CN115484980A - 药物配制品 - Google Patents

药物配制品 Download PDF

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CN115484980A
CN115484980A CN202180030962.XA CN202180030962A CN115484980A CN 115484980 A CN115484980 A CN 115484980A CN 202180030962 A CN202180030962 A CN 202180030962A CN 115484980 A CN115484980 A CN 115484980A
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T·R·克里斯琴
B·贾甘纳森
A·戴克斯特拉
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Abstract

本披露描述了稳定的水性配制品，其包含例如双特异性抗体构建体、缓冲液、糖和表面活性剂，该配制品的pH是4.8‑5.5。

Description

药物配制品
技术领域
本披露属于稳定的双特异性抗体构建体配制品的领域。
通过引用并入
通过援引以其全文并入的是与本文同时提交的计算机可读核苷酸/氨基酸序列表，并且其标识如下：名为“54910_Seqlisting.txt”的ASCII(文本)文件，345,249字节，创建于2020年4月28日。
背景技术
基于蛋白质的药物是临床(前)开发和商业产品中增长最快的治疗剂之一。与小化学药物相比，蛋白质药物在相对低的浓度下具有高特异性和活性，并且典型地提供对高影响疾病的疗法，这些高影响疾病是例如各种癌症、自身免疫疾病、和代谢障碍(Roberts,Trends Biotechnol.[生物技术趋势]2014年7月；32(7):372-80,Wang,Int J Pharm.[国际药学杂志]1999年8月20日；185(2):129-88)。
由于商业规模纯化方法的进步，因此现在可以在首次制造时以高纯度获得基于蛋白质的药物，例如重组蛋白质。然而，蛋白质仅临界稳定(marginally stable)并且极易受到化学和物理降解二者的影响。化学降解是指涉及共价键的修饰，如脱酰胺化、氧化、裂解、剪切/片段化、形成新的二硫桥键、水解、异构化或去糖基化。物理降解包括蛋白质去折叠、对表面的不希望的吸附、和聚集。处理这些物理和化学不稳定性是蛋白质药物开发中最具挑战性的任务之一(Chi等人,Pharm Res[药物研究],第20卷，第9期,2003年9月,第1325-1336页,Roberts,Trends Biotechnol.[生物技术趋势]2014年7月；32(7):372-80)。
由于化学和酶的原因，基于蛋白质的药物在制造过程或储存期间可能会发生剪切(片段化)。剪切是不希望的，因为它代表了亲本多肽的降解，并且在治疗性多肽的情况下，则可能降低效力。在生物学和生物技术应用中保持蛋白质稳定性和活性面临严重挑战。本领域需要优化的药物配制品，其提供治疗性蛋白的增强的稳定性并减少在配制、填充、运输、储存和施用期间的剪切、聚集、变性或降解，从而防止功能丧失和不良免疫原性反应。
发明内容
包括同时结合两种(或更多种)不同抗原的双特异性(和/或多特异性)抗体(例如双特异性T细胞接合
Figure BDA0003904969830000021
抗体构建体)的基于蛋白质的药物易于发生蛋白质不稳定。这延伸到包含半衰期延长形式(HLE形式)的那些抗体构建体，这些半衰期延长形式包括单链Fc形式(称为scFc)、异Fc(也称为hetFc或异源二聚体Fc、hFc)形式和人血清白蛋白的融合(也称为HSA或hALB)。
蛋白质不稳定，并且特别是剪切(片段化)，是生物技术行业面临的日益严峻的挑战。在液体配制品中，所有双特异性抗体构建体都容易剪切。剪切产生双特异性抗体构建体的低分子量(LMW)物质，并且导致无活性多肽。在更低(即更酸性的)pH液体配制品中，双特异性抗体构建体的剪切倾向于增加，但是聚集倾向于减少。在更高(即更碱性的)pH液体配制品中，双特异性抗体构建体的聚集倾向于增加，但是剪切倾向于减少。
出乎意料地，本披露鉴定了液体双特异性抗体构建体配制品的优化pH范围，该pH范围允许液体配制品在各种储存条件下保持稳定。例如，本文所提供的实例鉴定了液体配制品的特定pH范围(即pH 4.8-5.5)，其中当储存时，例如在如2-8℃或40℃下，双特异性抗体构建体的剪切(即，％低分子量物质的量)和液体配制品中双特异性抗体构建体的聚集(即％高分子量物质)两者均减少。如本文所述实例中所示，将pH在4.8-5.5范围内的液体配制品中的双特异性抗体构建体的剪切和聚集水平与pH在pH 4.8-5.5范围以外(即pH 4.2或pH 7.4)的液体配制品中的剪切和聚集水平进行比较。因此，当在相同的储存条件下时，与pH在该范围以外(例如，pH 4.2或pH 7.4)的情况下，包含双特异性抗体构建体的液体配制品相比，包含双特性抗体构建体并且pH范围在约pH 4.8至约5.5(例如，pH 5.2)的液体药物配制品更稳定，并且表现出改善的结构完整性。
在一个方面，本文所述的是一种稳定的水性药物配制品，其包含本文所述的双特异性抗体构建体、缓冲液、糖、和表面活性剂，其中药物配制品的pH范围为从4.8至5.5。在一些实施例中，配制品的pH范围为从4.5至5.3。在一些实施例中，配制品的pH为5.2。
在一些实施例中，在约40℃下储存一个月后，配制品包含双特异性抗体构建体的少于约10％(例如，9％、8％、7％、6％、5％、4％、3％或更少)的低分子量(LMW)物质。
在一些实施例中，在约2-8℃下储存一个月后，配制品包含双特异性抗体构建体的少于约10％(例如，9％、8％、7％、6％、5％、4％、3％或更少)的低分子量(LMW)物质。
在一些实施例中，在约40℃下储存一个月后，配制品包含双特异性抗体构建体的少于约5％(例如，4％、3％、2％、1％或更少)的高分子量(HMW)物质。
在一些实施例中，在约2-8℃下储存一个月后，配制品包含双特异性抗体构建体的少于约5％(例如，4％、3％、2％、1％或更少)的高分子量(HMW)物质。
在一些实施例中，在约40℃下储存一个月后，配制品中双特异性抗体构建体的相对效力大于约30％(例如，约35％、40％、50％、55％、60％或更多)。
在一些实施例中，完整
Figure BDA0003904969830000031
分子(即，主峰物质)在配制品中的百分比大于配制品中总蛋白质含量的95％。
在一些实施例中，双特异性抗体构建体包含与靶细胞表面抗原结合的第一结合结构域、与T细胞的表面上的人CD3结合的第二结合结构域。在一些实施例中，双特异性抗体构建体进一步包含第三结构域，该第三结构域以氨基到羧基顺序包含铰链-CH2结构域-CH3结构域-接头-铰链-CH2结构域-CH3结构域。在一些实施例中，双特异性抗体构建体的第一结合结构域和第二结合结构域中的每一者包含VH区和VL区。
在一些实施例中，双特异性抗体构建体是单链抗体构建体。
在一些实施例中，双特异性抗体构建体与靶细胞表面抗原(例如CDH19、MSLN、DLL3、FLT3、EGFRvlll、BCMA、PSMA、CD33、CD19、CD70、CLDN18.2或MUC17)结合。
在一些实施例中，双特异性抗体构建体的第一结合结构域包含以下列出的一组6个CDR：(a)SEQ ID NO:24-29，(b)SEQ ID NO:34-39，(c)SEQ ID NO:78-83，(d)SEQ ID NO:10-15，(e)SEQ ID NO:46-51，(f)SEQ ID NO:88-93，(g)SEQ ID NO:67-72，(h)SEQ ID NO:56-61，(i)SEQ ID NO:112-117，(j)SEQ ID NO:100-105，(k)SEQ ID NO:148-153、SEQ IDNO:157-162、或SEQ ID NO:166-171、或SEQ ID NO:175-180，(l)SEQ ID NO:132-137，或(m)SEQ ID NO:123-128。
在一些实施例中，双特异性抗体构建体的第一结合结构域包含VH区，该VH区包含与SEQ ID NO:30、40、84、16、17、52、94、73、62、118、154、163、172、181、106、138、143、或129中列出的氨基酸序列具有至少90％同一性(例如，91％、92％、93％、94％、95％、96％、97％、98％、99％、或100％同一性)的氨基酸序列。在一些实施例中，双特异性抗体构建体的第一结合结构域包含VH，该VH包含SEQ ID NO:30、40、84、16、17、52、94、73、62、118、154、163、172、181、106、138或143、或129中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体的第一结合结构域包含VL区，该VL区包含与SEQ ID NO:31、41、85、18、19、53、95、74、63、119、155、164、173、182、107、139、144、或130中列出的氨基酸序列具有至少90％同一性(例如，91％、92％、93％、94％、95％、96％、97％、98％、99％、或100％同一性)的氨基酸序列。在一些实施例中，双特异性抗体构建体的第一结合结构域包含VL，该VL包含SEQ ID NO:31、41、85、18、19、53、95、74、63、119、155、164、173、182、107、139、144、或130中列出的氨基酸序列。
在一些实施例中，其中第一结合结构域包含(a)VH区，该VH区包含SEQ ID NO:30中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:31中列出的氨基酸序列；(b)VH区，该VH区包含SEQ ID NO:40中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:41中列出的氨基酸序列；(c)VH区，该VH区包含SEQ ID NO:84中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:85中列出的氨基酸序列；(d)VH区，该VH区包含SEQ ID NO:16或17中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:18或19中列出的氨基酸序列；(e)VH区，该VH区包含SEQ ID NO:52中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:53中列出的氨基酸序列；(f)VH区，该VH区包含SEQ ID NO:94中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:95中列出的氨基酸序列；(g)VH区，该VH区包含SEQ ID NO:73中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:74中列出的氨基酸序列；(h)VH区，该VH区包含SEQID NO:62中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:63中列出的氨基酸序列；(i)VH区，该VH区包含SEQ ID NO:118中列出的氨基酸序列，以及VL区，该VL区包含SEQ IDNO:119中列出的氨基酸序列；(j)VH区，该VH区包含SEQ ID NO:154、163、172、或181中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:155、164,173、或182中列出的氨基酸序列；(k)VH区，该VH区包含SEQ ID NO:106中列出的氨基酸序列，以及VL区，该VL区包含SEQID NO:107中列出的氨基酸序列；(l)VH区，该VH区包含SEQ ID NO:138或143中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:139或144中列出的氨基酸序列；或(m)VH区，该VH区包含SEQ ID NO:129中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:130中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体的第二结合结构域包含SEQ ID NO:1-6中列出的一组6个CDR。
在一些实施例中，双特异性抗体构建体的第二结合结构域包含VH区，该VH区包含与SEQ ID NO:7中列出的氨基酸序列具有至少90％同一性(例如，91％、92％、93％、94％、95％、96％、97％、98％、99％、或100％同一性)的氨基酸序列。在一些实施例中，双特异性抗体构建体的第二结合结构域包含VH，该VH包含SEQ ID NO:7中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体的第二结合结构域包含VL区，该VL区包含与SEQ ID NO:8中列出的氨基酸序列具有至少90％同一性(例如，91％、92％、93％、94％、95％、96％、97％、98％、99％、或100％同一性)的氨基酸序列。在一些实施例中，双特异性抗体构建体的第二结合结构域包含VL，该VL包含SEQ ID NO:8中列出的氨基酸序列。
在一些实施例中，其中第二结合结构域包含(a)VH区，该VH区包含SEQ ID NO:7中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:8中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与CD19结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:85的氨基酸序列的抗CD19可变轻链结构域以及含有SEQID NO:84的氨基酸序列的抗CD19可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:86的氨基酸序列，和第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQID NO:87中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与MSLN结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:41的氨基酸序列的抗MSLN可变轻链结构域以及含有SEQID NO:40的氨基酸序列的抗MSLN可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:42的氨基酸序列，和第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQID NO:43、44或45中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与DLL3结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:74的氨基酸序列的抗DLL3可变轻链结构域以及含有SEQID NO:73的氨基酸序列的抗DLL3可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:75的氨基酸序列，和第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQID NO:76或77中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与FLT3结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:63的氨基酸序列的抗FLT3可变轻链结构域以及含有SEQID NO:62的氨基酸序列的抗FLT3可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:64的氨基酸序列，第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQ IDNO:65或66中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与EGFRvIII结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:31的氨基酸序列的抗EGFRvIII可变轻链结构域以及含有SEQ ID NO:30的氨基酸序列的抗EGFRvIII可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:32的氨基酸序列，第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQ ID NO:33中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与BCMA结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:95的氨基酸序列的抗BCMA可变轻链结构域以及含有SEQID NO:94的氨基酸序列的抗BCMA可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:96的氨基酸序列，第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQ IDNO:98或SEQ ID NO:97中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与PSMA结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:119或107的氨基酸序列的抗PSMA可变轻链结构域以及含有SEQ ID NO:118或106的氨基酸序列的抗PSMA可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:120或108的氨基酸序列，第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQ ID NO:121、122、109、110或111中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与CD33结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:18或19的氨基酸序列的抗CD33可变轻链结构域以及含有SEQ ID NO:16或17的氨基酸序列的抗CD33可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ IDNO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:189或190的氨基酸序列，第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQ ID NO:20、21、22或23中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与CDH19结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:53的氨基酸序列的抗CDH19可变轻链结构域以及含有SEQ ID NO:52的氨基酸序列的抗CDH19可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:54的氨基酸序列，第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQ ID NO:55中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与MUC17结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:155、164、173、或182的氨基酸序列的抗MUC17可变轻链结构域以及含有SEQ ID NO:154、163、172、或181的氨基酸序列的抗MUC17可变重链结构域，和第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。在一些实施例中，双特异性抗体构建体包含SEQ ID NO:156、165、174或183中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与cldn18.2结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:139或144的氨基酸序列的抗cldn18.2可变轻链结构域以及含有SEQ ID NO:138或143的氨基酸序列的抗cldn18.2可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:140或145的氨基酸序列，和第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQ ID NO:141、142、146或147中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与CD70结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:130的氨基酸序列的抗CD70可变轻链结构域以及含有SEQ ID NO:129的氨基酸序列的抗CD70可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。在一些实施例中，双特异性抗体构建体包含SEQ ID NO:131中列出的氨基酸序列。
本披露的药物配制品包含缓冲液。在一些实施例中，缓冲液是乙酸盐、谷氨酸盐、柠檬酸盐、琥珀酸盐、酒石酸盐、富马酸盐、马来酸盐、组氨酸、磷酸盐、和2-(N-吗啉代)乙磺酸盐或其组合。在一些实施例中，缓冲液在配制品中以从约5mM至约200mM(或约10mM至约50mM)的浓度范围存在。在一些实施例中，缓冲液以10mM的浓度存在于配制品中。
本披露的药物配制品包含糖。在一些实施例中，糖是单糖或二糖。在一些实施例中，糖是糖醇(例如山梨糖醇)。在一些实施例中，糖是蔗糖、海藻糖、甘露糖醇、山梨糖醇或其组合。在一些实施例中，糖以约从1％至约15％(w/V)(或约9％至约12％(w/V)或约5％至约12％(w/V)或约7％至约12％(w/V))的浓度范围存在于配制品中。
本披露的药物配制品包含表面活性剂。在一些实施例中，该表面活性剂是聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、泊洛沙姆188、泊洛沙姆407、曲拉通X-100、聚氧乙烯、PEG 3350、PEG 4000或其组合。在一些实施例中，表面活性剂以从0.004％至约0.5％(w/V)(或约0.001％至约0.01％(w/V)、或约0.001％至约0.5％(w/V)或约0.004％至约0.01％(w/V))的浓度范围存在于配制品中。
在一些实施例中，配制品的渗透压范围为约150mOsm至约500mOsm。在一些实施例中，配制品的渗透压不大于500mOsm/L、450mOsm/L、400mOsm/L或350mOsm/L。在一些实施例中，配制品接近等渗，例如250-350mOsm/L。
在一些实施例中，药物配制品包含10mM谷氨酸、9％(w/V)蔗糖和0.01％(w/V)聚山梨醇酯80，并且其中液体药物配制品的pH为5.2。在一些实施例中，双特异性抗体构建体以从约0.1mg/mL至约20mg/mL的浓度范围存在于配制品中。在一些实施例中，双特异性抗体构建体以1mg/mL、5mg/mL、10mg/mL或20mg/mL的浓度存在于配制品中。在一些实施例中，双特异性抗体以从约1000μg至约200mg的量范围存在于配制品中。
在一些实施例中，本披露的药物配制品是液体配制品。
在另一个方面，本文描述了治疗有需要的受试者的癌症的方法，该方法包括向受试者施用本披露的配制品。
应理解，虽然说明书中的多个实施例是使用“包含”语言呈现的，但在多种情况下，也可以使用“由……组成”或“基本上由……组成”语言来描述相关的实施例。本披露设想了被描述为“包含”一种特征的实施例，以包括“由所述特征组成”的实施例。应注意，术语“一种/一个”是指一种/一个或多种/多个，例如，“一种/一个免疫球蛋白分子”应理解为代表一种/一个或多种/多个免疫球蛋白分子。同样地，术语“一种/一个”、“一种或多种/一个或多个”以及“至少一种/至少一个(at least one)”可互换地使用。
还应理解，当描述值范围时，所描述的特征可以是在该范围内找到的单个值。例如，“从约pH 4.8至约pH 5.5的pH”可以是但不限于，pH 4.6、5.2、5.5等，以及这些值之间的任何值。另外，“从约pH 4.8至约pH 5.5的pH”不应被解释为意指所考虑配制品的pH在储存期间在pH 4.8至pH 5.5的范围内变化2个pH单位，而是指溶液的pH可以在该范围内挑选值，并且pH在约该pH下保持缓冲。
当使用术语“约”时，其意指所列举数字加上或减去所列举数字的5％、10％、15％或更多。预期的实际变化可从上下文确定。
在本文所述的任何范围内，该范围的端点包括在该范围内。然而，该描述还考虑了排除较低和/或较高端点的相同范围。从本申请的整体，包括附图和具体实施方式，本发明的另外的特征和变化对于本领域技术人员而言将是显而易见的，并且所有这些特征都旨在作为本发明的方面。同样，本文所述的本发明的特征可以重组成另外的实施例，这些实施例也旨在作为本发明的方面，无论这些特征的组合是否在上文作为本发明的一个方面或实施例具体提及。而且，只有本文所述的对本发明至关重要的限制才应被视为如此；本发明的缺少限制的变化(本文未描述为关键的)旨在作为本发明的方面。
本文引用的所有参考文献通过引用以其整体特此并入。
附图说明
图1是显示在更高pH的配制品情况下来自加速稳定性研究中的BiTE-I、BiTE-C、BiTE-D、和BiTE-G通过还原型毛细管电泳十二烷基硫酸钠(rCE SDS)的％低分子量(LMW)的图。
图2提供了显示在加速和建议储存条件下，BiTE-G在pH 4.2和pH 4.8液体配制品中的剪切速率的图。
图3A-3D提供了显示在pH 3.8、pH 4.8、pH 5.2和pH 7.4下，配制品中BiTE-D和BiTE-G的％LMW(由rCE评估)(图3A和3B)和％HMW(由SEC评估)(图3C和3D)的图。
具体实施方式
尽管目前治疗性生物技术产品具有高质量，并且重组人蛋白质和内源性人蛋白质的抗体具有相似性，但蛋白质不稳定性仍然是一个重要问题。生成重组蛋白(例如抗体)的过程可能会由于片段化或剪切而导致结构完整性的丧失(Vlasak等人,MAbs[单克隆抗体],3:253-263,2011；Wu等人,FEBS Lett.[欧洲生化学会联合会快报],588:935-941,2014)。本领域迫切需要增加治疗性蛋白的稳定性和结构完整性；并且优化的药物配制品可以有助于这样做。
特定的基于蛋白质的药物(如
Figure BDA0003904969830000121
抗体构建体分子)在液体配制品中经较长时间是不稳定的，并且尤其是在升高温度下(例如，制冷温度4℃及以上)不稳定。本披露基于的总体概念发现与具有更酸性pH(即小于4.8)或更碱性pH(即高于5.5)的液体配制品相比，本文所述液体药物配制品中双特异性抗体构建体的结构完整性在从4.8至5.5的pH范围内得到改善。如本文提供的实例所示，pH范围为从4.8至5.5的液体配制品导致液体配制品中的双特异性抗体构建体的最小剪切至无剪裁(以及最小聚集至无聚集)。
以前，需要将包含双特异性抗体构建体的配制品冻干，以便在pH 4.8-5.5的液体配制品中表现出本文观察到的稳定性(参见，例如，国际公开号WO 2018/114190和WO 2018/204907)。国际公开号WO 2018/204907中描述的冻干配制品包括有助于稳定双特异性抗体构建体的防腐剂(例如氯丁醇或对羟苯甲酸甲酯或苯甲醇)。在一些情况下，还通过另外的方式实现稳定性，例如通过降低配制品的pH。例如，国际公开号WO 2018/141910披露，包含双特异性抗体构建体并且具有低pH(即pH 4.0)的冻干配制品比在更碱性的pH(例如pH 6或更高)下具有相同抗体浓度的冻干配制品更稳定。相比之下，本披露的实例中所述的对优化的pH范围进行鉴定允许在不同时间点将包含双特异性抗体构建体的药物配制品作为液体配制品储存在4℃和更高温度(上至40℃)下。
在本披露中，术语“稳定性”、“稳定的”或“稳定化”涉及药物配制品的整体结构完整性，并特别地涉及活性成分(例如双特异性抗体构建体)本身的结构完整性，特别是在配制、填充、运输、储存和施用期间。例如，活性成分在本披露的药物配制品的上下文中的稳定性是由活性成分的片段化和/或剪切的量决定的。本文所用的“稳定水性配制品”是指液体(即非冻干)药物配制品，其包含本披露的双特异性抗体构建体，当在例如4℃下储存至少4周时，该双特异性抗体构建体具有最少至没有的双特异性抗体构建体的片段化或剪切。示例性稳定的水性配制品的pH为4.8-5.5(例如，pH 5.2)。如本文所用的“配制品”和“组合物”是同义词。
如本文所用的术语“剪切”或“片段化”是指通常通过蛋白质水解部分切割表达的蛋白质。所披露的药物配制品内双特异性抗体构建体的CDR的片段化可能会影响双特异性抗体构建体与靶标的结合，并且因此影响其效力。文献中很少有报道描述CDR中发生片段化的双特异性抗体构建体与靶标的结合亲和力发生改变；很可能，除非对CDR剪切物质进行纯化和测试，否则CDR中的低水平剪切可能会阻止通过效力测定可检测到的任何变化。铰链区的片段化可能对双特异性抗体构建体的功能有更多影响：产生的Fab片段将没有任何Fc介导的效应子功能，并且具有缩短的循环半衰期；如果与靶受体的相互作用需要全部两个Fab臂，则Fc-Fab片段可能根本无效。参见，Vlasak等人,mAbs[单克隆抗体],3:3,253-263,2011。
如本文所用，术语“低分子量(LMW)”物质是指由于剪切产生的双特异性抗体构建体的片段。
本文使用的术语“(蛋白质)聚集体”通常涵盖较高分子量的蛋白质物质，如“寡聚体”或“多聚体”，而不是所希望的确定物质(例如单体)。该术语在本文中可与术语“高分子量物质”和“HMW”互换地使用。蛋白质聚集体的大小(从小(二聚体)到大组件(亚可见或甚至可见颗粒)以及直径范围从纳米到微米)、形态(近似球状到针状)、蛋白质结构(天然相比于非天然/变性)、分子间键合的类型(共价相比于非共价)、可逆性和溶解性通常不同。可溶性聚集体覆盖约1至100nm的大小范围，并且蛋白质颗粒覆盖亚可见(约0.1-100.m)和可见(>100.m)范围。所有上述类型的蛋白质聚集体通常涵盖在该术语中。因此，术语“(蛋白质)聚集体”是指两种或更多种蛋白质单体的所有种类物理缔合或化学连接的非天然种类。
如本文所用，术语“聚集”是指分子之间的直接相互吸引，例如经由范德华力或化学键合。特别地，术语“聚集”被理解为蛋白质积聚和凝聚在一起。聚集体可以包括无定形聚集体、寡聚体，并且典型地称为高分子量(HMW)物质，即，具有比纯产物分子更高分子量的分子。
在一些实施例中，本披露描述了配制品，其包含以0.1-20mg/mL的量与人T细胞上的CD3结合的双特异性抗体构建体、缓冲液、糖和表面活性剂，其中该配制品具有从4.8-5.5(例如，pH 5.2)的pH范围。在一些实施例中，双特异性抗体构建体以这样的方式共同接合CD3和以下中的一种：人CDH19、人MSLN、人DLL3、人FLT3、人EGFRvlll、人BCMA、人PSMA、人CD33、人CD19、人CD70、人CLDN18.2或人MUC17，以便暂时将恶性细胞与T细胞连接，从而诱导T细胞介导的对结合的恶性细胞的杀伤。
配制品的各个方面描述如下。节标题的使用仅仅是为了便于阅读，而不是旨在限制本身。整个文件旨在被视为统一的披露，并且应理解，可以考虑本文所述的特征的所有组合。
抗原结合蛋白
“抗原结合蛋白”是包含结构域的蛋白质，该结构域与特定的靶抗原(如CD3和/或CDH19、MSLN、DLL3、FLT3、EGFRvlll、BCMA、PSMA、CD33、CD19、CD70、CLDN18.2、或MUC17)结合。抗原结合蛋白包含支架或框架部分，其允许抗原结合结构域采用促进抗原结合蛋白与抗原结合的构象。在示例性方面，抗原结合蛋白是抗体或免疫球蛋白，或抗原结合抗体片段。
术语“抗体”是指完整的抗原结合免疫球蛋白。“抗体”是一种抗原结合蛋白。抗体可以是IgA、IgD、IgE、IgG、或IgM抗体，包括IgG1、IgG2、IgG3或IgG4中的任一种。在多个实施例中，完整抗体包含两条全长重链和两条全长轻链。抗体具有可变区和恒定区。在IgG形式中，可变区通常为约100-110或更多个氨基酸，包含三个互补决定区(CDR)，主要负责抗原识别，并且与结合不同抗原的其他抗体差异很大。可变区通常包含至少三个重链CDR或三个轻链CDR(Kabat等人,1991,Sequences of Proteins of Immunological Interest[免疫相关蛋白质序列],Public Health Service[公共卫生署]N.I.H.,贝塞斯达,马里兰州；还参见Chothia和Lesk,1987,J.Mol.Biol.[分子生物学杂志]196:901-917；Chothia等人,1989,Nature[自然]342:877-883)，位于框架区内(由Kabat等人,1991指定框架区1-4、FR1、FR2、FR3、和FR4；还参见Chothia和Lesk,1987,同上)。恒定区允许抗体募集免疫系统的细胞和分子。
在一些实施例中，配制品的抗体是双特异性抗体，即结合两种不同靶标的抗体(例如，CD3和不同第二靶标)。
如本文所用，术语“双特异性”是指与两种不同靶抗原结合的抗体构建体，即，其包含第一结合结构域和第二结合结构域，其中该第一结合结构域与一种抗原或靶(例如，靶细胞表面抗原)结合，并且该第二结合结构域与另一种抗原或靶(例如，CD3)结合。因此，根据本披露的抗体构建体包含针对两种不同抗原或靶标的特异性。术语“靶细胞表面抗原”是指由细胞表达并且存在于细胞表面以使得为如本文所述的抗体构建体所接近的抗原结构。其可以是蛋白质，优选地蛋白质的细胞外部分，或碳水化合物结构，优选地蛋白质的碳水化合物结构，诸如糖蛋白。其优选地是肿瘤抗原。本发明还涵盖多特异性抗体构建体，诸如三特异性抗体构建体，后者包括三个结合结构域，或具有超过三种(例如四种、五种……)特异性的构建体。
如本文所理解的双特异性抗体和/或抗体构建体包括但不限于传统的双特异性免疫球蛋白(例如，BsIgG)、包含附加的抗原结合结构域的IgG(例如，轻链或重链的氨基或羧基末端连接到另外的抗原结合结构域，如单结构域抗体或成对抗体可变结构域(例如，Fv或scFv))、BsAb片段(例如，双特异性单链抗体)、双特异性融合蛋白(例如，与效应子部分融合的抗原结合结构域)和BsAb缀合物。参见，例如，Spiess等人,Molecular Immunology[分子免疫学]67(2)部分A:97-106(2015)，其描述了各种双特异性形式并通过引用并入文中。双特异性构建体的实例包括但不限于双抗体、单链双抗体、串联scFv、双特异性T细胞接合剂
Figure BDA0003904969830000151
形式(由通过接头连接的两个单链可变片段(scFv)组成的融合蛋白)、和Fab2双特异性抗体、以及包含全长抗体的工程化构建体。参见，例如，Chames和Baty,2009,mAbs[单克隆抗体]1[6]:1-9；和Holliger和Hudson,2005,Nature Biotechnology[自然生物技术]23[9]:1126-1136；Wu等人,2007,Nature Biotechnology[自然生物技术]25[11]:1290-1297；Michaelson等人,2009,mAbs[单克隆抗体]1[2]:128-141；国际专利公开号2009032782和2006020258；Zuo等人,2000,Protein Engineering[蛋白质工程]13[5]:361-367；美国专利申请公开号20020103345；Shen等人,2006,J Biol Chem[生物化学杂志]281[16]:10706-10714；Lu等人,2005,J Biol Chem[生物化学杂志]280[20]:19665-19672；以及Kontermann,2012MAbs[单克隆抗体]4(2):182，所有这些都明确地并入本文。
在一些实施例中，本文所述的配制品包含双特异性抗体构建体，该双特异性抗体构建体包含与靶细胞表面抗原结合的第一结合结构域、与T细胞表面上的人CD3结合的第二结合结构域，以及任选地按氨基到羧基的顺序包含铰链-CH2结构域-CH3结构域-接头-铰链-CH2结构域-CH3结构域的第三结构域。在一些实施例中，第一结合结构域和第二结合结构域中的每一者包含VH区和VL区。
如本文所用，术语“结合结构域”是指(特异性地)结合至靶分子(抗原)上的给定靶表位或给定靶位点/与该靶表位或靶位点相互作用/识别该靶表位或靶位点的结构域，这些靶分子(抗原)例如分别为CDH19、MSLN、DLL3、FLT3、EGFRvlll、BCMA、PSMA、CD33、CD19、CD70、CLDN18.2或MUC17以及CD3。第一结合结构域(识别例如CDH19、MSLN、DLL3、FLT3、EGFRvlll、BCMA、PSMA、CD33、CD19、CD70、CLDN18.2或MUC17)的结构和功能，以及优选地还有第二结合结构域(识别CD3)的结构和/或功能是基于抗体，例如全长或完整免疫球蛋白分子的结构和/或功能，和/或是从抗体或其片段的可变重链(VH)和/或可变轻链(VL)结构域中提取。优选地，第一结合结构域的特征在于存在三个轻链CDR(即VL区的CDR1、CDR2和CDR3)和/或三个重链CDR(即VH区的CDR1、CDR2和CDR3)。第二结合结构域优选地还包含允许靶结合的抗体的最小结构要求。更优选地，第二结合结构域包含至少三个轻链CDR(即VL区的CDR1、CDR2和CDR3)和/或三个重链CDR(即VH区的CDR1、CDR2和CDR3)。设想第一结合结构域和/或第二结合结构域是通过噬菌体展示或文库筛选方法产生或可获得的，而不是通过将CDR序列从预先存在的(单克隆)抗体移植到支架中产生或可获得的。
在一些实施例中，与靶细胞表面抗原结合的第一结合结构域和/或与CD3ε结合的第二结合结构域是人结合结构域。包含至少一个人结合结构域的抗体和抗体构建体避免了与具有非人(诸如啮齿动物(例如鼠类、大鼠、仓鼠或兔))可变区和/或恒定区的抗体或抗体构建体相关联的一些问题。这种啮齿动物来源的蛋白质的存在可以导致抗体或抗体构建体的快速清除，或者可以导致患者生成针对抗体或抗体构建体的免疫应答。为了避免使用啮齿动物衍生的抗体或抗体构建体，可以通过将人抗体功能引入到啮齿动物中以使啮齿动物产生完全人抗体来生成人或完全人抗体/抗体构建体。
在一些实施例中，抗原结合蛋白包含单链抗体构建体。scFv包含可变重链、scFv接头和可变轻链结构域。任选地，可变轻链的C末端附接至scFv接头的N末端，该接头的C末端附接至可变重链的N末端(N-vh-接头-vl-C)，虽然可以转换构型(N-vl-接头-vh-C)。可替代地，可变重链的C末端附接至scFv接头的N末端，该接头的C末端附接至可变轻链的N末端(N-vl-接头-vh-C)，虽然可以转换构型(N-vh-接头-v-C)。因此，scFv的描绘和说明中特别包括的是任一取向的scFv。
本披露的抗体构建体的至少两个结合结构域和可变结构域(VH/VL)可以包含或可以不包含肽接头(间隔肽)。根据本发明，术语“肽接头”包含这样的氨基酸序列：通过该氨基酸序列，本披露的抗体构建体的一个(可变和/或结合)结构域和另一(可变和/或结合)结构域的氨基酸序列彼此连接。肽接头也可以用于将第三结构域与本发明的抗体构建体的其他结构域融合。这种肽接头的基本技术特征在于它不包含任何聚合活性。适合的肽接头是在美国专利4,751,180和4,935,233或WO 88/09344中描述的那些，将其披露内容通过引用以其整体特此并入。肽接头也可用于将其他结构域或模块或区(如半衰期延长的结构域)附接到本文所述的双特异性抗体构建体。
在一些实施例中，第三结构域包含“Fc”或“Fc区”或“Fc结构域”，该“Fc”或“Fc区”或“Fc结构域”是指包含除第一恒定区免疫球蛋白结构域之外的抗体的恒定区的多肽。因此，“Fc结构域”是指IgA、IgD和IgG的最后两个恒定区免疫球蛋白结构域、IgE和IgM的最后三个恒定区免疫球蛋白结构域、和在这些结构域的N末端的柔性铰链。对于IgA和IgM，Fc可以包括J链。对于IgG，Fc结构域包含免疫球蛋白结构域Cγ2和Cγ3(Cγ2和Cγ3)以及Cγ1(Cγ1)和Cγ2(Cγ2)之间的下铰链区。双特异性抗体构建体优选地是IgG抗体(其包括几个亚类，包括但不限于IgG1、IgG2、IgG3、和IgG4)。尽管Fc区的边界可以变化，人IgG重链Fc区通常定义为在其羧基末端包括残基C226或P230，其中根据如在Kabat中的EU索引进行编号。在一些实施例中，对Fc区进行氨基酸修饰，例如，以改变与一种或多种FcγR受体或FcRn受体的结合。
在一些实施例中，本文所述的配制品包含双特异性抗体构建体，该双特异性抗体构建体与人CD3和人CDH19、或人CD3和人MSLN、或人CD3和人DLL3、或人CD3和人FLT3、或人CD3和人EGFRvIII、或人CD3和人BCMA、或人CD3和PSMA、或人CD3和人CD33、或人CD3和人CD19、人CD3和人CD70、或人CD3和人MUC17、或人CD3和人CLDN18.2结合。
在一些实施例中，双特异性抗体构建体的第一结合结构域包含以下列出的一组6个CDR：(a)SEQ ID NO:24-29，(b)SEQ ID NO:34-39，(c)SEQ ID NO:78-83，(d)SEQ ID NO:10-15，(e)SEQ ID NO:46-51，(f)SEQ ID NO:88-93，(g)SEQ ID NO:67-72，(h)SEQ ID NO:56-61，(i)SEQ ID NO:112-117，(j)SEQ ID NO:100-105，(k)SEQ ID NO:148-153、SEQ IDNO:157-162、或SEQ ID NO:166-171、或SEQ ID NO:175-180，(l)SEQ ID NO:132-137，或(m)SEQ ID NO:123-128。
在一些实施例中，双特异性抗体构建体的第一结合结构域包含VH区，该VH区包含与SEQ ID NO:30、40、84、16、17、52、94、73、62、118、154、163、172、181、106、138、143、或129中列出的氨基酸序列具有至少90％同一性(例如，91％、92％、93％、94％、95％、96％、97％、98％、99％、或100％同一性)的氨基酸序列。在一些实施例中，双特异性抗体构建体的第一结合结构域包含VH，该VH包含SEQ ID NO:30、40、84、16、17、52、94、73、62、118、154、163、172、181、106、138、143、或129中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体的第一结合结构域包含VL区，该VL区包含与SEQ ID NO:31、41、85、18、19、53、95、74、63、119、155、164、173、182、107、139、144、或130中列出的氨基酸序列具有至少90％同一性(例如，91％、92％、93％、94％、95％、96％、97％、98％、99％、或100％同一性)的氨基酸序列。在一些实施例中，双特异性抗体构建体的第一结合结构域包含VL，该VL包含SEQ ID NO:31、41、85、18、19、53、95、74、63、119、155、164、173、182、107、139、144、或130中列出的氨基酸序列。
在一些实施例中，其中第一结合结构域包含(a)VH区，该VH区包含SEQ ID NO:30中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:31中列出的氨基酸序列；(b)VH区，该VH区包含SEQ ID NO:40中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:41中列出的氨基酸序列；(c)VH区，该VH区包含SEQ ID NO:84中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:85中列出的氨基酸序列；(d)VH区，该VH区包含SEQ ID NO:16或17中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:18或19中列出的氨基酸序列；(e)VH区，该VH区包含SEQ ID NO:52中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:53中列出的氨基酸序列；(f)VH区，该VH区包含SEQ ID NO:94中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:95中列出的氨基酸序列；(g)VH区，该VH区包含SEQ ID NO:73中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:74中列出的氨基酸序列；(h)VH区，该VH区包含SEQID NO:62中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:63中列出的氨基酸序列；(i)VH区，该VH区包含SEQ ID NO:118中列出的氨基酸序列，以及VL区，该VL区包含SEQ IDNO:119中列出的氨基酸序列；(j)VH区，该VH区包含SEQ ID NO:154、163、172、或181中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:155、164、173、或182中列出的氨基酸序列；(k)VH区，该VH区包含SEQ ID NO:106中列出的氨基酸序列，以及VL区，该VL区包含SEQID NO:107中列出的氨基酸序列；(l)VH区，该VH区包含SEQ ID NO:138或143中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:139或144中列出的氨基酸序列；或(m)VH区，该VH区包含SEQ ID NO:129中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:130中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体的第二结合结构域包含SEQ ID NO:1-6中列出的一组6个CDR。
在一些实施例中，双特异性抗体构建体的第二结合结构域包含VH区，该VH区包含与SEQ ID NO:7中列出的氨基酸序列具有至少90％同一性(例如，91％、92％、93％、94％、95％、96％、97％、98％、99％、或100％同一性)的氨基酸序列。在一些实施例中，双特异性抗体构建体的第二结合结构域包含VH，该VH包含SEQ ID NO:7中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体的第二结合结构域包含VL区，该VL区包含与SEQ ID NO:8中列出的氨基酸序列具有至少90％同一性(例如，91％、92％、93％、94％、95％、96％、97％、98％、99％、或100％同一性)的氨基酸序列。在一些实施例中，双特异性抗体构建体的第二结合结构域包含VL，该VL包含SEQ ID NO:8中列出的氨基酸序列。
在一些实施例中，其中第二结合结构域包含(a)VH区，该VH区包含SEQ ID NO:7中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:8中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与CD19结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:85的氨基酸序列的抗CD19可变轻链结构域以及含有SEQID NO:84的氨基酸序列的抗CD19可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:86的氨基酸序列，和第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQID NO:87中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与MSLN结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:41的氨基酸序列的抗MSLN可变轻链结构域以及含有SEQID NO:40的氨基酸序列的抗MSLN可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:42的氨基酸序列，和第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQID NO:43、44或45中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与DLL3结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:74的氨基酸序列的抗DLL3可变轻链结构域以及含有SEQID NO:73的氨基酸序列的抗DLL3可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:75的氨基酸序列，和第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQID NO:76或77中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与FLT3结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:63的氨基酸序列的抗FLT3可变轻链结构域以及含有SEQID NO:62的氨基酸序列的抗FLT3可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:64的氨基酸序列，第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQ IDNO:65或66中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与EGFRvIII结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:31的氨基酸序列的抗EGFRvIII可变轻链结构域以及含有SEQ ID NO:30的氨基酸序列的抗EGFRvIII可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:32的氨基酸序列，第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQ ID NO:33中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与BCMA结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:95的氨基酸序列的抗BCMA可变轻链结构域以及含有SEQID NO:94的氨基酸序列的抗BCMA可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:96的氨基酸序列，第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQ IDNO:98或SEQ ID NO:97中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与PSMA结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:119或107的氨基酸序列的抗PSMA可变轻链结构域以及含有SEQ ID NO:118或106的氨基酸序列的抗PSMA可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:120或108的氨基酸序列，第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQ ID NO:121、122、109、110或111中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与CD33结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:18或19的氨基酸序列的抗CD33可变轻链结构域以及含有SEQ ID NO:16或17的氨基酸序列的抗CD33可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ IDNO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:189或190的氨基酸序列，第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQ ID NO:20、21、22或23中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与CDH19结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:53的氨基酸序列的抗CDH19可变轻链结构域以及含有SEQ ID NO:52的氨基酸序列的抗CDH19可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:54的氨基酸序列，第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQ ID NO:55中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与MUC17结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:155、164、173、或182的氨基酸序列的抗MUC17可变轻链结构域以及含有SEQ ID NO:154、163、172、或181的氨基酸序列的抗MUC17可变重链结构域，和第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。在一些实施例中，双特异性抗体构建体包含SEQ ID NO:156、165、174或183中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与cldn18.2结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:139或144的氨基酸序列的抗cldn18.2可变轻链结构域以及含有SEQ ID NO:138或143的氨基酸序列的抗cldn18.2可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。例如，在一个实施例中，双特异性抗体构建体包含第一结合结构域，该第一结合结构域包含SEQ ID NO:140或145的氨基酸序列，和第二结合结构域，该第二结合结构域包含SEQ ID NO:9的氨基酸序列。在一些实施例中，双特异性抗体构建体包含SEQ ID NO:141、142、146或147中列出的氨基酸序列。
在一些实施例中，双特异性抗体构建体包含与CD70结合的第一结合结构域，该第一结合结构域包含含有SEQ ID NO:130的氨基酸序列的抗CD70可变轻链结构域以及含有SEQ ID NO:129的氨基酸序列的抗CD70可变重链结构域，第二结合结构域，该第二结合结构域包含含有SEQ ID NO:7的氨基酸序列的抗CD3可变重链结构域以及含有SEQ ID NO:8的氨基酸序列的抗CD3可变轻链结构域。在一些实施例中，双特异性抗体构建体包含SEQ ID NO:131中列出的氨基酸序列。
在一些实施例中，配制品包含本文所述的抗原结合蛋白(例如，双特异性抗体构建体)，其量的范围为从约10mg至约50mg(或从约10mg至约20mg、或约20mg至约50mg、或约15mg至约20mg、或约20mg至约55mg)。在一些实施例中，配制品包含约10mg、约15mg、约20mg、约25mg、约30mg、约35mg、约40mg、约45mg、或约50mg的量的双特异性抗体构建体。
在一些实施例中，配制品包含浓度范围为从约1mg/mL至约20mg/mL(或从约1mg/mL至约8mg/mL或从约1mg/mL至约5mg/mL)的抗原结合蛋白(例如双特异性抗体构建体)。在一些实施例中，配制品包含浓度为约1mg/mL、约2mg/mL、约3mg/mL、约4mg/mL、约5mg/mL、约6mg/mL、约7mg/mL、约8mg/mL、约9mg/mL、约10mg/mL、约11mg/mL、约12mg/mL、约13mg/mL、约14mg/mL、约15mg/mL、约16mg/mL、约17mg/mL、约18mg/mL、约19mg/mL或约20mg/mL的双特异性抗体构建体。
在一些实施例中，配制品包含浓度范围为从约0.1至约8mg/mL(或从约0.5至约5mg/mL或从约1至约5mg/mL、或从约3至约6mg/mL)的双特异性抗体构建体。在一些实施例中，配制品包含浓度为约0.1mg/mL、约0.5mg/mL、约1mg/mL、约2mg/mL、约3mg/mL、约4mg/mL、约5mg/mL、约6mg/mL、约7mg/mL、或约8mg/mL的双特异性抗体构建体。
缓冲液
本发明的药物配制品包含缓冲液，该缓冲液任选地可以是乙酸盐、谷氨酸盐、柠檬酸盐、琥珀酸盐、酒石酸盐、富马酸盐、马来酸盐、组氨酸、磷酸盐、2-(N-吗啉代)乙磺酸盐或其组合。
通常采用缓冲液来控制配制品中的pH。在一些实施例中，以一定浓度添加缓冲液使液体配制品的pH保持在使得配制品中双特异性抗体构建体的剪切和聚集速率降低。在一些实施例中，液体配制品的pH为约pH 4.8至pH 5.5，或约pH 4至pH 5.5、或约pH 5.2。pH对配制品的影响可以使用几种途径中的任何一种或多种来表征，如加速稳定性研究和量热筛选研究(Remmele R.L.Jr.,等人,Biochemistry[生物化学],38(16):5241-7(1999))。
选择配制品中存在的缓冲液系统以在生理学上相容并且保持所希望的pH(例如，4.8至5.5之间，或5.2)。
缓冲液能以适于将配制品的pH维持在预定水平的任何量存在。缓冲液可以按约0.1mM和约1000mM(1M)之间、或约5mM和约200mM之间、或约5mM至约100mM之间、或约10mM和约50mM之间的浓度存在。适合的缓冲液浓度涵盖约200mM或更低的浓度。在一些实施例中，配制品中的缓冲液以约190mM、约180mM、约170mM、约160mM、约150mM、约140mM、约130mM、约120mM、约110mM、约100mM、约80mM、约70mM、约60mM、约50mM、约40mM、约30mM、约20mM、约10mM或约5mM的浓度存在。在一些实施例中，缓冲液的浓度为至少0.1、0.5、0.7、0.8、0.9、1.0、1.2、1.5、1.7、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、30、40、50、60、70、80、90、100、200、500、700、或900mM。在一些实施例中，缓冲液的浓度为在1、1.2、1.5、1.7、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、30、40、50、60、70、80、或90mM和100mM之间。在一些实施例中，缓冲液的浓度为在5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、30、或40mM和50mM之间。在一些实施例中，缓冲液的浓度为约10mM。
表面活性剂
本文所述的药物配制品包含表面活性剂。示例性表面活性剂包括但不限于聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、泊洛沙姆188、泊洛沙姆407、曲拉通X-100、聚氧乙烯、PEG 3350、PEG 4000或其组合。
本文所述的药物配制品包含单独的或呈不同比率的混合物的至少一种表面活性剂。在一些实施例中，配制品包含浓度为约0.001％至约5％w/v(或约0.001％至约0.5％、或约0.004％至约0.5％w/v、或约0.001％至约0.01％w/v或约0.004％至约0.01％w/v)的表面活性剂。在一些实施例中，配制品包含浓度为至少0.001％、至少0.002％、至少0.003％、至少0.004％、至少0.005％、至少0.007％、至少0.01％、至少0.05％、至少0.1％、至少0.2％、至少0.3％、至少0.4％、至少0.5％、至少0.6％、至少0.7％、至少0.8％、至少0.9％、至少1.0％、至少1.5％、至少2.0％、至少2.5％、至少3.0％、至少3.5％、至少4.0％、或至少4.5％w/v的表面活性剂。在一些实施例中，配制品包含浓度为约0.001％至约0.5％w/v的表面活性剂。在一些实施例中，配制品包含浓度为约0.001％至约0.01％w/v的表面活性剂。在一些实施例中，配制品包含浓度为约0.001％至约0.01％w/v的表面活性剂。在一些实施例中，配制品包含浓度为约0.001％、约0.002％、约0.003％、约0.004％、约0.005％、约0.006％、约0.007％、约0.008％、约0.009％、约0.01％、约0.05％、约0.1％、约0.2％、约0.3％、约0.4％至约0.5％w/v的表面活性剂。在一些实施例中，配制品包含以约0.001％至约0.01％w/v的浓度掺入的表面活性剂。在一些实施例中，表面活性剂是聚山梨醇酯80，聚山梨醇酯80以约0.01％w/v的浓度存在。
糖
本文所述的药物配制品包含糖。在一些实施例中，糖是单糖或二糖。在一些实施例中，该糖是葡萄糖、半乳糖、果糖、木糖、蔗糖、乳糖、麦芽糖、海藻糖、山梨糖醇、甘露糖醇或木糖醇或其组合。
在一些实施例中，药物配制品包含浓度为约0.01％至约40％w/v、或约00.1％至约20％w/v、或约1％至约15％、或约5％至约12％、或约7％至约12％w/v的糖。在一些实施例中，药物配制品包含浓度为至少0.5％、至少1％、至少2％、至少3％、至少4％、至少5％、至少6％、至少7％、至少8％、至少9％、至少10％、至少11％、至少12％、至少13％、至少14％、至少15％、至少16％、至少17％、至少18％、至少19％、至少20％、至少30％、或至少40％w/v的至少一种糖。在一些实施例中，药物配制品包含浓度为约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％w/v的至少一种糖。在一些实施例中，药物配制品包含浓度为约1％至约15％w/v的至少一种糖。在又另一个实施例中，药物配制品包含浓度为约7％、约7.5％、约8％、约8.5％、约9％、约9.5％、约10％、约10.5％、约11％、约11.5％、或约12％w/v的至少一种糖。在一些实施例中，药物配制品包含浓度为约7％至约12％w/v的至少一种糖。在一些实施例中，至少一种糖在配制品中的浓度为约9％w/v。在一些实施例中，糖是蔗糖，并且在配制品中以从约9％w/v至约12％w/v的范围存在。
在一些实施例中，药物配制品包含10mM谷氨酸、9％(w/V)蔗糖和0.01％(w/V)聚山梨醇酯80，其中药物配制品的pH为5.2。
在一些实施例中，药物配制品包含10mM乙酸盐、9％(w/V)蔗糖和0.01％(w/V)聚山梨醇酯80，其中药物配制品的pH为5.2。
稳定性
如实例中所述，对优化的pH范围(pH 4.8-pH 5.2)进行鉴定允许在不同时间点将包含双特异性抗体构建体的药物配制品作为液体配制品储存在4℃和40℃两者下。双特异性抗体构建体配制品的稳定性可以按几种方式进行量化。在一些实施例中，抗体配制品的稳定性通过尺寸排阻高效液相色谱(SE-HPLC)、尺寸排阻超高效液相色谱(SE-UHPLC)、阳离子交换高效液相色谱(CE-HPLC)、动态光散射、分析超离心(AUC)、场流分离(FFF)、等电聚焦以及离子交换色谱(IEX)来表征。在一些实施例中，抗体配制品的稳定性通过部分解离来表征，如通过十二烷基硫酸钠的毛细管电泳(CE-SDS)和/或十二烷基硫酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)测量的。在一些实施例中，配制品的稳定性通过还原型毛细管电泳-十二烷基硫酸钠(rCE-SDS)评估。rCE-SDS方法在还原条件下分离出重链(HC)、轻链(LC)、非糖基化的HC(NGHC)和其他次要的峰物质和基团。
在一些实施例中，配制品的稳定性特征在于在不同时间点的储存条件下双特异性抗体构建体的高分子量(HMW)物质的量，或在于双特异性抗体构建体的HMW物质的量的增加速率。在一些实施例中，在大约2-8℃(例如4℃)或40℃下储存一周、两周、一个月、三个月、六个月、十二个月、十八个月或两年时确定HMW物质的量。在一些实施例中，在大约2-8℃(例如4℃)或40℃下储存一周、两周、一个月、三个月、六个月、十二个月、十八个月或两年时确定HMW物质的增加速率。在一些实施例中，通过尺寸排阻色谱(SEC)来测量配制品中的双特异性抗体构建体的HMW物质。在一些实施例中，通过SE-UHPLC来测量配制品中的双特异性抗体构建体的HMW物质。
双特异性抗体构建体的稳定性和配制品保持双特异性抗体构建体的稳定性的能力，可以在延长的时间段(例如，数周或数月)内评估。在配制品的上下文中，稳定的配制品是其中的双特异性抗体构建体在储存后和加工过程(例如冷冻/解冻、机械混合和冻干)中基本上保持其物理和/或化学完整性和生物活性的配制品。例如，可以通过测量高分子量(HMW)聚集体形成、电荷特征的改变以及颗粒大小的变化的水平和/或速率来评估双特异性抗体构建体稳定性。
在一些实施例中，如本文所述的双特异性抗体构建体的任何特定物质，如完整
Figure BDA0003904969830000271
分子或主要物质、或高分子量(HMW)物质(即，聚集体)、或低分子量(LMW)物质(即，片段)的相对值是相对于总产物的各自的值来表示的。例如，在一些实施例中，10％或更少(例如，10％、9％、8％、7％、6％、5％、4％、3％、2％、1％或更少)的双特异性抗体构建体，在配制品中作为HMW物质存在。在一些实施例中，在2-8℃下储存一个月或更久(例如，持续一个月、持续三个月、持续六个月、持续12个月、持续十八个月、或持续两年)后，HMW物质的量在配制品中增加小于10％(例如，9％、8％、7％、6％、5％、4％、3％或更少)。在一些实施例中，在40℃下储存一个月或更久(例如，持续一周、持续两周、持续一个月、持续三个月、持续六个月、或持续一年)后，HMW物质的量在配制品中增加小于10％或更少(例如，10％、9％、8％、7％、6％、5％、4％、3％、2％、1％或更少)。在一些实施例中，通过尺寸排阻色谱(SEC)来测量配制品中的双特异性抗体构建体的HMW物质。在一些实施例中，通过SE-UHPLC来测量配制品中的双特异性抗体构建体的HMW物质。
在一些实施例中，配制品的稳定性特征在于在不同时间点的储存条件下双特异性抗体构建体的低分子量(LMW)物质的量，或在于双特异性抗体构建体的LMW物质的量的增加速率。在一些实施例中，在大约2-8℃下储存一个月、三个月、六个月、十二个月、十八个月或两年来确定LMW物质的量。在一些实施例中，在40℃下储存一周、两周、一个月、三个月、六个月或一年来确定LMW物质的量。在一些实施例中，在大约2-8℃下储存一个月、三个月、六个月、十二个月、十八个月或两年来确定LMW物质的增加速率。在一些实施例中，在40℃下储存一周、两周、一个月、三个月、六个月或一年来确定LMW物质的增加速率。在一些实施例中，通过rCE-SDS来测量配制品中的双特异性抗体构建体的LMW物质。
在一些实施例中，少于10％或更少(例如，10％、9％、8％、7％、6％、5％、4％、3％、2％、1％或更少)的双特异性抗体构建体，在配制品中作为LMW物质存在。在一些实施例中，在2-8℃下储存一个月或更久(例如，持续一个月、持续三个月、持续六个月、持续12个月、持续十八个月、或持续两年)后，LMW物质的量在配制品中增加小于10％(例如，9％、8％、7％、6％、5％、4％、3％或更少)。在一些实施例中，在40℃下储存一个月或更久(例如，持续一周、持续两周、持续一个月、持续三个月、持续六个月、或持续一年)后，LMW物质的量在配制品中增加小于10％或更少(例如，10％、9％、8％、7％、6％、5％、4％、3％、2％、1％或更少)。在一些实施例中，通过rCE-SDS来测量配制品中的双特异性抗体构建体的LMW物质。
在一些实施例中，完整
Figure BDA0003904969830000291
分子(即，主峰物质)在配制品中的百分比大于配制品中总蛋白质含量的90％(90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更多)。
在一个实施例中，液体配制品在约2-8℃下储存一个月后是稳定的，并且完整
Figure BDA0003904969830000292
分子(即，主峰物质)的百分比大于配制品中总蛋白含量的95％。在另一个实施例中，液体配制品在约40℃下储存一个月后是稳定的，并且完整
Figure BDA0003904969830000293
分子(即，主峰物质)的百分比大于配制品中总蛋白含量的95％。
本文所述的配制品的稳定性也可以通过电荷分布来表征，例如抗体的电荷变体峰的量的变化。例如，在一些实施例中，当在4℃下储存至少一个月(例如，持续一个月、三个月、六个月或十二个月)时，配制品中的酸性峰(例如，脱酰胺化，具有相对较低的等电点(pI)的电荷变体)的量增加少于2％(例如，2％、1.9％、1.8％、1.7％、1.6％、1.5％、1.4％、1.3％、1.2％、1.1％、1.0％、0.9％、0.8％、0.7％、0.6％、0.5％、或更少)。在一些实施例中，当在4℃下储存至少一个月(例如，持续一个月、三个月、六个月或十二个月)时，配制品中的碱性峰(例如，具有相对较高的pI的电荷变体)的量增加小于6％(例如，6％、5％、4％、3％、2％或1％)。
在一些实施例中，当在40℃下储存至少一周(例如，持续一周、两周、一个月或三个月)时，配制品中的酸性峰的量增加少于30％(例如，30％、25％、20％、15％、10％、9％、8％、7％、6％、4％、4％、3％、2％、1％或更少)。在一些实施例中，当在40℃下储存至少一周(例如，持续一周、两周、一个月或三个月)时，配制品中的碱性峰(例如，具有相对较高的pI的电荷变体)的量增加少于15％(例如，15％、10％、9％、8％、7％、6％、4％、4％、3％、2％、1％或更少)。
本文所述液体配制品的稳定性也可以通过确定储存条件下液体配制品中双特异性抗体构建体的相对效力水平来评估。例如，可以通过基于细胞的生物测定法测定双特异性抗体构建体的相对效力，该生物测定法通过癌细胞系中的发光损失来测量细胞死亡。通过比较测试样品响应与参考标准物的响应(相对效力)来确定测试样品的生物活性。在一些实施例中，如实例3中所述进行评估，在约40℃下储存一个月后，配制品中双特异性抗体构建体的相对效力大于约30％(例如，约35％、40％、50％、55％、60％)或更多。
配制品的治疗用途
本文所述的配制品可用作在有需要的受试者中治疗、改善癌症的药物配制品。术语“有需要的受试者”或“需要治疗的那些”包括已经患有障碍的那些以及有待预防障碍的那些。有需要的受试者或“患者”包括接受预防性或治疗性治疗的人和其他哺乳动物受试者。术语“治疗”是指治疗性治疗和预防性(prophylactic或preventative)措施两者。治疗包括将配制品应用或施用至来自具有疾病/障碍、疾病/障碍的症状或对疾病/障碍的倾向的患者的身体、分离的组织或细胞，目的是治疗、治愈、缓解、减轻、改变、补救、减轻、改善或影响疾病、疾病的症状或向疾病的倾向。
如本文使用的，术语“改善”是指通过将包含本文所述的抗原结合蛋白的配制品施用有需要的受试者，对患有如下文指明的肿瘤或癌症或转移性癌症的患者的疾病状态的任何改进。这种改善还可以被视为减缓或停止患者的肿瘤或癌症或转移性癌症的进展。本文使用的术语“防止”意指通过将包含本文所述的抗原结合蛋白(即双特异性抗体构建体)的配制品施用于有需要的受试者，避免患有如下文所述的肿瘤或癌症或转移性癌症的患者的发病或复发。
本披露提供了一种治疗癌症的方法，该方法包括向有需要的受试者施用治疗有效量的本文所述的重组蛋白或药物配制品。在某些实施例中，该受试者是人类。在某些实施例中，癌症是实体瘤。
在一些实施例中，该癌症是脑癌、膀胱癌、乳腺癌、透明细胞肾癌、子宫颈癌、结肠和直肠癌、子宫内膜癌、胃癌、头/颈鳞状细胞癌、唇和口腔癌、肝癌、肺鳞状细胞癌、黑色素瘤、间皮瘤、非小细胞肺癌(NSCLC)、非黑色素瘤皮肤癌、卵巢癌、口腔癌、胰腺癌、前列腺癌、肾细胞癌、肉瘤、小细胞肺癌(SCLC)、头颈部鳞状细胞癌(SCCHN)、三阴性乳腺癌或甲状腺癌。
在一些实施例中，该癌症是肾上腺皮质肿瘤、腺泡状软组织肉瘤、癌、软骨肉瘤、结直肠癌、韧带样瘤、促结缔组织增生性小圆细胞瘤、内分泌肿瘤、内胚窦瘤、上皮样血管内皮瘤、尤文肉瘤、生殖细胞肿瘤、肝母细胞瘤、肝细胞癌、黑色素瘤、肾瘤、成神经细胞瘤、非横纹肌肉瘤软组织肉瘤(NRSTS)、骨肉瘤、椎旁肉瘤、肾细胞癌、视网膜母细胞瘤、横纹肌肉瘤、滑膜肉瘤或威尔姆氏瘤。
在一些实施例中，该癌症是急性成淋巴细胞白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞性白血病(CLL)、或慢性髓性白血病(CML)。
在一些实施例中，该癌症是弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤、霍奇金淋巴瘤(HL)、套细胞淋巴瘤(MCL)、多发性骨髓瘤(MM)、骨髓增生异常综合征(MDS)、非霍奇金淋巴瘤(NHL)或小淋巴细胞淋巴瘤(SLL)。
实际上，可以治疗的癌症包括但不限于腺泡状横纹肌肉瘤，骨癌，肛门、肛管或肛肠癌，眼癌，肝内胆管癌，关节癌，颈、胆囊或胸膜癌，鼻、鼻腔或中耳癌，口腔癌，外阴癌，食管癌，胃肠道类癌肿瘤，下咽癌，喉癌，鼻咽癌，腹膜、网膜和肠系膜癌，咽癌，小肠癌，软组织癌，胃癌，睾丸癌，输尿管癌和膀胱癌。
施用途径
优选地，药物配制品通过胃肠外施用，例如静脉内、皮下、或肌肉内施用。肠胃外施用可以通过注射，例如推注注射，或通过输注，例如连续输注来实现。施用可通过贮库实现长期释放。在一些实施例中，通过初始推注、随后连续输注以维持药物产品的治疗循环水平静脉内施用配制品。在一些实施例中，配制品以一次性剂量施用。可以使用医疗装置施用药物配制品。用于施用药物配制品的医疗装置的实例描述于美国专利号4,475,196；4,439,196；4,447,224；4,447,233；4,486,194；4,487,603；4,596,556；4,790,824；4,941,880；5,064,413；5,312,335；5,312,335；5,383,851；和5,399,163中。
本披露还考虑了不间断地施用适合的配制品。作为非限制性实例，可以通过患者佩戴的小泵系统实现不间断或基本上不间断的给药，即连续给药，所述小泵系统用于计量治疗剂进入患者体内的流入量。药物配制品可以通过使用所述泵系统施用。这种泵系统在本领域中通常是已知的，并且通常依赖于含有待输注的治疗剂的药筒的定期更换。当在这种泵系统中更换药筒时，治疗剂不间断流入患者体内可能会发生暂时中断。在这种情况下，药筒替换之前的施用阶段和药筒替换之后的施用阶段仍将被认为在药物手段的含义内，并且本发明的方法一起构成这种治疗剂的一次“不间断施用”。
配制品的连续或不间断施用可以通过流体递送装置或小泵系统进行静脉内或皮下施用，该流体递送装置或小泵系统包括用于驱动流体离开储存器的流体驱动机制和用于致动该驱动机制的致动机制。用于皮下施用的泵系统可以包括用于穿透患者皮肤并将适合的配制品递送到患者体内的针或套管。所述泵系统可以独立于静脉、动脉或血管直接固定或附接至患者的皮肤，从而允许泵系统与患者皮肤之间的直接接触。泵系统可以附接至患者的皮肤上24小时至数天。泵系统可以是小尺寸的，其中储器适用于小体积。作为非限制性实例，待施用的适合的药物配制品的储器容积可以为0.1至50ml。
试剂盒
作为一个另外的方面，本文所述的是包含一种或多种本文所述的药物配制品的药剂盒，所述药物配制品以利于用于施用受试者的方式包装。在一个实施例中，此类药剂盒包括本文所述的配制品(例如，包含其中描述抗体的配制品)，所述配制品包装在容器中，例如在密封瓶、小管、单次使用或多次使用的小瓶、预填充式注射器、或预填充式注射装置中，所述药剂盒任选地具有贴附于容器上或包括在包装中的标签，该标签描述了化合物或配制品在实践该方法中的用途。在一个方面，该配制品被包装为一个单位剂型。该药剂盒可以进一步包括适于根据具体的施用途径施用该配制品的装置。优选地，药剂盒含有描述本文所述的抗体或本文所述的配制品的用途的标签。
本文所述的药物配制品能以多种形式配制，例如，以固体、液体、冷冻、气体或冻干形式，并且尤其可以是软膏、乳膏、透皮贴剂、凝胶、粉末、片剂、溶液，气溶胶、颗粒、丸剂、悬浮液、乳液、胶囊、糖浆、液体、酏剂、提取物、酊剂或流体提取物形式。
通常，对于本发明的药物配制品，可以想到多种储存和/或剂型，这取决于预期的施用途径、递送型式和所希望的剂量(参见，例如Remington's Pharmaceutical Sciences[雷明顿药物科学],第22版,Oslo,A.,编辑,(2012))。技术人员将意识到，特定剂型的这种选择可以例如影响抗体的物理状态、稳定性、体内释放速率和体内清除速率。
例如，药物配制品中的主要媒介物或载体在自然界中可以是水性或非水性的。适合的媒介物或载体可以是注射用水、生理盐水溶液或人造脑脊液，可能补充有配制品中常见的用于肠胃外施用的其他物质。中性缓冲盐水或与血清白蛋白混合的盐水是另外的示例性媒介物。
实例
材料与方法
使用多种技术对稳定性样品进行分析，从而监测药物产品的关键质量属性。在加速条件下进行以下稳定性指示测定：分别将SE-UHPLC(尺寸排阻超高效液相色谱)用于监测聚集，rCE-SDS和多属性方法(MAM)用于监测剪切，以及目视外观用于可见颗粒分析。
尺寸排阻超高效液相色谱(SE-UHPLC)基于蛋白质流体动力学体积的差异来分离蛋白质。具有较高流体动力学体积的分子比具有较小体积的分子更先洗脱。将样品加载到SE-UHPLC柱(BEH200，4.6x 300mm，(沃特斯公司(Waters Corporation)，186005226))上，等度分离并通过UV吸光度监测洗脱液。通过计算每个分离的组分与总积分面积相比的百分比来确定纯度。SE-UHPLC设置如下：流速：0.4mL/min，运行时间：12min，UV检测：280nm，柱温度：环境，靶蛋白质加载：6μg，蛋白质相容流动细胞：5mm。
还原型毛细管电泳-十二烷基硫酸钠(rCE-SDS)基于蛋白质在还原和变性条件下的流体动力学大小差异来分离蛋白质。蛋白质物质与SDS(阴离子洗涤剂)结合，并通过电动力学注射到填充有SDS凝胶缓冲液的裸露熔融石英毛细管中。在毛细管上施加电压，在此电压下，SDS包被的蛋白质由于在基于亲水聚合物的溶液中的迁移不同而被分离。蛋白质通过UV检测窗口时，通过光电二极管阵列(PDA)检测器检测。通过确定到达组分(reachcomponent)的校正峰面积百分比来评估纯度。rCE-SDS方法在还原条件下分离出重链(HC)、轻链(LC)、非糖基化的HC(NGHC)和其他次要的峰物质和基团。
实例1-通过CE-SDS评估，增加的pH降低了LMW物质的百分比
在加速稳定性研究中，评估了在不同pH(pH 4.2、4.8和5.5)下，
Figure BDA0003904969830000331
Figure BDA0003904969830000332
和
Figure BDA0003904969830000333
中每一个在以下配制品中的稳定性。将配制品在40℃下储存一个月，并且然后通过还原型毛细管电泳十二烷基硫酸钠(rCE SDS)分析LMW物质的水平：
测试的液体配制品：1mg/mL BiTE分子、10mM L-谷氨酸、9％(w/v)蔗糖、0.01％(w/v)聚山梨醇酯80。
如以下图1中和表1中所示，当与在相同储存条件下储存的pH 4.2的液体配制品相比时，pH 4.8和pH 5.2的液体配制品在40℃下储存1个月后，LMW物质的百分比降低。
表1.在40℃下储存1个月后的％LMW(rCE SDS)
Figure BDA0003904969830000341
实例2-通过MAM评估LMW物质
在40℃下储存一个月后，通过MAM(多属性方法学)评估在pH 4.2、pH 4.8和pH 7.4下液体配制品(实例中1所述)中BiTE-G的剪切百分比。简而言之，将样品在30kDa MWCO旋转过滤器上捕获，并且在过滤器上变性、还原，并且然后烷基化。随后，将样品缓冲交换到消化缓冲液中，并且然后用胰蛋白酶消化。将消化的样品离心，并且捕获胰蛋白酶肽。然后用人中性粒细胞弹性蛋白酶进行过滤器上的连续消化，并且收集所得肽并且与胰蛋白酶肽合并。通过在乙酸盐缓冲液(pH 4.8)中添加8M胍来淬灭消化。然后，使用Agilent 1290UPLC(Waters BEH C18柱)和Thermo Q Exactive Biopharma(使用数据依赖性采集)，通过LC-MS对肽进行分析。用MassAnalyzer搜索结果数据，从而确定序列覆盖率，并且使用Skyline工作簿进行定量。观察到的化学修饰在商业上可接受的范围内(数据未显示)。
实例3-BiTE分子
Figure BDA0003904969830000342
在pH大于4.2时保留效力
在2-8℃下储存两年后，还对在pH 4.2和pH 4.8下，
Figure BDA0003904969830000343
在液体配制品(实例1中所述)中的相对效力进行评估。简而言之，通过基于细胞的生物测定法测量
Figure BDA0003904969830000344
的效力，该生物测定法通过癌细胞系中的发光损失来测量细胞死亡。通过比较测试样品响应与参考标准物的响应(相对效力)来确定测试样品的生物活性。此测定表明，在2-8℃下储存两年后，在pH 4.2和pH 4.8两者下，
Figure BDA0003904969830000351
在液体配制品中表现出可接受水平的效力。
实例4-在不同pH下，
Figure BDA0003904969830000352
分子的剪切速率变化
通过rCE-SDS评估了在pH 4.2和pH 4.8下，
Figure BDA0003904969830000353
在液体配制品(实例1中所述)中的剪切速率。如以下图2和表2中所示，当在40℃下储存一个月后，与在pH 4.2下的液体配制品相比，在pH 4.8下的液体配制品显示出剪切水平下降27％。当在2-8℃下储存两年时，与在pH 4.2下的液体配制品相比，也在pH 4.8下的液体配制品中观察到剪切水平下降29％。
表2.在加速和建议的储存条件下，与pH 4.2配制品相比，pH 4.8下的剪切水平下降。
Figure BDA0003904969830000354
实例5-通过SE-UHLPC评估HMW物质
在2-8℃或-30℃下储存一个月、三个月、六个月、十二个月、十八个月和两年后，通过尺寸排阻超高效液相色谱(SE-UHLPC)评估实例1中所述的液体配制品(包含在pH 4.2和pH 4.8下的
Figure BDA0003904969830000355
)中的高分子量(HMW)物质百分比。分析表明，在2-8℃下的储存条件下，在所有测试时间点，在pH 4.2配制品和pH 4.8配制品两者中均观察到的
Figure BDA0003904969830000356
的HMW百分比小于0.35％(数据未显示)。分析还表明，在-30℃下的储存条件下，在所有测试时间点，在pH 4.2配制品和pH 4.8配制品两者中均观察到的
Figure BDA0003904969830000357
的HMW百分比小于1.3％(数据未显示)。
实例6-在各种储存条件下评估LMW和低的HMW两者
在以下列出的每种配制品中对
Figure BDA0003904969830000358
和
Figure BDA0003904969830000359
在各种液体配制品中的LMW和HMW物质百分比进行评估。通过还原型毛细管电泳(rCE)测定％LMW，并且通过尺寸排阻色谱(SEC)测定％HMW。测试的液体配制品如下：
配制品A：1mg/mL
Figure BDA0003904969830000361
分子、10mM L-谷氨酸、9％(w/v)蔗糖、0.01％(w/v)聚山梨醇酯80，pH 3.8；
配制品B：1mg/mL
Figure BDA0003904969830000362
分子、10mM L-谷氨酸、9％(w/v)蔗糖、0.01％(w/v)聚山梨醇酯80，pH 4.8；
配制品C：1mg/mL
Figure BDA0003904969830000363
分子、10mM L-谷氨酸、9％(w/v)蔗糖、0.01％(w/v)聚山梨醇酯80，pH 5.2；
配制品D：1mg/mL
Figure BDA0003904969830000364
分子、10mM乙酸盐、9％(w/v)蔗糖、0.01％(w/v)聚山梨醇酯80，pH 5.2；
配制品E：1mg/mL
Figure BDA0003904969830000365
分子、10mM磷酸盐、9％(w/v)蔗糖、0.01％(w/v)聚山梨醇酯80，pH 7.4。
结果示于以下图3A-3D和表3-6中：
表3.如通过rCE测定的
Figure BDA0003904969830000366
的LMW百分比
Figure BDA0003904969830000367
表4.如通过rCE测定的
Figure BDA0003904969830000368
的LMW百分比
Figure BDA0003904969830000371
表5.如通过SEC测定的
Figure BDA0003904969830000372
的HMW百分比。
Figure BDA0003904969830000373
Figure BDA0003904969830000381
表6.如通过SEC测定的
Figure BDA0003904969830000382
的HMW百分比。
Figure BDA0003904969830000383
如图3A-3D中所示，在4℃和40℃两者下储存四周后，与配制品A(pH 3.8)和配制品E(pH 7.4)相比，配制品B(pH 4.8)和配制品C(pH 5.2)显示出LMW和HMW物质两者的最低百分比。配制品D(pH 5.2)也显示出LMW和HMW两者的低百分比，表明配制品中的缓冲液选择不影响
Figure BDA0003904969830000384
分子的片段化。该实例中提供的数据表明，无论配制品中的缓冲液如何，对优化的pH范围(pH 4.8-pH 5.5)进行鉴定允许在不同时间点将包含双特异性抗体构建体的药物配制品作为液体配制品储存在4℃和40℃两者下。
序列表
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<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 4
Lys Tyr Ala Met Asn
1 5
<210> 5
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 5
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys Asp
<210> 6
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 6
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 7
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 7
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 8
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 8
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
20 25 30
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn
85 90 95
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 9
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 9
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
130 135 140
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
145 150 155 160
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
165 170 175
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
180 185 190
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
195 200 205
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
210 215 220
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245
<210> 10
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 10
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
1 5 10 15
Ala
<210> 11
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 11
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 12
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 12
Gln Gln Ser Ala His Phe Pro Ile Thr
1 5
<210> 13
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 13
Asn Tyr Gly Met Asn
1 5
<210> 14
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 14
Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe Gln
1 5 10 15
Gly
<210> 15
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 15
Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr
1 5 10
<210> 16
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 16
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 17
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 17
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 18
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 18
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Thr Val Ser Leu Gly
1 5 10 15
Glu Arg Thr Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asp Ser
20 25 30
Ser Thr Asn Lys Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Leu Ser Trp Ala Ser Thr Arg Glu Ser Gly Ile
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Asp Ser Pro Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Ser Ala His Phe Pro Ile Thr Phe Gly Cys Gly Thr Arg Leu Glu Ile
100 105 110
Lys
<210> 19
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 19
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Thr Val Ser Leu Gly
1 5 10 15
Glu Arg Thr Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asp Ser
20 25 30
Ser Thr Asn Lys Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Leu Ser Trp Ala Ser Thr Arg Glu Ser Gly Ile
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Asp Ser Pro Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Ser Ala His Phe Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile
100 105 110
Lys
<210> 20
<211> 505
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 20
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys
145 150 155 160
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser
180 185 190
Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu
210 215 220
Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr
225 230 235 240
Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser
245 250 255
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
260 265 270
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
275 280 285
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
290 295 300
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
305 310 315 320
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
325 330 335
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
355 360 365
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
385 390 395 400
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
405 410 415
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
420 425 430
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
435 440 445
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
450 455 460
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
465 470 475 480
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
485 490 495
Gly Gly Gly Thr Lys Leu Thr Val Leu
500 505
<210> 21
<211> 530
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 21
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala
65 70 75 80
Asp Lys Phe Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe
115 120 125
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met
145 150 155 160
Thr Gln Ser Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr
165 170 175
Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys
180 185 190
Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu
195 200 205
Leu Leu Ser Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe
210 215 220
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro
225 230 235 240
Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe
245 250 255
Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly
260 265 270
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
275 280 285
Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
290 295 300
Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
305 310 315 320
Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr
325 330 335
Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser
340 345 350
Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr
355 360 365
Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile
370 375 380
Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
385 390 395 400
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
405 410 415
Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr
420 425 430
Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn
435 440 445
Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu
450 455 460
Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser
465 470 475 480
Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln
485 490 495
Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg
500 505 510
Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His
515 520 525
His His
530
<210> 22
<211> 993
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 22
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys
145 150 155 160
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser
180 185 190
Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu
210 215 220
Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr
225 230 235 240
Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser
245 250 255
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
260 265 270
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
275 280 285
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
290 295 300
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
305 310 315 320
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
325 330 335
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
355 360 365
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
385 390 395 400
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
405 410 415
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
420 425 430
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
435 440 445
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
450 455 460
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
465 470 475 480
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
485 490 495
Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr
500 505 510
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
515 520 525
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
530 535 540
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
545 550 555 560
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
565 570 575
Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val
580 585 590
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
595 600 605
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
610 615 620
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
625 630 635 640
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
645 650 655
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
660 665 670
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
675 680 685
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
690 695 700
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
705 710 715 720
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
725 730 735
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
740 745 750
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys
755 760 765
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
770 775 780
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
785 790 795 800
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
805 810 815
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
820 825 830
Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys
835 840 845
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
850 855 860
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
865 870 875 880
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
885 890 895
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
900 905 910
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
915 920 925
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
930 935 940
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
945 950 955 960
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
965 970 975
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
980 985 990
Lys
<210> 23
<211> 511
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 23
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys
145 150 155 160
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser
180 185 190
Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu
210 215 220
Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr
225 230 235 240
Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser
245 250 255
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
260 265 270
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
275 280 285
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
290 295 300
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
305 310 315 320
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
325 330 335
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
355 360 365
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
385 390 395 400
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
405 410 415
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
420 425 430
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
435 440 445
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
450 455 460
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
465 470 475 480
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
485 490 495
Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His His His
500 505 510
<210> 24
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 24
Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr Leu Ser
1 5 10 15
<210> 25
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 25
Arg Ile Ser Arg Arg Phe Ser
1 5
<210> 26
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 26
Met Gln Ser Thr His Val Pro Arg Thr
1 5
<210> 27
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 27
Asn Tyr Gly Met His
1 5
<210> 28
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 28
Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val Arg
1 5 10 15
Gly
<210> 29
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 29
Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp Tyr
1 5 10 15
<210> 30
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 30
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ser Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 31
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 31
Asp Thr Val Met Thr Gln Thr Pro Leu Ser Ser His Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro
35 40 45
Pro Arg Leu Leu Ile Tyr Arg Ile Ser Arg Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Glu Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser
85 90 95
Thr His Val Pro Arg Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 32
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 32
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ser Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Thr Val Met Thr
130 135 140
Gln Thr Pro Leu Ser Ser His Val Thr Leu Gly Gln Pro Ala Ser Ile
145 150 155 160
Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr
165 170 175
Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro Pro Arg Leu Leu Ile
180 185 190
Tyr Arg Ile Ser Arg Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly
195 200 205
Ser Gly Ala Gly Thr Asp Phe Thr Leu Glu Ile Ser Arg Val Glu Ala
210 215 220
Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser Thr His Val Pro Arg
225 230 235 240
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys
245 250
<210> 33
<211> 506
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 33
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ser Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Thr Val Met Thr
130 135 140
Gln Thr Pro Leu Ser Ser His Val Thr Leu Gly Gln Pro Ala Ser Ile
145 150 155 160
Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr
165 170 175
Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro Pro Arg Leu Leu Ile
180 185 190
Tyr Arg Ile Ser Arg Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly
195 200 205
Ser Gly Ala Gly Thr Asp Phe Thr Leu Glu Ile Ser Arg Val Glu Ala
210 215 220
Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser Thr His Val Pro Arg
225 230 235 240
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Ser Gly Gly Gly Gly
245 250 255
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
260 265 270
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys
275 280 285
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
290 295 300
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
305 310 315 320
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
325 330 335
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
340 345 350
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr
355 360 365
Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val
385 390 395 400
Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr
405 410 415
Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro
420 425 430
Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly
435 440 445
Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser
450 455 460
Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu
465 470 475 480
Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val
485 490 495
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
500 505
<210> 34
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 34
Asp Tyr Tyr Met Thr
1 5
<210> 35
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 35
Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 36
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 36
Asp Arg Asn Ser His Phe Asp Tyr
1 5
<210> 37
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 37
Arg Ala Ser Gln Gly Ile Asn Thr Trp Leu Ala
1 5 10
<210> 38
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 38
Gly Ala Ser Gly Leu Gln Ser
1 5
<210> 39
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 39
Gln Gln Ala Lys Ser Phe Pro Arg Thr
1 5
<210> 40
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 40
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 41
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 41
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Thr Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys Ser Phe Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 42
<211> 239
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 42
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly
145 150 155 160
Ile Asn Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Leu Leu Ile Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys
210 215 220
Ser Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
225 230 235
<210> 43
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 43
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly
145 150 155 160
Ile Asn Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Leu Leu Ile Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys
210 215 220
Ser Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser
225 230 235 240
Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
245 250 255
Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
260 265 270
Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys
275 280 285
Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala
290 295 300
Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp
305 310 315 320
Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu
325 330 335
Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser
340 345 350
Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
355 360 365
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly
385 390 395 400
Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser
405 410 415
Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg
420 425 430
Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg
435 440 445
Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly
450 455 460
Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser
465 470 475 480
Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490
<210> 44
<211> 982
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 44
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly
145 150 155 160
Ile Asn Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Leu Leu Ile Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys
210 215 220
Ser Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser
225 230 235 240
Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
245 250 255
Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
260 265 270
Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys
275 280 285
Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala
290 295 300
Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp
305 310 315 320
Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu
325 330 335
Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser
340 345 350
Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
355 360 365
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly
385 390 395 400
Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser
405 410 415
Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg
420 425 430
Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg
435 440 445
Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly
450 455 460
Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser
465 470 475 480
Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly
485 490 495
Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
500 505 510
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
515 520 525
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
530 535 540
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
545 550 555 560
Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser
565 570 575
Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
580 585 590
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
595 600 605
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
610 615 620
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
625 630 635 640
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
645 650 655
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
660 665 670
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
675 680 685
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
690 695 700
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
705 710 715 720
Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
755 760 765
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
770 775 780
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
785 790 795 800
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
805 810 815
Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly
820 825 830
Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp
835 840 845
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
850 855 860
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
865 870 875 880
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
885 890 895
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
900 905 910
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
915 920 925
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
930 935 940
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
945 950 955 960
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
965 970 975
Ser Leu Ser Pro Gly Lys
980
<210> 45
<211> 982
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 45
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly
145 150 155 160
Ile Asn Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Leu Leu Ile Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys
210 215 220
Ser Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser
225 230 235 240
Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
245 250 255
Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
260 265 270
Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys
275 280 285
Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala
290 295 300
Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp
305 310 315 320
Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu
325 330 335
Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser
340 345 350
Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
355 360 365
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly
385 390 395 400
Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser
405 410 415
Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg
420 425 430
Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg
435 440 445
Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly
450 455 460
Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser
465 470 475 480
Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly
485 490 495
Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
500 505 510
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
515 520 525
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
530 535 540
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
545 550 555 560
Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser
565 570 575
Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
580 585 590
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
595 600 605
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
610 615 620
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
625 630 635 640
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
645 650 655
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
660 665 670
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
675 680 685
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
690 695 700
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
705 710 715 720
Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
755 760 765
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
770 775 780
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
785 790 795 800
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
805 810 815
Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly
820 825 830
Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp
835 840 845
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
850 855 860
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
865 870 875 880
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
885 890 895
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
900 905 910
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
915 920 925
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
930 935 940
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
945 950 955 960
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
965 970 975
Ser Leu Ser Pro Gly Lys
980
<210> 46
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 46
Ser Tyr Gly Met His
1 5
<210> 47
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 47
Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val Lys
1 5 10 15
Asp
<210> 48
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 48
Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 49
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 49
Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser
1 5 10
<210> 50
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 50
Gln Asp Thr Lys Arg Pro Ser
1 5
<210> 51
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 51
Gln Ala Trp Glu Ser Ser Thr Val Val
1 5
<210> 52
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 52
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 53
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 53
Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr
20 25 30
Ser Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr
35 40 45
Gln Asp Thr Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val
85 90 95
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Ser
100 105
<210> 54
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 54
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser
245
<210> 55
<211> 507
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 55
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu His His His His His His
500 505
<210> 56
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 56
Asn Ala Arg Met Gly Val Ser
1 5
<210> 57
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 57
His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys Asn
1 5 10 15
<210> 58
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 58
Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp Tyr
1 5 10
<210> 59
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 59
Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly
1 5 10
<210> 60
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 60
Ala Ala Ser Thr Leu Gln Ser
1 5
<210> 61
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 61
Leu Gln His Asn Ser Tyr Pro Leu Thr
1 5
<210> 62
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 62
Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala
20 25 30
Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu
35 40 45
Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 63
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 63
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys
100 105
<210> 64
<211> 246
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 64
Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala
20 25 30
Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu
35 40 45
Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr
180 185 190
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
210 215 220
Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu Thr Phe Gly Cys Gly
225 230 235 240
Thr Lys Val Glu Ile Lys
245
<210> 65
<211> 501
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 65
Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala
20 25 30
Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu
35 40 45
Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr
180 185 190
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
210 215 220
Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu Thr Phe Gly Cys Gly
225 230 235 240
Thr Lys Val Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu
500
<210> 66
<211> 989
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 66
Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala
20 25 30
Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu
35 40 45
Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr
180 185 190
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
210 215 220
Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu Thr Phe Gly Cys Gly
225 230 235 240
Thr Lys Val Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro
500 505 510
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
515 520 525
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
530 535 540
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
545 550 555 560
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
565 570 575
Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr
580 585 590
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
595 600 605
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
610 615 620
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
625 630 635 640
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
645 650 655
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
660 665 670
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
675 680 685
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
690 695 700
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
705 710 715 720
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys
755 760 765
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
770 775 780
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
785 790 795 800
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
805 810 815
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
820 825 830
Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu
835 840 845
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
850 855 860
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
865 870 875 880
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
885 890 895
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
900 905 910
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
915 920 925
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
930 935 940
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
945 950 955 960
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
965 970 975
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 67
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 67
Ser Tyr Tyr Trp Ser
1 5
<210> 68
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 68
Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 69
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 69
Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr
1 5 10
<210> 70
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 70
Arg Ala Ser Gln Arg Val Asn Asn Asn Tyr Leu Ala
1 5 10
<210> 71
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 71
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 72
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 72
Gln Gln Tyr Asp Arg Ser Pro Leu Thr
1 5
<210> 73
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 73
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 74
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 74
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Asn Asn Asn
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Arg Ser Pro
85 90 95
Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 75
<211> 241
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 75
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
210 215 220
Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys
<210> 76
<211> 496
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 76
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
210 215 220
Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
<210> 77
<211> 982
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 77
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
210 215 220
Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
500 505 510
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
515 520 525
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
530 535 540
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
545 550 555 560
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr
565 570 575
Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp
580 585 590
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
595 600 605
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
610 615 620
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
625 630 635 640
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
645 650 655
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
660 665 670
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
675 680 685
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
690 695 700
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
705 710 715 720
Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
755 760 765
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
770 775 780
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
785 790 795 800
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
805 810 815
Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly
820 825 830
Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp
835 840 845
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
850 855 860
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
865 870 875 880
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
885 890 895
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
900 905 910
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
915 920 925
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
930 935 940
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
945 950 955 960
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
965 970 975
Ser Leu Ser Pro Gly Lys
980
<210> 78
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 78
Ser Tyr Gly Met His
1 5
<210> 79
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 79
Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val Lys
1 5 10 15
Gly
<210> 80
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 80
Asp Arg Gly Thr Ile Phe Gly Asn Tyr Gly Leu Glu Val
1 5 10
<210> 81
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 81
Arg Ser Ser Gln Ser Leu Leu His Lys Asn Ala Phe Asn Tyr Leu Asp
1 5 10 15
<210> 82
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 82
Leu Gly Ser Asn Arg Ala Ser
1 5
<210> 83
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 83
Met Gln Ala Leu Gln Thr Pro Phe Thr
1 5
<210> 84
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 84
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Gly Thr Ile Phe Gly Asn Tyr Gly Leu Glu Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 85
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 85
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ile Ser Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Lys
20 25 30
Asn Ala Phe Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Phe Thr Phe Gly Cys Gly Thr Lys Val Asp Ile Lys
100 105 110
<210> 86
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 86
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ile Ser Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Lys
20 25 30
Asn Ala Phe Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Phe Thr Phe Gly Cys Gly Thr Lys Val Asp Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly
145 150 155 160
Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ala
165 170 175
Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Arg Asp Arg Gly Thr Ile Phe Gly Asn Tyr Gly Leu Glu Val Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Glu Val
245 250 255
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
260 265 270
Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met
275 280 285
Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg
290 295 300
Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val
305 310 315 320
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr
325 330 335
Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
340 345 350
Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr
355 360 365
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln
385 390 395 400
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
405 410 415
Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val
420 425 430
Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys
435 440 445
Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
450 455 460
Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala
465 470 475 480
Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly
485 490 495
Gly Thr Lys Leu Thr Val Leu
500
<210> 87
<211> 991
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 87
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ile Ser Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Lys
20 25 30
Asn Ala Phe Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Phe Thr Phe Gly Cys Gly Thr Lys Val Asp Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly
145 150 155 160
Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ala
165 170 175
Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Arg Asp Arg Gly Thr Ile Phe Gly Asn Tyr Gly Leu Glu Val Trp Gly
225 230 235 240
Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Glu Val
245 250 255
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
260 265 270
Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met
275 280 285
Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg
290 295 300
Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val
305 310 315 320
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr
325 330 335
Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
340 345 350
Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr
355 360 365
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln
385 390 395 400
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
405 410 415
Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val
420 425 430
Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys
435 440 445
Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
450 455 460
Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala
465 470 475 480
Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly
485 490 495
Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr
500 505 510
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
515 520 525
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
530 535 540
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
545 550 555 560
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
565 570 575
Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val
580 585 590
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
595 600 605
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
610 615 620
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
625 630 635 640
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
645 650 655
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
660 665 670
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
675 680 685
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
690 695 700
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
705 710 715 720
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His
755 760 765
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
770 775 780
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
785 790 795 800
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
805 810 815
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
820 825 830
Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser
835 840 845
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
850 855 860
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
865 870 875 880
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
885 890 895
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
900 905 910
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
915 920 925
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
930 935 940
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
945 950 955 960
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
965 970 975
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985 990
<210> 88
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 88
Asn His Ile Ile His
1 5
<210> 89
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 89
Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe Gln
1 5 10 15
Gly
<210> 90
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 90
Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr
1 5 10
<210> 91
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 91
Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 92
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 92
Tyr Thr Ser Arg Leu His Thr
1 5
<210> 93
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 93
Gln Gln Gly Asn Thr Leu Pro Trp Thr
1 5
<210> 94
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 94
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 95
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 95
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 96
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 96
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln
145 150 155 160
Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 97
<211> 986
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 97
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln
145 150 155 160
Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 98
<211> 504
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 98
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln
145 150 155 160
Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu His His His His His His
500
<210> 99
<211> 986
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 99
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln
145 150 155 160
Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 100
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 100
Asp Tyr Tyr Met Tyr
1 5
<210> 101
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 101
Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile Lys
1 5 10 15
Gly
<210> 102
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 102
Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr
1 5 10
<210> 103
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 103
Lys Ala Ser Gln Asn Val Asp Ala Asn Val Ala
1 5 10
<210> 104
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 104
Ser Ala Ser Tyr Val Tyr Trp
1 5
<210> 105
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 105
Gln Gln Tyr Asp Gln Gln Leu Ile Thr
1 5
<210> 106
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 106
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 107
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 107
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Ala Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Val Tyr Trp Asp Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Ala Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ser
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Gln Gln Leu Ile
85 90 95
Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 108
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 108
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 109
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 109
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu
<210> 110
<211> 986
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 110
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 111
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 111
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
755 760 765
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
770 775 780
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
785 790 795 800
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
805 810 815
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
820 825 830
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
835 840 845
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
850 855 860
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
865 870 875 880
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
885 890 895
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
900 905 910
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
915 920 925
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
930 935 940
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
945 950 955 960
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
965 970 975
Ser Leu Ser Leu Ser Pro Gly Lys
980
<210> 112
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 112
Asp Tyr Tyr Met Tyr
1 5
<210> 113
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 113
Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile Lys
1 5 10 15
Gly
<210> 114
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 114
Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr
1 5 10
<210> 115
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 115
Lys Ala Ser Gln Asn Val Asp Thr Asn Val Ala
1 5 10
<210> 116
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 116
Ser Ala Ser Tyr Val Tyr Trp
1 5
<210> 117
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 117
Gln Gln Tyr Asp Gln Gln Leu Ile Thr
1 5
<210> 118
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 118
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 119
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 119
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Val Tyr Trp Asp Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Ala Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ser
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Gln Gln Leu Ile
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 120
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 120
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 121
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 121
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu
<210> 122
<211> 986
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 122
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 123
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 123
Thr Tyr Ala Met Ser
1 5
<210> 124
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 124
Ala Ile Ser Gly Ser Gly Gly Arg Thr Phe Tyr Ala Glu Ser Val Glu
1 5 10 15
Gly
<210> 125
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 125
His Asp Tyr Ser Asn Tyr Pro Tyr Phe Asp Tyr
1 5 10
<210> 126
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 126
Arg Ala Ser Gln Ser Val Arg Ser Thr Tyr Leu Ala
1 5 10
<210> 127
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 127
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 128
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 128
Gln Gln Tyr Gly Asp Leu Pro Phe Thr
1 5
<210> 129
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 129
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Met Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Arg Thr Phe Tyr Ala Glu Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys His Asp Tyr Ser Asn Tyr Pro Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 130
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 130
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Ser Thr
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Ser Cys Gln Gln Tyr Gly Asp Leu Pro
85 90 95
Phe Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 131
<211> 986
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 131
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Met Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Arg Thr Phe Tyr Ala Glu Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys His Asp Tyr Ser Asn Tyr Pro Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly
130 135 140
Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala
145 150 155 160
Ser Gln Ser Val Arg Ser Thr Tyr Leu Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr
180 185 190
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Ser Cys
210 215 220
Gln Gln Tyr Gly Asp Leu Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 132
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 132
Gly Tyr Tyr Met His
1 5
<210> 133
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 133
Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 134
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 134
Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 135
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 135
Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala
1 5 10
<210> 136
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 136
Thr Ala Ser Ser Leu Gln Ser
1 5
<210> 137
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 137
Gln Gln Ala Asn Ser Phe Pro Ile Thr
1 5
<210> 138
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 138
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 139
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 139
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile
85 90 95
Thr Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 140
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 140
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys
245
<210> 141
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 141
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
290 295 300
Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys
305 310 315 320
Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu
325 330 335
Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val
340 345 350
Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu
385 390 395 400
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly
405 410 415
Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln
420 425 430
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe
435 440 445
Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly
450 455 460
Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu
465 470 475 480
Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly
485 490 495
Thr Lys Leu Thr Val Leu
500
<210> 142
<211> 990
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 142
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
290 295 300
Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys
305 310 315 320
Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu
325 330 335
Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val
340 345 350
Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu
385 390 395 400
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly
405 410 415
Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln
420 425 430
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe
435 440 445
Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly
450 455 460
Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu
465 470 475 480
Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly
485 490 495
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys
500 505 510
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
515 520 525
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
530 535 540
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
545 550 555 560
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
565 570 575
Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu
580 585 590
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
595 600 605
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
610 615 620
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
625 630 635 640
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
645 650 655
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
660 665 670
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
675 680 685
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
690 695 700
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
705 710 715 720
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly
725 730 735
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
740 745 750
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr
755 760 765
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
770 775 780
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
785 790 795 800
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
805 810 815
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
820 825 830
Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val
835 840 845
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
850 855 860
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
865 870 875 880
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
885 890 895
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
900 905 910
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
915 920 925
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
930 935 940
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
945 950 955 960
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
965 970 975
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985 990
<210> 143
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 143
Gln Val Gln Met Val Gln Ser Gly Ala Glu Val Lys Lys His Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 144
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 144
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile
85 90 95
Thr Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 145
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 145
Gln Val Gln Met Val Gln Ser Gly Ala Glu Val Lys Lys His Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys
245
<210> 146
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 146
Gln Val Gln Met Val Gln Ser Gly Ala Glu Val Lys Lys His Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
290 295 300
Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys
305 310 315 320
Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu
325 330 335
Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val
340 345 350
Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu
385 390 395 400
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly
405 410 415
Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln
420 425 430
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe
435 440 445
Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly
450 455 460
Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu
465 470 475 480
Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly
485 490 495
Thr Lys Leu Thr Val Leu
500
<210> 147
<211> 990
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 147
Gln Val Gln Met Val Gln Ser Gly Ala Glu Val Lys Lys His Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
290 295 300
Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys
305 310 315 320
Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu
325 330 335
Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val
340 345 350
Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu
385 390 395 400
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly
405 410 415
Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln
420 425 430
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe
435 440 445
Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly
450 455 460
Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu
465 470 475 480
Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly
485 490 495
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys
500 505 510
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
515 520 525
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
530 535 540
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
545 550 555 560
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
565 570 575
Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu
580 585 590
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
595 600 605
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
610 615 620
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
625 630 635 640
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
645 650 655
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
660 665 670
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
675 680 685
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
690 695 700
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
705 710 715 720
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly
725 730 735
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
740 745 750
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr
755 760 765
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
770 775 780
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
785 790 795 800
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
805 810 815
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
820 825 830
Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val
835 840 845
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
850 855 860
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
865 870 875 880
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
885 890 895
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
900 905 910
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
915 920 925
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
930 935 940
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
945 950 955 960
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
965 970 975
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985 990
<210> 148
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 148
Asn His Gly Met His
1 5
<210> 149
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 149
Gly Ile Trp Ser Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ala Val Lys
1 5 10 15
Gly
<210> 150
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 150
Ala Thr Tyr Thr Thr Gly Trp Ser Tyr Phe Asp Tyr
1 5 10
<210> 151
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 151
Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala Ser
1 5 10
<210> 152
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 152
Gln Asp Ala Lys Arg Pro Ser
1 5
<210> 153
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 153
Gln Ala Phe His Gln Ser Thr Trp Val
1 5
<210> 154
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 154
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn His
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Gly Ile Trp Ser Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ala Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Thr Tyr Thr Thr Gly Trp Ser Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 155
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 155
Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Ser Gly Gln Ser Pro Val Leu Val Ile Tyr
35 40 45
Gln Asp Ala Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Phe His Gln Ser Thr Trp Val
85 90 95
Phe Gly Cys Gly Thr Gln Leu Thr Val Leu
100 105
<210> 156
<211> 985
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 156
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn His
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Gly Ile Trp Ser Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ala Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Thr Tyr Thr Thr Gly Trp Ser Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu Thr Gln Pro Pro
130 135 140
Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile Thr Cys Ser Gly
145 150 155 160
Asp Lys Leu Gly Asp Lys Tyr Ala Ser Trp Tyr Gln Gln Lys Ser Gly
165 170 175
Gln Ser Pro Val Leu Val Ile Tyr Gln Asp Ala Lys Arg Pro Ser Gly
180 185 190
Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu
195 200 205
Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys Gln
210 215 220
Ala Phe His Gln Ser Thr Trp Val Phe Gly Cys Gly Thr Gln Leu Thr
225 230 235 240
Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
245 250 255
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala
260 265 270
Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala
275 280 285
Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn
290 295 300
Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile
305 310 315 320
Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu
325 330 335
Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe
340 345 350
Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val
385 390 395 400
Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala
405 410 415
Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln
420 425 430
Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr
435 440 445
Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr
450 455 460
Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu
465 470 475 480
Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
485 490 495
Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
500 505 510
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
515 520 525
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
530 535 540
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
545 550 555 560
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
565 570 575
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
580 585 590
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
595 600 605
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
610 615 620
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
625 630 635 640
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
645 650 655
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
660 665 670
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
675 680 685
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
690 695 700
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
705 710 715 720
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
725 730 735
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
740 745 750
Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
755 760 765
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
770 775 780
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
785 790 795 800
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
805 810 815
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
820 825 830
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
835 840 845
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
850 855 860
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
865 870 875 880
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
885 890 895
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
900 905 910
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
915 920 925
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
930 935 940
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
945 950 955 960
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
965 970 975
Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 157
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 157
Asn His Ala Met His
1 5
<210> 158
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 158
Gly Ile Trp Ser Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val Lys
1 5 10 15
Gly
<210> 159
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 159
Ala Thr Tyr Thr Thr Gly Trp Ser Tyr Phe Asp Tyr
1 5 10
<210> 160
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 160
Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala Ser
1 5 10
<210> 161
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 161
Gln Asp Arg Lys Arg Pro Ser
1 5
<210> 162
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 162
Gln Ala Tyr Asp Ala Ser Thr Trp Val
1 5
<210> 163
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 163
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn His
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Gly Ile Trp Ser Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Thr Tyr Thr Thr Gly Trp Ser Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 164
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 164
Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Ser Gly Gln Ser Pro Val Leu Val Ile Tyr
35 40 45
Gln Asp Arg Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Tyr Asp Ala Ser Thr Trp Val
85 90 95
Phe Gly Cys Gly Thr Gln Leu Thr Val Leu
100 105
<210> 165
<211> 985
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 165
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn His
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Gly Ile Trp Ser Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Thr Tyr Thr Thr Gly Trp Ser Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu Thr Gln Pro Pro
130 135 140
Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile Thr Cys Ser Gly
145 150 155 160
Asp Lys Leu Gly Asp Lys Tyr Ala Ser Trp Tyr Gln Gln Lys Ser Gly
165 170 175
Gln Ser Pro Val Leu Val Ile Tyr Gln Asp Arg Lys Arg Pro Ser Gly
180 185 190
Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu
195 200 205
Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys Gln
210 215 220
Ala Tyr Asp Ala Ser Thr Trp Val Phe Gly Cys Gly Thr Gln Leu Thr
225 230 235 240
Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
245 250 255
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala
260 265 270
Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala
275 280 285
Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn
290 295 300
Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile
305 310 315 320
Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu
325 330 335
Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe
340 345 350
Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val
385 390 395 400
Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala
405 410 415
Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln
420 425 430
Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr
435 440 445
Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr
450 455 460
Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu
465 470 475 480
Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
485 490 495
Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
500 505 510
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
515 520 525
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
530 535 540
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
545 550 555 560
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
565 570 575
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
580 585 590
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
595 600 605
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
610 615 620
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
625 630 635 640
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
645 650 655
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
660 665 670
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
675 680 685
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
690 695 700
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
705 710 715 720
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
725 730 735
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
740 745 750
Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
755 760 765
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
770 775 780
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
785 790 795 800
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
805 810 815
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
820 825 830
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
835 840 845
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
850 855 860
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
865 870 875 880
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
885 890 895
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
900 905 910
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
915 920 925
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
930 935 940
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
945 950 955 960
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
965 970 975
Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 166
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 166
Gly Tyr Tyr Trp Ser
1 5
<210> 167
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 167
Asp Ile Asp Ala Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 168
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 168
Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Asn
1 5 10
<210> 169
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 169
Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala Ser
1 5 10
<210> 170
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 170
Gln Asp Arg Lys Arg Pro Ser
1 5
<210> 171
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 171
Gln Ala Trp Gly Ser Ser Thr Ala Val
1 5
<210> 172
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 172
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asp Ala Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Asn Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 173
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 173
Ser Tyr Glu Leu Thr Gln Pro Ser Ser Val Ser Val Pro Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr
35 40 45
Gln Asp Arg Lys Arg Pro Ser Gly Val Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Gly Ser Ser Thr Ala Val
85 90 95
Phe Gly Cys Gly Thr Lys Leu Thr Val Leu
100 105
<210> 174
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 174
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asp Ala Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Asn Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu Thr Gln Pro Ser Ser
130 135 140
Val Ser Val Pro Pro Gly Gln Thr Ala Ser Ile Thr Cys Ser Gly Asp
145 150 155 160
Lys Leu Gly Asp Lys Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln
165 170 175
Ser Pro Val Leu Val Ile Tyr Gln Asp Arg Lys Arg Pro Ser Gly Val
180 185 190
Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr
195 200 205
Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys Gln Ala
210 215 220
Trp Gly Ser Ser Thr Ala Val Phe Gly Cys Gly Thr Lys Leu Thr Val
225 230 235 240
Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
500 505 510
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
515 520 525
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
530 535 540
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
545 550 555 560
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr
565 570 575
Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp
580 585 590
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
595 600 605
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
610 615 620
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
625 630 635 640
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
645 650 655
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
660 665 670
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
675 680 685
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
690 695 700
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
705 710 715 720
Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
755 760 765
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
770 775 780
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
785 790 795 800
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
805 810 815
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
820 825 830
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
835 840 845
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
850 855 860
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
865 870 875 880
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
885 890 895
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
900 905 910
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
915 920 925
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
930 935 940
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
945 950 955 960
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
965 970 975
Ser Leu Ser Leu Ser Pro Gly Lys
980
<210> 175
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 175
Gly Tyr Tyr Trp Ser
1 5
<210> 176
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 176
Asp Ile Asp Tyr Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 177
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 177
Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Tyr
1 5 10
<210> 178
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 178
Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala Asn
1 5 10
<210> 179
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 179
His Asp Asn Lys Arg Pro Ser
1 5
<210> 180
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 180
Gln Ala Tyr Gly Ile Ser Ser Ala Val
1 5
<210> 181
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 181
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asp Tyr Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 182
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 182
Ser Tyr Glu Leu Thr Gln Pro Ala Ser Ala Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala
20 25 30
Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Ile Leu Val Ile Tyr
35 40 45
His Asp Asn Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Tyr Gly Ile Ser Ser Ala Val
85 90 95
Phe Gly Cys Gly Thr Lys Leu Thr Val Leu
100 105
<210> 183
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 183
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asp Tyr Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu Thr Gln Pro Ala Ser
130 135 140
Ala Ser Val Ser Pro Gly Gln Thr Ala Ser Ile Thr Cys Ser Gly Asp
145 150 155 160
Lys Leu Gly Asp Lys Tyr Ala Asn Trp Tyr Gln Gln Lys Pro Gly Gln
165 170 175
Ser Pro Ile Leu Val Ile Tyr His Asp Asn Lys Arg Pro Ser Gly Ile
180 185 190
Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr
195 200 205
Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys Gln Ala
210 215 220
Tyr Gly Ile Ser Ser Ala Val Phe Gly Cys Gly Thr Lys Leu Thr Val
225 230 235 240
Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
500 505 510
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
515 520 525
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
530 535 540
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
545 550 555 560
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr
565 570 575
Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp
580 585 590
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
595 600 605
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
610 615 620
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
625 630 635 640
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
645 650 655
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
660 665 670
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
675 680 685
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
690 695 700
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
705 710 715 720
Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
755 760 765
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
770 775 780
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
785 790 795 800
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
805 810 815
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
820 825 830
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
835 840 845
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
850 855 860
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
865 870 875 880
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
885 890 895
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
900 905 910
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
915 920 925
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
930 935 940
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
945 950 955 960
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
965 970 975
Ser Leu Ser Leu Ser Pro Gly Lys
980
<210> 184
<211> 989
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 184
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro
500 505 510
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
515 520 525
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
530 535 540
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
545 550 555 560
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
565 570 575
Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr
580 585 590
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
595 600 605
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
610 615 620
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
625 630 635 640
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
645 650 655
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
660 665 670
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
675 680 685
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
690 695 700
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
705 710 715 720
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys
755 760 765
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
770 775 780
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
785 790 795 800
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
805 810 815
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
820 825 830
Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu
835 840 845
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
850 855 860
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
865 870 875 880
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
885 890 895
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
900 905 910
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
915 920 925
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
930 935 940
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
945 950 955 960
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
965 970 975
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 185
<211> 987
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 185
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro
500 505 510
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
515 520 525
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
530 535 540
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
545 550 555 560
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
565 570 575
Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr
580 585 590
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
595 600 605
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
610 615 620
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
625 630 635 640
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
645 650 655
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
660 665 670
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
675 680 685
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
690 695 700
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
705 710 715 720
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro
755 760 765
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
770 775 780
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
785 790 795 800
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
805 810 815
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys
820 825 830
Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val
835 840 845
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
850 855 860
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
865 870 875 880
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
885 890 895
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
900 905 910
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
915 920 925
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
930 935 940
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
945 950 955 960
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
965 970 975
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 186
<211> 501
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 186
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Cys Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu
500
<210> 187
<211> 989
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 187
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Cys Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro
500 505 510
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
515 520 525
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
530 535 540
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
545 550 555 560
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
565 570 575
Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr
580 585 590
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
595 600 605
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
610 615 620
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
625 630 635 640
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
645 650 655
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
660 665 670
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
675 680 685
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
690 695 700
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
705 710 715 720
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys
755 760 765
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
770 775 780
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
785 790 795 800
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
805 810 815
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
820 825 830
Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu
835 840 845
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
850 855 860
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
865 870 875 880
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
885 890 895
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
900 905 910
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
915 920 925
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
930 935 940
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
945 950 955 960
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
965 970 975
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 188
<211> 987
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 188
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Cys Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro
500 505 510
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
515 520 525
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
530 535 540
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
545 550 555 560
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
565 570 575
Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr
580 585 590
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
595 600 605
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
610 615 620
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
625 630 635 640
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
645 650 655
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
660 665 670
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
675 680 685
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
690 695 700
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
705 710 715 720
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro
755 760 765
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
770 775 780
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
785 790 795 800
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
805 810 815
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys
820 825 830
Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val
835 840 845
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
850 855 860
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
865 870 875 880
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
885 890 895
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
900 905 910
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
915 920 925
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
930 935 940
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
945 950 955 960
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
965 970 975
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 189
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 189
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys
145 150 155 160
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser
180 185 190
Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu
210 215 220
Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr
225 230 235 240
Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys
245 250
<210> 190
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 190
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys
145 150 155 160
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser
180 185 190
Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu
210 215 220
Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr
225 230 235 240
Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
245 250

Claims (32)

1.一种稳定的水性药物配制品，其包含
(a)双特异性抗体构建体，
(b)糖，
(c)表面活性剂，和
(d)缓冲液，
其中该配制品的pH是从约4.8至约5.5。
2.如权利要求1所述的配制品，其中该配制品的pH是从约4.8至约5.3。
3.如权利要求1或2所述的配制品，其中该配制品的pH是约5.2。
4.如权利要求1-3中任一项所述的配制品，其中该糖是单糖或二糖。
5.如权利要求1-4中任一项所述的配制品，其中该糖是葡萄糖、半乳糖、果糖、木糖、蔗糖、乳糖、麦芽糖、海藻糖、山梨糖醇、甘露糖醇或木糖醇。
6.如权利要求1-5中任一项所述的配制品，其中该表面活性剂是非离子型表面活性剂。
7.如权利要求1-6中任一项所述的配制品，其中该表面活性剂是聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、泊洛沙姆188、泊洛沙姆407或曲拉通x-100。
8.如权利要求7所述的配制品，其中该表面活性剂是聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60或聚山梨醇酯80。
9.如权利要求7所述的配制品，其中该表面活性剂是泊洛沙姆188或泊洛沙姆407。
10.如权利要求1-9中任一项所述的配制品，其中该缓冲液是乙酸盐缓冲液、谷氨酸盐缓冲液、柠檬酸盐缓冲液、乳酸缓冲液、琥珀酸盐缓冲液、酒石酸盐缓冲液、富马酸盐缓冲液、马来酸盐缓冲液、组氨酸缓冲液或磷酸盐缓冲液。
11.如权利要求1-10中任一项所述的配制品，其中该配制品包含浓度为从约0.1mg/ml至约20mg/ml的该双特异性抗体构建体。
12.如权利要求1-12中任一项所述的配制品，其中该双特异性抗体构建体包含与靶细胞表面抗原结合的第一结合结构域和与T细胞表面上的人CD3结合的第二结合结构域。
13.如权利要求12所述的配制品，其进一步包含第三结构域，该第三结构域以氨基到羧基顺序包含铰链-CH2结构域-CH3结构域-接头-铰链-CH2结构域-CH3结构域。
14.如权利要求13所述的配制品，其中该第一结合结构域和第二结合结构域中的每一者包含VH区和VL区。
15.如权利要求13或权利要求14所述的配制品，其中该双特异性抗体构建体是单链抗体构建体。
16.如权利要求12-15中任一项所述的组合物，其中该靶细胞表面抗原是CDH19、MSLN、DLL3、FLT3、EGFR、EGFRvlll、BCMA、PSMA、CD33、CD19、CD70、MUC17或CLDN18.2。
17.如权利要求12-16中任一项所述的组合物，其中该双特异性抗体构建体的第一结合结构域包含以下列出的一组6个CDR：(a)SEQ ID NO:24-29，(b)SEQ ID NO:34-39，(c)SEQID NO:78-83，(d)SEQ ID NO:10-15，(e)SEQ ID NO:46-51，(f)SEQ ID NO:88-93，(g)SEQID NO:67-72，(h)SEQ ID NO:56-61，(i)SEQ ID NO:112-117，(j)SEQ ID NO:100-105，(k)SEQ ID NO:148-153、SEQ ID NO:157-162、或SEQ ID NO:166-171、或SEQ ID NO:175-180，(l)SEQ ID NO:132-137，或(m)123-128。
18.如权利要求12-17中任一项所述的组合物，其中该双特异性抗体构建体的第二结合结构域包含SEQ ID NO:1-6中列出的一组6个CDR。
19.如权利要求12-18中任一项所述的组合物，其中该第一结合结构域包含：
(a)VH区，该VH区包含SEQ ID NO:30中列出的氨基酸序列，以及VL区，该VL区包含SEQID NO:31中列出的氨基酸序列；
(b)VH区，该VH区包含SEQ ID NO:40中列出的氨基酸序列，以及VL区，该VL区包含SEQID NO:41中列出的氨基酸序列；
(c)VH区，该VH区包含SEQ ID NO:84中列出的氨基酸序列，以及VL区，该VL区包含SEQID NO:85中列出的氨基酸序列；
(d)VH区，该VH区包含SEQ ID NO:16或17中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:18或19中列出的氨基酸序列；
(e)VH区，该VH区包含SEQ ID NO:52中列出的氨基酸序列，以及VL区，该VL区包含SEQID NO:53中列出的氨基酸序列；
(f)VH区，该VH区包含SEQ ID NO:94中列出的氨基酸序列，以及VL区，该VL区包含SEQID NO:95中列出的氨基酸序列；
(g)VH区，该VH区包含SEQ ID NO:73中列出的氨基酸序列，以及VL区，该VL区包含SEQID NO:74中列出的氨基酸序列；
(h)VH区，该VH区包含SEQ ID NO:62中列出的氨基酸序列，以及VL区，该VL区包含SEQID NO:63中列出的氨基酸序列；
(i)VH区，该VH区包含SEQ ID NO:118中列出的氨基酸序列，以及VL区，该VL区包含SEQID NO:119中列出的氨基酸序列；
(j)VH区，该VH区包含SEQ ID NO:154、163、172、或181中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:155、164、173、或182中列出的氨基酸序列；
(k)VH区，该VH区包含SEQ ID NO:106中列出的氨基酸序列，以及VL区，该VL区包含SEQID NO:107中列出的氨基酸序列；
(l)VH区，该VH区包含SEQ ID NO:138或143中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:139或144中列出的氨基酸序列；或
(m)VH区，该VH区包含SEQ ID NO:129中列出的氨基酸序列，以及VL区，该VL区包含SEQID NO:130中列出的氨基酸序列。
20.如权利要求12-19中任一项所述的组合物，其中该第二结合结构域包含VH区，该VH区包含SEQ ID NO:7中列出的氨基酸序列，以及VL区，该VL区包含SEQ ID NO:8中列出的氨基酸序列。
21.如权利要求12-20中任一项所述的配制品，其中该双特异性抗体构建体包含以下列出的氨基酸序列：SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:33、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:55、SEQ ID NO:65、SEQ IDNO:66、SEQ ID NO:55、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:87、SEQ ID NO:97、SEQ IDNO:98、SEQ ID NO:99、SEQ ID NO:109、SEQ ID NO:110、SEQ ID NO:111、SEQ ID NO:121、SEQ ID NO:122、SEQ ID NO:131、SEQ ID NO:141、SEQ ID NO:142、SEQ ID NO:146、SEQ IDNO:147、SEQ ID NO:156、SEQ ID NO:165、SEQ ID NO:174、SEQ ID NO:183、SEQ ID NO:184、SEQ ID NO:185、SEQ ID NO:186、SEQ ID NO:187、或SEQ ID NO:188。
22.如权利要求1-21中任一项所述的配制品，其中在约40℃下储存一个月后，该配制品包含该双特异性抗体构建体的少于约10％的低高分子量(LMW)剪切产物。
23.如权利要求22所述的配制品，其中在约40℃下储存一个月后，该配制品包含该双特异性抗体构建体的少于约8％的低高分子量(LMW)剪切产物。
24.如权利要求22或23所述的配制品，其中在约40℃下储存一个月后，该配制品包含该双特异性抗体构建体的少于约5％的低高分子量(LMW)剪切产物。
25.如权利要求22-24中任一项所述的配制品，其中在约40℃下储存一个月后，该配制品包含该双特异性抗体构建体的少于约3％的低高分子量(LMW)剪切产物。
26.如权利要求22-25中任一项所述的配制品，其中在约40℃下储存一个月后，该配制品包含该双特异性抗体构建体的少于约5％的高分子量(HMW)聚集体。
27.如权利要求22-26中任一项所述的配制品，其中在约40℃下一个月后，该双特异性抗体构建体的相对效力大于约30％。
28.如权利要求22-26中任一项所述的配制品，其中在约40℃下一个月后，该双特异性抗体构建体的相对效力大于约50％。
29.如权利要求22-26中任一项所述的配制品，其中在约40℃下一个月后，该双特异性抗体构建体的相对效力大于约60％。
30.一种治疗有需要的受试者的癌症的方法，该方法包括向该受试者施用如权利要求1-29中任一项所述的配制品。
31.如权利要求30所述的方法，其中该方法进一步包括在向该受试者施用之前用药学上可接受的液体稀释该配制品。
32.如权利要求30或31所述的方法，其中通过静脉内施用来施用该配制品。
CN202180030962.XA 2020-04-29 2021-04-28 药物配制品 Pending CN115484980A (zh)

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