆活性峰值。

5.根据权利要求1至4中任一项的方法，其中所述FIX融合蛋白展现出约5％至约10％的血浆活性谷值。

6.根据权利要求1和3至5中任一项的方法，其中所述插入位点对应于选自以下的氨基酸：SEQ ID NO:2的氨基酸149、SEQ ID NO:2的氨基酸162、SEQ ID NO:2的氨基酸166、SEQID NO:2的氨基酸174及其任何组合。

7.根据权利要求1和3至6中任一项的方法，其中所述XTEN包含至少约6个氨基酸、至少约12个氨基酸、至少约36个氨基酸、至少约42个氨基酸、至少约72个氨基酸、至少约144个氨基酸或至少约288个氨基酸。

8.根据权利要求1和3至7中任一项的方法，其中所述XTEN包含与选自SEQ ID NO:34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、202、203、204、205、206、207、208、209、210、211、212、213、214、230及其任何组合的氨基酸序列至少约80％、至少约85％、至少约90％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％或约100％相同的氨基酸序列。

9.根据权利要求1和3至8中任一项的方法，其中所述XTEN包括AE72。

10.根据权利要求1和3至9中任一项的方法，其中所述FIX融合蛋白还包含第二XTEN，其中所述XTEN在对应于SEQ ID NO:2的氨基酸166的插入位点处插入所述FIX多肽内，并且其中所述第二XTEN与所述FIX多肽的C端融合。

11.根据权利要求1和3至10中任一项的方法，其中所述FIX融合蛋白还包含Fc结构域。

12.根据权利要求2至11中任一项的方法，其中所述FIX融合蛋白还包含第二Fc结构域。

13.根据权利要求12的方法，其中所述FIX融合蛋白还包含两条多肽链，其中第一多肽链包含与所述Fc结构域融合的FIX多肽，并且第二多肽链包含第二Fc结构域，其中所述第一Fc结构域和所述第二Fc结构域通过共价键缔合。

14.根据权利要求1至13中任一项的方法，其中所述FIX多肽是R338L FIX变体。

15.根据权利要求1至14中任一项的方法，其中所述FIX融合蛋白包含第一链和第二链，其中：

(a)所述第一链包含：

(i)具有338L突变的FIX多肽；

(ii)任选地，XTEN，其中所述XTEN在对应于SEQ ID NO:2的氨基酸166的插入位点处插入所述FIX多肽内，并且其中所述XTEN包含具有至少约72个氨基酸的氨基酸序列；和

(iii)第一Fc结构域，其中所述第一Fc结构域与所述FIX多肽融合；且

(b)所述第二链包含第二Fc结构域；

其中所述第一Fc结构域和所述第二Fc结构域通过共价键缔合。