T细胞调节多肽和其使用方法
文献发布时间:2024-04-18 19:58:30
交叉引用
本申请要求2021年3月19日提交的美国临时专利申请号63/163,265的权益,所述临时专利申请以全文引用的方式并入本文中。
以引用的方式并入以文本文件提供的序列表
序列表以文本文件“CUEB-139WO_SeqListing_ST25.txt”的形式一起提供,创建于2022年3月15日并且大小为672KB。文本文件的内容以全文引用的方式并入本文中。
引言
适应性免疫反应涉及存在于T细胞表面的T细胞受体(TCR)与非共价存在于抗原呈递细胞(APC)表面的小肽抗原通过主要组织相容性复合体(MHC;在人中也称为人白细胞抗原(HLA)复合体)的接合。此接合代表免疫系统的靶向机制并且为T细胞调节(活化或抑制)和效应功能所必需的分子间相互作用。在表位特异性细胞靶向之后,通过存在于APC上的共刺激蛋白与T细胞的对应共刺激蛋白接合使所靶向的T细胞活化。两种信号(表位/TCR结合和APC共刺激蛋白与T细胞共刺激蛋白接合)为驱动T细胞特异性以及活化或抑制所需的。APC上的共刺激蛋白也称为“免疫调节”蛋白,因为它们在结合T细胞上的共刺激蛋白时调节T细胞的活性,并且特异性调节随APC上的何种免疫调节蛋白结合至T细胞上的何种共刺激蛋白而变。TCR对给定表位具特异性;然而,T细胞的共刺激蛋白不为表位特异性的,而是实际上通常在所有T细胞上或在大T细胞亚群上表达。
发明内容
本公开提供了单链T细胞调节多肽(TMP)和其二聚体,所述单链T细胞调节多肽和其二聚体包含免疫调节多肽(“MOD”)、I类HLA多肽(I类HLA重链多肽和β2微球蛋白多肽)以及肽表位(例如癌症相关肽或病毒肽),所述KRAS肽将表位呈递至T细胞受体。TMP可用于调节T细胞的活性,并且用于调节个体的免疫反应。
附图说明
图1A至图1B提供了野生型人β2M多肽的氨基酸序列(图1A;SEQ ID NO:448)以及具有R12C取代的β2M多肽的氨基酸序列(图1B;SEQ ID NO:449)。
图2A至图2M提供了免疫球蛋白Fc多肽的氨基酸序列(分别为SEQ ID NO:450-462)。
图3A至图3E提供了野生型HLA-A*0201(图3A;SEQ ID NO:463)和变体(图3B至图3E;分别为SEQ ID NO:464、373、465-464)的氨基酸序列。
图4A至图4E提供了野生型HLA-A*1101(图4A;SEQ ID NO:467)和变体(图4B至图4E;分别为SEQ ID NO:468、374、469-470)的氨基酸序列。
图5A至图5E提供了野生型HLA-A*2402(图5A;SEQ ID NO:471)和变体(图5B至图5E;分别为SEQ ID NO:472、375、473-474)的氨基酸序列。
图6A至图6E提供了野生型HLA-A*3303(图6A;SEQ ID NO:475)和变体(图6B至图6E;分别为SEQ ID NO:476、376、477-478)的氨基酸序列。
图7A至图7B提供了HLA-A重链氨基酸序列(图7A;分别为SEQ ID NO:377、599、378、600、379、601、380、602以及381)和共有序列(图7B;SEQ ID NO:479)的比对。
图8A至图8B提供了HLA-B重链氨基酸序列(图8A;分别为SEQ ID NO:480-486)和共有序列(图8B;SEQ ID NO:487)的比对。
图9A至图9B提供了HLA-C重链氨基酸序列(图9A;分别为SEQ ID NO:488-496)和共有序列(图9B;SEQ ID NO:497)的比对。
图10提供了HLA-E、HLA-F以及HLA-G重链(分别为SEQ ID NO:498-500)中的每一者的共有氨基酸序列。可变氨基酸(aa)位置指示为依序编号的“X”残基;氨基酸84、139以及236的位置加双下划线。
图11提供了HLA-A(SEQ ID No:479)、HLA-B(SEQ ID NO:487)、HLA-C(SEQ ID NO:497)、HLA-E(SEQ ID NO:498)、HLA-F(SEQ ID NO:499)以及HLA-G(SEQ ID NO:500)的共有氨基酸序列的比对。
图12提供了TMP中的免疫调节多肽的位置的实例的示意图描述。
图13提供了二硫键键联的TMP的示意图描述。
图14提供了甲胎蛋白的氨基酸序列(SEQ ID NO:501)。
图15A至图15E提供了WT-1多肽的氨基酸序列(分别为SEQ ID NO:502-508)。
图16A至图16B提供了HPV E6多肽(图16A;SEQ ID NO:507)和HPV E7多肽(图16B;SEQ ID NO:508)的氨基酸序列。
图17A至图17D提供了野生型IL-2多肽(图17A;SEQ ID NO:509)、IL-2Rα(图17B;SEQ ID NO:510)、IL-2Rβ(图17C;SEQ ID NO:511)以及IL-2Rγ(图17D;SEQ ID NO:512)的氨基酸序列。
图18A至图18T提供了示例性TMP的氨基酸序列(分别为SEQ ID NO:513-532)。
图19A至图19D提供了示例性TMP的氨基酸序列(分别为SEQ ID NO:533-536)。
图20A至图20G提供了示例性TMP的氨基酸序列(分别为SEQ ID NO:537-543)。
图21A至图21D提供了具有刚性肽接头的示例性TMP的氨基酸序列(分别为SEQ IDNO:544-547)。
图22A至图22D提供了HLA-E重链的氨基酸序列(分别为SEQ ID NO:548、382、549、383)。
图23A至图23D提供了HLA-G重链的氨基酸序列(分别为SEQ ID NO:550、384、551、385)。
图24A至图24M提供了MUC-1多肽的氨基酸序列(分别为SEQ ID NO:552-564)。
图25A至图25C提供了存活素多肽的氨基酸序列(分别为SEQ ID NO:565-567)。
图26A至图26B提供了巨细胞病毒多肽的氨基酸序列(分别为SEQ ID NO:568-569)。
定义
术语“多核苷酸”和“核酸”在本文中可互换地用于指任何长度的核苷酸(核糖核苷酸或脱氧核糖核苷酸)的聚合形式。因此,此术语包括但不限于单链、双链或多链DNA或RNA、基因组DNA、cDNA、DNA-RNA杂合物,或包含嘌呤和嘧啶碱基或其他天然的、化学或生物化学修饰的、非天然或衍生的核苷酸碱基的聚合物。
术语“肽”、“多肽”以及“蛋白质”在本文中可互换使用,并且指任何长度的氨基酸的聚合形式,其可包括编码和非编码氨基酸、化学或生物化学修饰或衍生的氨基酸以及具有修饰的肽骨架的多肽。此外,如本文所用,“多肽”是指包括对天然序列的修饰(诸如缺失、添加以及取代)(如本领域技术人员已知的,通常在自然界中为保守的)的蛋白质,只要所述蛋白质维持所需活性即可。这些修饰可为有意的,如通过定点诱变,或可为偶然的,诸如通过产生蛋白质的宿主的突变,或由于聚合酶链反应(PCR)扩增或其他重组DNA方法引起的错误。本文提到已知多肽中的特定残基或残基编号应理解为是指野生型多肽中所述位置的氨基酸。在野生型多肽的序列因添加或缺失一个或多个氨基酸而改变的情况下,一般技术人员将理解,提到的特定残基或残基编号将相应地改变,以便指改变的多肽中的相同特定氨基酸,所述相同特定氨基酸将被理解为位于改变的位置编号处。举例来说,如果MHC I类多肽因在N端添加一个氨基酸而改变,那么提到位置84或位置84的特定残基将被理解为指示在改变的多肽上位置85的氨基酸。同样地,本文提到在特定位置的特定氨基酸的取代,例如Y84应理解为是指野生型多肽中位置84的氨基酸的氨基酸取代。因此,Y84C取代被理解为Cys残基对存在于野生型序列中的Tyr残基的取代。如果例如野生型多肽被改变,从而使野生型氨基酸的位置84的氨基酸变为替代氨基酸,那么对位置84的氨基酸的取代将被理解为是指对替代氨基酸的取代。如果在这种情况下,多肽还因添加或缺失一个或多个氨基酸而被改变,那么提到取代将被理解为是指对在改变的位置编号处的替代氨基酸的取代。提到多肽(例如MHC I类多肽)中的“非天然存在的Cys残基”,意味着多肽在对应野生型多肽中没有Cys的位置包含Cys残基。这可通过其中半胱氨酸取代存在于野生型序列中的氨基酸的常规蛋白质工程化来实现。
多核苷酸或多肽与另一多核苷酸或多肽具有某一“序列同一性”百分比,意味着当比对时,所述百分比的碱基或氨基酸为相同的,并且当比较这两个序列时,位于相同的相对位置。可以许多不同的方式确定序列同一性。为了确定序列同一性,可使用各种方便的方法和计算机程序(例如BLAST、T-COFFEE、MUSCLE、MAFFT等)来比对序列,所述各种方便的方法和计算机程序可在万维网上在包括以下的网址获得:ncbi.nlm.nili.gov/BLAST、ebi.ac.uk/Tools/msa/tcoffee/、ebi.ac.uk/Tools/msa/muscle/、mafft.cbrc.jp/alignment/software/。参见例如Altschul等(1990),J.Mol.Biol.215:403-10。除非另外说明,否则通过如Altschul等((1990)J.Mol.Biol.215:403)中所描述的BLAST(基本局部比对检索工具)使用默认参数来确定如本文中所提到的“序列同一性”。
术语“保守氨基酸取代”是指蛋白质中具有类似侧链的氨基酸残基的可互换性。举例来说,具有脂族侧链的一组氨基酸由甘氨酸、丙氨酸、缬氨酸、亮氨酸以及异亮氨酸组成;具有脂族-羟基侧链的一组氨基酸由丝氨酸和苏氨酸组成;具有含酰胺的侧链的一组氨基酸由天冬酰胺和谷氨酰胺组成;具有芳族侧链的一组氨基酸由苯丙氨酸、酪氨酸以及色氨酸组成;具有碱性侧链的一组氨基酸由赖氨酸、精氨酸以及组氨酸组成;具有酸性侧链的一组氨基酸由谷氨酸盐和天冬氨酸组成;并且具有含硫侧链的一组氨基酸由半胱氨酸和甲硫氨酸组成。示例性保守氨基酸取代组为:缬氨酸-亮氨酸-异亮氨酸、苯丙氨酸-酪氨酸、赖氨酸-精氨酸、丙氨酸-缬氨酸-甘氨酸以及天冬酰胺-谷氨酰胺。
如本文所用的术语“免疫学突触”或“免疫突触”通常指适应性免疫反应的两个相互作用的免疫细胞之间的天然界面,包括例如抗原呈递细胞(APC)或靶细胞与效应细胞(例如淋巴细胞、效应T细胞、自然杀伤细胞等)之间的界面。APC与T细胞之间的免疫突触通常通过T细胞抗原受体与主要组织相容性复合体分子的相互作用起始,例如如Bromley等,AnnuRev Immunol.2001;19:375-96中所描述;所述参考文献的公开内容以全文引用的方式并入本文中。
“T细胞”包括表达CD3的所有类型的免疫细胞,包括T辅助细胞(CD4
如本文所用,术语“免疫调节多肽”(本文中也称为“MOD”)意指一种多肽,所述多肽特异性结合T细胞上的同源共刺激多肽(本文中也称为“co-MOD”),从而提供一种信号,除由例如TCR/CD3复合体与加载有肽的主要组织相容性复合体(MHC)多肽结合所提供的原始信号外,所述信号也介导T细胞反应(包括但不限于增殖、活化、分化等)。如本文中所论述,MOD可包括但不限于野生型多肽的野生型或变体,诸如细胞因子(例如IL-2)、CD7、B7-1(CD80)、B7-2(CD86)、PD-L1、PD-L2、4-1BBL、OX40L、Fas配体(FasL)、可诱导共刺激配体(ICOS-L)、细胞间粘附分子(ICAM)、CD30L、CD40、CD70、CD83、HLA-G、MICA、MICB、HVEM、淋巴细胞毒素β受体、3/TR6、ILT3、ILT4、HVEM、结合Toll配体受体的激动剂或抗体以及与B7-H3特异性结合的配体。本公开的TMP的免疫调节结构域或“MOD”可结合存在标靶T细胞上的同源共刺激多肽。
如本文所用,术语“体内”是指在体内发生的任何方法或程序。
如本文所用,“体外”是指在体外发生的任何方法或程序。
如本文所用,“异源”意指分别在天然核酸或蛋白质中未被发现的核苷酸或多肽。
如本文所用,“重组”意味着特定核酸(DNA或RNA)为克隆、限制、聚合酶链反应(PCR)和/或连结步骤的各种组合的产物,从而产生具有可与在自然系统中发现的内源性核酸区别开的结构性编码或非编码序列的构建体。编码多肽的DNA序列可从cDNA片段或从一系列合成寡核苷酸组装,以提供能够从细胞中或无细胞转录和翻译系统中所含的重组转录单元表达的合成核酸。
术语“重组表达载体”或“DNA构建体”在本文中可互换地用于指包含载体和至少一个插入物的DNA分子。重组表达载体通常出于表达和/或增殖一个或多个插入物的目的而产生,或用于构建其他重组核苷酸序列。一个或多个插入物可能会或可能不会可操作地连接至启动子序列并且可能会或可能不可操作地连接至DNA调控序列。
如本文所用,术语“亲和力”是指两种剂(例如抗体和抗原)可逆结合的平衡常数并且以解离常数(K
如本文所用,术语“结合”(例如参考TMP结合至T细胞上的多肽(例如T细胞受体))是指两个分子之间的非共价相互作用。非共价结合是指两个分子之间因例如静电、疏水、离子和/或氢键相互作用而直接缔合,包括诸如盐桥和水桥等相互作用。“亲和力”是指非共价结合的强度,增加的结合亲和力与更低的K
术语“治疗(treatment/treating)”等在本文中通常用于意指获得所需药理学和/或生理学效应。效应就完全或部分预防疾病或其症状来说可为预防性的和/或就部分或完全治愈疾病和/或可归因于疾病的有害作用来说可为治疗性的。如本文所用的“治疗”涵盖对哺乳动物的疾病或症状的任何治疗,并且包括:(a)预防受试者中发生疾病或症状,所述受试者可能易于获得疾病或症状但尚未被诊断为患有疾病或症状;(b)抑制疾病或症状,即抑制其发展;和/或(c)缓和疾病,即使得疾病消退。可在疾病或损伤发作之前、期间或之后施用治疗剂。在治疗使患者的不希望的临床症状稳定或减轻的情况下,对持续的疾病的治疗特别受关注。此类治疗理想地在受影响的组织完全损失功能之前进行。本发明疗法将理想地在疾病的症状性阶段期间并且在一些情况下在疾病的症状性阶段之后施用。
术语“个体”、“受试者”、“宿主”以及“患者”在本文中可互换使用并且指需要诊断、治疗或疗法的任何哺乳动物受试者。哺乳动物包括例如人、非人灵长类动物、啮齿动物(例如大鼠;小鼠)、兔类动物(例如兔)、有蹄类动物(例如牛、绵羊、猪、马、山羊、等)等。除非另外指出,否则术语“个体”、“受试者”、“宿主”以及“患者”是指人。
除非另有指示,否则术语“基本上”旨在涵盖“完全”与“很大程度上但不完全”两者。举例来说,“基本上不诱导细胞溶解”的Ig Fc意指根本不诱导细胞溶解或很大程度上不诱导细胞溶解的Ig Fc。
如本文所用,结合量使用的术语“约”表明所述量可改变所陈述量的10%。举例来说,“约100”意指90-110的量。在约用于范围的上下文中时,提到范围的较低量时所用的“约”意味着所述较低量包括比范围的较低量低10%的量,并且提到范围的较高量时所用的“约”意味着所述较高量包括比范围的较高量高10%的量。举例来说,约100至约1000意味着范围从90延伸至1100。
如本文所用,术语“MHC重链多肽”统指存在于TMP中的MHC重链多肽的结构域。举例来说,MHC重链多肽可包含α1、α2以及α3结构域。
在进一步描述本公开之前,应了解本公开不限于所描述的特定实施方案,因而当然可改变。还应了解,本文所用的术语仅用于描述特定实施方案的目的,并且不旨在具限制性,因为本公开的范围将仅受所附权利要求书限制。
在提供值的范围的情况下,应了解除非上下文另外明确指示,否则本公开内涵盖在所述范围的上限与下限之间以下限单位的十分之一为间隔的各中间值以及所述所陈述的范围内的任何其他所陈述的值或中间值。这些更小的范围的上限和下限可独立地包括在所述更小的范围内,并且也涵盖在本公开内,受所陈述范围内的任何具体排除的限值限制。在所陈述的范围包括一个或两个限值的情况下,排除这些被包括的限值中的一者或两者的范围也被包括在本公开内。
除非另外定义,否则本文所用的所有技术和科学术语具有与本公开所属领域一般技术人员通常所理解相同的含义。虽然类似或等效于本文所描述的方法和材料的任何方法和材料也可用于实践或测试本公开,但现描述了优选方法和材料。本文提到的所有出版物以引用的方式并入本文中,以与所引用的出版物结合公开和描述所述方法和/或材料。
除非上下文另外明确指示,否则如本文和随附权利要求书中所用,单数形式“一个(种)(a/an)”和“所述”包括复数指示物。因此,举例来说,提到“T细胞调节多肽”包括多种此类多肽并且提到“MOD”包括提到本领域技术人员已知的一种或多种MOD和其等效物等。还应注意,可起草权利要求书以排除任何任选元件。因而,此陈述旨在充当结合所要求元素的叙述使用诸如“仅仅”、“仅”等排他性术语或使用“否定”限制的前置基础。
应理解,为清楚起见,在单独实施方案的上下文中所描述的本公开的某些特征也可组合提供于单个实施方案中。相反地,为简便起见,在单个实施方案的上下文中所描述的本公开的各种特征也可单独或以任何适合的亚组合提供。与本公开有关的实施方案的所有组合特定地由本公开涵盖并且在本文中公开,如同每种组合个别地并且明确地被公开一般。此外,各个实施方案和其元素的所有亚组合也特定地由本公开涵盖并且在本文中公开,如同每种此类亚组合个别地并且明确地在本文中公开一般。
本文所论述的出版物仅仅由于其在本申请的提交日期之前公开而提供。本文中的任何内容均不应被视为承认本公开不被授权先于此类出版物。另外,所提供的公布日期可不同于可能需要单独证实的实际公布日期。
具体实施方式
本公开提供了包含MOD并且包含表位呈递肽的T细胞调节多肽。TMP可用于调节T细胞的活性,并且用于调节个体的免疫反应。
T细胞调节多肽
本公开提供了一种T细胞调节多肽(TMP),其中TMP为单链多肽,所述单链多肽包含:i)当结合至主要组织相容性复合体(MHC)多肽时将表位呈递至T细胞受体(TCR)的肽;ii)第一MHC多肽;iii)第二MHC多肽;以及iv)一个或多个MOD;以及任选地,免疫球蛋白(Ig)Fc多肽或非Ig支架。如下文所论述,例如当TMP包含Ig Fc(例如IgG1 Fc时),单链TMP可自组装成二聚体。两个单链TMP中的Ig Fc多肽之间将自发形成二硫键,从而键合两个单链TMP以形成均二聚体。
如本文所用,术语“肽表位”(在本文中有时称为“肽”或“表位”)意指当肽结合至MHC复合体时将表位呈递至TCR的肽。
一般说来,TMP结合至具有co-MOD和TCR的T细胞,所述TCR与相同TMP结合具有相同co-MOD但具有基本上不结合肽/MHC复合体的TCR的第二T细胞的亲和力相比以更大(例如大25%)的亲和力结合TMP的肽/MHC复合体。
在一些情况下,TMP按从N端到C端的顺序包含以下组分:i)肽表位;ii)第一MHC多肽;iii)第二MHC多肽;iv)一个或多个MOD;以及v)Ig Fc多肽。在一些情况下,TMP按从N端到C端的顺序包含以下组分:i)肽表位;ii)β2M多肽;iii)I类MHC重链多肽;iv)一个或多个MOD;以及v)Ig Fc多肽。如下文所论述,可在两个或更多个组分之间插入肽接头。在图12中此组分排列称为MOD位置2。
在一些情况下,TMP按从N端到C端的顺序包含以下组分:i)肽表位;ii)第一MHC多肽;iii)第二MHC多肽;iv)Ig Fc多肽;以及v)一个或多个MOD。在一些情况下,TMP按从N端到C端的顺序包含以下组分:i)肽表位;ii)β2M多肽;iii)I类MHC重链多肽;iv)Ig Fc多肽;以及v)一个或多个MOD。如下文所论述,可在两个或更多个组分之间插入肽接头。在图12中此组分排列称为MOD位置3。
在一些情况下,TMP按从N端到C端的顺序包含以下组分:i)一个或多个MOD;ii)肽表位;iii)第一MHC多肽;iv)第二MHC多肽;以及v)Ig Fc多肽。在一些情况下,TMP按从N端到C端的顺序包含以下组分:i)一个或多个MOD;ii)肽表位;iii)β2M多肽;iv)I类MHC重链多肽;以及v)Ig Fc多肽。如下文所论述,可在两个或更多个组分之间插入肽接头。在图12中此组分排列称为MOD位置4。
MOD可包含野生型(“wt”)MOD或野生型MOD的变体。在MOD包含变体的情况下,它可展现降低的与其co-MOD的结合,包括例如降低的与co-MOD的一个或多个链或结构域的结合。在此类情况下,降低的MOD对其co-MOD的亲和力与肽对TCR的亲和力的组合可提供增强的TMP选择性。可使用纯化的MOD和纯化的co-MOD通过生物层干涉术(BLI)来确定MOD与其co-MOD之间的结合亲和力。可使用纯化的TMP和co-MOD通过BLI来确定存在于TMP中的MOD与其co-MOD之间的结合亲和力。BLI方法为本领域技术人员熟知的。参见例如Lad等(2015)J.Biomol.Screen.20(4):498-507;以及Shah和Duncan(2014)J.Vis.Exp.18:e51383。除非本文中另外说明,否则如2020年6月25日所公布的公布的PCT申请WO 2020/132138中所描述,使用BLI来确定MOD对co-MOD的亲和力或TMP上的MOD对co-MOD的亲和力。参见例如段落[0056]-[0057]。
肽表位
如上文所论述,TMP包含通常长度为至少约4个氨基酸的肽表位,并且当肽存在于MHC/肽复合体(例如HLA/肽复合体)中时将表位呈递至T细胞(即,呈递至存在于T细胞表面的TCR)。
存在于本公开的TMP中的肽表位可具有至少4个氨基酸的长度,例如4-20aa(例如4个氨基酸(aa)、5aa、6aa、7aa、8aa、9aa、10aa、11aa、12aa、13aa、14aa、15aa、16aa、17aa、18aa、19aa或20aa),包括长度范围为6-15aa、8-12aa、8-10aa、9-11aa、5-10aa、10-15aa以及15-20aa。在一些情况下,肽的长度为8、9、10或11个氨基酸。
存在于TMP中的肽表位为由T细胞特异性结合的肽,即表位由表位特异性T细胞(即具有对表位具特异性的TCR的T细胞)特异性结合。
在一些情况下,存在于TMP中的表位肽呈递对HLA-A、HLA-B、HLA-C、HLA-E、HLA-F或HLA-G等位基因具特异性的表位。在一个实施方案中,存在于TMP中的表位肽呈递限于HLA-A*0101、A*0201、A*0301、A*1101、A*2301、A*2402、A*2407、A*3303和/或A*3401的表位。在一个实施方案中,存在于TMP中的表位肽呈递限于HLA-B*0702、B*0801、B*1502、B*3802、B*4001、B*4601和/或B*5301的表位。在一个实施方案中,存在于TMP中的表位肽呈递限于C*0102、C*0303、C*0304、C*0401、C*0602、C*0701、C*702、C*0801和/或C*1502的表位。
本公开的TMP包含除与癌症相关的KRAS肽外的肽表位。换句话说,存在于TMP中的肽不为与癌症相关的KRAS肽。举例来说,存在于TMP中的肽表位不为KRAS多肽的约4个氨基酸至约20个氨基酸的肽,其中KRAS多肽可具有以下氨基酸序列:MTEYKLVVVGAGGVGKSALTIQLIQNHFVD EYDPTIEDSYRKQVVIDGET CLWDILDTAG QEEYSAMRDQ YMRTGEGFLCVFAINNTKSFEDIHHYREQI KRVKDSEDVP MVLVGNKCDLPSRTVDTKQA QDLARSYGIP FIETSAKTRQGVDDAFYTLVREIRKHKEKM SKDGKKKKKK SKTKCVIM(SEQ ID NO:1)。举例来说,存在于TMP公开内容中的肽表位不为以下肽中的任一者:VVVGAGDVGK(SEQ ID NO:2);VVGAGDVGK(SEQ IDNO:3);VVVGARGVGK(SEQ ID NO:4);VVGARGVGK(SEQ ID NO:5);LVVVGADGV(SEQ ID NO:6)、LVVVGAVGV(SEQ ID NO:7)、LVVVGACGV(SEQ ID NO:8)、KLVVVGADGV(SEQ ID NO:9)、KLVVVGAVGV(SEQ ID NO:10)、KLVVVGACGV(SEQ ID NO:11)、LLVVGADGV(SEQ ID NO:12)、LLVVGAVGV(SEQ ID NO:13)、LLVVGACGV(SEQ ID NO:14)、FLVVVGADGV(SEQ ID NO:15)、FLVVVGAVGV(SEQ ID NO:16)、FLVVVGACGV(SEQ ID NO:17);KLVVVGAGDV(SEQ ID NO:18);KLVVVGARGV(SEQ ID NO:19);GAGDVGKSAL(SEQ ID NO:20);AGDVGKSAL(SEQ ID NO:21);DVGKSALTI(SEQ ID NO:22);GAVGVGKSAL(SEQ ID NO:23);AVGVGKSAL(SEQ ID NO:24);YKLVVVGAV(SEQ ID NO:25);ARGVGKSAL(SEQ ID NO:26);GARGVGKSAL(SEQ ID NO:27);EYKLVVVGAR(SEQ ID NO:28);RGVGKSALTI(SEQ ID NO:29);LVVVGARGV(SEQ ID NO:30);GADGVGKSAL(SEQ ID NO:31);ACGVGKSAL(SEQ ID NO:32);GACGVGKSAL(SEQ ID NO:33);VVGAVGVGK(SEQ ID NO:34)、VVVGAVGVGK(SEQ ID NO:35)、VGAVGVGKS(SEQ ID NO:36)、VGAVGVGKSA(SEQ ID NO:37)、AVGVGKSALT(SEQ ID NO:38)、GAVGVGKSA(SEQ ID NO:39)、LVVVGAVGVG(SEQ ID NO:40)以及KLVVVGAVG(SEQ ID NO:41)。
适合的肽表位包括但不限于存在于癌症相关抗原中的表位。癌症相关抗原为本领域中已知的;参见例如Cheever等(2009)Clin.Cancer Res.15:5323。癌症相关抗原包括但不限于α-叶酸受体;碳酸酐酶IX(CAIX);CD19;CD20;CD22;CD30;CD33;CD44v7/8;癌胚抗原(CEA);上皮糖蛋白-2(EGP-2);上皮糖蛋白-40(EGP-40);叶酸结合蛋白(FBP);胎儿乙酰胆碱受体;神经节糖苷抗原GD2;Her2/neu;IL-13R-a2;κ轻链;LeY;L1细胞粘附分子;黑素瘤相关抗原(MAGE);MAGE-A1;间皮素;MUC1;NKG2D配体;癌胚抗原(h5T4);前列腺干细胞抗原(PSCA);前列腺特异性膜抗原(PSMA);肿瘤相关糖蛋白-72(TAG-72);血管内皮生长因子受体-2(VEGF-R2)。参见例如Vigneron等(2013)Cancer Immunity 13:15;以及Vigneron(2015)BioMed Res.Int’l Article ID 948501;以及表皮生长因子受体(EGFR)vIII多肽(参见例如Wong等(1992)Proc.Natl.Acad.Sci.USA 89:2965;以及Miao等(2014)PLoSOne9:e94281)。
在一些情况下,适合的肽表位为以下多肽的长度为4-20aa(例如6-15aa、8-12aa、8-10aa、9-11aa、5-10aa、10-15aa以及15-20aa)的肽片段:MUC1多肽、LMP2多肽、表皮生长因子受体(EGFR)vIII多肽、HER-2/neu多肽、黑色素瘤抗原家族A 3(MAGE A3)多肽、p53多肽、突变体p53多肽、NY-ESO-1多肽、叶酸水解酶(前列腺特异性膜抗原;PSMA)多肽、癌胚抗原(CEA)多肽、由T细胞识别的黑色素瘤抗原(melanA/MART1)多肽、Ras多肽、gp100多肽、蛋白酶3(PR1)多肽、bcr-abl多肽、酪氨酸酶多肽、存活素多肽、前列腺特异性抗原(PSA)多肽、hTERT多肽、肉瘤转位断点多肽、滑膜肉瘤X(SSX)断点多肽、EphA2多肽、酸性磷酸酶、前列腺(PAP)多肽、黑素瘤凋亡抑制剂(ML-IAP)多肽、上皮细胞粘附分子(EpCAM)多肽、ERG(TMPRSS2 ETS融合)多肽、NA17多肽、成对盒-3(PAX3)多肽、间变性淋巴瘤激酶(ALK)多肽、雄激素受体多肽、周期蛋白B1多肽、N-myc原癌基因(MYCN)多肽、Ras同源物基因家族成员C(RhoC)多肽、酪氨酸酶相关蛋白-2(TRP-2)多肽、间皮素多肽、前列腺干细胞抗原(PSCA)多肽、黑素瘤相关抗原-1(MAGE A1)多肽、细胞色素P4501B1(CYP1B1)多肽、胎盘特异性蛋白1(PLAC1)多肽、BORIS多肽(也称为CCCTC结合因子或CTCF)、ETV6-AML多肽、乳癌抗原NY-BR-1多肽(也称为含有锚蛋白重复结构域的蛋白质30A)、G蛋白信号传导调控剂(RGS5)多肽、由T细胞识别的鳞状细胞癌抗原(SART3)多肽、碳酸酐酶IX多肽、成对盒-5(PAX5)多肽、OY-TES1(睾丸抗原;也称为顶体酶结合蛋白)多肽、精子蛋白17多肽、淋巴细胞特异性蛋白酪氨酸激酶(LCK)多肽、高分子量黑素瘤相关抗原(HMW-MAA)、A激酶锚定蛋白-4(AKAP-4)、滑膜肉瘤X断点2(SSX2)多肽、X抗原家族成员1(XAGE1)多肽、B7同源物3(B7H3;也称为CD276)多肽、豆荚蛋白多肽(LGMN1;也称为天冬酰胺酰内肽酶)、具有Ig和EGF同源性结构域-2的酪氨酸激酶(Tie-2;也称为血管生成素-1受体)多肽、P抗原家族成员4(PAGE4)多肽、血管内皮生长因子受体2(VEGF2)多肽、MAD-CT-1多肽、成纤维细胞活化蛋白(FAP)多肽、血小板源性生长因子受体β(PDGFβ)多肽、MAD-CT-2多肽或Fos相关抗原-1(FOSL)多肽。
癌症相关抗原的氨基酸序列为本领域中已知的;参见例如MUC1(GenBankCAA56734);LMP2(GenBank CAA47024);EGFRvIII(GenBank NP_001333870);HER-2/neu(GenBank AAI67147);MAGE-A3(GenBank AAH11744);p53(GenBank BAC16799);NY-ESO-1(GenBank CAA05908);PSMA(GenBank AAH25672);CEA(GenBank AAA51967);melan/MART1(GenBank NP_005502);Ras(GenBank NP_001123914);gp100(GenBank AAC60634);bcr-abl(GenBank AAB60388);酪氨酸酶(GenBank AAB60319);存活素(GenBank AAC51660);PSA(GenBank CAD54617);hTERT(GenBank BAC11010);SSX(GenBank NP_001265620);Eph2A(GenBank NP_004422);PAP(GenBank AAH16344);ML-IAP(GenBank AAH14475);EpCAM(GenBank NP_002345);ERG(TMPRSS2 ETS融合物)(GenBank ACA81385);PAX3(GenBankAAI01301);ALK(GenBank NP_004295);雄激素受体(GenBank NP_000035);周期蛋白B1(GenBank CAO99273);MYCN(GenBank NP_001280157);RhoC(GenBank AAH52808);TRP-2(GenBank AAC60627);间皮素(GenBank AAH09272);PSCA(GenBank AAH65183);MAGE A1(GenBank NP_004979);CYP1B1(GenBank AAM50512);PLAC1(GenBank AAG22596);BORIS(GenBank NP_001255969);ETV6(GenBank NP_001978);NY-BR1(GenBank NP_443723);SART3(GenBank NP_055521);碳酸酐酶IX(GenBank EAW58359);PAX5(GenBank NP_057953);OY-TES1(GenBank NP_115878);精子蛋白17(GenBank AAK20878);LCK(GenBankNP_001036236);HMW-MAA(GenBank NP_001888);AKAP-4(GenBank NP_003877);SSX2(GenBank CAA60111);XAGE1(GenBank NP_001091073;XP_001125834;XP_001125856;以及XP_001125872);B7H3(GenBank NP_001019907;XP_947368;XP_950958;XP_950960;XP_950962;XP_950963;XP_950965;以及XP_950967);LGMN1(GenBank NP_001008530);TIE-2(GenBank NP_000450);PAGE4(GenBank NP_001305806);VEGFR2(GenBank NP_002244);MAD-CT-1(GenBank NP_005893NP_056215);FAP(GenBank NP_004451);PDGFβ(GenBank NP_002600);MAD-CT-2(GenBank NP_001138574);以及FOSL(GenBank NP_005429)。例如Cheever等(2009)Clin.Cancer Res.15:5323和其中所引用的参考文献;Wagner等(2003)J.Cell.Sci.116:1653;Matsui等(1990)Oncogene 5:249;Zhang等(1996)Nature 383:168中也论述了这些多肽。
AFP肽
在一些情况下,TMP包含甲胎蛋白(AFP)肽作为肽表位。在一些情况下,存在于TMP中的AFP肽表位可为与图14中所展示的AFP氨基酸序列具有至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列的长度为4-20aa(例如6-15aa、8-12aa、8-10aa、9-11aa、5-10aa、10-15aa以及15-20aa)的肽。
适合于包括在TMP中的AFP肽的实例包括但不限于AITRKMAAT(449-457;SEQ IDNO:42);AYTKKAPQL(434-442;SEQ ID NO:43);LLNQHACAV(218-226;SEQ ID NO:44);KLVLDVAHV(257-265;SEQ ID NO:45);FMNKFIYEI(158-166;SEQ ID NO:46);SIPLFQVPE(135-143;SEQ ID NO:47);LLNFTESRT(12-20;SEQ ID NO:48);FVQEATYKF(54-62;SEQ IDNO:49);ATYKEVSKM(58-66;SEQ ID NO:50);KEVSKMVKD(61-69;SEQ ID NO:51);RHNCFLAHK(121-129;SEQ ID NO:52);ATAATCCQL(456-464;SEQ ID NO:53);YIQESQALA(404-412;SEQID NO:54);QLTSSELMAI(441-450;SEQ ID NO:55);KLSQKFTKV(242-250;SEQ ID NO:56);KELRESSLL(211-219;SEQ ID NO:57);SLVVDETYV(514-522;SEQ ID NO:58);ILLWAARYD(178-186;SEQ ID NO:59);KIIPSCCKA(187-195;SEQ ID NO:60);CRGDVLDCL(270-278;SEQID NO:61);QQDTLSNKI(291-299;SEQ ID NO:62);TMKQEFLINL(547-556;SEQ ID NO:63);NLVKQKPQI(555-563;SEQ ID NO:64);AVIADFSGL(570-578;SEQ ID NO:65);LLACGEGAA(469-477;SEQ ID NO:66);LACGEGAAD(470-478;SEQ ID NO:67);KAPQLTSSEL(438-447;SEQID NO:68);YICSQQDTL(287-295;SEQ ID NO:69);TECCKLTTL(300-308;SEQ ID NO:70);CTAEISLADL(37-46;SEQ ID NO:71);VTKELRESSL(209-218;SEQ ID NO:72);IMSYICSQQD(284-293;SEQ ID NO:73);TRTFQAITV(232-240;SEQ ID NO:74);FQKLGEYYL(419-427;SEQID NO:75);RVAKGYQEL(372-380;SEQ ID NO:76);SYQCTAEISL(34-43;SEQ ID NO:77);KQEFLINLV(549-557;SEQ ID NO:78);MKWVESIFL(1-9;SEQ ID NO:79);PVNPGVGQC(492-500;SEQ ID NO:80);AADIIIGHL(476-484;SEQ ID NO:81);QVPEPVTSC(140-148;SEQ IDNO:82);TTLERGQCII(306-315;SEQ ID NO:83);KMAATAATC(453-461;SEQ ID NO:84);QAQGVALQTM(539-548;SEQ ID NO:85);FQAITVTKL(235-243;SEQ ID NO:86);LLEKCFQTE(380-388;SEQ ID NO:87);VAYTKKAPQ(433-441;SEQ ID NO:88);KYIQESQAL(403-411;SEQID NO:89);GVALQTMKQ(542-550;SEQ ID NO:90);GQEQEVCFA(585-593;SEQ ID NO:91);SEEGRHNCFL(117-126;SEQ ID NO:92);RHPFLYAPTI(169-178;SEQ ID NO:93);TEIQKLVLDV(253-262;SEQ ID NO:94);RRHPQLAVSV(360-369;SEQ ID NO:95);GEYYLQNAFL(423-432;SEQ ID NO:96);NRRPCFSSLV(507-516;SEQ ID NO:97);LQTMKQEFLI(545-554;SEQ ID NO:98);IADFSGLLEK(572-581;SEQ ID NO:99);GLLEKCCQGQ(577-586;SEQ ID NO:100);TLSNKITEC(294-302;SEQ ID NO:101);LQDGEKIMSY(278-287;SEQ ID NO:102);GLFQKLGBY(417-425;SEQ ID NO:103);NEYGIASILD(24-33;SEQ ID NO:104);KMVKDALTAI(65-74;SEQID NO:105);FLASFVHEY(350-358;SEQ ID NO:106);以及AQFVQEATY(52-60;SEQ ID NO:107)。图14中所展示的氨基酸序列中的肽的位置提供于括号中,随后为序列标识。
在一些情况下,适合于包括在TMP中的AFP肽选自由以下组成的组:FMNKFIYEI(158-166;SEQ ID NO:46);LLNFTESRT(12-20;SEQ ID NO:48);YIQESQALA(404-412;SEQ IDNO:54);QLTSSELMAI(441-450;SEQ ID NO:55);ILLWAARYD(178-186;SEQ ID NO:59);TMKQEFLINL(547-556;SEQ ID NO:63);NLVKQKPQI(SEQ ID NO:64);YICSQQDTL(287-295;SEQ ID NO:69);MKWVESIFL(1-9;SEQ ID NO:79);PVNPGVGQC(492-500;SEQ ID NO:80);FQAITVTKL(235-243;SEQ ID NO:86);以及GVALQTMKQ(542-550;SEQ ID NO:90)。
在一些情况下,适合于包括在TMP中的AFP肽选自由以下组成的组:KYIQESQAL(SEQID NO:89);EYYLQNAFL(SEQ ID NO:108);AYTKKAPQL(SEQ ID NO:43);EYSRRHPQL(SEQ IDNO:109);AYEEDRETF(SEQ ID NO:110);SYANRRPCF(SEQ ID NO:111);CFAEEGQKL(SEQ IDNO:112);RSCGLFQKL(SEQ ID NO:113);IFLIFLLNF(SEQ ID NO:114);KPEGLSPNL(SEQ IDNO:115);FMNKFIYEI(SEQ ID NO:46);以及GLSPNLNRFL(SEQ ID NO:116)。
在一些情况下,存在于TMP中的AFP肽呈递HLA-A*2402限制性表位。呈递HLA-A*2402限制性表位的AFP肽的非限制性实例包括:KYIQESQAL(SEQ ID NO:89);EYYLQNAFL(SEQID NO:108);AYTKKAPQL(SEQ ID NO:43);EYSRRHPQL(SEQ ID NO:109);RSCGLFQKL(SEQ IDNO:113)以及AYEEDRETF(SEQ ID NO:110)。
在一些情况下,存在于TMP中的AFP肽为KYIQESQAL(SEQ ID NO:89)。在一些情况下,存在于TMP中的AFP肽为EYYLQNAFL(SEQ ID NO:108)。在一些情况下,存在于TMP中的AFP肽为AYTKKAPQL(SEQ ID NO:43)。在一些情况下,存在于TMP中的AFP肽为EYSRRHPQL(SEQ IDNO:109)。在一些情况下,存在于TMP中的AFP肽为RSCGLFQKL(SEQ ID NO:113)。
在一些情况下,存在于TMP中的AFP肽呈递HLA-A*0201限制性表位。呈递HLA-A*0201限制性表位的AFP肽的非限制性实例包括:FMNKFIYEI(SEQ ID NO:46);以及GLSPNLNRFL(SEQ ID NO:116)。
WT1肽
在一些情况下,TMP包含威尔姆氏瘤-1(WT-1)肽作为肽表位。WT-1同种型的氨基酸序列呈现于图3A至图3E中。呈递一种或多种表位的WT-1肽在本文中称为“WT-1肽”或“WT-1表位”。在一些情况下,存在于TMP中的WT-1表位可为与图15A至图15E中任一者所展示的WT-1氨基酸序列具有至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列的长度为4-20aa(例如6-15aa、8-12aa、8-10aa、9-11aa、5-10aa、10-15aa以及15-20aa)的肽。
适合于包括在TMP中的WT-1肽的实例包括但不限于CMTWNQMNLGATLKG(SEQ ID NO:117)、WNQMNLGATLKGV AA(SEQ ID NO:118)、CMTWNYMNLGATLKG(SEQ ID NO:119)、WNYMNLGATLKGVAA(SEQ ID NO:120)、MTWNQMNLGATL KGV(SEQ ID NO:121)、TWNQMNLGATLKGVA(SEQ ID NO:122)、CMTWNLMNLGATLKG(SEQ ID NO:123)、MTWNLMNLGATLKGV(SEQ ID NO:124)、TWNLMNLGATLKGVA(SEQ ID NO:125)、WNLMNLGATLKGVAA(SEQ ID NO:126)、MNLGATLK(SEQ ID NO:127)、MTWNYMNLGATLKGV(SEQ ID NO:128)、TWNYMNLG ATLKGVA(SEQ ID NO:129)、CMTWNQMNLGATLKGVA(SEQ ID NO:130)、CMTWNLMNLGATLKGVA(SEQ ID NO:131)、CMTWNY MNLGATLKGVA(SEQ ID NO:132)、GYLRNPTAC(SEQ ID NO:133)、GALRNPTAL(SEQID NO:134)、YALRNPTAC(SEQ ID NO:135)、GLLRNPTAC(SEQ ID NO:136)、RYRPHPGAL(SEQ IDNO:137)、YQRPHPGAL(SEQ ID NO:138)、RLRPHPGAL(SEQ ID NO:139)、RIRPHPGAL(SEQ IDNO:140)、QFPNHSFKHEDPMGQ(SEQ ID NO:141)、HSFKHEDPY(SEQ ID NO:142)、QFPNHSFKHEDPM(SEQ ID NO:143)、QFPNHSFKHEDPY(SEQ ID NO:144)、KRPFMCAYPGCNK(SEQ ID NO:145)、KRPFMCAYPGCYK(SEQ ID NO:146)、FMCAYPGCY(SEQ ID NO:147)、FMCAYPGCK(SEQ ID NO:148)、KRPFMCAYPGCNKRY(SEQ ID NO:149)、SEKRPFMCAYP GCNK(SEQ ID NO:150)、KRPFMCAYPGCYKRY(SEQ ID NO:151)、NLMNLGATL(SEQ ID NO:152)、VLDFAPPGA(SEQ ID NO:153);RMFPNAPYL(SEQ ID NO:154);CMTWNQMN(SEQ ID NO:155);CYTWNQMNL(SEQ ID NO:156);NYMNLGATL(SEQ ID NO:157);YMFPNAPYL(SEQ ID NO:158);SLGEQQYSV(SEQ ID NO:159);CMTWNQMNL(SEQ ID NO:160);以及NQMNLGATL(SEQ ID NO:161)。在一些情况下,存在于TMP中的WT-1肽为CMTWNQMN(SEQ ID NO:155)。在一些情况下,存在于TMP中的WT-1肽为CYTWNQMNL(SEQ ID NO:156)。
在一些情况下,存在于TMP中的WT-1肽呈递HLA-A*2402限制性表位。呈递HLA-A*2402限制性表位的WT-1肽包括例如CMTWNQMN(SEQ ID NO:155);NYMNLGATL(SEQ ID NO:157)(WT-1 239-247;Q240Y);CYTWNQMNL(SEQ ID NO:156)(WT-1235-243);CMTWNQMNL(SEQID NO:160)(WT-1 235-243);NQMNLGATL(SEQ ID NO:161)(WT-1 239-247);以及NLMNLGATL(SEQ ID NO:152)(WT-1 239-247;Q240L)。
在一些情况下,存在于TMP中的WT-1肽呈递HLA-A*0201限制性表位。呈递HLA-A*0201限制性表位的WT-1肽包括例如VLDFAPPGA(SEQ ID NO:153)(WT-1 37-45);RMFPNAPYL(SEQ ID NO:154)(WT-1 126-134);YMFPNAPYL(SEQ ID NO:158)(WT-1126-134;R126Y);SLGEQQYSV(SEQ ID NO:159)(WT-1 187-195);以及NLMNLGATL(SEQ ID NO:152)(WT-1 239-247;Q240L)。
HPV肽
在一些情况下,TMP包含人乳头瘤病毒(HPV)肽作为肽表位。适合于包括在TMP中的HPV肽可为HPV E6多肽或HPV E7多肽的肽。HPV表位可为多种基因型中的任一者的HPV的表位,包括例如HPV16、HPV18、HPV31、HPV33、HPV35、HPV39、HPV45、HPV51、HPV52、HPV56、HPV58、HPV59、HPV68、HPV73或HPV82。在一些情况下,表位为HPV E6表位。在一些情况下,表位为HPVE7表位。HPV E6多肽的氨基酸序列呈现于图3A中。HPV E7多肽的氨基酸序列呈现于图3B中。呈递一个或多个表位的HPV肽在本文中称为“HPV肽”或“HPV表位”。在一些情况下,存在于TMP中的HPV表位为与图16A中所展示的HPV E6氨基酸序列或图16B中所展示的HPV E7氨基酸序列具有至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列的长度为4-20aa(例如6-15aa、8-12aa、8-10aa、9-11aa、5-10aa、10-15aa以及15-20aa)的肽。
适合于包括在TMP中的HPV E6肽的实例包括但不限于E618-26(KLPQLCTEL;SEQ IDNO:162);E6 26-34(LQTTIHDII;SEQ ID NO:163);E6 49-57(VYDFAFRDL;SEQ ID NO:164);E6 52-60(FAFRDLCIV;SEQ ID NO:165);E6 75-83(KFYSKISEY;SEQ ID NO:166);以及E680-88(ISEYRHYCY;SEQ ID NO:167)。
适合于包括在TMP中的HPV E7肽的实例包括但不限于E7 7-15(TLHEYMLDL;SEQ IDNO:168);E7 11-19(YMLDLQPET;SEQ ID NO:169);E7 44-52(QAEPDRAHY;SEQ ID NO:170);E7 49-57(RAHYNIVTF(SEQ ID NO:171);E7 61-69(CDSTLRLCV;SEQ ID NO:172);以及E767-76(LCVQSTHVDI;SEQ ID NO:173);E7 82-90(LLMGTLGIV;SEQ ID NO:174);E7 86-93(TLGIVCPI;SEQ ID NO:175);以及E7 92-93(LLMGTLGIVCPI;SEQ ID NO:176)。
在一些情况下,适合于包括在TMP中的HPV肽为结合HLA-A24的HPV E6肽(例如为HLA-A2401限制性表位)。非限制性实例包括:VYDFAFRDL(SEQ ID NO:164);CYSLYGTTL(SEQID NO:177);EYRHYCYSL(SEQ ID NO:178);KLPQLCTEL(SEQ ID NO:162);DPQERPRKL(SEQ IDNO:179);HYCYSLYGT(SEQ ID NO:180);DFAFRDLCI(SEQ ID NO:181);LYGTTLEQQY(SEQ IDNO:182);HYCYSLYGTT(SEQ ID NO:183);EVYDFAFRDL(SEQ ID NO:184);EYRHYCYSLY(SEQ IDNO:185);VYDFAFRDLC(SEQ ID NO:186);YCYSIYGTTL(SEQ ID NO:187);VYCKTVLEL(SEQ IDNO:188);VYGDTLEKL(SEQ ID NO:189);以及LTNTGLYNLL(SEQ ID NO:190)。
在一些情况下,适合于包括在TMP中的HPV肽选自由以下组成的组:DLQPETTDL(SEQID NO:191);TLHEYMLDL(SEQ ID NO:168);TPTLHEYML(SEQ ID NO:168);RAHYNIVTF(SEQ IDNO:171);GTLGIVCPI(SEQ ID NO:192);EPDRAHYNI(SEQ ID NO:193);QLFLNTLSF(SEQ IDNO:194);FQQLFLNTL(SEQ ID NO:195);以及AFQQLFLNTL(SEQ ID NO:196)。
在一些情况下,适合的HPV肽呈递HLA-A*2401限制性表位。呈递HLA-A*2401限制性表位的HPV肽的非限制性实例包括:VYDFAFRDL(SEQ ID NO:164);RAHYNIVTF(SEQ ID NO:171);CDSTLRLCV(SEQ ID NO:172);以及LCVQSTHVDI(SEQ ID NO:173)。
MUC1肽
在一些情况下,TMP包含粘蛋白-1(MUC-1)肽作为肽表位。在一些情况下,适合的MUC1肽为包含与图24A至图24M中任一者所展示的MUC1氨基酸序列具有至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列的MUC1多肽的长度为至少4-20aa(例如6-15aa、8-12aa、8-10aa、9-11aa、5-10aa、10-15aa以及15-20aa)的肽。
适合的MUC1肽的非限制性实例包括:i)STAPPAHGV(SEQ ID NO:197);ii)STAPPVHNV(SEQ ID NO:198);iii)SLAPPVHNV(SEQ ID NO:199);iv)SLAPPAHGV(SEQ ID NO:200);v)SAPDTRPAP(SEQ ID NO:201);vi)VTSAPDTRPAPGSTAPPAHG(SEQ ID NO:202);vii)PDTRPAPGSTAPPAHGVTSA(SEQ ID NO:203);以及viii)LLLLTVLTV(SEQ ID NO:204)。
在一些情况下,存在于TMP中的MUC1肽呈递对HLA-A、HLA-B、HLA-C、HLA-E、HLA-F或HLA-G等位基因具特异性的表位。在一个实施方案中,存在于TMP中的MUC1肽呈递限于HLA-A*0101、A*0201、A*0301、A*1101、A*2301、A*2402、A*2407、A*3303和/或A*3401的表位。在一个实施方案中,存在于TMP中的表位肽呈递限于HLA-B*0702、B*0801、B*1502、B*3802、B*4001、B*4601和/或B*5301的表位。在一个实施方案中,存在于TMP中的表位肽呈递限于C*0102、C*0303、C*0304、C*0401、C*0602、C*0701、C*702、C*0801和/或C*1502的表位。
作为一个实例,MUC1肽STAPPAHGV(SEQ ID NO:197)当结合至包含β2M多肽和A*1101HLA-A重链的HLA复合体时呈递表位。作为另一实例,MUC1肽STAPPAHGV(SEQ ID NO:197)当结合至包含β2M多肽和A*0201HLA-A重链的HLA复合体时呈递表位。作为另一实例,MUC1肽STAPPVHNV(SEQ ID NO:198)当结合至包含β2M多肽和A*0201HLA-A重链的HLA复合体时呈递表位。作为另一实例,MUC1肽SLAPPVHNV(SEQ ID NO:199)当结合至包含β2M多肽和A*0201HLA-A重链的HLA复合体时呈递表位。作为另一实例,MUC1肽SLAPPAHGV(SEQ ID NO:200)当结合至包含β2M多肽和A*0201HLA-A重链的HLA复合体时呈递表位。
MAGE-A4肽
在一些情况下,TMP包含黑素瘤相关抗原4(MAGE-A4)肽作为肽表位。在一些情况下,适合的MAGE-A4肽为包含与以下智人(Homo sapiens)MAGE-A4氨基酸序列具有至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列的MAGE-A4多肽的长度为4-20aa(例如6-15aa、8-12aa、8-10aa、9-11aa、5-10aa、10-15aa以及15-20aa)的肽片段:
MSSEQKSQHC KPEEGVEAQE EALGLVGAQA PTTEEQEAAV SSSSPLVPGT LEEVPAAESAGPPQSPQGAS ALPTTISFTC WRQPNEGSSS QEEEGPSTSP DAESLFREAL SNKVDELAHF LLRKYRAKELVTKAEMLERV IKNYKRCFPV IFGKASESLK MIFGIDVKEV DPASNTYTLV TCLGLSYDGL LGNNQIFPKTGLLIIVLGTIAMEGDSASEE EIWEELGVMG VYDGREHTVY GEPRKLLTQDWVQENYLEYR QVPGSNPARYEFLWGPRALA ETSYVKVLEHVVRVNARVRI AYPSLREAAL LEEEEGV(SEQ ID NO:205)。
作为实例,适合的MAGE-A4肽具有氨基酸序列GVYDGREHTV(SEQ ID NO:206;p230-239);并且具有10个氨基酸的长度。作为另一实例,适合的MAGE-A4肽具有氨基酸序列NYKRCFPVI(SEQ ID NO:207;p143-151);并且具有9个氨基酸的长度。作为另一实例,适合的MAGE-A4肽具有氨基酸序列EVDPASNTY(SEQ ID NO:208);并且具有9个氨基酸的长度。作为另一实例,适合的MAGE-A4肽具有氨基酸序列SESLKMIF(SEQ ID NO:209);并且具有8个氨基酸的长度。作为另一实例,适合的MAGE-A4肽具有氨基酸序列SESLICMIF(SEQ ID NO:210);并且具有9个氨基酸的长度。
在一些情况下,MAGE-A4肽为HLA限制性的。举例来说,肽GVYDGREHTV(SEQ ID NO:206)为HLA-A2限制性的。
NY-ESO-1肽
在一些情况下,TMP包含癌症/睾丸抗原-1(CTAG1B)肽作为肽表位。CTAG1B也称为LAGE2、LAGE3或NY-ESO-1(纽约食管鳞状细胞癌1)。因此,在一些情况下,TMP包含NY-ESO-1肽作为肽表位。在一些情况下,适合的NY-ESO-1肽为包含与以下NY-ESO-1氨基酸序列具有至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列的NY-ESO-1多肽的长度为4-20aa(例如6-15aa、8-12aa、8-10aa、9-11aa、5-10aa、10-15aa以及15-20aa)的肽片段:
MQAEGRGTGG STGDADGPGG PGIPDGPGGN AGGPGEAGAT GGRGPRGAGA ARASGPGGGAPRGPHGGAAS GLNGCCRCGA RGPESRLLEF YLAMPFATPM EAELARRSLA QDAPPLPVPGVLLKEFTVSGNILTIRLTAA DHRQLQLSIS SCLQQLSLLM WITQCFLPVF LAQPPSGQRR(SEQ ID NO:211)。
作为一个实例,适合的NY-ESO-1肽具有氨基酸序列SLLMWITQCFL(SEQ ID NO:212);并且具有11个氨基酸的长度。作为另一实例,适合的NY-ESO-1肽具有氨基酸序列SLLMWITQC(SEQ ID NO:213);并且具有9个氨基酸的长度。作为另一实例,适合的NY-ESO-1肽具有氨基酸序列QLSLLMWIT SEQ ID NO:214);并且具有9个氨基酸的长度。作为另一实例,适合的NY-ESO-1肽具有氨基酸序列SLLMWITQCFLPVF(SEQ ID NO:215);并且具有14个氨基酸的长度(NY-ESO-1
存活素肽
在一些情况下,TMP包含存活素肽作为肽表位。存活素在本领域中也称为含杆状病毒IAP重复5(BIRC5)以及凋亡抑制剂4(IAP4)。在一些情况下,适合的存活素肽为包含与图25A至图25C中任一者所展示的氨基酸序列具有至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列的存活素多肽的长度为4-20aa(例如6-15aa、8-12aa、8-10aa、9-11aa、5-10aa、10-15aa以及15-20aa)的肽片段。
作为一个实例,适合的存活素肽具有氨基酸序列ELTLGEFLKL(SEQ ID NO:228;存活素95-104);并且具有10个氨基酸的长度。作为另一实例,适合的存活素肽具有氨基酸序列TLGEFLKLDRERAKN(SEQ ID NO:229);并且具有15个氨基酸的长度。作为另一实例,适合的存活素肽具有氨基酸序列QMFFCF(SEQ ID NO:230);并且具有6至10个氨基酸的长度。作为另一实例,适合的存活素肽具有氨基酸序列DLAQMFFCFKELEGW(SEQ ID NO:231);并且具有15个氨基酸的长度。作为另一实例,适合的存活素肽具有氨基酸序列AQMFFCFKEL(SEQ IDNO:232);并且具有10个氨基酸的长度。作为另一实例,适合的存活素肽具有氨基酸序列QMFFCFKEL(SEQ ID NO:233);并且具有9个氨基酸的长度。
间皮素肽
在一些情况下,TMP包含间皮素肽作为肽表位。在一些情况下,适合的间皮素肽为包含与以下间皮素氨基酸序列具有至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列的间皮素多肽的长度为4-20aa(例如6-15aa、8-12aa、8-10aa、9-11aa、5-10aa、10-15aa以及15-20aa)的肽片段:
MALPTARPLL GSCGTPALGS LLFLLFSLGW VQPSRTLAGETGQEAAPLDG VLANPPNISSLSPRQLLGFPCAEVSGLSTERVRELAVALA QKNVKLSTEQ LRCLAHRLSE PPEDLDALPLDLLLFLNPDAFSGPQACTRF FSRITKANVD LLPRGAPERQRLLPAALACW GVRGSLLSEA DVRALGGLACDLPGRFVAESAEVLLPRLVS CPGPLDQDQQ EAARAALQGG GPPYGPPSTWSVSTMDALRG LLPVLGQPIIRSIPQGIVAA WRQRSSRDPSWRQPERTILR PRFRREVEKT ACPSGKKARE IDESLIFYKKWELEACVDAALLATQMDRVN AIPFTYEQLD VLKHKLDELYPQGYPESVIQ HLGYLFLKMS PEDIRKWNVTSLETLKALLEVNKGHEMSPQ VATLIDRFVK GRGQLDKDTL DTLTAFYPGYLCSLSPEELS SVPPSSIWAVRPQDLDTCDP RQLDVLYPKARLAFQNMNGS EYFVKIQSFL GGAPTEDLKA LSQQNVSMDLATFMKLRTDAVLPLTVAEVQ KLLGPHVEGL KAEERHRPVRDWILRQRQDD LDTLGLGLQG GIPNGYLVLDLSMQEALSGTPCLLGPGPVL TVLALLLAST LA(SEQ ID NO:234)
适合的间皮素肽的非限制性实例包括以下间皮素肽:间皮素A2(20-28)肽SLLFLLFSL(SEQ ID NO:235);间皮素A2(530-538)肽VLPLTVAEV(SEQ ID NO:236);间皮素A3(83-91)肽ELAVALAQK(SEQ ID NO:237);间皮素A3(225-233)肽ALQGGGPPY(SEQ ID NO:238);间皮素A24(435-443)肽FYPGYLCSL(SEQ ID NO:239);以及间皮素A24(475-483)肽LYPKARLAF(SEQ ID NO:240)。
MART-1肽
在一些情况下,TMP包含由T细胞识别的黑色素瘤抗原-1(MART-1)肽作为肽表位。在一些情况下,适合的MART-1肽为包含与以下MART-1氨基酸序列具有至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列的MART-1多肽的长度为4-20aa(例如6-15aa、8-12aa、8-10aa、9-11aa、5-10aa、10-15aa以及15-20aa)的肽片段:MPREDAHFIY GYPKKGHGHS YTTAEEAAGI GILTVILGVL LLIGCWYCRRRNGYRALMDK SLHVGTQCAL TRRCPQEGFD HRDSKVSLQE KNCEPVVPNA PPAYEKLSAE QSPPPYSP(SEQ ID NO:241)。作为一个非限制性实例,适合的MART-1肽具有以下氨基酸序列:ELAGIGILTV(SEQ ID NO:242);并且具有10个氨基酸的长度。
非经典HLA肽
在一些情况下,TMP包含非经典HLA肽作为肽表位。举例来说,在一些情况下,适合的非经典HLA肽为HLA-G多肽的长度为4-20aa(例如6-15aa、8-12aa、8-10aa、9-11aa、5-10aa、10-15aa以及15-20aa)的肽片段。作为一个非限制性实例,适合的HLA-G肽具有以下氨基酸序列:VMAPRTLFL(SEQ ID NO:243);并且具有9个氨基酸的长度。
病毒肽
在一些情况下,TMP包含病毒肽表位作为肽表位。适合的肽表位包括但不限于存在于感染性病原体中的表位,例如由病毒编码多肽呈递的表位。病毒感染性病原体的实例包括例如腺病毒、腺病毒相关病毒、α病毒(披膜病毒(Togavirus))、东方马脑炎病毒(Easternequine encephalitis virus)、东方马脑脊髓炎病毒、委内瑞拉马脑脊髓炎(Venezuelanequine encephalomyelitis)疫苗株TC-83、西方型马脑脊髓炎病毒(Western equineencephalomyelitis virus)、沙粒病毒、淋巴细胞性脉络丛脑膜炎病毒(非亲神经株)、塔卡里伯病毒复合体(Tacaribe virus complex)、本雅病毒(Bunyavirus)、布尼安维拉病毒(Bunyamwera virus)、立谷热病毒(Rift Valley fever virus)疫苗株MP-12、切昆贡亚热病毒(Chikungunya virus)、卡西病毒(Calcivirus)、冠状病毒、牛痘病毒、黄病毒(披膜病毒)组B虫媒病毒、登革热病毒(Dengue virus)血清型1、2、3以及4、黄热病毒疫苗株17D、肝炎A、B、C、D以及E病毒、巨细胞病毒、爱泼斯坦巴尔病毒(Epstein Barr virus)、东方马脑炎病毒、单纯性疱疹1型和2型、带状疱疹、人疱疹病毒6型和7型、C型肝炎病毒(HVC)、B型肝炎病毒(HBV)、A型、B型以及C型流感病毒、乳多空病毒、新城疫病毒、麻疹病毒、腮腺炎病毒、副流感病毒1型、2型、3型以及4型、多瘤病毒(JC病毒、BK病毒)、呼吸道合胞病毒、人细小病毒(B19)、A型和B型柯萨奇病毒(Coxsackie virus)、埃可病毒(Echovirus)、脊髓灰质炎病毒、鼻病毒、类天花(轻型天花病毒)、天花(重型天花病毒)、白痘呼肠孤病毒、科罗拉多壁虱热病毒、人轮状病毒以及环状病毒(科罗拉多蜱传热病毒(Colorado tick fever virus))、狂犬病病毒、水疱性口炎病毒、风疹病毒(风疹)、塞姆利基森林病毒(Semliki Forestvirus)、圣路易脑炎病毒(St.Louis encephalitis virus)、委内瑞拉人马脑炎病毒、委内瑞拉马脑脊髓炎病毒、沙粒病毒(也称为南美出血热病毒(South American HemorrhagicFever virus))、Flexal、淋巴细胞性脉络丛脑膜炎病毒(LCM)(亲神经株)、汉他病毒(Hantavirus)包括汉坦病毒(Hantaan virus)、立谷热病毒、日本脑炎病毒、黄热病毒、猴痘病毒、人免疫缺陷病毒(HIV)1型和2型、人T细胞亲淋巴性病毒(HTLV)1型和2型、猴免疫缺陷病毒(SIV)、水疱性口炎病毒、瓜纳里托病毒(Guanarito virus)、拉沙热病毒(Lassa fevervirus)、胡宁病毒(Junin virus)、马秋波病毒(Machupo virus)、萨比亚病毒(Sabia)、克里米亚-刚果出血热病毒(Crimean-Congo hemorrhagic fever virus)、埃博拉病毒(Ebolavirus)、马伯格氏病毒(Marburg virus)、蜱传脑炎病毒复合体(flavi)(包括中央欧洲蜱传脑炎、远东蜱传脑炎)、汉扎洛瓦病毒(Hanzalova)、海普病毒(Hypr)、库姆灵厄病毒(Kumlinge)、卡萨努森林病(Kyasanur Forest disease)、鄂木斯克出血热(Omskhemorrhagic fever)以及苏联春夏型脑炎病毒(Russian Spring Summer encephalitisviruses)、猴疱疹病毒(疱疹B或猴B病毒)、弥猴疱疹病毒1(疱疹B病毒)、马麻疹病毒(亨德拉病毒(Hendra virus)和亨德拉样病毒)、尼帕病毒(Nipah virus)、重型天花病毒(天花病毒)、轻型天花病毒(类天花)、非洲猪瘟病毒、非洲马瘟病毒、赤羽病病毒(Akabane virus)、禽流感病毒(高致病性)、蓝舌病病毒、骆驼痘病毒、经典猪瘟病毒、反刍动物考德里氏体(Cowdria ruminantium)(心水病)、口蹄疫病毒、山羊痘病毒、日本脑炎病毒、结节性皮肤病病毒、恶性卡他热病毒(Malignant catarrhal fever virus)、梅那哥病毒(Menanglevirus)、新城疫病毒(VVND)、水疱性口炎病毒(外来)以及寨卡病毒(Zika virus)。由此类病毒编码的抗原为本领域中已知的;适合用于TMP中的肽表位可包括来自任何已知病毒抗原的肽。在一些情况下,特别地排除HPV抗原。在一些情况下,特别地排除HBV抗原。在一些情况下,病毒表位为存在于由感染大多数人类群体的病毒编码的病毒抗原中的表位,其中此类病毒包括例如巨细胞病毒(CMV)、爱泼斯坦-巴尔病毒(EBV)、人乳头瘤病毒、流感病毒、腺病毒等。
流感病毒肽的一个非限制性实例为流感病毒基质蛋白(M1)肽,例如具有氨基酸序列GILGFVFTL(SEQ ID NO:244)并且具有9个氨基酸的长度的M1(58-66)。EBV肽的一个非限制性实例为具有氨基酸序列IVTDFSVIK(SEQ ID NO:245)并且具有9个氨基酸的长度的EBV核酸酶抗原3B(EBNA3B)肽。EBV肽的另一非限制性实例为具有氨基酸序列AVFDRKSDAK(SEQID NO:246)并且具有9个氨基酸的长度的EBNA3B肽。
在一些情况下,TMP包含CMV肽作为肽表位。在一些情况下,存在于TMP中的CMV肽表位为来自CMV pp65的肽。在一些情况下,存在于TMP中的CMV肽表位为来自CMV gB(糖蛋白B)的肽。
举例来说,在一些情况下,存在于TMP中的CMV肽表位为具有4-20aa的长度(例如CMV多肽的长度为6-15aa、8-12aa、8-10aa、9-11aa、5-10aa、10-15aa以及15-20aa)并且包含与图26A中所展示的CMV pp65多肽的氨基酸序列或与图26B中所展示的CMV gB多肽的氨基酸序列具有至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列的CMV多肽的肽。
作为一个非限制性实例,存在于TMP中的CMV肽表位具有氨基酸序列NLVPMVATV(SEQ ID NO:247)并且具有9个氨基酸的长度。
在一些情况下,存在于TMP中的CMV表位呈递对HLA-A、HLA-B、HLA-C、HLA-E、HLA-F或HLA-G等位基因具特异性的表位。在一些情况下,存在于TMP中的表位肽呈递限于HLA-A*0101、A*0201、A*0301、A*1101、A*2301、A*2402、A*2407、A*3303和/或A*3401的表位。在一些情况下,存在于TMP中的CMV表位呈递限于HLA-B*0702、B*0801、B*1502、B*3802、B*4001、B*4601和/或B*5301的表位。在一些情况下,存在于TMP中的CMV表位呈递限于C*0102、C*0303、C*0304、C*0401、C*0602、C*0701、C*702、C*0801和/或C*1502的表位。作为一个实例,在一些情况下,TMP包含:a)具有氨基酸序列NLVPMVATV(SEQ ID NO:247)并且具有9个氨基酸的长度的CMV肽表位;b)HLA-A*0201I类重链多肽;以及c)β2M多肽。
在一些情况下,存在于TMP中的CMV表位包含具有氨基酸序列ATVQGQNLK(SEQ IDNO:248)并且具有9个氨基酸的长度的CMV肽。在一些情况下,存在于TMP中的CMV表位包含具有氨基酸序列VMAPRTLIL(SEQ ID NO:249)以及具有9个氨基酸的长度的CMV肽。
在一些情况下,TMP包含SARS-CoV-2肽。在一些情况下,存在于TMP中的SARS-CoV-2肽为来自SARS-CoV-2编码表面糖蛋白的SARS-CoV-2肽并且选自由以下组成的组:NLTTRTQL(SEQ ID NO:250);LPPAYTNSF(SEQ ID NO:251);KVFRSSVLH(SEQ ID NO:252);LPFFSNVTW(SEQ ID NO:253);PFFSNVTWF(SEQ ID NO:254);RFDNPVLPF(SEQ ID NO:255);LPFNDGVYF(SEQ ID NO:256);GVYFASTEK(SEQ ID NO:257);TEKSNIIRGW(SEQ ID NO:258);TLDSKTQSL(SEQ ID NO:259);GVYYHKNNK(SEQ ID NO:260);YYHKNNKSW(SEQ ID NO:261);VYSSANNCTF(SEQ ID NO:262);FEYVSQPFL(SEQ ID NO:263);EYVSQPFLM(SEQ ID NO:264);FVFKNIDGY(SEQ ID NO:265);TPINLVRDL(SEQ ID NO:266);LPQGFSAL(SEQ ID NO:267);LPIGINITRF(SEQ ID NO:268);INITRFQTL(SEQ ID NO:269);LLALHRSYL(SEQ ID NO:270);WTAGAAAYY(SEQ ID NO:271);YYVGYLQPRTF(SEQ ID NO:272);YLQPRTFLL(SEQ ID NO:273);YLQPRTFL(SEQ ID NO:274);SETKCTLKSF(SEQ ID NO:275);TLKSFTVEK(SEQ ID NO:276);QPTESIVRF(SEQ ID NO:277);RFPNITNLCPF(SEQ ID NO:278);GEVFNATRF(SEQ ID NO:279);NATRFASVY(SEQ ID NO:280);LYNSASFSTF(SEQ ID NO:281);NSASFSTFK(SEQ ID NO:282);RQIAPGQTGK(SEQ ID NO:283);KIADYNYKL(SEQ ID NO:284);NYNYLYRLF(SEQ ID NO:285);RLFRKSNLK(SEQ ID NO:286);KPFERDISTEI(SEQ ID NO:287);YFPLQSYGF(SEQ ID NO:288);QPYRVVVL(SEQ ID NO:289);PYRVVVLSF(SEQ ID NO:290);GPKKSTNLV(SEQ ID NO:291);TSNQVAVLY(SEQ ID NO:292);VYSTGSNVF(SEQ ID NO:293);AEHVNNSY(SEQ ID NO:294);IPIGAGICASY(SEQ ID NO:295);SPRRARSVA(SEQ ID NO:296);VASQSIIAY(SEQ ID NO:297);SIIAYTMSL(SEQ IDNO:298);LGAENSVAY(SEQ ID NO:299);AYSNNSIAIPTNF(SEQ ID NO:300);IPTNFTISV(SEQ ID NO:301);TEILPVSMTK(SEQ ID NO:302);QEVFAQVKQIY(SEQ ID NO:303);KQIYKTPPIK(SEQ ID NO:304);IYKTPPIKDF(SEQ ID NO:305);LLFNKVTLA(SEQ ID NO:306);TLADAGFIK(SEQ ID NO:307);LADAGFIKQY(SEQ ID NO:308);ADAGFIKQY(SEQ ID NO:309);VLPPLLTDEMIAQY(SEQ ID NO:310);IPFAMQMAY(SEQ ID NO:311);SSTASALGK(SEQ IDNO:312);VLNDILSRL(SEQ ID NO:313);RLDKVEAEV(SEQ ID NO:314);VEAEVQIDRL(SEQ IDNO:315);AEVQIDRLI(SEQ ID NO:316);LITGRLQSL(SEQ ID NO:317);RLQSLQTYV(SEQ IDNO:318);AEIRASANL(SEQ ID NO:319);ASANLAATK(SEQ ID NO:320);HLMSFPQSA(SEQ IDNO:321);FPQSAPHGVVF(SEQ ID NO:322);APHGVVFL(SEQ ID NO:323);VTYVPAQEK(SEQ IDNO:324);TYVPAQEKNF(SEQ ID NO:325);REGVFVSNGTHW(SEQ ID NO:326);GTHWFVTQR(SEQID NO:327);TVYDPLQPELDSFK(SEQ ID NO:328);KEIDRLNEV(SEQ ID NO:329);QELGKYEQYIKW(SEQ ID NO:330);YEQYIKWPW(SEQ ID NO:331);QYIKWPW YI(SEQ ID NO:332);FIAGLIAIV(SEQ ID NO:333);以及SEPVLKG VKL(SEQ ID NO:334)。
在一些情况下,SARS-CoV-2肽表位具有氨基酸序列RLQSLQTYV(SEQ ID NO:318);并且具有9个氨基酸的长度。在一些情况下,SARS-CoV-2肽表位具有氨基酸序列YLQPRTFLL(SEQ ID NO:273);并且具有9个氨基酸的长度。
在一些情况下,肽表位为来自SARS-CoV-2编码膜糖蛋白的SARS-CoV-2肽。在一些情况下,存在于TMP中的SARS-CoV-2肽为来自SARS-CoV-2编码膜糖蛋白的SARS-CoV-2肽并且选自由以下组成的组:GTITVEELK(SEQ ID NO:335);EELKKLLEQW(SEQ ID NO:336);KLLEQWNLV(SEQ ID NO:337);FAYANRNRF(SEQ ID NO:338);YANRNRFLY(SEQ ID NO:339);SYFIASFRLF(SEQ IDNO:340);RLFARTRSM(SEQ ID NO:341);VPLHGTIL(SEQ ID NO:342);SELVIGAVIL(SEQ ID NO:343);HLRIAGHHL(SEQ ID NO:344);RIAGHHLGR(SEQ ID NO:345);KEITVATSRTL(SEQ ID NO:346);ATSRTLSYYK(SEQ ID NO:347);ASQRVAGDSGFAAY(SEQ IDNO:348);以及VAGDSGFAAY(SEQ ID NO:349)。
在一些情况下,肽表位为来自SARS-CoV-2编码核衣壳磷蛋白的SARS-CoV-2肽。在一些情况下,肽表位为来自SARS-CoV-2编码核衣壳磷蛋白的SARS-CoV-2肽并且选自由以下组成的组:LPNNTASWF(SEQ ID NO:350);KFPRGQGVPI(SEQ ID NO:351);NTNSSPDDQIGYY(SEQID NO:352);SPRWYFYYL(SEQ ID NO:353);LLLDRLNQL(SEQ ID NO:354);KAYNVTQAF(SEQ IDNO:355);QELIRQGTDYKHW(SEQ ID NO:356);ASAFFGMSR(SEQ ID NO:357);SRIGMEVTPSGTW(SEQ ID NO:358);GMEVTPSGTWL(SEQ ID NO:359);TPSGTWLTY(SEQ ID NO:360);AYKTFPPTEPK(SEQ ID NO:361);以及LPAADLDDF(SEQ ID NO:362)。
MHC多肽
如上文所提到的,TMP包括MHC多肽。出于本公开的目的,术语“主要组织相容性复合体(MHC)多肽”意在包括各种物种的MHC多肽,包括人MHC(也称为人白细胞抗原(HLA))多肽、啮齿动物(例如小鼠、大鼠等)MHC多肽以及其他哺乳动物物种(例如兔类动物、非人灵长类动物、犬、猫、有蹄类动物(例如马、牛、绵羊、公山羊等)的MHC多肽等。术语“MHC多肽”意在包括I类MHC多肽(例如β-2微球蛋白(“β2M”)和MHC I类重链)。
在一些情况下,第一MHC多肽为MHC I类β2M多肽,并且第二MHC多肽为MHC I类重链(H链)(“MHC-H”))。在其他实例中,第一MHC多肽为MHC I类重链多肽;并且第二MHC多肽为β2M多肽。在一些情况下,β2M与MHC-H链来源于人;即,MHC-H链为HLA重链或其变体。除非另外明确陈述,否则TMP不包括MHC I类重链的膜锚定结构域(跨膜区),或MHC I类重链的足以使所得TMP锚定表达它的细胞(例如真核细胞,诸如哺乳动物细胞)的一部分。在一些情况下,存在于TMP中的MHC I类重链不包括信号肽、跨膜结构域或与天然MHC I类重链相关的细胞内结构域(细胞质尾)。因此,例如在一些情况下,存在于TMP中的MHC I类重链仅包括MHC I类重链的α1、α2以及α3结构域。在一些情况下,存在于TMP中的MHC I类重链具有约270个氨基酸(aa)至约290aa的长度。在一些情况下,存在于TMP中的MHC I类重链具有270aa、271aa、272aa、273aa、274aa、275aa、276aa、277aa、278aa、279aa、280aa、281aa、282aa、283aa、284aa、285aa、286aa、287aa、288aa、289aa或290aa的长度。
MHC I类重链
在一些情况下,存在于TMP中的MHC I类重链多肽包含与图3至图11中所展示的人HLA重链多肽中的任一者的氨基酸序列的全部或部分(例如50、75、100、150、200或250个连续氨基酸)具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列。在一些情况下,MHC I类重链具有270aa、271aa、272aa、273aa、274aa、275aa、276aa、277aa、278aa、279aa、280aa、281aa、282aa、283aa、284aa、285aa、286aa、287aa、288aa、289aa或290aa的长度。在一些情况下,存在于TMP中的MHC I类重链多肽包含图3至图11中所展示的氨基酸序列中的任一者的1-30、1-5、5-10、10-15、15-20、20-25或25-30个氨基酸插入、缺失和/或取代(除重链共有序列中指示为可变的那些位置外)。如上文所提到的,MHC I类重链通常不包括跨膜或胞质结构域。作为实例,TMP的MHC I类重链多肽可包含与人HLA-A重链多肽的氨基酸25-300(缺乏全部或基本上全部的前导、跨膜以及细胞质序列)或氨基酸25-365(缺乏前导子)具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列。
在一些情况下,TMP的MHC多肽为人MHC多肽,其中人MHC多肽也称为“人白细胞抗原”(“HLA”)多肽。在一些情况下,TMP的MHC多肽为I类HLA多肽,例如β2-微球蛋白多肽或I类HLA重链多肽。I类HLA重链多肽包括HLA-A重链多肽、HLA-B重链多肽、HLA-C重链多肽、HLA-E重链多肽、HLA-F重链多肽以及HLA-G重链多肽。
在一些情况下,TMP包含HLA-A重链多肽。可合并至TMP中的HLA-A重链肽序列或其部分包括但不限于等位基因:A*0101、A*0201、A*0301、A*1101、A*2301、A*2402、A*2407、A*3303以及A*3401。所述等位基因中的任一者可包含选自以下的在位置84、139以及236中的一者或多者处的突变(如图3至图6中所示:位置84的酪氨酸至丙氨酸(Y84A);位置84的酪氨酸至半胱氨酸(Y84C);位置139的丙氨酸至半胱氨酸(A139C);以及位置236的丙氨酸至半胱氨酸的取代(A236C)。此外,还可使用与那些HLA-A等位基因的序列的全部或部分(例如50、75、100、150、200或250个连续氨基酸)具有至少75%(例如至少80%、至少85%、至少90%、至少95%、至少98%、至少99%)或100%的氨基酸序列同一性的HLA-A序列(例如它可包含1-25、1-5、5-10、10-15、15-20、20-25或25-30个氨基酸插入、缺失和/或取代)。以下提供一些实例。
HLA-A02
在一些情况下,TMP的MHC I类重链多肽可包含与图3A中所展示的氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列。在一些情况下,适合于包括在TMP中的HLA-A重链多肽包含图3A中所展示的氨基酸序列。此HLA-A重链多肽也称为“HLA-A*0201”或简单地为“HLA-A02”。如WO 2018/119114和WO2020/132138中所描述,TMP可相对于野生型HLA-A02包含一个或多个突变,包括用于提供Cys残基,所述Cys残基可形成二硫键,例如(i)在β2M与MHC I类重链之间,和/或(ii)在MHC重链与将肽表位连接至β2M多肽的接头之间,和/或(iii)MHC I类重链多肽内的链内二硫键。
为了促进此类二硫键的形成,可在重链多肽中提供一个或多个非天然存在的Cys残基。举例来说,MHC I类重链多肽包含与以下氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列:
A)图3C中所展示的HLA-A02(Y84C;A236C)氨基酸序列,其中氨基酸84为Cys,并且其中氨基酸236为Cys。在一些情况下,Cys-136与包含R12C取代的变体β2M多肽的Cys-12形成二硫键;或
B)图3D中所展示的HLA-A02(Y84A;A236C)氨基酸序列,其中氨基酸84为Ala并且氨基酸236为Cys。在一些情况下,Cys-236与包含R12C取代的变体β2M多肽的Cys-12形成链间二硫键;或
C)图3E中所展示的HLA-A02(Y84C;A139C)氨基酸序列,其中氨基酸84为Cys并且氨基酸139为Cys。在一些情况下,Cys-84与Cys-139形成链内二硫键。
如上文所提到,在一些情况下,MHC I类重链多肽包含与图3B中所展示的HLA-A02(Y84A;A236野生型)氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列,其中氨基酸84为Tyr,并且氨基酸236为Ala。
HLA-A11(HLA-A*1101)
在一些情况下,TMP的MHC I类重链多肽可包含与图4A中所展示的氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列。在一些情况下,适合于包括在TMP中的HLA-A重链多肽包含图4A中所展示的氨基酸序列。此HLA-A重链多肽也称为“HLA-A*1101”或简单地为“HLA-A11”。变体可包括例如包含与以下氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列的MHC I类重链多肽:
A)图4B中所展示的HLA-A11(Y84A;A236野生型)氨基酸序列,其中氨基酸84为Tyr,并且氨基酸236为Ala;
B)图4C中所展示的HLA-A11(Y84C;A236C)氨基酸序列,其中氨基酸84为Cys,并且其中氨基酸236为Cys;
C)图4D中所展示的HLA-A11(Y84A;A236C)氨基酸序列,其中氨基酸84为Ala并且氨基酸236为Cys。在一些情况下,Cys-236与包含R12C取代的变体β2M多肽的Cys-12形成链间二硫键;以及
D)图4E中所展示的HLA-A11(Y84C;A139C)氨基酸序列,其中氨基酸84为Cys并且氨基酸139为Cys。在一些情况下,Cys-84与Cys-139形成链内二硫键。
HLA-A24(HLA-A*2402)
在一些情况下,TMP的MHC I类重链多肽可包含与图5A中所展示的氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列。在一些情况下,适合于包括在TMP中的HLA-A重链多肽包含图5A中所展示的氨基酸序列。此HLA-A重链多肽也称为“HLA-A*2402”或简单地为“HLA-A24”。变体可包括例如包含与以下氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列的MHC I类重链多肽:
A)图5B中所展示的HLA-A24(Y84A;A236野生型)氨基酸序列,其中氨基酸84为Tyr,并且氨基酸236为Ala;
B)图5C中所展示的HLA-A24(Y84C;A236C)氨基酸序列,其中氨基酸84为Cys,并且其中氨基酸236为Cys;
C)图5D中所展示的HLA-A24(Y84A;A236C)氨基酸序列,其中氨基酸84为Ala并且氨基酸236为Cys。在一些情况下,Cys-236与包含R12C取代的变体β2M多肽的Cys-12形成链间二硫键;以及
D)图5E中所展示的HLA-A24(Y84C;A139C)氨基酸序列,其中氨基酸84为Cys并且氨基酸139为Cys。在一些情况下,Cys-84与Cys-139形成链内二硫键。
HLA-A33(HLA-A*3303)
在一些情况下,TMP的MHC I类重链多肽可包含与图6A中所展示的氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列。在一些情况下,适合于包括在TMP中的HLA-A重链多肽包含图6A中所展示的氨基酸序列。此HLA-A重链多肽也称为“HLA-A*3303”或简单地为“HLA-A33”。变体可包括例如包含与以下氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列的MHC I类重链多肽:
A)图6B中所展示的HLA-A24(Y84A;A236野生型)氨基酸序列,其中氨基酸84为Tyr,并且氨基酸236为Ala;
B)图6C中所展示的HLA-A24(Y84C;A236C)氨基酸序列,其中氨基酸84为Cys,并且其中氨基酸236为Cys;
C)图6D中所展示的HLA-A24(Y84A;A236C)氨基酸序列,其中氨基酸84为Ala并且氨基酸236为Cys。在一些情况下,Cys-236与包含R12C取代的变体β2M多肽的Cys-12形成链间二硫键;以及
D)图6E中所展示的HLA-A24(Y84C;A139C)氨基酸序列,其中氨基酸84为Cys并且氨基酸139为Cys。在一些情况下,Cys-84与Cys-139形成链内二硫键。
图7至图9提供了成熟HLA I类重链氨基酸序列(没有前导序列或跨膜结构域或细胞内结构域)的比对。图7A中比对的氨基酸序列为以下等位基因的HLA-A I类重链:A*0101、A*0201、A*0301、A*1101、A*2301、A*2402、A*2407、A*3303以及A*3401。图8A中比对的氨基酸序列为以下等位基因的HLA-B I类重链:B*0702、B*0801、B*1502、B*3802、B*4001、B*4601以及B*5301。图9A中比对的氨基酸序列为以下等位基因的HLA-C I类重链:C*0102、C*0303、C*0304、C*0401、C*0602、C*0701、C*0801以及C*1502。比对中指示的是可引入半胱氨酸残基(例如通过取代)以形成二硫键从而稳定HLA H链-β2M复合体的位置(成熟蛋白质的84和139)。比对中还示出了(成熟多肽的)位置236,所述位置可被半胱氨酸残基取代从而可与β2M形成间链二硫键(例如在aa 12处)。侧接残基84、139以及236的框示出了所述六个五残基集合的任一侧的五个氨基酸的组,所述六个五残基集合表示aac1(用于“氨基酸聚类1”)、aac2(用于“氨基酸聚类2”)、aac3(用于“氨基酸聚类3”)、aac4(用于“氨基酸聚类4”)、aac5(用于“氨基酸聚类5”)以及aac6(用于“氨基酸聚类6”),所述氨基酸可由独立地选自以下的1至5个氨基酸置换:(i)任何天然存在的氨基酸或(ii)除脯氨酸或甘氨酸外的任何天然存在的氨基酸。
图7A、图8A以及图9A分别提供了成熟HLA-A、HLA-B以及HLA-C I类重链的氨基酸序列的比对。提供了成熟蛋白质(没有前导序列或跨膜结构域或细胞内结构域)的细胞外部分的序列。还示出了aa残基84、139以及236以及可由独立地选自以下的1至5个氨基酸置换的其侧翼残基(aac1至aac6)的位置:(i)任何天然存在的氨基酸或(ii)除脯氨酸或甘氨酸外的任何天然存在的氨基酸。图7B、图8B以及图9B分别提供了提供于图7A、图8A以及图9A中的HLA-A、HLA-B以及HLA-C序列的共有氨基酸序列。共有序列将可变氨基酸位置显示为依序编号的“X”残基,并且氨基酸84、139以及236的位置加双下划线。
关于图7A,在一些情况下:i)aac1(氨基酸聚类1)可为氨基酸序列GTLRG(SEQ IDNO:363)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如L由I、V、A或F置换);ii)aac2(氨基酸聚类2)可为氨基酸序列YNQSE(SEQ ID NO:364)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如N由Q置换,Q由N置换,和/或E由D置换);iii)aac3(氨基酸聚类3)可为氨基酸序列TAADM(SEQ ID NO:365)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如T由S置换,A由G置换,D由E置换,和/或M由L、V或I置换);iv)aac4(氨基酸聚类4)可为氨基酸序列AQTTK(SEQ ID NO:366)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如A由G置换,Q由N置换,或T由S置换,且或K由R或Q置换);v)aac5(氨基酸聚类5)可为氨基酸序列VETRP(SEQ ID NO:367)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如V由I或L置换,E由D置换,T由S置换,和/或R由K置换);和/或vi)aac6(氨基酸聚类6)可为氨基酸序列GDGTF(SEQ ID NO:368)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如D由E置换,T由S置换,或F由L、W或Y置换)。
关于图8A,在一些情况下:i)aac1(氨基酸聚类1)可为氨基酸序列RNLRG(SEQ IDNO:369)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如N由T或I置换;和/或L由A置换;和/或第二R由L置换;和/或G由R置换);ii)aac2(氨基酸聚类2)可为氨基酸序列YNQSE(SEQ ID NO:364)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如N由Q置换,Q由N置换,和/或E由D置换);iii)aac3(氨基酸聚类3)可为氨基酸序列TAADT(SEQ ID NO:370)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如第一T由S置换;和/或A由G置换;和/或D由E置换;和/或第二T由S置换);iv)aac4(氨基酸聚类4)可为氨基酸序列AQITQ(SEQ ID NO:371)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如A由G置换;和/或第一Q由N置换;和/或I由L或V置换;和/或T由S置换;和/或第二Q由N置换);v)aac5(氨基酸聚类5)可为氨基酸序列VETRP(SEQ ID NO:367)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如V由I或L置换,E由D置换,T由S置换,和/或R由K置换);和/或vi)aac6(氨基酸聚类6)可为氨基酸序列GDRTF(SEQ ID NO:372)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如D由E置换;和/或T由S置换;和/或R由K或H置换;和/或F由L、W或Y置换)。
关于图9A,在一些情况下:i)aac1(氨基酸聚类1)可为氨基酸序列RNLRG(SEQ IDNO:369)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如N由K置换;和/或L由A或I置换;和/或第二R由H置换;和/或G由T或S置换);ii)aac2(氨基酸聚类2)可为氨基酸序列YNQSE(SEQ ID NO:364)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如N由Q置换,Q由N置换,和/或E由D置换);iii)aac3(氨基酸聚类3)可为氨基酸序列TAADT(SEQ ID NO:370)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如第一T由S置换;和/或A由G置换;和/或D由E置换;和/或第二T由S置换);iv)aac4(氨基酸聚类4)可为氨基酸序列AQITQ(SEQ ID NO:371)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如A由G置换;和/或第一Q由N置换;和/或I由L置换;和/或第二Q由N或K置换);v)aac5(氨基酸聚类5)可为氨基酸序列VETRP(SEQ ID NO:367)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如V由I或L置换,E由D置换,T由S置换,和/或R由K或H置换);和/或vi)aac6(氨基酸聚类6)可为氨基酸序列GDGTF(SEQ ID NO:368)或所述序列有一个或两个氨基酸缺失或用其他天然存在的氨基酸取代(例如D由E置换;和/或T由S置换;和/或F由L、W或Y置换)。
非经典HLA-E、HLA-F以及HLA-G MHC I类重链
在一些情况下,TMP包含非经典MHC I类重链多肽。在非经典HLA重链多肽或其部分之中,可合并至TMP中的包括但不限于HLA-E、HLA-F以及HLA-G等位基因的那些HLA重链多肽或其部分。HLA-E、HLA-F以及HLA-G重链多肽(以及HLA-A、B以及C等位基因)的氨基酸序列可在万维网hla.alleles.org/nomenclature/index.html、欧洲生物信息学协会(www(dot)ebi(dot)ac(dot)uk)(其为欧洲分子生物学实验室(EMBL)的一部分)以及国家生物技术信息中心(www(dot)ncbi(dot)nlm(dot)nih(dot)gov)找到。
适合的HLA-E等位基因的非限制性实例包括但不限于HLA-E*0101(HLA-E*01:01:01:01)、HLA-E*01:03(HLA-E*01:03:01:01)、HLA-E*01:04、HLA-E*01:05、HLA-E*01:06、HLA-E*01:07、HLA-E*01:09以及HLA-E*01:10。其中,同种型HLA-E*0101和HLA-E*01:03特别需要注意,因为这些同种型为高度普遍的等位基因,并且相差仅1个氨基酸(位置107的Arg或Gly)。举例来说,图22A至图22D中提供了适合的HLA-E重链多肽的氨基酸序列,其中图22A提供了HLA-E*01:01(野生型)的氨基酸序列;图22B提供了具有Y84C和A2346C取代的HLA-E*01:01的氨基酸序列;图22C提供了HLA-E*01:03(野生型)的氨基酸序列;并且图22D提供了具有Y84C和A2346C取代的HLA-E*01:03的氨基酸序列。
适合的HLA-F等位基因的非限制性实例包括但不限于HLA-F*0101(HLA-F*01:01:01:01)、HLA-F*01:02、HLA-F*01:03(HLA-F*01:03:01:01)、HLA-F*01:04、HLA-F*01:05以及HLA-F*01:06。适合的HLA-G等位基因的非限制性实例包括但不限于HLA-G*0101(HLA-G*01:01:01:01)、HLA-G*01:02、HLA-G*01:03(HLA-G*01:03:01:01)、HLA-G*01:04(HLA-G*01:04:01:01)、HLA-G*01:06、HLA-G*01:07、HLA-G*01:08、HLA-G*01:09:HLA-G*01:10、HLA-G*01:10、HLA-G*01:11、HLA-G*01:12、HLA-G*01:14、HLA-G*01:15、HLA-G*01:16、HLA-G*01:17、HLA-G*01:18:HLA-G*01:19、HLA-G*01:20以及HLA-G*01:22。其中,同种型HLA-G*0101(HLA-G*01:01:01:01)和HLA-G*01:04(HLA-G*01:04:01:01)特别需要注意,因为这些同种型为高度普遍的等位基因。举例来说,图23A至图23D中提供了适合的HLA-G重链多肽的氨基酸序列,其中图23A提供了HLA-G*01:01(野生型)的氨基酸序列;图23B提供了具有Y84C和A2346C取代的HLA-G*01:01的氨基酸序列;图23C提供了HLA-G*01:04(野生型)的氨基酸序列;并且图23D提供了具有Y84C和A2346C取代的HLA-G*01:04的氨基酸序列。
图10中提供了没有全部或基本上全部的前导、跨膜以及细胞质序列的那些HLA E、HLA-F以及HLA-G等位基因的共有序列,并且与图11中的上述HLA-A、HLA-B以及HLA-C等位基因的共有序列比对。
图10提供了HLA-E、HLA-F以及HLA-G中的每一者的共有序列,可变aa位置指示为依序编号的“X”残基的并且aa 84、139以及236的位置加双下划线。
图11提供了图7至图11中给出的HLA-A、HLA-B、HLA-C、HLA-E、HLA-F以及HLA-G的共有氨基酸序列的比对。各序列中的可变残基列为“X”,移除依序编号。还示出了指示有侧接的五氨基酸聚类的aa 84、139以及236的位置,所述侧接的五氨基酸聚类可由独立地选自以下的1至5个氨基酸置换:(i)任何天然存在的氨基酸或(ii)除脯氨酸或甘氨酸外的任何天然存在的氨基酸。
如图11中关于共有序列所示,上述HLA-E、HLA-F和/或HLA-G等位基因中的任一者可包含在位置84、139和/或236中的一者或多者处的取代。在一些情况下,取代可选自:位置84酪氨酸至丙氨酸(Y84A)或半胱氨酸(Y84C),或在HLA-F的情况下,R84A或R84C取代;位置139丙氨酸至半胱氨酸(A139C),或在HLA-F的情况下,V139C;以及位置236的丙氨酸至半胱氨酸取代(A236C)。此外,还可使用与图11中所示的全部或部分(例如50、75、100、150、200或250个连续氨基酸)的其相应共有序列具有至少75%(例如至少80%、至少85%、至少90%、至少95%、至少98%、至少99%)或100%的氨基酸序列同一性的HLA-E、HLA-F和/或HLA-G序列(例如除其中列举的可变残基处的改变外,序列还可包含1-25、1-5、5-10、10-15、15-20、20-25或25-30个氨基酸插入、缺失和/或取代)。
β-2微球蛋白
TMP的β2-微球蛋白(β2M)多肽可为人β2M多肽、非人灵长类动物β2M多肽、鼠β2M多肽等。在一些情况下,β2M多肽包含与图1A中所展示的氨基酸序列(野生型人β2M)具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列。在一些情况下,存在于TMP中的β2M多肽包含图1A中所展示的氨基酸序列(野生型人β2M)。
在一些情况下,存在于TMP中的MHC多肽相对于参考MHC多肽包含单个氨基酸取代(其中参考MHC多肽可为野生型MHC多肽),其中所述单个氨基酸取代用半胱氨酸(Cys)残基取代氨基酸。此类半胱氨酸残基可与存在于TMP的MHC重链中的天然存在的或非天然存在的半胱氨酸残基形成二硫键。如本文所用,提到MHC I类多肽中的“非天然存在的Cys残基”意味着多肽在对应野生型多肽中不存在Cys的位置包含Cys残基。这可通过其中半胱氨酸取代存在于野生型序列中的氨基酸的常规蛋白质工程化来实现。
在一些情况下,存在于TMP中的β2M多肽包含与图1B中所展示的氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列,其中氨基酸12为Cys;即,其中β2M因R12C取代包含在位置12的非天然存在的Cys。在一些情况下,存在于TMP中的β2M多肽包含图1B中所展示的氨基酸序列。
链内和链间二硫键
在一些情况下,TMP包含一个或多个链内二硫键。图13提供了此类二硫键键联的TMP的示意图描述。此外,在TMP包含Ig Fc多肽的情况下,TMP可为二聚化的,使得一个或多个链间二硫键键联两个TMP中的Ig Fc多肽,以形成均二聚体。在一些情况下,二聚化TMP包含:i)链间二硫键(例如存在于两个TMP中的Ig Fc多肽之间的一个或两个二硫键);以及ii)一个或多个链内二硫键。
在其中TMP的肽表位通过包含Cys的接头键联至β2M多肽的一些情况下,所述一个或多个链内二硫键中的至少一者使接头中的Cys键联至TMP中的MHC I类重链中的Cys。在一些情况下,TMP包含β2M多肽中的Cys和MHC I类重链中的Cys;并且TMP包含键联β2M多肽中的Cys与MHC I类重链中的Cys的链内二硫键。在一些情况下,TMP包含:a)第一链内二硫键,所述第一链内二硫键键联:i)存在于肽表位与TMP中的β2M多肽之间的接头中的Cys;与ii)存在于TMP中的MHC I类重链中的第一Cys;以及b)第二链内二硫键,所述第二链内二硫键键联:i)存在于TMP中的β2M多肽中的Cys;与ii)MHC I类重链中的第二Cys。以下更详细地论述含Cys的接头。
一般说来,TMP中二硫键的潜在位置为其中TMP中的残基相隔5埃或更小的距离的位置。此类位置代表其中Cys残基(若非天然存在)可取代存在于多肽中的残基的潜在位置。举例来说,TMP中的Cys残基潜在地可经由TMP中彼此相隔通常不超过约5埃的两个Cys残基之间的二硫键键联。在一些情况下,Cys残基中的一者或两者为非天然存在的。TMP的β2M多肽和MHC I类重链中距离彼此不超过5埃的氨基酸代表当用Cys取代时可形成TMP中的二硫键的氨基酸。类似地,接头中的Cys残基与MHC重链中天然存在的或非天然存在的Cys残基之间可形成二硫键,其中两个Cys残基彼此相隔不超过约5埃。然而,值得注意的是,并非所有相隔约5埃或更小的残基对均将适合于形成二硫键或提供稳定所得TMP或提供增强的表达的二硫键。
TMP可包含例如:i)肽表位(例如长度为4个氨基酸至约25个氨基酸的肽,当所述肽与MHC多肽复合时其由TCR结合);ii)第一MHC多肽;iii)肽与第一MHC多肽之间的肽接头,其中肽接头包含Cys残基,并且其中第一MHC多肽为包含引入Cys残基的氨基酸取代的β2M多肽;iv)第二MHC多肽,其中第二MHC多肽为包含Y84C取代和A236C取代(基于HLA-A*0201(展示于图3A中)的氨基酸编号,或在另一I类重链等位基因中的对应位置)的I类重链,其中TMP包含肽接头(肽与第一MHC多肽之间的肽接头)中的Cys残基与在MHC I类重链多肽的氨基酸位置84的Cys残基之间的第一链内二硫键,并且其中TMP包含β2M多肽中所引入的Cys残基与在MHC I类重链多肽的氨基酸位置236的Cys之间的第二链内二硫键;v)至少一个MOD;以及任选的vi)Ig Fc多肽。图13中示意性地展示了此类链内二硫键。
图3C、图4C、图5C以及图6C中所展示了包含Y84C取代和A236C取代(基于HLA-A*0201(展示中图3A)的氨基酸编号,或在另一I类重链等位基因中的对应位置)的MHC I类重链的非限制性实例。
在一些情况下,TMP包含HLA-A I类重链多肽。在一些情况下,存在于TMP(例如包含一个或多个链内二硫键的TMP)中的HLA-A重链多肽包含与图7A中所展示的HLA-A*0101、HLA-A*0201、HLA-A*0301、HLA-A*1101、HLA-A*2301、HLA-A*2402、HLA-A*2407、HLA-A*3303或HLA-A*3401氨基酸序列具有至少95%、至少98%或至少99%的氨基酸序列同一性的氨基酸序列,其中HLA-A重链多肽包含:i)Y84C取代;并且其中氨基酸236为Ala(例如如图3B、图4B、图5B以及图6B中所展示);ii)Y84C和A236C取代(例如如图3C、图4C、图5C以及图6C中所展示);或iii)Y84A取代和A236C取代(例如如图3D、图4D、图5D以及图6D中所展示)。
在一些情况下,存在于TMP中的HLA-A重链多肽包含与以下序列中的一者具有至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列:
(i)图3C中所示的HLA-A*0201(Y84C;A236C)氨基酸序列(SEQ ID NO:373),其中氨基酸84为Cys并且氨基酸236为Cys;
(ii)图4C中所示的HLA-A*1101(Y84C;A236C)氨基酸序列(SEQ ID NO:374),其中氨基酸84为Cys并且氨基酸236为Cys;
(iii)图5C中所示的HLA-A*2402(Y84C;A236C)氨基酸序列(SEQ ID NO:375),其中氨基酸84为Cys并且氨基酸236为Cys;
(iv)图6C中所示的HLA-A*3303(Y84C;A236C)氨基酸序列(SEQ ID NO:376),其中氨基酸84为Cys并且氨基酸236为Cys。
在一些情况下,存在于TMP中的HLA-A重链多肽包含与以下序列中的一者具有至少95%、至少98%或至少99%的氨基酸序列同一性的氨基酸序列:
(i)图7A中所示的HLA-A*0101氨基酸序列(SEQ ID NO:377),其中氨基酸84为Cys并且氨基酸236为Cys;
(ii)图7A中所示的HLA-A*0301氨基酸序列(SEQ ID NO:378),其中氨基酸84为Cys并且氨基酸236为Cys;
(iii)图7A中所示的HLA-A*2301氨基酸序列(SEQ ID NO:379),其中氨基酸84为Cys并且氨基酸236为Cys;
(iv)图7A中所示的HLA-A*2407氨基酸序列(SEQ ID NO:380),其中氨基酸84为Cys并且氨基酸236为Cys;
(v)图7A中所示的HLA-A*3401氨基酸序列(SEQ ID NO:381),其中氨基酸84为Cys并且氨基酸236为Cys。
在一些情况下,TMP包含HLA-E I类重链多肽。在一些情况下,存在于TMP(例如包含一个或多个链内二硫键的TMP)中的HLA-E重链多肽包含与图22A至图22D中所展示的氨基酸序列中的任一者具有至少95%、至少98%或至少99%或100%的氨基酸序列同一性的氨基酸序列。
在一些情况下,存在于TMP中的HLA-E重链多肽包含与以下序列中的一者具有至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列:
(i)图22B中所示的HLA-E*01:01(Y84C;A236C)氨基酸序列(SEQ ID NO:382),其中氨基酸84为Cys并且氨基酸236为Cys;
(ii)图22D中所示的HLA-E*01:03(Y84C;A236C)氨基酸序列(SEQ ID NO:383),其中氨基酸84为Cys并且氨基酸236为Cys;
在一些情况下,TMP包含HLA-G I类重链多肽。在一些情况下,存在于TMP(例如包含一个或多个链内二硫键的TMP)中的HLA-G重链多肽包含与图23A至图23D中所展示的氨基酸序列中的任一者具有至少95%、至少98%或至少99%或100%的氨基酸序列同一性的氨基酸序列。
在一些情况下,存在于TMP中的HLA-G重链多肽包含与以下序列中的一者具有至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列:
(i)图23B中所示的HLA-G*01:01(Y84C;A236C)氨基酸序列(SEQ ID NO:384),其中氨基酸84为Cys并且氨基酸236为Cys;
(ii)图23D中所示的HLA-G*01:04(Y84C;A236C)氨基酸序列(SEQ ID NO:385),其中氨基酸84为Cys并且氨基酸236为Cys;
HLA/肽结合分析
可使用许多熟知方法中的任一者来确定给定肽是否结合I类HLA(包含HLA重链和β2M多肽)并且当结合至HLA复合体时可有效地将表位呈递至TCR。分析包括结合分析和T细胞活化分析,包括基于细胞的结合分析、生物化学结合分析、T细胞活化分析、ELISPOT分析、细胞毒性分析以及用肽-HLA四聚体检测抗原特异性T细胞。公布的科学文献中以及公布的PCT申请WO2020132138A1中描述了此类分析,所述参考文献的公开内容关于特异性结合分析明确地以引用的方式并入本文中,特别地包括段落[00217]-[00225]。
作为另一实例,使用荧光或重金属标签产生肽-HLA复合体的多聚体(例如四聚体)。然后可使用多聚体经由流式细胞术(FACS)或大量血细胞计数(CyTOF)鉴定和定量特定T细胞。表位特异性T细胞的检测提供肽结合HLA分子能够结合至抗原特异性T细胞的子集上的特定TCR的直接证据。参见例如Klenerman等(2002)Nature Reviews Immunol.2:263。
免疫调节多肽(MOD)
在一些情况下,存在于TMP中的MOD为野生型(“wt”)MOD。如上文所论述,在其他情况下,存在于TMP中的MOD为野生型MOD的变体,与对应野生型MOD对co-MOD的亲和力相比,所述变体对co-MOD具有降低的亲和力。展现降低的对co-MOD的亲和力的适合的MOD可相对于野生型MOD具有1个氨基酸(aa)至20aa的差异。举例来说,在一些情况下,存在于TMP中的变体MOD的氨基酸序列与对应野生型MOD相差1aa、2aa、3aa、4aa、5aa、6aa、7aa、8aa、9aa或10aa。作为另一实例,在一些情况下,存在于TMP中的变体MOD的氨基酸序列与对应野生型MOD相差11aa、12aa、13aa、14aa、15aa、16aa、17aa、18aa、19aa或20aa。
如上文所论述,MOD可包含野生型MOD的变体,所述变体可展现降低的与其co-MOD的结合,包括例如降低的与co-MOD的一个或多个链或结构域的结合。举例来说,与对应野生型MOD对co-MOD的亲和力相比,存在于TMP中的变体MOD可以小至少10%、小至少15%、小至少20%、小至少25%、小至少30%、小至少35%、小至少40%、小至少45%、小至少50%、小至少55%、小至少60%、小至少65%、小至少70%、小至少75%、小至少80%、小至少85%、小至少90%、小至少95%或小超过95%的亲和力结合其co-MOD。
MOD与其co-MOD的示例性配对包括但不限于下表1中所示的那些MOD对和其co-MOD:
表1
如图12中示意性地展示,一个或多个MOD可存在于TMP中的多个位置中的任一者处。图12展示了变体IL-2多肽的两个拷贝的位置;然而,如本文所描述,MOD可为任何数目的MOD以及多个MOD中的任一者。如图12中所展示,MOD可为:1)MHC I类重链的C端以及Ig Fc多肽的N端;换句话说,在MHC I类重链多肽与Ig Fc多肽之间,在图12中它被称为“位置2”;2)Ig Fc多肽的C端,在图12中它被称为“位置3”;或3)肽表位的N端,在图12中它被称为“位置4”。
公布的文献中描述了野生型免疫调节多肽和变体(包括亲和力降低的变体)(诸如PD-L1、CD80、CD86、4-1BBL以及IL-2),例如公布的PCT申请WO2020132138A1和WO2019/051091,所述专利的公开内容关于PD-L1、CD80、CD86、4-1BBL、IL-2的MOD和特定变体MOD明确地以引用的方式并入本文中,特别地包括WO2020132138A1的段落[00260]-[00455]和WO2019/051091的段落[00157]-[00352]。
特别受关注的是为细胞因子IL-2的变体的MOD。野生型IL-2结合至T细胞表面的IL-2受体(IL-2R)。野生型IL-2对IL-2R具有强亲和力并且将结合以活化大多数或基本上所有CD8+T细胞。由于此原因,已知合成形式的野生型IL-2(诸如药物阿地白介素(Aldesleukin))(商标名
在一些情况下,IL-2受体为包含α链(IL-2Rα;也称为CD25)、β链(IL-2Rβ;也称为CD122)以及γ链(IL-2Rγ;也称为CD132)的异三聚多肽。人IL-2、人IL-2Rα、IL2Rβ以及IL-2Rγ的氨基酸序列为已知的。参见例如上文所论述的公布的PCT申请WO2020132138A1和WO2019/051091。举例来说,野生型IL-2多肽可具有图17A中所展示的氨基酸序列。图17B、图17C以及图17D中分别展示了人IL-2Rα、人IL-2Rβ以及人IL-2Rγ的氨基酸序列。
在一些情况下,本公开的IL-2变体MOD展现降低的与IL-2Rα的结合,从而使IL-2变体对Treg的活化最小化或基本上降低。或者或另外,在一些情况下,本公开的IL-2变体MOD展现降低的与IL-2Rβ和/或IL-2Rγ的结合,使得IL-2变体MOD对IL-2R展现总体降低的亲和力。在一些情况下,本公开的IL-2变体MOD展现两种特性,即,它展现降低的或基本上没有与IL-2Rα的结合,并且还展现降低的与IL-2Rβ和/或IL-2Rγ的结合,使得IL-2变体多肽对IL-2R展现总体降低的亲和力。举例来说,在H16和F42处具有取代的IL-2变体显示降低的与IL-2Rα和IL-2Rβ的结合。参见Quayle等,Clin Cancer Res;26(8)2020年4月15日,所述参考文献公开了与野生型IL2结合相比,具有H16A和F42A取代的IL-2多肽对人IL-2Rα和IL-2Rβ的结合亲和力分别降低了110倍和3倍,这主要归因于这些相互作用中的每一者的解离速率更快。包含此类变体(包括展现降低的与IL-2Rα和IL-2Rβ的结合的变体)的TMP显示优先结合至含有对TMP上的肽表位具特异性的标靶TCR的T细胞上的IL-2受体并且将其活化的能力,并且因此不太可能将IL-2递送至非标靶T细胞,即,不含特异性结合TMP上的肽表位的TCR的T细胞。换句话说,IL-2变体MOD与T细胞上其共刺激多肽的结合基本上由MHC-表位部分的结合而非由IL-2的结合驱动。
因此,适合的IL-2变体MOD包括包含一种氨基酸序列的多肽,所述氨基酸序列与图17A中所展示的野生型IL-2氨基酸序列具有至少90%、至少95%、至少98%或至少99%的氨基酸序列同一性;并且相较于图17A中所展示的野生型IL-2氨基酸序列具有一个或多个氨基酸差异。在一些情况下,与包含图17A中所展示的野生型IL-2氨基酸序列的IL-2多肽的结合亲和力相比,本公开的此类变体IL-2多肽展现降低的与IL-2R的结合亲和力。举例来说,在一些情况下,与包含图17A中所展示的野生型IL-2氨基酸序列的IL-2多肽对IL-2R(例如包含包括图17B至图17D中所展示的氨基酸序列的多肽的IL-2R)的结合亲和力相比,当在相同条件下分析时,变体IL-2多肽以小至少10%、小至少15%、小至少20%、小至少25%、小至少30%、小至少35%、小至少40%、小至少45%、小至少50%、小至少55%、小至少60%、小至少65%、小至少70%、小至少75%、小至少80%、小至少85%、小至少90%、小至少95%或小超过95%的结合亲和力结合IL-2R。
在一些情况下,适合的变体IL-2多肽包含与以下氨基酸序列具有至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列:APTSSSTKKTQLQLEALLLD LQMILNGINN YKNPKLTRML TAKFYMPKKA TELKHLQCLEEELKPLEEVL NLAQSKNFHLRPRDLISNIN VIVLELKGSE TTFMCEYADE TATIVEFLNRWITFCQSIIS TLT(SEQ ID NO:386),即,变体IL-2多肽具有野生型IL-2的氨基酸序列但具有H16A和F42A取代(以粗体显示)。或者,可使用前述序列,但在H16和/或F42处具有除Ala外的取代,例如可使用H16T替代H16A。在一些情况下,存在于TMP中的变体IL-2多肽包含以下氨基酸序列:APTSSSTKKT QLQLEALLLDLQMILNGINN YKNPKLTRML TAKFYMPKKATELKHLQCLEEELKPLEEVL NLAQSKNFHLRPRDLISNINVIVLELKGSE TTFMCEYADE TATIVEFLNRWITFCQSIIS TLT(SEQ ID NO:387)。在一些情况下,存在于TMP中的变体IL-2多肽包含以下氨基酸序列:APTSSSTKKT QLQLETLLLDLQMILNGINN YKNPKLTRML TAKFYMPKKA TELKHLQCLEEELKPLEEVL NLAQSKNFHL RPRDLISNINVIVLELKGSE TTFMCEYADE TATIVEFLNRWITFCQSIIS TLT(SEQ ID NO:388)。在一些情况下,TMP包含此类变体IL-2多肽的两个拷贝。
在一些情况下,存在于TMP中的MOD为PD-L1多肽。在一些情况下,TMP的PD-L1多肽包含与以下PD-L1胞外域氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列:FT VTVPKDLYVVEYGSNMTIEC KFPVEKQLDL AALIVYWEMEDKNIIQFVHG EEDLKVQHSS YRQRARLLKDQLSLGNAALQITDVKLQDAG VYRCMISYGG ADYKRITVKV NAPYNKINQRILVVDPVTSE HELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKL FNVTSTLRIN TTTNEIFYCT FRRLDPEENHTAELVIPGNILNVSIKI(SEQ ID NO:389)。
在一些情况下,存在于TMP中的MOD为4-1BBL多肽。在一些情况下,TMP的4-1BBL多肽包含与以下4-1BBL氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列:DPAGLLDLRQG MFAQLVAQNVLLIDGPLSWY SDPGLAGVSLTGGLSYKEDT KELVVAKAGV YYVFFQLELR RVVAGEGSGSVSLALHLQPLRSAAGAAALA LTVDLPPASS EARNSAFGFQGRLLHLSAGQ RLGVHLHTEA RARHAWQLTQGATVLGLFRVTPEIPA(SEQ ID NO:390)。
在一些情况下,存在于TMP中的MOD为ICOS-L多肽。在一些情况下,TMP的ICOS-L多肽包含与以下ICOS-L氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列:QEKEVRAMVG SDVELSCACPEGSRFDLNDV YVYWQTSESKTVVTYHIPQN SSLENVDSRY RNRALMSPAG MLRGDFSLRLFNVTPQDEQKFHCLVLSQSL GFQEVLSVEV TLHVAANFSVPVVSAPHSPS QDELTFTCTS INGYPRPNVYWINKTDNSLLDQALQNDTVF LNMRGLYDVV SVLRIARTPS VNIGCCIENVLLQQNLTVGS QTGNDIGERDKITENPVSTG EKNAATWSIL(SEQ ID NO:391)。
在一些情况下,多聚体多肽的T细胞调节多肽为OX40L多肽。在一些情况下,TMP的OX40L多肽包含与以下OX40L氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列:LQVSHRYPRIQSIKVQFTEYK KEKGFILTSQ KEDEIMKVQNNSVIINCDGF YLISLKGYFS QEVNISLHYQKDEEPLFQLKKVRSVNSLMV ASLTYKDKVY LNVTTDNTSL DDFHVNGGELILIHQNPGEF CVL(SEQ IDNO:392)。
在一些情况下,多聚体多肽的T细胞调节多肽为PD-L2多肽。在一些情况下,多聚体多肽的PD-L2多肽包含与PD-L2氨基酸序列的氨基酸20-273具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列:L FTVTVPKELY IIEHGSNVTL ECNFDTGSHV NLGAIT ASLQ KVENDTSPHR ERATLLEEQLPLGKASFHIP QVQVRDEGQY QCIIIYGVAW DYKYLTLKVK ASYRKINTHI LKVPETDEVELTCQATGYPLAEVSWPNVSV PANTSHSRTP EGLYQVTSVL RLKPPPGRNF SCVFWNTHVR ELTLASIDLQ SQMEPRTHPT(SEQ ID NO:393)。
在一些情况下,存在于TMP中的MOD为CD80多肽。在一些情况下,TMP的CD80多肽包含与以下CD80氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列:VIHVTK EVKEVATLSCGHNVSVEELA QTRIYWQKEK KMVLTMMSGDMNIWPEYKNR TIFDITNNLS IVILALRPSDEGTYECVVLKYEKDAFKREH LAEVTLSVKA DFPTPSISDF EIPTSNIRRIICSTSGGFPE PHLSWLENGEELNAINTTVS QDPETELYAVSSKLDFNMTT NHSFMCLIKY GHLRVNQTFN WNTTKQEHFP DN(SEQ IDNO:394)。
在一些情况下,存在于TMP中的MOD为CD86多肽。在一些情况下,TMP的CD86多肽包含与以下CD86氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列:APLKIQAYFNETADLPCQFANSQNQSLSELVVFWQDQENLVLNEVYLGKEKFDSVHSKYMNRTSFDSDSWTLRLHNLQIKDKGLYQCIIHHKKPTGMIRIHQMNSELSVLANFSQPEIVPISNITENVYINLTCSSIHGYPEPKKMSVLLRTKNSTIEYDGIMQKSQDNVTELYDVSISLSVSFPDVTSNMTIFCILETDKTRLLSSPFSIELEDPQPPPDHIP(SEQ ID NO:395)。
在一些情况下,存在于TMP中的MOD为FasL多肽,例如FasL多肽的细胞外结构域。在一些情况下,TMP的FasL多肽包含与以下FasL细胞外结构域氨基酸序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列:QLFHLQKE LAELRESTSQ MHTASSLEKQ IGHPSPPPEK KELRKVAHLT GKSNSRSMPLEWEDTYGIVLLSGVKYKKGG LVINETGLYF VYSKVYFRGQ SCNNLPLSHKVYMRNSKYPQ DLVMMEGKMMSYCTTGQMWA RSSYLGAVFNLTSADHLYVN VSELSLVNFE ESQTFFGLYK L(SEQ ID NO:396)。
支架多肽
TMP可包含Fc多肽或可包含另一适合的支架多肽。
适合的支架多肽包括基于抗体的支架多肽和不基于抗体的支架。不基于抗体的支架包括例如白蛋白、XTEN(延长重组)多肽、转铁蛋白、Fc受体多肽、弹性蛋白样多肽(参见例如Hassouneh等(2012)Methods Enzymol.502:215;例如包含(Val-Pro-Gly-X-Gly;SEQ IDNO:446)的五肽重复单元的多肽,其中X为除脯氨酸外的任何氨基酸)、白蛋白结合多肽、丝样多肽(参见例如Valluzzi等(2002)Philos Trans R Soc Lond B Biol Sci.357:165)、丝-弹性蛋白样多肽(SELP;参见例如Megeed等(2002)Adv Drug Deliv Rev.54:1075)等。适合的XTEN多肽包括例如WO 2009/023270、WO 2010/091122、WO 2007/103515、US2010/0189682以及US2009/0092582中公开的那些XTEN多肽;还参见Schellenberger等(2009)NatBiotechnol.27:1186)。适合的白蛋白多肽包括例如人血清白蛋白。
在一些情况下,适合的支架多肽将为半衰期延长的多肽。因此,在一些情况下,与缺乏支架多肽的对照TMP相比,适合的支架多肽使TMP的体内半衰期(例如血清半衰期)增加。举例来说,在一些情况下,与缺乏支架多肽的对照TMP相比,支架多肽使TMP的体内半衰期(例如血清半衰期)增加至少约10%、至少约15%、至少约20%、至少约25%、至少约50%、至少约2倍、至少约2.5倍、至少约5倍、至少约10倍、至少约25倍、至少约50倍、至少约100倍或超过100倍。作为实例,在一些情况下,与缺乏Fc多肽的对照TMP相比,Fc多肽使TMP的体内半衰期(例如血清半衰期)增加至少约10%、至少约15%、至少约20%、至少约25%、至少约50%、至少约2倍、至少约2.5倍、至少约5倍、至少约10倍、至少约25倍、至少约50倍、至少约100倍或超过100倍。
Fc多肽
在一些情况下,TMP包含Ig Fc多肽。Ig Fc多肽在本文中也称为“Fc多肽”。TMP的IgFc多肽可为人IgG1 Fc、人IgG2 Fc、人IgG3Fc、人IgG4 Fc等或野生型Ig Fc多肽的变体。变体包括天然存在的变体、非天然存在的变体以及它们的组合。
在一些情况下,存在于TMP中的Fc多肽包含与图2A至图2M中任一者所展示的Fc氨基酸序列具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或100%的氨基酸序列同一性的氨基酸序列。
在一些情况下,存在于TMP中的Fc多肽为IgG1 Fc多肽,或IgG1Fc多肽的变体。举例来说,在一些情况下,存在于TMP中的Fc多肽包含与图2A中所展示的人IgG1 Fc多肽具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或100%的氨基酸序列同一性的氨基酸序列。作为另一实例,在一些情况下,存在于TMP中的Fc多肽包含与图2B中所展示的Fc多肽具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或100%的氨基酸序列同一性的氨基酸序列;其中Ig Fc多肽包含在位置14的Ala以及在位置15的Ala。在以上实施方案中的任一者中,Ig Fc多肽可具有N77取代;即,Ig Fc多肽可在位置77具有除Asn外的氨基酸,其中在一些情况下,Ig Fc多肽具有在位置77的Ala。在一些情况下,存在于TMP中的Fc多肽包含图2A中所展示的氨基酸序列。在一些情况下,存在于TMP中的Fc多肽包含图2B中所展示的氨基酸序列。
在一些情况下,存在于TMP中的Fc多肽为IgG1 Fc多肽,或IgG1Fc多肽的变体,其中变体包括天然存在的变体、非天然存在的变体以及它们的组合。举例来说,在一些情况下,存在于TMP中的Fc多肽包含与图2C中所展示的人IgG1 Fc多肽具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或100%的氨基酸序列同一性的氨基酸序列;其中Ig Fc多肽包含在位置136的Glu以及在位置138的Met。作为另一实例,在一些情况下,存在于TMP中的Fc多肽包含与图2D中所展示的人IgG1Fc多肽具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或100%的氨基酸序列同一性的氨基酸序列;其中Ig Fc多肽具有在位置14和15的Ala;并且其中Fc多肽包含在位置136的Glu以及在位置138的Met。在以上实施方案中的任一者中,Ig Fc多肽可具有N77取代;即,Ig Fc多肽可在位置77具有除Asn外的氨基酸,其中在一些情况下,Ig Fc多肽具有在位置77的Ala。在一些情况下,存在于TMP中的Fc多肽包含图2C中所展示的氨基酸序列。在一些情况下,存在于TMP中的Fc多肽包含图2D中所展示的氨基酸序列。
在一些情况下,存在于TMP中的Fc多肽包含图2E中所展示的氨基酸序列(包含L234F取代、L235E取代以及P331S取代的人IgG1Fc;其中L234对应于图3I中所展示的氨基酸序列的氨基酸14;L235对应于图2E中所展示的氨基酸序列的氨基酸15;并且P331对应于图2E中所展示的氨基酸序列的氨基酸111)。在一些情况下,存在于TMP中的Fc多肽包含图2F中所展示的氨基酸序列,所述氨基酸序列包含N279A取代(图2F中所展示的氨基酸序列的N77A)。
在一些情况下,Fc多肽包含与图2G中所展示的人IgG2 Fc多肽具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或100%的氨基酸序列同一性的氨基酸序列;例如Fc多肽包含与图2G中所展示的人IgG2 Fc多肽的氨基酸99-325(例如其中Ig Fc多肽具有约227个氨基酸的长度)具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或100%的氨基酸序列同一性的氨基酸序列。在一些情况下,Fc多肽包含与图2H中所展示的人IgG3 Fc多肽具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或100%的氨基酸序列同一性的氨基酸序列;例如Fc多肽包含与图2H中所展示的人IgG3 Fc多肽的氨基酸19-246(例如其中Ig Fc多肽具有约228个氨基酸的长度)具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或100%的氨基酸序列同一性的氨基酸序列。在一些情况下,Fc多肽包含与图2J中所展示的人IgM Fc多肽具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或100%的氨基酸序列同一性的氨基酸序列;例如Fc多肽包含与图2J中所展示的人IgM Fc多肽的氨基酸1-276具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或100%的氨基酸序列同一性的氨基酸序列。在一些情况下,Fc多肽包含与图2K中所展示的人IgA Fc多肽具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或100%的氨基酸序列同一性的氨基酸序列;例如Fc多肽包含与图2K中所展示的人IgA Fc多肽的氨基酸1-234具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或100%的氨基酸序列同一性的氨基酸序列。
在一些情况下,Fc多肽包含与图2M中所展示的人IgG4 Fc多肽具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或100%的氨基酸序列同一性的氨基酸序列。在一些情况下,Fc多肽包含与图2M中所展示的人IgG4 Fc多肽的氨基酸100至327(例如其中Ig Fc多肽具有约228个氨基酸的长度)具有至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%、至少约99%或100%的氨基酸序列同一性的氨基酸序列。
在一些情况下,IgG4 Fc多肽包含以下氨基酸序列:PPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:397)。
在一些情况下,TMP中所用的Ig Fc将包含野生型序列中的氨基酸的一个或多个取代,使得所述Ig Fc基本上不诱导细胞溶解。举例来说,在一些情况下,存在于TMP中的Fc多肽包含图2A(人IgG1 Fc)中所展示的氨基酸序列,除了L234(图2A中所展示的氨基酸序列的L14)用除亮氨酸外的氨基酸取代,或L235(图2A中所展示的氨基酸序列的L15)用除亮氨酸外的氨基酸取代。实例包括L234A(L14A)取代;以及L235A(L15A)取代。
接头
TMP可包括一个或多个肽接头,即包含一段连续的两个或更多个氨基酸的接头,其中一个或多个接头位于以下中的一者或多者之间:i)MHC I类重链多肽与Ig Fc多肽,其中此类接头在本文中称为“L1”;ii)MOD与MHC I类多肽,其中此类接头在本文中称为“L2”;iii)第一MOD与第二MOD,其中此类接头在本文中称为“L3”;iv)肽与MHC I类多肽;以及v)肽表位与β2M多肽。
如本文所用,短语“TMP的任何两个组分之间的任选肽接头”是指TMP内任何两个邻近多肽之间的肽接头。举例来说,如本文所用,短语“TMP的任何两个组分之间的任选肽接头”是指以下中的一者或多者之间的肽接头:i)肽表位与β2M多肽;ii)β2M多肽与MHC I类重链多肽;iii)MHC I类重链多肽与Ig Fc多肽;iv)MHC I类重链多肽与MOD;v)Ig Fc多肽与MOD;以及vi)第一MOD与第二MOD。如下文所论述,接头可为可挠性肽接头,包括短可挠性肽接头;或刚性肽接头。
适合的接头(也称为“间隔子”)可容易地选择并且可为许多适合的长度中的任一者,诸如1个氨基酸至25个氨基酸、3个氨基酸至20个氨基酸、2个氨基酸至15个氨基酸、3个氨基酸至12个氨基酸,包括4个氨基酸至10个氨基酸、5个氨基酸至9个氨基酸、6个氨基酸至8个氨基酸或7个氨基酸至8个氨基酸。适合的接头的长度可为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25个氨基酸。在一些情况下,接头具有25个氨基酸至50个氨基酸的长度,例如长度为25至30、30至35、35至40、40至45或45至50个氨基酸。
可挠性肽接头
示例性可挠性肽接头包括甘氨酸聚合物(G)
示例性可挠性肽接头包括例如(GGGGS)n(SEQ ID NO:572);也称为“G4S”接头),其中n为1、2、3、4、5、6、7、8、9或10。在一些情况下,接头包含氨基酸序列(GGGGS)n(SEQ ID NO:572),其中n为1、2、3、4、5、6、7、8、9或10。在一些情况下,接头包含氨基酸序列(GGGGS)n(SEQID NO:407),其中n为2。在一些情况下,接头包含氨基酸序列(GGGGS)n(SEQ ID NO:408),其中n为3。在一些情况下,接头包含氨基酸序列(GGGGS)n(SEQ ID NO:409),其中n为4。在一些情况下,接头包含氨基酸序列(GGGGS)n(SEQ ID NO:410),其中n为7。在一些情况下,接头包含氨基酸序列AAAGG(SEQ ID NO:411)。具有氨基酸序列AAAGG(SEQ ID NO:411)的接头也适合。在本公开的TMP中,β2M多肽可通过(GGGGS)n(SEQ ID NO:572)接头连接至MHC重链多肽,其中n为1、2、3、4、5、6、7、8、9或10,例如其中n=3,n=4,或n=7。
如本公开中所用,“短可挠性肽接头”意指包含少于15个氨基酸(即2-14个氨基酸)的可挠性肽接头。举例来说,短可挠性肽接头可包含2-4、2-5或3-6个氨基酸(例如GGS接头),或4-8、5-10或10-14个氨基酸。此范围内包括包含2、3、4、5、6、7、8、9、10、11、12、13或14个氨基酸的可挠性肽接头。
刚性肽接头
在一些情况下,肽接头为刚性肽接头。如本文所用,术语“刚性肽接头”是指包含一段连续的两个或更多个氨基酸的接头,所述接头通过维持结构域之间基本上固定的距离/空间隔离有效地将蛋白质结构域隔开,从而降低或基本上消除此类结构域之间不利的相互作用。刚性肽接头为本领域中已知的并且当在溶液中时通常采用相对明确界定的构象。刚性肽接头包括在溶液中具有特定二级和/或三级结构的那些接头;并且通常具有足以赋予接头二级或三级结构的长度。刚性肽接头包括富含脯氨酸的肽接头,以及具有非可挠性螺旋结构(诸如α-螺旋结构)的肽接头。例如Chen等(2013)Adv.Drug Deliv.Rev.65:1357;以及Klein等(2014)Protein Engineering,Design&Selection27:325中描述了刚性肽接头。
刚性肽接头的实例包括例如(EAAAK)n(SEQ ID NO:573)、A(EAAAK)n(SEQ ID NO:574))、A(EAAAK)nA(SEQ ID NO:575)、A(EAAAK)nALEA(EAAAK)nA(SEQ ID NO:576)、(Lys-Pro)n(SEQ ID NO:577)、(Glu-Pro)n(SEQ ID NO:578)、(Thr-Pro-Arg)n(SEQ ID NO:579)以及(Ala-Pro)n(SEQ ID NO:580),其中n为1至20的整数(例如n为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20)。包含EAAAK(SEQ ID NO:412)的适合的刚性肽接头的非限制性实例包括EAAAK(SEQ ID NO:412)、(EAAAK)
一般说来,在TMP包含刚性肽接头和/或短可挠性肽接头的情况下,TMP可包括TMP的任何两个组分之间的刚性肽接头和/或短可挠性肽接头,但通常,将如下使用一个或多个刚性肽接头和/或短可挠性肽接头。
(i)在包含一个或多个位置2MOD的TMP中-在以下中的一者或多者之间:i)MHC I类重链多肽与MOD;ii)MOD与Ig Fc多肽;以及iii)在存在多个串联的MOD的情况下,在第一MOD与第二MOD之间。
(ii)在包含一个或多个位置3MOD的TMP中-在以下中的一者或多者之间:i)Ig Fc多肽与MOD;以及ii)在存在多个串联的MOD的情况下,在第一MOD与第二MOD之间。
(iii)在包含一个或多个位置4MOD的TMP中-在以下中的一者或多者之间:i)表位与MOD;ii)MHC I类重链多肽与Ig Fc多肽;以及iii)在存在多个串联的MOD的情况下,在第一MOD与第二MOD之间。
因此,本公开因此提供了增加在位置2、位置3或位置4包含一个或多个MOD的TMP的热稳定性的方法。
已发现与TMP相同但对于更长的可挠性肽接头(诸如(G4S)3(即,(GGGGS)3)接头(SEQ ID NO:408))相比,在具有一个或多个位置3MOD的TMP中,使用在Ig Fc多肽与MOD之间的刚性肽接头或短可挠性肽接头而不是可挠性肽接头可增强所得TMP的热稳定性。虽然不希望受特定理论约束,据信刚性肽接头或短可挠性肽接头降低或预防TMP内MOD与可与包含15个或更多个氨基酸的可挠性肽接头一起存在的其他多肽的相互作用,从而如下文所描述使用加速稳定性分析所测量产生增强的热稳定性。
在一些情况下,当在具有一个或多个位置3MOD的TMP的Ig Fc多肽与MOD之间插入时,如通过下文所描述的37℃加速热稳定性分析所测量,与包括为(GGGGS)3接头(SEQ IDNO:408)的可挠性肽接头而不是刚性肽接头或短可挠性肽接头的对照TMP的热稳定性相比,使用刚性肽接头或短可挠性肽接头使热稳定性增加至少约10%、至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%、至少约两倍、至少约三倍、至少约四倍、至少约五倍、至少约六倍、至少约七倍、至少约八倍或至少约10倍。
在一些情况下,当在具有一个或多个位置3MOD的TMP的Ig Fc多肽与MOD之间插入时,如通过下文所描述的42℃加速热稳定性分析所测量,与包括为(GGGGS)3接头(SEQ IDNO:408)的可挠性肽接头而不是刚性肽接头或短可挠性肽接头的对照TMP的热稳定性相比,使用刚性肽接头或短可挠性肽接头使热稳定性增加至少约10%、至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%、至少约两倍、至少约三倍、至少约四倍、至少约五倍、至少约六倍、至少约七倍、至少约八倍或至少约10倍。
可如下进行加速热稳定性分析。可使用在4℃、37℃以及42℃下进行的加速稳定性分析来评估二聚化TMP的热稳定性。使二聚化TMP的组合物在每毫升溶液10mg二聚化TMP的浓度下在溶液(含有500mM NaCl的磷酸盐缓冲盐水(PBS),pH 7.4)中在指示温度下保持14天的时间。在1天、7天以及14天之后,使用尺寸排阻色谱法确定溶液中剩余单体的百分比。PBS溶液如下:10.14mM磷酸氢二钠、1.76mM磷酸二氢钾、2.7mM KCl以及0.5M NaCl;pH 7.4。
含半胱氨酸的接头
如上文所提到,在一些情况下,接头肽包括半胱氨酸残基,所述半胱氨酸残基可与存在于TMP多肽链中别处的半胱氨酸残基形成链内二硫键。举例来说,如上文所论述,在一些情况下,TMP或二聚化TMP(诸如均二聚体)包含肽表位与β2M多肽之间的接头,所述接头包括半胱氨酸残基,所述半胱氨酸残基与存在于TMP中的MHC I类重链多肽中的半胱氨酸残基形成链内二硫键。举例来说,在一些情况下,其中TMP或二聚化TMP(诸如均二聚体)包含肽表位与β2M多肽之间的含有半胱氨酸的接头,接头中的半胱氨酸残基与存在于TMP中的MHC I类重链多肽中的氨基酸236(例如通过A236C取代形成)处的半胱氨酸残基形成链内二硫键。
在一些情况下,肽与β2M多肽之间的肽接头包含氨基酸序列GCGGS(SEQ ID NO:435)。在一些情况下,肽与β2M多肽之间的肽接头包含氨基酸序列GCGGS(GGGGS)n(SEQ IDNO:436),其中n为1、2、3、4、5、6、7、8、9或10;例如1、2或3。在一些情况下,肽与β2M多肽之间的肽接头包含氨基酸序列GCGGS(GGGGS)n(SEQ ID NO:437),其中n为2。
在一些情况下,肽与β2M多肽之间的肽接头包含氨基酸序列CGGGS(SEQ ID NO:438)。在一些情况下,肽接头包含氨基酸序列CGGGS(GGGGS)n(SEQ ID NO:439),其中n为1、2、3、4、5、6、7、8、9或10;例如1、2或3。
在一些情况下,肽与β2M多肽之间的肽接头包含氨基酸序列GGCGS(SEQ ID NO:440)。在一些情况下,肽接头包含氨基酸序列GGCGS(GGGGS)n(SEQ ID NO:441),其中n为1、2、3、4、5、6、7、8、9或10,例如1、2或3。
在一些情况下,肽与β2M多肽之间的肽接头包含氨基酸序列GGGCS(SEQ ID NO:442)。在一些情况下,肽接头包含氨基酸序列GGGCS(GGGGS)n(SEQ ID NO:443),其中n为1、2、3、4、5、6、7、8、9或10,例如1、2或3。
在一些情况下,肽与β2M多肽之间的肽接头包含氨基酸序列GGGGC(SEQ ID NO:444)。在一些情况下,肽接头包含氨基酸序列GGGGC(GGGGS)n(SEQ ID NO:445),其中n为1、2、3、4、5、6、7、8、9或10,例如1、2或3。
二聚化TMP
在一些情况下,TMP可形成二聚体。换句话说,本公开提供了一种包含两个TMP的二聚体的多肽。因此,本公开提供了一种蛋白质,所述蛋白质为包含彼此共价键联的两个TMP的二聚化TMP。二聚体的共价键联可为第一TMP中的Ig Fc多肽与第二TMP中的Ig Fc多肽之间的一个或多个二硫键。仅作为一个实例,Ig Fc可为人IgG1 Fc多肽的变体,所述变体具有基本上降低的实现补体依赖性细胞毒性(CDC)或抗体依赖性细胞细胞毒性(ADCC)的能力(例如图2B或图2D的Ig Fc多肽)。当TMP包含Ig Fc多肽时,TMP通常将通过与另一TMP的IgFc多肽自发形成二硫键自组装成二聚体。因此,例如第一TMP中的Ig Fc多肽与第二TMP可通过一个或多个二硫键彼此键联。在许多情况下,两个TMP的氨基酸序列将彼此相同并且包含自发形成一个或多个二硫键的Ig Fc多肽,从而形成为均二聚体的二聚化TMP。
因此,本公开提供了一种蛋白质,所述蛋白质包含:a)第一TMP;以及b)第二TMP,所述第二TMP任选可与第一TMP相同,其中第一和第二TMP彼此共价键联。共价键联可为第一TMP中的Ig Fc多肽与第二TMP中的Ig Fc多肽之间的二硫键。
如果需要,那么各TMP的Ig Fc多肽可包含种间二聚化序列,例如容许两个不同TMP选择性地二聚化的“杵臼”序列。种间结合序列有利于与其同源多肽序列(即,种间序列和其对应种间序列),特别是基于Ig Fc序列变体的那些形成异二聚体。此类种间多肽序列包括杵臼,以及有助于形成一个或多个二硫键的杵臼序列。举例来说,一个种间结合对包含IgG1的CH3结构域界面中的T366Y和Y407T突变体对,或其他免疫球蛋白的对应残基。参见Ridgway等,Protein Engineering 9:7,617-621(1996)。第二种间结合对涉及通过T366W取代形成杵,以及在互补Ig Fc序列上通过三重取代T366S、L368A以及Y407V形成臼。参见Xu等mAbs 7:1,231-242(2015)。另一种间结合对具有含有Y349C、T366S、L368A以及Y407V取代的第一Fc多肽以及含有S354C和T366W取代的第二Ig Fc多肽(Y349C与S354C之间可形成二硫键)。参见例如Brinkmann和Konthermann,mAbs 9:2,182–212(2015)。在存在或不存在杵臼修饰的情况下,可通过在Ig Fc多肽之间形成二硫键(例如铰链区二硫键)来稳定Ig Fc多肽序列。因此,在一些情况下,二聚化TMP可为异二聚体,包含氨基酸序列不相同的两个TMP链。
还可使用种间二聚化序列来使TMP能够键联至可为TMP提供其他官能团的非TMP分子。举例来说,TMP可键联至包含结合至癌症相关抗原的多肽的分子(例如抗体或其结合片段,诸如scFv),从而使TMP能够局部化至包含癌症相关抗原的组织。
其他多肽
除上文所描述的那些外,TMP的多肽链还可包括一个或多个多肽以及缀合药物。上文所论述的公布的PCT申请WO2020132138A1和WO2019/051091中描述了适合的其他多肽(包括表位标签和亲和力结构域)以及药物缀合物,所述专利的公开内容关于表位标签、亲和力结构域以及药物缀合物明确地以引用的方式并入本文中,特别地包括WO2020132138A1的段落[00498]-[00508]和WO2019/051091的段落[00353]-[00363]。一个或多个其他多肽可包括在TMP多肽链的N端、TMP多肽链的C端或TMP的多肽链的内部。如上文所论述,还可通过使用种间序列使其他多肽缀合至TMP。
示例性TMP和二聚化TMP
在以下论述中,示例性TMP的论述旨在涵盖TMP与包含两个TMP的二聚化TMP两者,其中TMP通过连接两个TMP的一个或多个共价键(例如在两个TMP中的Ig Fc多肽之间自发形成的一个或多个二硫键)连接。此类二聚化TMP可为i)包含两个TMP的均二聚体,其中两个TMP具有相同氨基酸序列,或ii)包含两个TMP的异二聚体,其中两个TMP的氨基酸序列彼此不同。
在一些情况下,TMP包含以下组分:i)肽表位;ii)第一MHC I类多肽,其中第一MHCI类多肽为β2M多肽;iii)第二MHC I类多肽,其中第二MHC I类多肽为MHC I类重链多肽;iv)至少一个MOD;以及v)Ig Fc多肽。TMP可包含组分中的一者或多者之间的一个或多个肽接头。
在TMP包含一个或多个位置2MOD的情况下,可在以下之间插入一个或多个肽接头:i)肽与β2M多肽;ii)β2M多肽与MHC I类重链多肽;iii)MHC I类重链多肽与MOD;iv)MOD与IgFc多肽与MOD;以及vi)在TMP包含两个或更多个串联的MOD的情况下,在MOD之间。如上文所论述,在此类TMP中,可在以下中的一者或多者之间插入刚性肽接头或短可挠性肽接头:i)MHC I类重链多肽与MOD;ii)MOD与Ig Fc多肽;以及iii)在存在多个串联的MOD的情况下,在第一MOD与第二MOD(对于其他串联的MOD诸如此类)之间。在一些情况下,刚性肽接头包含选自以下的氨基酸序列:EAAAK(SEQ ID NO:412)、A(EAAAK)n(SEQ ID NO:582)、A(EAAAK)nA(SEQ ID NO:583)、(AP)n(SEQ ID NO:584)、(EP)n(SEQ ID NO:585)以及(KP)n(SEQ ID NO:586),其中n为1至10的整数(例如n为1、2、3、4、5、6、7、8、9或10)。在一些情况下,短可挠性肽接头将包含2-4、2-5、3-6、4-8、5-10或10-14个氨基酸。在一些情况下,短可挠性肽接头为GGS。一般说来,将在不通过刚性肽接头或短可挠性肽接头连接的组分之间插入可挠性肽接头,其中肽与β2M多肽之间的接头还可包含如上文所论述的含Cys的接头。
在TMP包含一个或多个位置3MOD的情况下,可在以下之间插入一个或多个肽接头:i)肽与β2M多肽;ii)β2M多肽与MHC I类重链多肽;iii)MHC I类重链多肽与Ig Fc多肽;iv)Ig Fc多肽与MOD;以及v)在TMP包含两个或更多个串联的MOD的情况下,在MOD之间。如上文所论述,在此类TMP中,可在以下中的一者或多者之间插入刚性肽接头或短可挠性肽接头:i)Ig Fc多肽与MOD;以及ii)在存在多个串联的MOD的情况下,在MOD中的一者或多者之间,例如当存在两个串联的MOD时在第一MOD与第二MOD之间。在一些情况下,刚性肽接头包含选自以下的氨基酸序列:EAAAK(SEQ ID NO:412)、A(EAAAK)n(SEQ ID NO:582)、A(EAAAK)nA(SEQ ID NO:583)、(AP)n(SEQ ID NO:584)、(EP)n(SEQ ID NO:585)以及(KP)n(SEQ ID NO:586),其中n为1至10的整数(例如n为1、2、3、4、5、6、7、8、9或10)。在一些情况下,短可挠性肽接头将包含2-4、2-5、3-6、4-8、5-10或10-14个氨基酸。在一些情况下,短可挠性肽接头为GGS。一般说来,将在不通过刚性肽接头或短可挠性肽接头连接的组分之间插入可挠性肽接头,其中肽与β2M多肽之间的接头还可包含如上文所论述的含Cys的接头。
如上文所提到,在一些情况下,存在于TMP中的至少一个MOD为野生型MOD。在其他情况下,与对应野生型MOD对co-MOD的亲和力相比,存在于TMP中的至少一个MOD为展现降低的对co-MOD的亲和力的变体MOD。
在一些情况下,肽表位为AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽、间皮素肽或病毒肽(例如CMV肽);其中此类肽如上文所描述。
在以上TMP中,在一些情况下,第二MHC多肽为包含与HLA-A*0201多肽、HLA-A*1101多肽或HLA-A24多肽、HLA-E多肽(诸如HLA-E*0101或HLA-E*01.03)或HLA-G多肽(诸如HLA-G*0101或和HLA-G*01:04)具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的氨基酸序列的HLA重链。在一些情况下,HLA重链多肽为HLA-A*0201多肽。在一些情况下,HLA重链多肽为包含Y84C取代和/或A236C取代的HLA-A*0201多肽。在一些情况下,HLA重链多肽为包含Y84C取代和/或A236C取代的HLA-A*1101多肽。在一些情况下,HLA重链多肽为包含Y84C取代和/或A236C取代的HLA-E*0101或HLA-E*01.03*0201多肽。在一些情况下,HLA重链多肽为包含Y84C取代和/或A236C取代的HLA-G*0101或和HLA-G*01:04A*1101多肽。
在一些情况下,TMP包含两个MOD,其中两个MOD具有相同氨基酸序列,例如MOD为与具有图17A的序列wt.IL-2相比展现降低的对IL2R的α链与β链的结合亲和力的变体IL-2多肽,例如包含H16A和F42A取代的变体IL-2多肽,或包含H16T和F42A取代的变体IL-2多肽。
在一些情况下,Ig Fc多肽为基本上不诱导细胞溶解的人IgG1 Fc多肽的变体,例如诸如图2B或图2D中所示包含L234A和L235A取代的IgG1 Fc多肽。
在一些情况下,TMP包含在位置3的MOD,其中HLA重链多肽为野生型或变体HLA-A*0201多肽,例如包含与图3A、图3B、图3C、图3D或图3E中的一者的HLA-A*0201多肽的至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的HLA-A*0201多肽,任选包含Y84取代和/或A236C取代。在一些情况下,Ig Fc多肽为基本上不引起细胞溶解的人IgG1 Fc多肽的变体,例如如图2B或图2D中所示包含L234A和L235A取代的人IgG1 Fc多肽。在一些情况下,MOD为与具有图17A的序列的wt.IL-2相比展现降低的对IL2R的α链与β链的结合亲和力的变体IL-2多肽,例如包含H16A和F42A取代的变体IL-2多肽,或包含H16T和F42A取代的变体IL-2多肽。在一些情况下,肽为AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽、间皮素肽或病毒肽(例如CMV肽);其中此类肽如上文所描述。在一些情况下,TMP包含变体IL-2MOD与存在于TMP中的Ig Fc多肽之间的刚性肽接头,其中刚性肽接头包含选自以下的氨基酸序列:EAAAK(SEQ ID NO:412)、A(EAAAK)n(SEQID NO:582)、A(EAAAK)nA(SEQ ID NO:583)、(AP)n(SEQ ID NO:584)、(EP)n(SEQ ID NO:585)以及(KP)n(SEQ ID NO:586),其中n为1至10的整数(例如n为1、2、3、4、5、6、7、8、9或10)。在一些情况下,TMP包含变体IL-2MOD的两个拷贝。在一些情况下,TMP包含变体IL-2MOD的两个拷贝,并且TMP包含以下之间的刚性肽接头:a)第一变体IL-2MOD与存在于TMP中的IgFc多肽;以及b)第一变体IL-2MOD与第二变体IL-2MOD之间,其中刚性肽接头包含选自以下的氨基酸序列:EAAAK(SEQ ID NO:412)、A(EAAAK)n(SEQ ID NO:582)、A(EAAAK)nA(SEQ IDNO:583)、(AP)n(SEQ ID NO:584)、(EP)n(SEQ ID NO:585)以及(KP)n(SEQ ID NO:586),其中n为1至10的整数(例如n为1、2、3、4、5、6、7、8、9或10)。或者,在一些情况下,TMP包含变体IL-2MOD与存在于TMP中的Ig Fc多肽之间的短可挠性肽接头,其中短可挠性肽接头包含2-4、2-5、3-6、4-8、5-10或10-14个氨基酸。在一些情况下,短可挠性肽接头为GGS。
在一些情况下,TMP包含在位置3的MOD,其中HLA重链多肽为野生型或变体HLA-A*1101多肽,例如包含与图4A、图4B、图4C、图4D或图4E中的一者的HLA-A*1101多肽的至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的HLA-A*1101多肽,任选包含Y84取代和/或A236C取代。在一些情况下,Ig Fc多肽为基本上不引起细胞溶解的人IgG1 Fc多肽的变体,例如如图2B或图2D中所示包含L234A和L235A取代的人IgG1 Fc多肽。在一些情况下,MOD为与具有图17A的序列的wt.IL-2相比展现降低的对IL2R的α链与β链的结合亲和力的变体IL-2多肽,例如包含H16A和F42A取代的变体IL-2多肽,或包含H16T和F42A取代的变体IL-2多肽。在一些情况下,肽为AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽、间皮素肽或病毒肽(例如CMV肽);其中此类肽如上文所描述。在一些情况下,TMP包含变体IL-2MOD与存在于TMP中的Ig Fc多肽之间的刚性肽接头,其中刚性肽接头包含选自以下的氨基酸序列:EAAAK(SEQ ID NO:412)、A(EAAAK)n(SEQID NO:582)、A(EAAAK)nA(SEQ ID NO:583)、(AP)n(SEQ ID NO:584)、(EP)n(SEQ ID NO:585)以及(KP)n(SEQ ID NO:586),其中n为1至10的整数(例如n为1、2、3、4、5、6、7、8、9或10)。在一些情况下,TMP包含变体IL-2MOD的两个拷贝。在一些情况下,TMP包含变体IL-2MOD的两个拷贝,并且TMP包含以下之间的刚性肽接头:a)第一变体IL-2MOD与存在于TMP中的IgFc多肽;以及b)第一变体IL-2MOD与第二变体IL-2MOD之间,其中刚性肽接头包含选自以下的氨基酸序列:EAAAK(SEQ ID NO:412)、A(EAAAK)n(SEQ IDNO:582)、A(EAAAK)nA(SEQ IDNO:583)、(AP)n(SEQ ID NO:584)、(EP)n(SEQ ID NO:585)以及(KP)n(SEQ ID NO:586),其中n为1至10的整数(例如n为1、2、3、4、5、6、7、8、9或10)。或者,在一些情况下,TMP包含变体IL-2MOD与存在于TMP中的Ig Fc多肽之间的短可挠性肽接头,其中短可挠性肽接头包含2-4、2-5、3-6、4-8、5-10或10-14个氨基酸。在一些情况下,短可挠性肽接头为GGS。
在一些情况下,TMP包含在位置3的MOD,其中HLA重链多肽为野生型或变体HLA-A*2402多肽,例如包含与图5A、图5B、图5C、图5D或图5E中的一者的HLA-A*2402多肽的至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%的氨基酸序列同一性的HLA-A*2402多肽,任选包含Y84取代和/或A236C取代。在一些情况下,Ig Fc多肽为基本上不引起细胞溶解的人IgG1 Fc多肽的变体,例如如图2B或图2D中所示包含L234A和L235A取代的人IgG1 Fc多肽。在一些情况下,MOD为与具有图17A的序列的wt.IL-2相比展现降低的对IL2R的α链与β链的结合亲和力的变体IL-2多肽,例如包含H16A和F42A取代的变体IL-2多肽,或包含H16T和F42A取代的变体IL-2多肽。在一些情况下,肽为AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽、间皮素肽或病毒肽(例如CMV肽);其中此类肽如上文所描述。在一些情况下,TMP包含变体IL-2MOD与存在于TMP中的Ig Fc多肽之间的刚性肽接头,其中刚性肽接头包含选自以下的氨基酸序列:EAAAK(SEQ ID NO:412)、A(EAAAK)n(SEQID NO:582)、A(EAAAK)nA(SEQ ID NO:583)、(AP)n(SEQ ID NO:584)、(EP)n(SEQ ID NO:585)以及(KP)n(SEQ ID NO:586),其中n为1至10的整数(例如n为1、2、3、4、5、6、7、8、9或10)。在一些情况下,TMP包含变体IL-2MOD的两个拷贝。在一些情况下,TMP包含变体IL-2MOD的两个拷贝,并且TMP包含以下之间的刚性肽接头:a)第一变体IL-2MOD与存在于TMP中的IgFc多肽;以及b)第一变体IL-2MOD与第二变体IL-2MOD之间,其中刚性肽接头包含选自以下的氨基酸序列:EAAAK(SEQ ID NO:412)、A(EAAAK)n(SEQ ID NO:582)、A(EAAAK)nA(SEQ IDNO:583)、(AP)n(SEQ ID NO:584)、(EP)n(SEQ ID NO:585)以及(KP)n(SEQ ID NO:586),其中n为1至10的整数(例如n为1、2、3、4、5、6、7、8、9或10)。或者,在一些情况下,TMP包含变体IL-2MOD与存在于TMP中的Ig Fc多肽之间的短可挠性肽接头,其中短可挠性肽接头包含2-4、2-5、3-6、4-8、5-10或10-14个氨基酸。在一些情况下,短可挠性肽接头为GGS。
如上文所论述,TMP可包括一个或多个链内二硫键。举例来说,TMP可包含具有R12C取代的β2M多肽以及具有A236C取代的I类MHC重链多肽;使得在β2M多肽的位置12的Cys与在I类MHC重链多肽的位置236的Cys之间形成二硫键。作为另一实例,TMP可包含i)通过包含GCGGS(GGGGS)
TMP可包括:a)G2C/Y84C二硫键而不包括R12C/A236C二硫键;以及b)至少一个在位置2或3的MOD。TMP可包括:a)R12C/A236C二硫键而不包括G2C/Y84C二硫键;以及至少一个在位置2或3的MOD。TMP可包括:a)G2C/Y84C二硫键和R12C/A236C二硫键;以及b)以及至少一个在位置2或3的MOD。
在一些情况下,TMP包含MHC I类重链多肽,所述MHC I类重链多肽包含(i)HLA-A0201(Y84A;A236C)多肽,所述多肽包含在位置84的Ala以及在位置236的Cys,或(ii)HLA-A0201(Y84C;A139C)多肽,所述多肽包含在位置84和139的Cys,或(iii)HLA-A0201(Y84C;A236)多肽,所述多肽包含在位置84的Cys以及在位置236的丙氨酸;其中实例展示于图3B至图3E中。
在一些情况下,TMP包含MHC I类重链多肽,所述MHC I类重链多肽包含(i)HLA-A*1101(Y84A;A236C)多肽,所述多肽包含在位置84的Ala以及在位置236的Cys,或(ii)HLA-A*1101(Y84C;A236C)多肽,所述多肽包含在位置84和236的Cys,或(iii)HLA-A*1101(Y84C;A236)多肽,所述多肽包含在位置84的Cys以及在位置236的丙氨酸;其中实例展示于图4B至图4E中。
在一些情况下,TMP包含MHC I类重链,所述MHC I类重链包含(i)HLA-A24(Y84A;A236C)多肽,所述多肽包含在位置84的Ala以及在位置236的Cys,或(ii)HLA-A24(Y84C;A236C)多肽,所述多肽包含在位置84和236的Cys,或(iii)HLA-A24(Y84C;A236)多肽,所述多肽包含在位置84的Cys以及在位置236的丙氨酸;其中实例展示于图5B至图5E中。
包括在TMP中的肽可为以上所描述的肽中的任一者。在图19A至图19D中,“(X)”表示如上文所描述的肽表位,例如AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽、间皮素肽或病毒肽(例如CMV肽)。类似地,在图18A至图18T中,“(X)”表示如上文所描述的肽表位,例如AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽、间皮素肽或病毒肽(例如CMV肽)。
如上文所提到的,在一些情况下,TMP包含一个或多个刚性肽接头。作为非限制性实例,如图21A至图21D中所示,“(XX)”表示刚性肽接头;并且“(X)”表示如上文所描述的肽表位,例如AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽、间皮素肽或病毒肽(例如CMV肽)。在一些情况下,刚性肽接头包含选自以下的氨基酸序列:EAAAK(SEQ IDNO:412)、A(EAAAK)n(SEQ ID NO:582)、A(EAAAK)nA(SEQ ID NO:583)、(AP)n(SEQ ID NO:584)、(EP)n(SEQ ID NO:585)以及(KP)n(SEQ ID NO:586),其中n为1至10的整数(例如n为1、2、3、4、5、6、7、8、9或10)。
在一些情况下,TMP包含呈如图12中所示的位置2或位置3排列的MOD,其中HLA重链多肽为野生型或变体HLA-A*0201多肽,例如包含A236C取代或如图3A至图3E中任一项所示的序列的HLA-A*0201多肽或其变体。在一些情况下,Ig Fc多肽为基本上不引起细胞溶解的人IgG1 Fc多肽,例如如图2B和图2D中所示包含L234A和L235A取代的人IgG1 Fc多肽。在一些情况下,TMP包含(i)MHC I类重链多肽中的两个Cys残基之间,(ii)β2M与重链多肽之间,和/或MHC I类重链中的Cys与肽表位与β2M多肽之间的接头中的Cys之间的链内二硫键。在一些情况下,MOD为包含H16A和F42A取代或H16T和F42A取代的变体IL-2多肽。
在一些情况下,TMP包含呈如图12中所示的位置2或位置3排列的MOD,其中HLA重链多肽为野生型或变体HLA-A24多肽(也称为HLA-A*2402),例如包含A236C取代或图5A至图5E中任一项所示的氨基酸序列的HLA-A*2402多肽或其变体。在一些情况下,Ig Fc多肽为基本上不引起细胞溶解的人IgG1 Fc多肽,例如如图2B或图2D中所示包含L234A和L235A取代的人IgG1 Fc多肽。在一些情况下,TMP包含(i)MHC I类重链多肽中的两个Cys残基之间,(ii)β2M与重链多肽之间,和/或MHC I类重链中的Cys与肽表位与β2M多肽之间的接头中的Cys之间的链内二硫键。在一些情况下,MOD为包含H16A和F42A取代或H16T和F42A取代的变体IL-2多肽。
在一些情况下,TMP包含呈如图12中所示的位置2或位置3排列的MOD,其中HLA重链多肽为如本文所公开的野生型或变体HLA-A*1101多肽,例如包含A236C取代或具有如图4A至图4E中的一者中所示的氨基酸序列的HLA-A*1101多肽或其变体。在一些情况下,Ig Fc多肽为基本上不引起细胞溶解的人IgG1 Fc多肽,例如如图2B或图2D中所示包含L234A和L235A取代的人IgG1 Fc多肽。在一些情况下,TMP包含(i)MHC I类重链多肽中的两个Cys残基之间,(ii)β2M与重链多肽之间,和/或MHC I类重链中的Cys与肽表位与β2M多肽之间的接头中的Cys之间的链内二硫键。在一些情况下,MOD为包含H16A和F42A取代或H16T和F42A取代的变体IL-2多肽。
TMP可包括:a)G2C/Y84C二硫键而不包括R12C/A236C二硫键;以及b)至少一个在位置2或3的MOD。TMP可包括:a)R12C/A236C二硫键而不包括G2C/Y84C二硫键;以及至少一个在位置2或3的MOD。TMP可包括:a)G2C/Y84C二硫键以及R12C/A236C二硫键;以及b)以及至少一个在位置2或3的MOD。
在一些情况下,TMP包含MHC I类重链多肽,所述MHC I类重链多肽包含(i)HLA-A0201(Y84A;A236C)多肽,所述多肽包含在位置84的Ala以及在位置236的Cys,或(ii)HLA-A0201(Y84C;A139C)多肽,所述多肽包含在位置84和139的Cys,或(iii)HLA-A0201(Y84C;A236)多肽,所述多肽包含在位置84的Cys以及在位置236的丙氨酸,例如如图3A至图3E中所展示。
在一些情况下,TMP包含MHC I类重链多肽,所述MHC I类重链多肽包含(i)HLA-A*1101(Y84A;A236C)多肽,所述多肽包含在位置84的Ala和在位置236的Cys,或(ii)HLA-A*1101(Y84C;A236C)多肽,所述多肽包含在位置84和236的Cys,或(iii)HLA-A*1101(Y84C;A236)多肽,所述多肽包含在位置84的Cys以及在位置236的丙氨酸,例如如图4A至图4E中所展示。
在一些情况下,TMP包含第二多肽,所述第二多肽包含(i)HLA-A24(Y84A;A236C)多肽,所述多肽包含在位置84的Ala和在位置236的Cys,或(ii)HLA-A24(Y84C;A236C)多肽,所述多肽包含在位置84和236的Cys,或(iii)HLA-A24(Y84C;A236)多肽,所述多肽包含在位置84的Cys以及在位置236的丙氨酸,例如如图5A至图5E中所展示。
作为非限制性实例,TMP可包含如图19A至图19D中任一者所展示的氨基酸序列,其中“(X)”为AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽、间皮素肽或病毒肽(例如CMV肽)。
作为其他非限制性实例,TMP可包含如图18A至图18T中任一者所展示的氨基酸序列,其中“(X)”为AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽、间皮素肽或病毒肽(例如CMV肽)。
作为其他非限制性实例,TMP可包含如图20A至图20G中任一者所展示的氨基酸序列。下表2中概括了存在于图20A至图20G中所展示的TMP中的构建体编号、MHC重链等位基因以及肽表位。
表2
存在于图20A至图20G中所展示的构建体中的任一者中的肽可用不同的肽取代。举例来说,存在于图20A至图20G中所展示的构建体中的任一者中的肽可用如上文所描述的AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽或间皮素肽取代。
核酸、重组表达载体以及经过修饰的宿主细胞
本公开提供了一种核酸,所述核酸包含编码本公开的TMP的核苷酸序列。在一些情况下,编码TMP的核苷酸序列可操作地连接至一个或多个转录控制元件。在一些情况下,转录控制元件为在真核细胞中具功能的启动子。在一些情况下,核酸存在于重组表达载体中。
因此,本公开提供了包含编码TMP的核酸的重组表达载体。在一些情况下,重组表达载体为非病毒载体。在一些情况下,重组表达载体为病毒构建体,例如重组腺病毒相关病毒构建体(参见例如美国专利号7,078,387)、重组腺病毒构建体、重组慢病毒构建体、重组逆转录病毒构建体、非整合病毒载体等。
适合的表达载体为本领域技术人员熟知的。参见例如公布的PCT申请WO2020132138A1和WO2019/051091,所述专利的公开内容关于此类表达载体明确地以引用的方式并入本文中,特别地包括WO2020132138A1的段落[00515]-[00520]和WO2019/051091的段落[00401]-[00406]。
本公开还提供了一种基因修饰的宿主细胞,其中所述宿主细胞为用如上文所描述的核酸或表达载体基因修饰的。
适合的宿主细胞包括真核细胞,诸如酵母细胞、昆虫细胞以及哺乳动物细胞。在一些情况下,宿主细胞为哺乳动物细胞系的细胞。适合的哺乳动物细胞系包括人细胞系、非人灵长类动物细胞系、啮齿动物(例如小鼠、大鼠)细胞系等。适合的哺乳动物细胞系包括但不限于HeLa细胞(例如美国典型培养物保藏中心(ATCC)编号CCL-2)、CHO细胞(例如ATCC编号CRL9618、CCL61、CRL9096)、293细胞(例如ATCC编号CRL-1573)、Vero细胞、NIH 3T3细胞(例如ATCC编号CRL-1658)、Huh-7细胞、BHK细胞(例如ATCC编号CCL10)、PC12细胞(ATCC编号CRL1721)、COS细胞、COS-7细胞(ATCC编号CRL1651)、RAT1细胞、小鼠L细胞(ATCC编号CCLI.3)、人胚胎肾(HEK)细胞(ATCC编号CRL1573)、HLHepG2细胞等。
在一些情况下,宿主细胞为已经过基因修饰以使其不合成内源性MHCβ2M的哺乳动物细胞。
在一些情况下,宿主细胞为已经过基因修饰以使其不合成内源性MHC I类重链的哺乳动物细胞。在一些情况下,宿主细胞为已经过基因修饰以使其不合成内源性MHCβ2M并且使其不合成内源性MHC I类重链的哺乳动物细胞。
产生T细胞调节多肽的方法
可通过在体外在适合的培养基中培养本公开的基因修饰的宿主细胞来产生本公开的TMP,其中此类培养使得产生TMP。举例来说,可用包含编码本公开的TMP的核苷酸序列的重组表达载体对哺乳动物宿主细胞(例如CHO细胞)进行基因修饰;并且可将基因修饰的哺乳动物宿主细胞在适合的培养基中离体培养,使得基因修饰的哺乳动物宿主细胞产生TMP。可例如从在其中培养基因修饰的哺乳动物宿主细胞的培养基和/或从基因修饰的哺乳动物宿主细胞的细胞溶解产物分离TMP。可使用多种充分确定的方法中的任一者分离TMP。在TMP在其C端包含Ig Fc多肽的情况下,细胞内处理可从Ig Fc多肽的C端移除C端Lys残基;参见例如van den Bremer等(2015)mAbs7:4;以及Sissolak等(2019)J.IndustrialMicrobiol.&Biotechnol.46:1167。并且如上文所提到,各自包含Ig Fc多肽(例如IgG1 Fc)的两个TMP可自发形成两个TMP的均二聚体,其中个别TMP通过其相应Ig Fc部分之间的一个或多个二硫键连接。
组合物
本公开提供了包含如本文所公开的TMP或二聚化TMP的组合物,包括药物组合物。本公开提供了包含核酸或重组表达载体的组合物,包括药物组合物。
包含TMP或二聚化TMP的组合物
除TMP或二聚化TMP外,组合物还可包含一种或多种药学上可接受的赋形剂,诸如载体、稀释剂、缓冲剂、盐、增溶剂、表面活性剂、稳定剂或可例如辅助制造过程;保护、支持或增强稳定性、生物可用性和/或患者可接受性的其他添加剂。药学上可接受的赋形剂为本领域技术人员熟知的。
在以可注射剂的形式将TMP或二聚化TMP直接施用(例如皮下、腹膜内、肌肉内和/或静脉内)至组织中的情况下,可以即用剂型的形式提供制剂,所述即用剂型可直接注射或输注至患者中或与盐水溶液混合以便输注,或可能呈非水性形式(例如可复水储存稳定粉末)或水性形式,诸如由药学上可接受的载体和赋形剂组成的液体。还可提供制剂以便增强施用之后TMP的血清半衰期。举例来说,TMP或二聚化TMP可提供于脂质体制剂中,以胶体形式或其他用于延长血清半衰期的常规技术制备。还可以控制释放或缓释形式提供制剂。
液体组合物制剂中TMP或二聚化TMP的浓度可在广泛范围内改变(例如小于约0.1%,通常等于或至少为按重量计约2%至高达20%至50%或更多)。此范围内包括约5至约15mg/mL、约8至约12mg/mL、约9至约11mg/mL,包括约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以及约15mg/mL的浓度。浓度可取决于许多因素,包括液体组合物中TMP的稳定性。
在一些情况下,TMP或二聚化TMP存在于液体组合物中。在一些情况下,组合物包含:a)TMP或二聚化TMP;以及b)盐水(例如0.9% NaCl)。在一些情况下,组合物为无菌的并且适合于向人受试者施用。
调节T细胞活性的方法
本公开提供了一种选择性调节表位特异性T细胞(例如对存在于TMP中的肽表位,诸如癌症相关肽或病毒肽或病毒相关肽具特异性的T细胞)的活性的方法,所述方法包括使T细胞与TMP或二聚化TMP接触,其中使T细胞与TMP或二聚化TMP接触可选择性调节表位特异性T细胞的活性。在一些情况下,接触发生在体外。在一些情况下,接触发生在体内。
在TMP或二聚化TMP包括为活化多肽的MOD并且肽为癌症相关肽的情况下,使T细胞与TMP或二聚化TMP接触可活化表位特异性T细胞,从而增加T细胞对表达癌症相关肽表位癌细胞的细胞毒性活性和/或增加表位特异性T细胞的数目。在TMP或二聚化TMP包括为活化多肽的MOD并且肽为病毒肽或病毒相关肽的情况下,使T细胞与TMP或二聚化TMP接触使表位特异性T细胞活化,使T细胞对表达所述病毒肽或病毒相关肽的病毒感染细胞的细胞毒性活性增加和/或使表位特异性T细胞的数目增加。
在一些情况下,当向施用有需要的个体时,TMP或二聚化TMP诱导表位特异性T细胞反应与表位非特异性T细胞反应两者。换句话说,在一些情况下,当向有需要的个体施用时,TMP(i)通过调节第一T细胞的活性诱导表位特异性T细胞反应,所述第一T细胞展示对存在于TMP中的肽表位具特异性的TCR与结合至存在于TMP中的MOD的co-MOD;并且(ii)通过调节第二T细胞的活性诱导表位非特异性T细胞反应,所述第二T细胞展示对存在于TMP中的除肽表位外的表位具特异性的TCR,以及结合至存在于TMP中的MOD的co-MOD。表位特异性T细胞反应与表位非特异性T细胞反应的比率为至少2:1、至少5:1、至少10:1、至少15:1、至少20:1、至少25:1、至少50:1或至少100:1。表位特异性T细胞反应与表位非特异性T细胞反应的比率为约2:1至约5:1、约5:1至约10:1、约10:1至约15:1、约15:1至约20:1、约20:1至约25:1、约25:1至约50:1或约50:1至约100:1或超过100:1。此比率通过测量对标靶肽表位(例如癌症相关肽;病毒肽或病毒相关肽)具特异性的T细胞的数目的增加与不对所述标靶表位具特异性的T细胞的数目的增加来确定。举例来说,可使用常规流式细胞术方法。当存在活化MOD(诸如变体IL-2)时,“调节T细胞的活性”可包括以下中的一者或多者:i)活化细胞毒性(例如CD8
如上文所论述,在一些情况下,当向有需要的个体施用时,TMP或二聚化TMP诱导表位特异性T细胞增殖。表位特异性T细胞的百分比增加可通过常规流式细胞术方法来测量。因此,在与TMP接触之后,例如对肽表位具特异性的总CD8+T细胞的百分比可增加至少约10%、至少约15%、至少约20%、至少约25%、至少约50%、至少约75%、至少约2倍、至少约2.5倍、至少约3倍、至少约4倍或高于4倍。
本公开提供了一种选择性递送MOD至靶T细胞的方法,所述方法包括使混合T细胞群体与TMP或二聚化TMP接触,其中混合T细胞群体包含靶T细胞和非靶T细胞,其中靶T细胞对存在于TMP或二聚化TMP内的肽表位具特异性,并且其中接触步骤将存在于TMP或二聚化TMP内的一个或多个MOD递送至靶T细胞。在一些情况下,T细胞群体在体外。在一些情况下,T细胞群体在个体的体内。在一些情况下,所述方法包括向个体施用TMP或二聚化TMP。在某一情况下,靶T细胞为细胞毒性T细胞。在一些情况下,混合T细胞群体为从个体获得的体外混合T细胞群体,并且接触步骤引起靶T细胞的活化和/或增殖,从而产生活化和/或增殖靶T细胞的群体;在这些实例中的一些中,所述方法还包括向个体施用活化和/或增殖靶T细胞的群体。
本公开提供了一种检测从个体获得的混合T细胞群体中结合所关注的表位(例如癌症表位;病毒表位)的靶T细胞的存在的方法,所述方法包括:a)在体外使混合T细胞群体与TMP或二聚化TMP接触,其中TMP或二聚化TMP包含所关注的肽表位;以及b)检测响应于所述接触的T细胞的活化和/或增殖,其中活化和/或增殖的T细胞指示靶T细胞的存在。
治疗方法
本公开提供了一种治疗个体的方法,所述方法包括向个体施用有效治疗个体的量的TMP或二聚化TMP或编码TMP的一种或多种核酸。还提供了一种供在治疗人或非人动物体的方法中使用的TMP或二聚化TMP。在一些情况下,本公开的治疗方法包括向有需要的个体施用包含编码TMP或二聚化TMP的核苷酸序列的一种或多种重组表达载体。在一些情况下,本公开的治疗方法包括向有需要的个体施用包含编码TMP或二聚化TMP的核苷酸序列的一种或多种核酸(例如mRNA分子)。在一些情况下,治疗方法包括向有需要的个体施用TMP或二聚化TMP。可治疗的疾患包括例如癌症,诸如表达AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽、间皮素肽或病毒肽(例如CMV肽)的癌症。可治疗的疾患包括感染性疾病,例如由病毒感染引起的疾病。
治疗癌症
可向有需要的个体施用本公开的TMP或二聚化TMP以治疗个体的癌症,其中所述癌症表达或过表达存在于TMP中的肽(例如AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽、间皮素肽或病毒肽(例如CMV肽))。举例来说,癌症可为其中癌细胞表达或过表达AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽或间皮素肽的癌症。本公开提供了一种治疗个体的癌症的方法,所述方法包括向个体施用有效量的TMP或二聚化TMP,或包含编码TMP的核苷酸序列的一种或多种核酸(例如表达载体;mRNA;等),其中TMP或二聚化TMP包含展示T细胞表位的肽,并且其中TMP或二聚化TMP包含活化MOD。在一些情况下,TMP或二聚化TMP的有效量为如下量,所述量当作为单一疗法或作为组合疗法的一部分(例如如下文所论述,作为使用免疫检查点抑制剂的组合疗法的一部分)以一个或多个剂量向有需要的个体施用时,降低个体的总体肿瘤负荷,即体内癌症的量,或者使患者的总肿瘤负荷保持相对稳定持续充足的时间段,以使患者如通过标准RECIST准则所确定具有被证实的“稳定疾病”。
在一些情况下,TMP或二聚化TMP的有效量为如下量,所述量当作为单一疗法或作为组合疗法的一部分(例如作为使用免疫检查点抑制剂的组合疗法的一部分)以一个或多个剂量向有需要的个体施用时,如下文所论述,使得肿瘤尺寸减小充足的量,并且持续充足的时间段,以使患者如通过标准RECIST准则所确定具有被证实的“部分反应”。
在一些情况下,TMP或二聚化TMP的有效量为如下量,所述量当作为单一疗法或作为组合疗法的一部分(例如作为使用免疫检查点抑制剂的组合疗法的一部分)以一个或多个剂量向有需要的个体施用时,使得肿瘤尺寸减小充足的量,并且持续充足的时间段,以使患者如通过标准RECIST准则所确定具有被证实的“完全反应”。
在一些情况下,TMP或二聚化TMP的有效量为如下量,所述量当作为单一疗法或作为组合疗法的一部分(例如作为使用免疫检查点抑制剂的组合疗法的一部分)以一个或多个剂量向有需要的个体施用时,与施用TMP或二聚化TMP之前或在未施用TMP或二聚化TMP的情况下个体中癌细胞的数目相比,使个体中癌细胞的数目减少至少10%、至少15%、至少20%、至少25%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%或至少95%。
在一些情况下,TMP或二聚化TMP的有效量为如下量,所述量当作为单一疗法或作为组合疗法的一部分(例如作为使用免疫检查点抑制剂的组合疗法的一部分)以一个或多个剂量向有需要的个体施用时,使个体中癌细胞的数目减少,包括达到基本上不可检测的水平。
在一些情况下,TMP或二聚化TMP的有效量为当作为单一疗法或作为组合疗法的一部分(例如作为使用免疫检查点抑制剂的组合疗法的一部分)以一个或多个剂量向有需要的个体(具有肿瘤的个体)施用时使个体的肿瘤体积减小的量。举例来说,在一些情况下,TMP或二聚化TMP的有效量为如下量,所述量当作为单一疗法或作为组合疗法的一部分(例如作为使用免疫检查点抑制剂的组合疗法的一部分)以一个或多个剂量向有需要的个体(具有肿瘤的个体)施用时,与施用TMP或二聚化TMP之前或在未施用TMP或二聚化TMP的情况下个体的肿瘤体积相比,使个体的肿瘤体积减小至少10%、至少15%、至少20%、至少25%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%或至少95%。肿瘤体积使用公式(长度x宽度x宽度)/2来确定,其中长度表示最大肿瘤直径并且宽度表示垂直肿瘤直径。
在一些情况下,TMP或二聚化TMP的有效量为如下量,所述量当以一个或多个剂量向有需要的个体施用时,使个体的存活时间增加。举例来说,在一些情况下,TMP或二聚化TMP的有效量为如下量,所述量当作为单一疗法或作为组合疗法的一部分(例如作为使用免疫检查点抑制剂的组合疗法的一部分)以一个或多个剂量向有需要的个体施用时,与在未施用TMP或二聚化TMP的情况下个体的预期存活时间相比,使个体的存活时间增加至少1个月、至少2个月、至少3个月、3个月至6个月、6个月至1年、1年至2年、2年至5年、5年至10年或超过10年。
在一些情况下,TMP或二聚化TMP的有效量为如下量,所述量当作为单一疗法或作为组合疗法的一部分(例如作为使用免疫检查点抑制剂的组合疗法的一部分)以一个或多个剂量向有需要的个体施用时,与施用TMP或二聚化TMP之前或在未施用TMP或二聚化TMP的情况下个体中循环肿瘤DNA(“ctDNA”)的水平相比,使患者中的ctDNA水平降低至少10%、至少15%、至少20%、至少25%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%或至少95%。ctDNA的水平可使用任何已知方法来确定;参见例如Cescon等(2020)Nature Cancer 1:276。
可用本公开的方法治疗的癌症包括其中癌细胞表达AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽、间皮素肽、MART1肽或病毒肽(例如CMV肽、流感病毒肽、EBV肽等)的癌症。
举例来说,可使用包括AFP肽的TMP或二聚化TMP来治疗癌症,诸如肝细胞癌、胰腺癌、胃癌、结肠直肠癌、肝胚细胞瘤或卵巢卵黄囊瘤。
作为另一实例,可使用包括WT-1肽的TMP或二聚化TMP来治疗癌症,诸如表达WT-1的癌症。表达WT1的癌症包括白血病、促结缔组织增生小圆形细胞肿瘤、胃癌、结肠癌、肺癌、乳腺癌、生殖细胞肿瘤、卵巢癌、子宫癌、甲状腺癌、肝癌、肾癌、卡波西肉瘤(Kaposi'ssarcoma)、肉瘤、肝细胞癌、威尔姆氏瘤、急性骨髓性白血病(AML)、骨髓发育异常综合征(MDS)、非小细胞肺癌(NSCLC)、骨髓瘤、胰腺癌、结肠直肠癌、间皮瘤、软组织肉瘤、成神经细胞瘤以及成肾细胞瘤。
作为另一实例,可使用包括HPV肽的TMP或二聚化TMP来治疗癌症,诸如表达HPV的(HPV
作为另一实例,可使用包括MUC-1肽的TMP或二聚化TMP来治疗表达或过表达MUC-1的癌症。实例包括腺癌和血液学恶性肿瘤。实例包括例如多发性骨髓瘤;B细胞淋巴瘤;乳腺癌;肺癌;卵巢癌;胰腺癌;结肠直肠癌;前列腺癌;肾癌;急性骨髓性白血病;间皮瘤;甲状腺癌;头颈癌;胃癌;尿路上皮癌;宫颈癌;以及卵巢子宫内膜癌。
作为另一实例,可使用包括MAGE A4肽的TMP或二聚化TMP来治疗MAGE-A4阳性的癌症。MAGE-A4阳性的癌症包括例如黑素瘤、膀胱癌、头颈癌、肺癌、食管癌、乳腺癌、结肠癌以及卵巢癌。
作为另一实例,可使用包括NY-ESO-1肽的TMP或二聚化TMP来治疗肺癌、食管癌、乳腺癌、胰腺癌、结肠直肠癌以及卵巢癌。
作为另一实例,可使用包括存活素肽的TMP或二聚化TMP来治疗食管癌(例如食管鳞状细胞癌)、黑素瘤、乳腺癌以及白血病。
作为另一实例,可使用包括间皮素肽的TMP或二聚化TMP来治疗表达间皮素的癌症,诸如间皮瘤、胰腺癌、卵巢癌以及肺腺癌。
治疗感染性疾病
本公开提供了一种治疗个体的感染(例如由病原病毒感染)的方法。本公开的方法可增加个体中的表位特异性T细胞的数目和/或活性。在一些情况下,表位特异性T细胞为对存在于病毒感染细胞上的表位具特异性的T细胞,并且使表位特异性T细胞与TMP接触使T细胞对病毒感染细胞的细胞毒性活性增加。在一些情况下,表位特异性T细胞为对存在于病毒感染细胞上的表位具特异性的T细胞,并且使表位特异性T细胞与TMP接触使表位特异性T细胞的数目增加。
因此,本公开提供了一种治疗个体的病毒感染的方法,所述方法包括向个体施用有效量的TMP或二聚化TMP,或一种或多种包含编码TMP的核苷酸序列的核酸,其中TMP包含为病毒表位的T细胞表位,并且其中TMP包含刺激(“活化”)MOD。在一些情况下,TMP或二聚化TMP的有效量为如下量,所述量当以一种或多种剂量向有需要的个体施用时,使个体中的病毒感染细胞的数目减少。举例来说,在一些情况下,TMP或二聚化TMP的有效量为如下量,所述量当以一种或多种剂量向有需要的个体施用时,与施用TMP或二聚化TMP之前或在未施用TMP或二聚化TMP的情况下个体中的病毒感染细胞的数目相比,使个体中的病毒感染细胞的数目减少至少10%、至少15%、至少20%、至少25%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%或至少95%。在一些情况下,TMP或二聚化TMP的有效量为如下量,所述量当以一种或多种剂量向有需要的个体施用时,使个体中的病毒感染细胞的数目减少至不可检测的水平。
在一些情况下,TMP或二聚化TMP的有效量为如下量,所述量当以一种或多种剂量向有需要的个体施用时,使个体中的病毒(例如病毒粒子)的数目减少。举例来说,在一些情况下,TMP或二聚化TMP的有效量为如下量,所述量当以一种或多种剂量向有需要的个体施用时,与施用TMP或二聚化TMP之前或在未施用TMP或二聚化TMP的情况下个体中的病毒的数目相比,使个体中的病毒的数目减少至少10%、至少15%、至少20%、至少25%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%或至少95%。在一些情况下,TMP或二聚化TMP的有效量为如下量,所述量当以一种或多种剂量向有需要的个体施用时,使个体中的病毒的数目减少至不可检测的水平。个体中的病毒的数目可使用用于确定病毒负荷的许多熟知方法中的任一者来确定,其中此类方法包括例如使用聚合酶链反应法来确定病毒的基因组拷贝。
剂量
适合的TMP或二聚化TMP的剂量可由主治医师或其他合格医务人员根据各种临床因素来确定。如医学技术中所熟知,用于任一患者的剂量取决于许多因素,包括患者的体型、体表面积、年龄、要施用的特定多肽或核酸、患者的性别、施用时间和途径、一般健康以及同时施用的其他药物。可以介于每千克体重0.1mg与20mg之间,例如每千克体重0.1mg至10mg之间,例如每千克体重0.5mg至5mg之间、每千克体重1mg至5mg之间;每千克体重5mg至10mg之间;每千克体重10mg至15mg之间;每千克体重15mg至20mg之间的量施用TMP或二聚化TMP,然而,尤其考虑上述因素,也设想超过此示例性范围的剂量。如果方案为连续输注,那么它还可在每千克体重每分钟1μg至10mg范围内。可以每千克体重约1mg至50mg,例如每千克体重约1mg至约5mg、每千克体重约5mg至约10mg、每千克体重约10mg至约15mg、每千克体重约15mg至约20mg、每千克体重约20mg至约25mg、每千克体重约25mg至约30mg、每千克体重约30mg至约35mg、每千克体重约35mg至约40mg或每千克体重约40mg至约50mg的量施用TMP或二聚化TMP。示例性的TMP或二聚化TMP的量包括每千克体重1mg至5mg、每千克体重5mg至10mg、每千克体重约1mg至约5mg以及每千克体重约5mg至约10mg。
根据在人体流体或组织中所测量的所施用的剂的滞留时间和浓度,本领域技术人员可容易地估计给药的重复率。在成功治疗之后,可能需要使患者经历维持疗法以防止疾病状态复发,其中TMP或二聚化TMP以在每千克体重约1mg至约5mg、每千克体重约5mg至约10mg、每千克体重约10mg至约15mg、每千克体重约15mg至约20mg范围内的维持剂量或超过每千克体重20mg的量施用。
本领域技术人员将容易理解,剂量水平可随特定TMP或二聚化TMP、症状的严重程度以及受试者对副作用的敏感性而改变。给定化合物的优选剂量可由本领域技术人员通过多种手段容易地确定。
在一些情况下,施用多个剂量的TMP或二聚化TMP、核酸或重组表达载体。TMP或二聚化TMP、核酸或重组表达载体的施用频率可根据多种因素中的任一者(例如症状的严重程度等)而改变。举例来说,在一些情况下,TMP或二聚化TMP、核酸或重组表达载体每月一次、每月两次、每月三次、每隔一周(qow)、每周一次(qw)、每两周一次、每三周一次、每四周一次、每周两次(biw)、每周三次(tiw)、每周四次、每周五次、每周六次、每隔一天(qod)、每天(qd)、一天两次(qid)或一天三次(tid)进行施用。在静脉内施用TMP或二聚化TMP的情况下,在治疗开始时通常可采用每周一次、每两周一次、每三周一次或每四周一次或每月一次施用。
施用TMP或二聚化TMP、核酸或重组表达载体的持续时间(例如施用TMP或二聚化TMP、核酸或重组表达载体的时间段)可根据多种因素中的任一者(例如患者反应等)而改变。举例来说,可历时在约一天至约一周、约两周至约四周、约一个月至约两个月、约两个月至约四个月、约四个月至约六个月、约六个月至约八个月、约八个月至约1年、约1年至约2年或约2年至约4年或更久的范围内的时间段施用TMP或二聚化TMP、核酸或重组表达载体。
施用途径
使用适合于药物递送的任何可用的方法和途径(包括体内和体外方法以及全身和局部施用途径)向个体施用活性剂(TMP或二聚化TMP、核酸或重组表达载体)。
通常将经由静脉内施用递送本公开的TMP或二聚化TMP,但也可使用其他常规的和药学上可接受的施用途径,包括瘤内、瘤周、肌肉内、淋巴管内、气管内、颅内、皮下、真皮内、表面施加、动脉内、经直肠、经鼻、经口以及其他经肠和肠胃外施用途径。如果需要,那么可将施用途径组合,或根据TMP或二聚化TMP和/或所需效应进行调整。可以单个剂量或以多个剂量施用TMP或二聚化TMP或核酸或重组表达载体。
组合疗法
可将TMP或二聚化TMP与一种或多种其他治疗剂或治疗性治疗组合向有需要的个体施用。适合的TMP或二聚化TMP的剂量将为与使用TMP或二聚化TMP(上文所描述)的单一疗法相同的剂量或可小于或大于单一疗法剂量。
可在与施用一种或多种其他治疗剂相同的时间或在不同的时间向有需要的个体施用TMP或二聚化TMP。
因此,举例来说,治疗方法可包括TMP或二聚化TMP和至少一种其他治疗剂的共施用。“共施用”意味着向个体施用TMP或二聚化TMP与至少一种其他治疗剂两者(虽然不一定同时),以达成治疗作用,所述治疗作用为施用TMP或二聚化TMP与至少一种其他治疗剂两者的结果。TMP或二聚化TMP与至少一种其他治疗剂的施用可为基本上同时的,例如可在施用至少一种其他治疗剂约1分钟至约24小时内(例如约1分钟内、约5分钟内、约15分钟内、约30分钟内、约1小时内、约4小时内、约8小时内、约12小时内或约24小时内)向个体施用TMP或二聚化TMP。在一些情况下,向正在经历用至少一种其他治疗剂治疗或已经历过用至少一种其他治疗剂治疗的个体施用TMP或二聚化TMP。TMP或二聚化TMP与至少一种其他治疗剂的施用可发生在不同的时间和/或以不同频率进行。
癌症治疗中的组合疗法
可将TMP或二聚化TMP与一种或多种其他治疗剂或治疗性治疗组合向有需要的个体施用。适合的TMP或二聚化TMP的剂量通常将与使用TMP的单一疗法(上文所描述)的剂量相同或可小于或大于单一疗法剂量。适合的其他治疗剂包括例如:i)免疫检查点抑制剂;ii)癌症化学治疗剂;以及iii)一种或多种其他TMP或二聚化TMP。适合的其他治疗性治疗包括例如辐射、手术(例如手术切除肿瘤)等。
在一些情况下,所述方法包括向有需要的个体施用:a)包含TMP或二聚化TMP的第一组合物;以及b)包含免疫检查点抑制剂的第二组合物。在一些情况下,所述方法包括向有需要的个体施用:a)包含TMP或二聚化TMP的第一组合物;以及b)包含第二TMP或二聚化TMP的第二组合物。
可在与施用一种或多种其他治疗剂相同的时间或在不同的时间向有需要的个体施用TMP或二聚化TMP。
因此,举例来说,治疗方法可包括TMP或二聚化TMP和至少一个其他治疗剂的共施用。“共施用”意味着向个体施用TMP或二聚化TMP与至少一种其他治疗剂两者(虽然不一定同时),以实现治疗作用,所述治疗作用是施用TMP或二聚化TMP与至少一种其他治疗剂两者的结果。TMP或二聚化TMP与至少一种其他治疗剂的施用可为基本上同时的,例如可在施用至少一种其他治疗剂约1分钟至约24小时内(例如约1分钟内、约5分钟内、约15分钟内、约30分钟内、约1小时内、约4小时内、约8小时内、约12小时内或约24小时内)向个体施用TMP或二聚化TMP。在一些情况下,向正在经历用至少一种其他治疗剂治疗或已经历过用至少一种其他治疗剂治疗的个体施用TMP或二聚化TMP。TMP或二聚化TMP与至少一种其他治疗剂的施用可发生在不同的时间和/或以不同频率进行。
作为另一实例,治疗方法可包括TMP或二聚化TMP和免疫检查点抑制剂(诸如对免疫检查点具特异性的抗体)的共施用。“共施用”意味着向个体施用TMP或二聚化TMP与对免疫检查点具特异性的抗体两者(虽然不一定同时),以实现治疗作用,所述治疗作用是施用TMP或二聚化TMP与免疫检查点抑制剂两者的结果。TMP或二聚化TMP与对免疫检查点具特异性的抗体的施用可为基本上同时的,例如可在施用对免疫检查点具特异性的抗体约1分钟至约24小时内(例如约1分钟内、约5分钟内、约15分钟内、约30分钟内、约1小时内、约2小时内、约4小时内、约8小时内、约12小时内或约24小时内)向个体施用TMP或二聚化TMP。或者,TMP或二聚化TMP与免疫检查点抑制剂可按不同时程施用,包括不同天数和不同周数以及不同频率。在一些情况下,向正在经历用对免疫检查点具特异性的抗体治疗或已经历过用对免疫检查点具特异性的抗体治疗的个体施用TMP或二聚化TMP。
示例性免疫检查点抑制剂包括靶向免疫检查点多肽的抑制剂,诸如CD27、CD28、CD40、CD122、CD96、CD73、CD47、OX40、GITR、CSF1R、JAK、PI3Kδ、PI3Kγ、TAM、精氨酸酶、CD137(也称为4-1BB)、ICOS、A2AR、B7-H3、B7-H4、BTLA、CTLA-4、LAG3、TIM3、VISTA、CD96、TIGIT、CD122、PD-1、PD-L1以及PD-L2。在一些情况下,免疫检查点多肽为选自以下的刺激检查点分子:CD27、CD28、CD40、ICOS、OX40、GITR、CD122以及CD137。在一些情况下,免疫检查点多肽为选自以下的抑制检查点分子:A2AR、B7-H3、B7-H4、BTLA、CTLA-4、IDO、KIR、LAG3、PD-1、TIM3、CD96、TIGIT以及VISTA。
在一些情况下,免疫检查点抑制剂为对免疫检查点具特异性的抗体。适合的抗免疫检查点抗体包括但不限于纳武单抗(nivolumab)(Bristol-Myers Squibb)、派姆单抗(pembrolizumab)(Merck)、皮地利珠单抗(pidilizumab)(Curetech)、AMP-224(GlaxoSmithKline/Amplimmune)、MPDL3280A(Roche)、MDX-1105(Medarex,Inc./BristolMyer Squibb)、MEDI-4736(Medimmune/AstraZeneca)、阿维鲁单抗(arelumab)(MerckSerono)、伊匹单抗(ipilimumab)(YERVOY,(Bristol-Myers Squibb)、曲美木单抗(tremelimumab)(Pfizer)、皮地利珠单抗(CureTech,Ltd.)、IMP321(Immutep S.A.)、MGA271(Macrogenics)、BMS-986016(Bristol-Meyers Squibb)、利丽单抗(lirilumab)(Bristol-Myers Squibb)、乌瑞鲁单抗(urelumab)(Bristol-Meyers Squibb)、PF-05082566(Pfizer)、IPH2101(Innate Pharma/Bristol-Myers Squibb)、MEDI-6469(MedImmune/AZ)、CP-870,893(Genentech)、莫加珠单抗(Mogamulizumab)(Kyowa HakkoKirin)、万利鲁单抗(Varlilumab)(CelIDex Therapeutics)、阿维单抗(Avelumab)(EMDSerono)、加利昔单抗(Galiximab)(Biogen Idec)、AMP-514(Amplimmune/AZ)、AUNP 12(Aurigene和Pierre Fabre)、吲哚莫德(Indoximod)(NewLink Genetics)、NLG-919(NewLink Genetics)、INCB024360(Incyte);KN035;以及它们的组合。举例来说,在一些情况下,免疫检查点抑制剂为抗PD-1抗体。适合的抗PD-1抗体包括例如纳武单抗、派姆单抗(也称为MK-3475)、皮地利珠单抗、SHR-1210、PDR001以及AMP-224。在一些情况下,抗PD-1单克隆抗体为纳武单抗、派姆单抗或PDR001。美国专利公布号2017/0044259中描述了适合的抗PD1抗体。对于皮地利珠单抗,参见例如Rosenblatt等(2011)J.Immunother.34:409-18。在一些情况下,免疫检查点抑制剂为抗CTLA-4抗体。在一些情况下,抗CTLA-4抗体为伊匹单抗或曲美木单抗。用于曲美木单抗,参见例如Ribas等(2013)J.Clin.Oncol.31:616-22。在一些情况下,免疫检查点抑制剂为抗PD-L1抗体。在一些情况下,抗PD-L1单克隆抗体为BMS-935559、MEDI4736、MPDL3280A(也称为RG7446)、KN035或MSB0010718C。在一些实施方案中,抗PD-L1单克隆抗体为MPDL3280A(阿特珠单抗(atezolizumab))或MEDI4736(德瓦鲁单抗(durvalumab))。对于德瓦鲁单抗,参见例如WO 2011/066389。对于阿特珠单抗,参见例如美国专利号8,217,149。
在此类检查点抑制剂之中,针对PD-1、PD-L1以及CTLA-4的抗体为最常见的,其中至少纳武单抗、曲美木单抗、派姆单抗、伊匹单抗、赛米单抗(cemiplimab)、阿特珠单抗、阿维单抗、替雷利珠单抗(tisleizumab)以及德瓦鲁单抗已由FDA和/或美国以外的管理机构批准。本公开的TMP和二聚化TMP还可与检查点抑制剂的组合(例如(i)针对PD-1或PD-L1抗体与(ii)针对CTLA-4的抗体的组合)共施用。
在一些情况下,至少一种其他治疗剂包含一种或多种其他TMP或二聚化TMP。在一些情况下,所述方法包括向有需要的个体施用:a)包含第一TMP的第一组合物;以及b)包含第二TMP的第二组合物,其中第二TMP为不同于第一TMP的TMP,例如包含不同肽表位和/或一个或多个不同MOD。
用于治疗病毒感染的组合疗法
在一些情况下,所述方法包括向有需要的个体施用:a)包含TMP或二聚化TMP的第一组合物;以及b)包含第二抗病毒治疗剂的第二组合物。抗病毒剂为本领域中已知的,并且可使用任何已知抗病毒剂作为第二治疗剂。
适合于治疗的受试者
适合于用本公开的方法治疗的受试者包括患有癌症的个体,包括已被诊断为患有癌症的个体、已针对癌症进行治疗但未能对治疗作出反应的个体以及已针对癌症进行治疗并且最初作出反应但随后对治疗来说变得难治的个体。适合于治疗的受试者包括患有其中癌细胞表达或过表达癌症相关肽(诸如AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽、间皮素肽或病毒肽(例如CMV肽))的癌症的个体。
举例来说,在TMP或二聚化TMP包括AFP肽的情况下,适合于用此类TMP或二聚化TMP治疗的受试者包括患有肝细胞癌、胰腺癌、胃癌、结肠直肠癌、肝胚细胞瘤或卵巢卵黄囊瘤的个体。
作为另一实例,在TMP或二聚化TMP包括WT-1肽的情况下,适合于用此类TMP或二聚化TMP治疗的受试者包括患有白血病、促结缔组织增生小圆形细胞肿瘤、胃癌、结肠癌、肺癌、乳腺癌、生殖细胞肿瘤、卵巢癌、子宫癌、甲状腺癌、肝癌、肾癌、卡波西肉瘤、肉瘤、肝细胞癌、威尔姆氏瘤、急性骨髓性白血病(AML)、骨髓发育异常综合征(MDS)、非小细胞肺癌(NSCLC)、骨髓瘤、胰腺癌、结肠直肠癌、间皮瘤、软组织肉瘤、成神经细胞瘤或成肾细胞瘤的个体。
作为另一实例,在TMP或二聚化TMP包括HPV肽的情况下,适合于用此类TMP或二聚化TMP治疗的受试者包括患有头颈癌、宫颈癌、前列腺癌、卵巢癌或生殖肛门癌的个体。在TMP或二聚化TMP包含HPV肽表位的情况下,可向有需要的个体施用TMP或二聚化TMP以治疗个体的宫颈癌。在TMP或二聚化TMP包含HPV肽表位的情况下,可向有需要的个体施用TMP或二聚化TMP以治疗个体的前列腺癌。在TMP或二聚化TMP包含HPV肽表位的情况下,可向有需要的个体施用TMP或二聚化TMP以治疗个体的卵巢癌。在一些情况下,向已感染HPV并且具有意义未明的非典型性细胞(ACUS)的个体施用TMP或二聚化TMP。在一些情况下,向已感染HPV并且有过异常巴氏涂片(pap smear)结果的个体施用TMP或二聚化TMP。在一些情况下,向已感染HPV并且已被诊断为患有宫颈癌前驱病变(例如鳞状上皮内病变)的个体施用TMP或二聚化TMP。
作为另一实例,在TMP或二聚化TMP包括MUC-1肽的情况下,适合于用此类TMP或二聚化TMP治疗的受试者包括患有多发性骨髓瘤、B细胞淋巴瘤、乳腺癌、肺癌、卵巢癌、胰腺癌、结肠直肠癌、前列腺癌、肾癌、急性骨髓性白血病、间皮瘤、甲状腺癌、头颈癌、胃癌、尿路上皮癌、宫颈癌或卵巢子宫内膜癌的个体。
作为另一实例,在TMP或二聚化TMP包括MAGE A4肽的情况下,适合于用此类TMP或二聚化TMP治疗的受试者包括患有黑素瘤、膀胱癌、头颈癌、肺癌、食管癌、乳腺癌、结肠癌或卵巢癌的个体。
作为另一实例,在TMP或二聚化TMP包括NY-ESO-1肽的情况下,适合于用此类TMP或二聚化TMP治疗的受试者包括患有肺癌、食管癌、乳腺癌、胰腺癌、结肠直肠癌或卵巢癌的个体。
作为另一实例,在TMP或二聚化TMP包括存活素肽的情况下,适合于用此类TMP或二聚化TMP治疗的受试者包括患有食管癌(例如食管鳞状细胞癌)、黑素瘤、乳腺癌或白血病的个体。
作为另一实例,在TMP或二聚化TMP包括间皮素肽的情况下,适合于用此类TMP或二聚化TMP治疗的受试者包括患有间皮瘤、胰腺癌、卵巢癌或肺腺癌的个体。
在一些情况下,受试者为正在经历用免疫检查点抑制剂治疗的个体。在一些情况下,受试者为已经历过用免疫检查点抑制剂治疗但尽管接受了此类治疗其疾病仍发生进展的个体。在一些情况下,受试者为正在经历用癌症化学治疗剂治疗或已经历过用癌症化学治疗剂治疗的个体。在一些情况下,受试者为正准备经历用免疫检查点抑制剂治疗、正在经历用免疫检查点抑制剂治疗或已经历过用免疫检查点抑制剂治疗的个体。在一些情况下,受试者为正准备经历用癌症化学治疗剂、放射治疗、手术和/或使用另一治疗剂治疗;正在经历用癌症化学治疗剂、放射治疗、手术和/或使用另一治疗剂治疗;或已经历过用癌症化学治疗剂、放射治疗、手术和/或使用另一治疗剂治疗的个体。
检测方法
TMP或二聚化TMP可用于诊断应用和治疗应用。如下文所论述,当用于诊断应用时,TMP或二聚化TMP还可包含可检测标记,使得通过检测可检测标记来检测TMP或二聚化TMP与靶T细胞的结合。当用于此类诊断应用时,TMP或二聚化TMP可不包括一个或多个MOD,并且在此类情况下,无MOD的TMP或二聚化TMP被称为抗原呈递多肽(“APP”),在此情况下,为呈递肽表位的多肽。像TMP一样,APP也可为二聚化的。因此,以下与使用TMP和二聚化TMP的检测方法有关的论述旨在同样适用于使用APP和二聚化APP。
因此,本公开提供了一种检测抗原特异性T细胞的存在和/或活化的方法。所述方法包括使T细胞与本公开的TMP/APP或二聚化TMP/APP接触;以及检测TMP/APP或二聚化TMP/APP与T细胞的结合和/或T细胞的活化。本公开提供了一种检测抗原特异性T细胞的方法,所述方法包括使T细胞与本公开的TMP/APP或二聚化TMP/APP接触,其中TMP/APP或二聚化TMP/APP与T细胞的结合表明T细胞对存在于TMP/APP或二聚化TMP/APP中的肽表位具特异性,换句话说,T细胞包含对存在于TMP/APP或二聚化TMP/APP中的肽表位具特异性的T细胞受体。
在一些情况下,TMP/APP或二聚化TMP/APP包含可检测标记。适合的可检测标记包括但不限于放射性同位素、荧光多肽或产生荧光产物的酶以及产生有色产物的酶。在TMP/APP或二聚化TMP/APP包含可检测标记的情况下,通过检测可检测标记来检测TMP/APP或二聚化TMP/APP与T细胞的结合。
在一些情况下,TMP/APP或二聚化TMP/APP包含适合用于体内成像,例如适合用于正电子发射断层扫描(PET)、单光子发射断层扫描(SPECT)、近红外(NIR)光学成像、x射线成像、计算机辅助断层扫描(CAT)或磁共振成像(MRI)或其他体内成像方法的可检测标记。适合用于体内成像的标记的实例包括钆螯合物(例如钆与DTPA(二亚乙基三胺五乙酸)的螯合物、DTPA-二甲基酰胺(BMA)、DOTA(十二烷四乙酸)或HP-DO3A(1,4,7-三(羧基甲基)-10-(2'-羟丙基)-1,4,7,10-四氮杂环十二烷))、铁螯合物、镁螯合物、锰螯合物、铜螯合物、铬螯合物、碘基材料以及放射性核素。适合的放射性核素包括但不限于
适合的荧光蛋白包括但不限于绿色荧光蛋白(GFP)或其变体、GFP的蓝色荧光变体(BFP)、GFP的青色荧光变体(CFP)、GFP的黄色荧光变体(YFP)、增强型GFP(EGFP)、增强型CFP(ECFP)、增强型YFP(EYFP)、GFPS65T、Emerald、Topaz(TYFP)、Venus、Citrine、mCitrine、GFPuv、去稳定化EGFP(dEGFP)、去稳定化ECFP(dECFP)、去稳定化EYFP(dEYFP)、mCFPm、Cerulean、T-Sapphire、CyPet、YPet、mKO、HcRed、t-HcRed、DsRed、DsRed2、DsRed-单体、J-Red、dimer2、t-dimer2(12)、mRFP1、pocilloporin、海肾GFP、Monster GFP、paGFP、Kaede蛋白以及粘着斑蛋白(kindling protein)、藻胆蛋白以及藻胆蛋白缀合物,包括B-藻红素、R-藻红素以及别藻蓝素。荧光蛋白的其他实例包括mHoneydew、mBanana、mOrange、dTomato、tdTomato、mTangerine、mStrawberry、mCherry、mGrape1、mRaspberry、mGrape2、mPlum(Shaner等(2005)Nat.Methods 2:905-909)等。如例如Matz等(1999)NatureBiotechnol.17:969-973中所描述的来自珊瑚虫物种的多种荧光和有色蛋白中的任一者均适合使用。
适合的酶包括但不限于辣根过氧化物酶(HRP)、碱性磷酸酶(AP)、β-半乳糖苷酶(GAL)、葡糖-6-磷酸脱氢酶、β-N-乙酰氨基葡糖苷酶、β-葡萄糖醛酸酶、转化酶、黄嘌呤氧化酶、荧光虫荧光素酶、葡萄糖氧化酶(GO)等。
在一些情况下,使用可检测标记的对TMP/APP或二聚化TMP/APP具特异性的抗体来检测TMP/APP或二聚化TMP/APP与T细胞的结合。对TMP/APP或二聚化TMP/APP具特异性的抗体可包含可检测标记,诸如放射性同位素、荧光多肽或产生荧光产物的酶或产生有色产物的酶。
在一些情况下,正在检测的T细胞存在于包含多个T细胞的样品中。举例来说,所检测的T细胞可存在于包含10至10
HLA/肽结合分析
可使用许多熟知方法中的任一者来确定给定肽(例如包含癌症相关表位的肽)是否结合I类HLA(包含HLA重链和β2M多肽)并且当结合至HLA复合体时可有效地将表位呈递至TCR。分析包括结合分析和T细胞活化分析,包括基于细胞的结合分析、生物化学结合分析、T细胞活化分析、ELISPOT分析、细胞毒性分析以及用肽-HLA四聚体检测抗原特异性T细胞。公布的科学文献中以及公布的PCT申请WO2020132138A1中描述了此类分析,所述参考文献的公开内容关于特异性结合分析明确地以引用的方式并入本文中,特别地包括段落[00217]-[00225]。
作为另一实例,使用荧光或重金属标签产生肽-HLA复合体的多聚体(例如四聚体)。然后可使用多聚体经由流式细胞术(FACS)或大量血细胞计数(CyTOF)鉴定和定量特定T细胞。表位特异性T细胞的检测提供肽结合HLA分子能够结合至抗原特异性T细胞的子集上的特定TCR的直接证据。参见例如Klenerman等(2002)Nature Reviews Immunol.2:263。
本公开的非限制性方面的实例
方面集合A
上文所描述的本发明主题的方面(包括实施方案)单独或与一个或多个其他方面或实施方案组合可为有益的。在不限制前述描述的情况下,以下提供本公开的某些非限制性方面。如在阅读本公开后将对本领域技术人员来说显而易见的,可使用个别编号的方面中的每一者或与先前或之后个别编号的方面中的任一者组合。这旨在为诸多个方面的所有此类组合提供支持并且不限于下文明确提供的方面的组合:
方面1.一种单链T细胞调节多肽(TMP),所述单链T细胞调节多肽包含:
i)包含在癌细胞或病毒上表达的表位的肽,其中所述肽具有约4个氨基酸至约25个氨基酸的长度,并且其中所述肽不是KRAS肽;
ii)第一主要组织相容性复合体(MHC)多肽;
iii)第二MHC多肽,以及
iv)至少一个免疫调节多肽,
其中所述第一主要组织相容性复合体(MHC)多肽为β2-微球蛋白多肽;并且其中所述第二MHC多肽为MHC I类重链多肽,任选其中所述TMP包含免疫球蛋白(Ig)Fc多肽,以及任选的一个或多个肽接头,所述任选的一个或多个肽接头键联所述TMP的一个或多个组分。
方面2.如方面1所述的TMP,其中所述肽为甲胎蛋白(AFP)肽。
方面3.如方面2所述的TMP,其中所述AFP肽包含选自由以下组成的组的氨基酸序列:AITRKMAAT(SEQ ID NO:42);AYTKKAPQL(SEQ ID NO:43);LLNQHACAV(SEQ ID NO:44);KLVLDVAHV(SEQ ID NO:45);FMNKFIYEI(SEQ ID NO:46);SIPLFQVPE(SEQ ID NO:47);LLNFTESRT(SEQ ID NO:48);FVQEATYKF(SEQ ID NO:49);ATYKEVSKM(SEQ ID NO:50);KEVSKMVKD(SEQ ID NO:51);RHNCFLAHK(SEQ ID NO:52);ATAATCCQL(SEQ ID NO:53);YIQESQALA(SEQ ID NO:54);QLTSSELMAI(SEQ ID NO:55);KLSQKFTKV(SEQ ID NO:56);KELRESSLL(SEQ ID NO:57);SLVVDETYV(SEQ ID NO:58);ILLWAARYD(SEQ ID NO:59);KIIPSCCKA(SEQ ID NO:60);CRGDVLDCL(SEQ ID NO:61);QQDTLSNKI(SEQ ID NO:62);TMKQEFLINL(SEQ ID NO:63);NLVKQKPQI(SEQ ID NO:64);AVIADFSGL(SEQ ID NO:65);LLACGEGAA(SEQ ID NO:66);LACGEGAAD(SEQ ID NO:67);KAPQLTSSEL(SEQ ID NO:68);YICSQQDTL(SEQ ID NO:69);TECCKLTTL(SEQ ID NO:70);CTAEISLADL(SEQ ID NO:71);VTKELRESSL(SEQ ID NO:72);IMSYICSQQD(SEQ ID NO:73);TRTFQAITV(SEQ ID NO:74);FQKLGEYYL(SEQ ID NO:75);RVAKGYQEL(SEQ ID NO:76);SYQCTAEISL(SEQ ID NO:77);KQEFLINLV(SEQ ID NO:78);MKWVESIFL(SEQ ID NO:79);PVNPGVGQC(SEQ ID NO:80);AADIIIGHL(SEQ ID NO:81);QVPEPVTSC(SEQ ID NO:82);TTLERGQCII(SEQ ID NO:83);KMAATAATC(SEQ ID NO:84);QAQGVALQTM(SEQ ID NO:85);FQAITVTKL(SEQ ID NO:86);LLEKCFQTE(SEQ ID NO:87);VAYTKKAPQ(SEQ ID NO:88);KYIQESQAL(SEQ ID NO:89);GVALQTMKQ(SEQ ID NO:90);GQEQEVCFA(SEQ ID NO:91);SEEGRHNCFL(SEQ ID NO:92);RHPFLYAPTI(SEQ ID NO:93);TEIQKLVLDV(SEQ ID NO:94);RRHPQLAVSV(SEQ ID NO:95);GEYYLQNAFL(SEQ ID NO:96);NRRPCFSSLV(SEQ ID NO:97);LQTMKQEFLI(SEQ ID NO:98);IADFSGLLEK(SEQ ID NO:99);GLLEKCCQGQ(SEQ ID NO:100);TLSNKITEC(SEQ ID NO:101);LQDGEKIMSY(SEQ ID NO:102);GLFQKLGBY(SEQ ID NO:103);NEYGIASILD(SEQ ID NO:104);KMVKDALTAI(SEQ ID NO:105);FLASFVHEY(SEQ ID NO:106);以及AQFVQEATY(SEQ ID NO:107)。
方面4.如方面1所述的TMP,其中所述肽为威尔姆氏瘤-1(WT-1)肽。
方面5.如方面4所述的TMP,其中所述WT-1肽表位包含选自由以下组成的组的氨基酸序列:NLMNLGATL(SEQ ID NO:152)、NYMNLGATL(SEQ ID NO:157)、CMTWNQMNLGATLKG(SEQID NO:117)、WNQMNLGATLKGVAA(SEQ ID NO:118)、CMTWNY MNLGATLKG(SEQ ID NO:119)、WNYMNLGATLKGVAA(SEQ ID NO:120)、MTWNQMNLGATLKGV(SEQ ID NO:121)、TWNQMNLGATLKGVA(SEQ ID NO:122)、CMTWNLMNLGATLKG(SEQ ID NO:123)、MTWNLMNLGATLKGV(SEQ IDNO:124)、TWNLMNLGA TLKGVA(SEQ ID NO:125)、WNLMNLGATLKGVAA(SEQ IDNO:126)、MNLGATLK(SEQ ID NO:127)、MTWNYMNLGATLKGV SEQ ID NO:128)、TWNYMNLGATLKGVA(SEQ IDNO:129)、CMTWNQMNLGATLKGVA(SEQ ID NO:130)、CMTWNLMNLGA TLKGVA(SEQ ID NO:131)、CMTWNYMNLGATLKGVA(SEQ ID NO:132)、GYLRNPTAC(SEQ ID NO:133)、GALRNPTAL(SEQ IDNO:134)、YALRNPTAC(SEQ ID NO:135)、GLLRNPTAC(SEQ ID NO:136)、RYRPHPGAL(SEQ IDNO:137)、YQRPHPGAL(SEQ ID NO:138)、RLRPHPGAL(SEQ ID NO:139)、RIRPHPGAL(SEQ IDNO:140)、QFPNHSFKHEDPMGQ(SEQ ID NO:141)、HSFKHEDPY(SEQ ID NO:142)、QFPNHSFKHEDPM(SEQ ID NO:143)、QFPNHSFKHEDPY(SEQ ID NO:144)、KRPFMCAYPGCNK(SEQ ID NO:145)、KRPFMCAYPGCYK(SEQ ID NO:146)、FMCAYPGCY(SEQ ID NO:147)、FMCAYPGCK(SEQ ID NO:148)、KRPFMCAYPG CNKRY(SEQ ID NO:149)、SEKRPFMCAYPGCNK(SEQ ID NO:150)、KRPFMCAYPGCYKRY(SEQ ID NO:151)、NLMNLGATL(SEQ ID NO:152)、VLDFAPPGA(SEQ ID NO:153)、RMFPNAPYL(SEQ ID NO:154)、CMTWNQMN(SEQ ID NO:155)、CYTWNQMNL(SEQ ID NO:156)、NYMNLGATL(SEQ ID NO:157)、YMFPNAPYL(SEQ ID NO:158)、SLGEQQYSV(SEQ ID NO:159)、CMTWNQMNL(SEQ ID NO:160)以及NQMNLGATL(SEQ ID NO:161)。
方面6.如方面4所述的TMP,其中所述WT-1肽包含氨基酸序列CMTWNQMNL(SEQ IDNO:160)、CYTWNQMNL(SEQ ID NO:156)、NYMNLGATL(SEQ ID NO:157)、VLDFAPPGA(SEQ IDNO:153)、YMFPNAPYL(SEQ ID NO:158)、SLGEQQYSV(SEQ ID NO:159)、RMFPNAPYL(SEQ IDNO:154)以及NLMNLGATL(SEQ ID NO:152)。
方面7.如方面4所述的TMP,其中所述第一MHC多肽为β2M多肽,并且其中所述第二MHC多肽包含与HLA-A*2402多肽具有至少95%的氨基酸序列同一性的氨基酸序列,并且其中所述表位选自由以下组成的组:RMFPNAPYL(SEQ ID NO:154)、CYTWNQMNL(SEQ ID NO:156)以及NYMNLGATL(SEQ ID NO:157)。
方面8.如方面4所述的TMP,其中所述第一MHC多肽为β2M多肽,并且其中所述第二MHC多肽包含与HLA-A*0201多肽具有至少95%的氨基酸序列同一性的氨基酸序列,并且其中所述表位选自由以下组成的组:VLDFAPPGA(SEQ ID NO:153)、RMFPNAPYL(SEQ ID NO:154)以及YMFPNAPYL(SEQ ID NO:158)。
方面9.如方面1所述的TMP,其中所述肽为人乳头瘤病毒(HPV)肽表位。
方面10.如方面9所述的TMP,其中所述HPV肽表位为E6 18-26(KLPQLCTEL;SEQ IDNO:162);E6 26-34(LQTTIHDII;SEQ ID NO:163);E6 49-57(VYDFAFRDL;SEQ ID NO:164);E6 52-60(FAFRDLCIV;SEQ ID NO:165);E6 75-83(KFYSKISEY;SEQ ID NO:166);E6 80-88(ISEYRHYCY;SEQ ID NO:167);E7 7-15(TLHEYMLDL;SEQ ID NO:168);E7 11-19(YMLDLQPET;SEQ ID NO:169);E7 44-52(QAEPDRAHY;SEQ ID NO:170);E7 49-57(RAHYNIVTF(SEQ ID NO:171);E7 61-69(CDSTLRLCV;SEQ ID NO:172);以及E7 67-76(LCVQSTHVDI;SEQ ID NO:173);E7 82-90(LLMGTLGIV;SEQ ID NO:174);E7 86-93(TLGIVCPI;SEQ ID NO:175);或E7 92-93(LLMGTLGIVCPI;SEQ ID NO:176)。
方面11.如方面9所述的TMP,其中所述HPV肽表位包含:
a)HPV E6氨基酸序列VYDFAFRDL(SEQ ID NO:164);或
b)选自由以下组成的组的HPV E7氨基酸序列:RAHYNIVTF(SEQ ID NO:171);CDSTLRLCV(SEQ ID NO:172);以及LCVQSTHVDI(SEQ ID NO:173)。
方面12.如方面1所述的TMP,其中所述肽为MUC-1肽。
方面13.如方面12所述的TMP,其中所述MUC-1肽包含选自由以下组成的组的氨基酸序列:STAPPAHGV(SEQ ID NO:197);STAPPVHNV(SEQ ID NO:198);SLAPPVHNV(SEQ ID NO:199);SLAPPAHGV(SEQ ID NO:200);SAPDTRPAP(SEQ ID NO:201);VTSAPDTRPAPGSTAPPAHG(SEQ ID NO:202);PDTRPAPGSTAPP AHGVTSA(SEQ ID NO:203);以及LLLLTVLTV(SEQ ID NO:204)。
方面14.如方面1所述的TMP,其中所述肽为黑素瘤相关抗原-4(MAGE-A4)肽。
方面15.如方面14所述的TMP,其中所述MAGE-A4肽包含选自以下的氨基酸序列:GVYDGREHTV(SEQ ID NO:206)、NYKRCFPVI(SEQ ID NO:207)、EVDPASNTY(SEQ ID NO:208)、SESLKMIF(SEQ ID NO:209)以及SESLICMIF(SEQ ID NO:210)。
方面16.如方面1所述的TMP,其中所述肽为NY-ESO-1肽。
方面17.如方面16所述的TMP,其中所述NY-ESO-1肽包含选自以下的氨基酸序列:SLLMWITQCFL(SEQ ID NO:212)、SLLMWITQC(SEQ ID NO:213)、QLSLLMWIT(SEQ ID NO:214)以及SLLMWITQCFLPVF(SEQ ID NO:215)。
方面18.如方面1所述的TMP,其中所述肽为存活素肽。
方面19.如方面18所述的TMP,其中所述存活素肽包含选自以下的氨基酸序列:TLGEFLKLDRERAKN(SEQ ID NO:229)、QMFFCF(SEQ ID NO:230)、DLAQMFFCFKELEGW(SEQ IDNO:231)、AQMFFCFKEL(SEQ ID NO:232)以及QMFFCFKEL(SEQ ID NO:233)。
方面20.如方面1所述的TMP,其中所述肽为间皮素肽。
方面21.如方面20所述的TMP,其中所述间皮素肽包含选自以下的氨基酸序列:SLLFLLFSL(SEQ ID NO:235)、VLPLTVAEV(SEQ ID NO:236)、ELAVALAQK(SEQ ID NO:237)、ALQGGGPPY(SEQ ID NO:238)、FYPGYLCSL(SEQ ID NO:239)以及LYPKARLAF(SEQ ID NO:240)。
方面22.如方面1所述的TMP,其中所述肽为病毒抗原的肽。
方面23.如方面22所述的TMP,其中所述病毒抗原为巨细胞病毒(CMV)多肽。
方面24.如方面23所述的TMP,其中所述CMV多肽为CMV pp65多肽。
方面25.如方面24所述的TMP,其中所述肽具有氨基酸序列NLVPMVATV(SEQ ID NO:247)并且具有9个氨基酸的长度。
方面26.如方面1-25中的任一方面所述的TMP,其中所述β2M多肽与所述MHC重链多肽通过二硫键连接,所述二硫键连接所述β2M多肽中的Cys残基和所述MHC重链多肽中的Cys残基,任选其中在所述β2M多肽的氨基酸残基12处的Cys以二硫键键合至在所述MHC重链多肽的氨基酸残基236处的Cys。
方面27.如方面1-26中任一项所述的TMP,其中所述β2-微球蛋白多肽通过包含Cys的第一接头连接至所述肽,并且其中二硫键键联存在于所述第一接头中的Cys与存在于所述MHC重链多肽中的Cys,任选其中所述第一接头包含序列CGGGS(GGGGS)n(SEQ ID NO:439)或GCGGS(GGGGS)n(SEQ ID NO:436),其中n为1-10的整数,例如2或3,并且二硫键键联所述接头中的所述Cys与取代所述MHC重链多肽的Tyr84的Cys。
方面28.如方面1-27中任一项所述的TMP,其中所述MHC重链多肽包含与选自由HLA-A*0201多肽、HLA-A*1101多肽、HLA-A*3303多肽、HLA-A*2401多肽组成的组的HLA-A多肽、HLA-E多肽以及HLA-G多肽具有至少95%的氨基酸序列同一性的氨基酸序列。
方面29.如方面1-28中任一项所述的TMP,其中所述至少一个免疫调节多肽为选自由以下组成的组的活化免疫调节多肽的野生型或变体:IL-2、4-1BBL、CD80、CD86或它们的组合,任选其中所述至少一个免疫调节多肽中的至少一者为变体免疫调节多肽,与对应野生型免疫调节多肽对同源共刺激多肽的亲和力相比,所述变体免疫调节多肽展现降低的对所述同源共刺激多肽的亲和力。
方面30.如方面29所述的TMP,其中所述至少一个免疫调节多肽为IL-2的变体,所述变体展现降低的对IL-2Rα和IL-2Rβ的结合亲和力,任选其中所述变体IL-2多肽包含i)H16A取代和F42A取代;或ii)H16T取代和F42A取代。
方面31.如方面29或30所述的TMP,所述TMP包含所述免疫调节多肽的两个拷贝。
方面32.如方面31所述的TMP,其中所述免疫调节多肽的所述两个拷贝为串联的,任选其中在所述两个拷贝之间插入肽接头。
方面33.如方面1-32中任一项所述的TMP,所述TMP包含Ig Fc多肽。
方面34.如方面33所述的TMP,其中所述Ig Fc多肽基本上不诱导细胞溶解,任选其中所述Ig Fc多肽包含选自以下的一个或多个氨基酸取代:N297A、L234A、L235A、L234F、L235E以及P331S。
方面35.如方面33或方面34所述的TMP,其中所述Ig Fc多肽包含与图2A至图2M中任一者所展示的氨基酸序列具有至少95%的氨基酸序列同一性的氨基酸序列。
方面36.如方面1-35中任一项所述的TMP,所述TMP按从N端到C端的顺序包含:
i)所述肽;
ii)任选的肽接头;
iii)所述β2M多肽;
iv)任选的肽接头;
v)所述MHC I类重链多肽;
vi)任选的肽接头;
vii)Ig Fc多肽;
viii)任选的肽接头;以及
ix)所述一个或多个免疫调节多肽。
方面37.如方面1-35中任一项所述的TMP,所述TMP按从N端到C端的顺序包含:
i)所述肽;
ii)任选的肽接头;
iii)所述β2M多肽;
iv)任选的肽接头;
v)所述MHC I类重链多肽;
vi)任选的肽接头;
vii)所述一个或多个免疫调节多肽;
viii)任选的肽接头;以及
ix)Ig Fc多肽。
方面38.如方面1-37中任一项所述的TMP,其中所述任选肽接头中的每一者如果存在,那么独立地选自由以下组成的组:
i)CGGGS(GGGGS)n(SEQ ID NO:439),其中n为1-10的整数;
ii)GCGGS(GGGGS)n(SEQ ID NO:436),其中n为1-10的整数;
iii)(GGGGS)n(GCGGS)(SEQ ID NO:447),其中n为1-10的整数;
iv)(GGGGS)n(SEQ ID NO:572),其中n为1-10的整数;
v)AAAGG(SEQ ID NO:411);
vi)(AP)n,其中n为1-10的整数(SEQ ID NO:584);
vii)(EP)n,其中n为1-10的整数(SEQ ID NO:585);
viii)(KP)n,其中n为1-10的整数(SEQ ID NO:586);以及
ix)包含EAAAK(SEQ ID NO:412)的肽。
方面39.如方面1-37中任一项所述的TMP,其中所述任选肽接头中的每一者如果存在,那么独立地选自由以下组成的组:
i)CGGGS(GGGGS)n(SEQ ID NO:588),其中n为2、3或4;
ii)GCGGS(GGGGS)n(SEQ ID NO:589),其中n为2、3或4;
iii)(GGGGS)n(GCGGS)(SEQ ID NO:590),其中n为2、3或4;
iv)(GGGGS)n(SEQ ID NO:591),其中n为2、3或4;
v)AAAGG(SEQ ID NO:411);
vi)(AP)n,其中n为2-10(SEQ ID NO:592);
vii)(EP)n,其中n为2-10(SEQ ID NO:593);
viii)(KP)n,其中n为2-10(SEQ ID NO:594);以及
ix)AEAAAKEAAAKA(SEQ ID NO:419)。
方面40.如方面36或方面37所述的TMP,其中所述β2M多肽通过第一接头连接至所述肽,所述第一接头包含序列CGGGS(GGGGS)n(SEQ ID NO:439)或GCGGS(GGGGS)n(SEQ IDNO:436),其中n为1-10的整数,例如2或3,
其中所述MHC重链多肽包含在残基84处的Cys以及在残基236处的Cys,
其中所述β2M多肽包含在残基12处的Cys,
其中在所述β2M多肽的氨基酸残基12处的所述Cys以二硫键键合至在所述MHC重链多肽的氨基酸残基236处的Cys,
其中二硫键键联所述接头中的所述Cys与取代所述MHC重链多肽的Tyr84的Cys,
其中所述β2M多肽通过(GGGGS)n接头(SEQ ID NO:572)连接至所述MHC重链多肽,其中n为1、2、3、4、5、6、7、8、9或10,例如其中n=3或7,
其中所述MHC重链多肽包含与选自由以下组成的组的HLA-A多肽具有至少95%的氨基酸序列同一性的氨基酸序列:HLA-A*0201多肽、HLA-A*1101多肽、HLA-A*3303多肽以及HLA-A*2401多肽,
其中所述至少一个免疫调节多肽为IL-2的变体,所述变体包含i)H16A取代和F42A取代;或ii)H16T取代和F42A取代,并且
其中所述多肽包含两个免疫调节多肽,所述两个免疫调节多肽为相同的、串联的,并且包含IL-2的变体,所述变体包含i)H16A取代和F42A取代;或ii)H16T取代和F42A取代。
方面41.如方面1-39中任一项所述的TMP,其中所述TMP包含如图13A至图13D以及图18A至图18T中任一者所展示的氨基酸序列,其中(X)为所述肽,并且其中(X)为如方面2-25中任一项所述的肽。
方面42.如方面1-41中任一项所述的TMP,其中所述TMP包含:(a)至少一个刚性肽接头,任选其中所述TMP包含所述Ig Fc多肽与所述一个或多个免疫调节多肽中的一者之间的刚性肽接头;和/或(b)至少一个短可挠性肽接头,所述至少一个短可挠性肽接头包含2-14个氨基酸,任选其中所述TMP包含所述Ig Fc多肽与所述一个或多个免疫调节多肽中的一者之间的短可挠性肽接头。
方面43.如方面42所述的TMP,其中所述TMP包含至少一个刚性肽接头,并且其中各刚性肽接头独立地选自由以下组成的组:i)(AP)n,其中n为1-10的整数(SEQ ID NO:584);ii)(EP)n,其中n为1-10的整数(SEQ ID NO:585);iii)(KP)n,其中n为1-10的整数(SEQ IDNO:586);以及iv)包含EAAAK(SEQ ID NO:412)的肽。
方面44.如方面42所述的TMP,其中所述TMP包含至少一个刚性肽接头,并且其中各刚性肽接头独立地选自由以下组成的组:
i)(AP)n,其中n为2-6(SEQ ID NO:595);
ii)(EP)n,其中n为2-6(SEQ ID NO:596);
iii)(KP)n,其中n为2-6(SEQ ID NO:597);以及
iv)A(EAAAK)nA(SEQ ID NO:598),其中n为1或2。
方面45.一种蛋白质,所述蛋白质包含(i)均二聚体,所述均二聚体包含两个相同的如方面1-44中任一项所述的TMP,任选其中所述两个TMP通过一个或多个二硫键连接至彼此,所述一个或多个二硫键使一个TMP的免疫球蛋白(Ig)Fc多肽连接至另一TMP的所述IgFc多肽,或(ii)异二聚体,所述异二聚体包含两个不同的如方面1-44中任一项所述的TMP,任选其中所述两个TMP通过种间结合序列连接至彼此。
方面46.一种药物组合物,所述药物组合物包含根据方面1-44中任一项所述的TMP。
方面47.一种药物组合物,所述药物组合物包含如方面45所述的蛋白质。
方面48.一种核酸,所述核酸包含根据方面1-44中任一项所述的核苷酸序列TMP。
方面49.一种选择性调节对癌症相关肽表位具特异性的T细胞的活性的方法,所述方法包括使所述T细胞与根据方面1-44中任一项所述的TMP或根据方面45所述的蛋白质接触,其中所述接触选择性调节所述表位特异性T细胞的活性。
方面50.一种治疗患有癌症的患者的所述癌症的方法,所述方法包括向所述患者施用有效量的包含根据方面1-44中任一项所述的TMP、根据方面45所述的蛋白质的药物组合物或根据方面46或方面47所述的药物组合物。
方面51.如方面50所述的方法,所述方法还包括向所述患者共施用免疫检查点抑制剂,任选其中所述免疫检查点抑制剂为对PD-L1、PD-1或CTLA4具特异性的抗体。
方面52.一种治疗患有感染的患者的所述感染的方法,所述方法包括向所述患者施用有效量的包含根据方面1、9-11以及22-44中任一项所述的TMP、根据方面45所述的蛋白质的药物组合物或根据方面46或方面47所述的药物组合物。
方面52.一种治疗患有感染的患者的所述感染的方法,所述方法包括向所述患者施用有效量的包含根据方面1、9-11以及22-44中任一项所述的TMP、根据方面45所述的蛋白质的药物组合物或根据方面46或方面47所述的药物组合物。
方面53.一种增加T细胞调节多肽(TMP)的热稳定性的方法,所述T细胞调节多肽包含:
i)在癌细胞上或病毒上表达的肽表位,其中所述肽具有约4个氨基酸至约20个氨基酸的长度;
ii)第一主要组织相容性复合体(MHC)多肽,其中所述第一MHC多肽为β2-微球蛋白(β2M)多肽;
iii)第二MHC多肽,其中所述第二MHC多肽为MHC I类重链多肽;
iv)一个或多个免疫调节多肽(MOD);以及
v)免疫球蛋白(Ig)Fc多肽,
其中,当所述TMP包含一个或多个位置-2MOD时,所述方法包括在以下中的一者或多者之间插入刚性肽接头或短可挠性接头:(i)所述MHC I类重链多肽与MOD以及(ii)所述Ig Fc多肽与MOD,并且任选地,当存在两个或更多个MOD时,在所述两个或更多个MOD中的至少两者之间,并且
其中,当所述TMP包含一个或多个位置3MOD时,所述方法包括在所述Ig Fc多肽与MOD之间,并且任选地当存在两个或更多个MOD时在所述两个或更多个MOD中的至少两者之间插入刚性肽接头或短可挠性接头。
方面54.根据方面53所述的方法,其中各刚性肽接头独立地选自由以下组成的组:
i)(AP)n,其中n为1-10的整数(SEQ ID NO:584);
ii)(EP)n,其中n为1-10的整数(SEQ ID NO:585);
iii)(KP)n,其中n为1-10的整数(SEQ ID NO:586);以及
iv)包含EAAAK(SEQ ID NO:412)的肽。
方面55.根据方面53所述的方法,其中所述TMP包含至少一个刚性肽接头,并且其中各刚性肽接头独立地选自由以下组成的组:
i)(AP)n,其中n为2-6(SEQ ID NO:595);
ii)(EP)n,其中n为2-6(SEQ ID NO:596);
iii)(KP)n,其中n为2-6(SEQ ID NO:597);以及
iv)A(EAAAK)nA(SEQ ID NO:598),其中n为1或2。
方面56.根据方面53所述的方法,其中各短可挠性肽接头独立地选自由包含选自由以下组成的组的氨基酸数目的可挠性肽接头组成的组:2-4aa、2-5aa、3-6aa、4-8aa、5-10aa以及10-14aa。
方面57.根据方面53所述的方法,其中各短可挠性肽接头独立地选自由以下组成的组:2-4个氨基酸(aa)、2-5aa、3-6aa以及4-8aa,并且任选其中所述短可挠性肽接头为GGS。
方面58.根据方面53所述的方法,其中所述肽表位为AFP肽、WT1肽、HPV肽、MUC1肽、MAGE A4肽、NY-ESO-1肽、存活素肽、间皮素肽或病毒肽。
方面59.根据方面49-58中任一项所述的方法,其中所述蛋白质为均二聚体,所述均二聚体包含两个相同的如方面1-44中任一项所述的TMP,任选其中所述两个TMP通过一个或多个二硫键连接至彼此,所述一个或多个二硫键使一个TMP的免疫球蛋白(Ig)Fc多肽连接至另一TMP的所述Ig Fc多肽。
方面集合B
上文所描述的本发明主题的方面(包括实施方案)单独或与一个或多个其他方面或实施方案组合可为有益的。在不限制前述描述的情况下,以下提供本公开的某些非限制性方面。如在阅读本公开后将对本领域技术人员来说显而易见的,可使用个别编号的方面中的每一者或与先前或之后个别编号的方面中的任一者组合。这旨在为诸多个方面的所有此类组合提供支持并且不限于下文明确提供的方面的组合:
方面1.一种单链T细胞调节多肽(TMP),所述单链T细胞调节多肽包含:
i)包含在癌细胞上表达的表位的肽,其中所述肽具有约7个氨基酸至约16个氨基酸,任选8个氨基酸至12个氨基酸的长度,并且其中所述肽不是KRAS肽;
ii)第一主要组织相容性复合体(MHC)多肽;
iii)第二MHC多肽,以及
iv)至少一个免疫调节多肽,
其中所述第一主要组织相容性复合体(MHC)多肽为β2-微球蛋白多肽;并且其中所述第二MHC多肽为MHC I类重链多肽,任选其中所述TMP包含免疫球蛋白(Ig)Fc多肽,以及任选的一个或多个肽接头,所述任选的一个或多个肽接头键联所述TMP的一个或多个组分。
方面2.如方面1所述的TMP,其中所述肽为甲胎蛋白(AFP)肽、威尔姆氏瘤-1(WT-1)肽、人乳头瘤病毒(HPV)肽表位、MUC-1肽、黑素瘤相关抗原-4(MAGE-A4)肽、NY-ESO-1肽、存活素肽、间皮素肽或病毒抗原的肽。
方面3.如方面1所述的TMP,其中:
(a)所述β2M多肽与所述MHC重链多肽通过二硫键连接,所述二硫键连接所述β2M多肽中的Cys残基和所述MHC重链多肽中的Cys残基,任选其中在所述β2M多肽的氨基酸残基12处的Cys以二硫键键合至在所述MHC重链多肽的氨基酸残基236处的Cys;
(b)所述β2-微球蛋白多肽通过包含Cys的第一接头连接至所述肽,并且其中二硫键键联存在于所述第一接头中的Cys与存在于所述MHC重链多肽中的Cys,任选其中所述第一接头包含序列CGGGS(GGGGS)n(SEQ ID NO:439)或GCGGS(GGGGS)n(SEQ ID NO:436),其中n为1-10的整数,例如2或3,并且二硫键键联所述接头中的所述Cys与取代所述MHC重链多肽的Tyr84的Cys;或
(c)所述β2M多肽与所述MHC重链多肽通过二硫键连接,所述二硫键连接所述β2M多肽中的Cys残基和所述MHC重链多肽中的Cys残基,任选其中在所述β2M多肽的氨基酸残基12处的Cys以二硫键键合至在所述MHC重链多肽的氨基酸残基236处的Cys,并且所述β2-微球蛋白多肽通过包含Cys的第一接头连接至所述肽,并且其中二硫键键联存在于所述第一接头中的Cys与存在于所述MHC重链多肽中的Cys,任选其中所述第一接头包含序列CGGGS(GGGGS)n(SEQ ID NO:439)或GCGGS(GGGGS)n(SEQ ID NO:436),其中n为1-10的整数,例如2或3,并且二硫键键联所述接头中的所述Cys与取代所述MHC重链多肽的Tyr84的Cys。
方面4.如方面1所述的TMP,其中所述MHC重链多肽包含与选自由HLA-A*0201多肽、HLA-A*1101多肽、HLA-A*3303多肽、HLA-A*2401多肽组成的组的HLA-A多肽、HLA-E多肽以及HLA-G多肽具有至少95%的氨基酸序列同一性的氨基酸序列。
方面5.如方面1所述的TMP,其中所述至少一个免疫调节多肽为选自由以下组成的组的活化免疫调节多肽的野生型或变体:IL-2、4-1BBL、CD80、CD86或它们的组合,任选其中所述至少一个免疫调节多肽中的至少一者为变体免疫调节多肽,与对应野生型免疫调节多肽对同源共刺激多肽的亲和力相比,所述变体免疫调节多肽展现降低的对所述同源共刺激多肽的亲和力。
方面6.如方面5所述的TMP,其中所述至少一个免疫调节多肽为IL-2的变体,所述变体展现降低的对IL-2Rα和IL-2Rβ的结合亲和力,任选其中所述变体IL-2多肽包含i)H16A取代和F42A取代;或ii)H16T取代和F42A取代。
方面7.如方面1所述的TMP,所述TMP包含Ig Fc多肽,任选其中所述Ig Fc包含与图2A至图2M中所展示的氨基酸序列中的任一者具有至少95%的氨基酸序列同一性的氨基酸序列。
方面8.如方面7所述的TMP,其中所述Ig Fc多肽基本上不诱导细胞溶解,任选其中所述Ig Fc多肽包含选自以下的一个或多个氨基酸取代:N297A、L234A、L235A、L234F、L235E以及P331S。
方面9.如方面1所述的TMP,所述TMP按从N端到C端的顺序包含:
i)所述肽;
ii)任选的肽接头;
iii)所述β2M多肽;
iv)任选的肽接头;
v)所述MHC I类重链多肽;
vi)任选的肽接头;
vii)Ig Fc多肽;
viii)任选的肽接头;以及
ix)所述一个或多个免疫调节多肽;或
i)所述肽;
ii)任选的肽接头;
iii)所述β2M多肽;
iv)任选的肽接头;
v)所述MHC I类重链多肽;
vi)任选的肽接头;
vii)所述一个或多个免疫调节多肽;
viii)任选的肽接头;以及
ix)Ig Fc多肽。
方面10.如方面1所述的TMP,其中所述任选肽接头中的每一者如果存在,那么独立地选自由以下组成的组:
i)CGGGS(GGGGS)n,其中n为1-10的整数,任选其中n为2、3或4;
ii)GCGGS(GGGGS)n,其中n为1-10的整数,任选其中n为2、3或4;
iii)(GGGGS)n(GCGGS),其中n为1-10的整数,任选其中n为2、3或4;
iv)(GGGGS)n,其中n为1-10的整数,任选其中n为2、3、4或7;
v)AAAGG;
vi)(AP)n,其中n为1-10的整数,任选其中n为2-10;
vii)(EP)n,其中n为1-10的整数,任选其中n为2-10;
viii)(KP)n,其中n为1-10的整数,任选其中n为2-10;以及
ix)包含EAAAK的肽,任选为包含AEAAAKEAAAKA的肽。
方面11.如方面1所述的TMP,其中所述TMP包含如图13A至图13D以及图18A至图18T中任一者所展示的氨基酸序列,其中(X)为如方面2所述的肽。
方面12.如方面1所述的TMP,其中所述TMP包含:
(a)至少一个刚性肽接头,任选其中所述TMP包含所述Ig Fc多肽与所述一个或多个免疫调节多肽中的一者之间的刚性肽接头;和/或
(b)至少一个包含2-14个氨基酸的短可挠性肽接头,任选其中所述TMP包含所述IgFc多肽与所述一个或多个免疫调节多肽中的一者之间的短可挠性肽接头。
方面13.如方面12所述的TMP,其中所述TMP包含至少一个刚性肽接头,并且其中各刚性肽接头独立地选自由以下组成的组:
i)(AP)n,其中n为1-10的整数;
ii)(EP)n,其中n为1-10的整数;
iii)(KP)n,其中n为1-10的整数;以及
iv)包含EAAAK的肽。
方面14.一种TMP,所述TMP包含(i)均二聚体,所述均二聚体包含两个相同的如方面1-13中任一项所述的TMP,任选其中所述两个TMP通过一个或多个二硫键连接至彼此,所述一个或多个二硫键将一个TMP的免疫球蛋白(Ig)Fc多肽连接至另一TMP的所述Ig Fc多肽,或(ii)异二聚体,所述异二聚体包含两个不同的如方面1-13中任一项所述的TMP,任选其中所述两个TMP通过种间结合序列连接至彼此。
方面15.一种药物组合物,所述药物组合物包含根据方面1-13中任一项所述的TMP。
方面16.一种核酸,所述核酸包含编码根据方面1-13中任一项所述的TMP的核苷酸序列。
方面17.一种选择性调节对癌症相关肽表位具特异性的T细胞的活性的方法,所述方法包括使所述T细胞与根据方面1-13中任一项所述的TMP接触,其中所述接触选择性调节所述表位特异性T细胞的活性。
方面18.一种治疗患有癌症的患者的所述癌症的方法,所述方法包括向所述患者施用有效量的根据方面15所述的药物组合物。
方面19.如方面18所述的方法,所述方法还包括向所述患者共施用一种或多种免疫检查点抑制剂,任选其中所述一种或多种免疫检查点抑制剂包含对PD-L1、PD-1、CTLA4或TIGIT具特异性的抗体。
虽然已参考特定实施方案描述本公开,但本领域技术人员应理解,在不背离本公开的真实精神和范围的情况下,可作出各种改变并且等效物可被取代。此外,可作出许多修改以使特定情况、材料、物质组成、方法、方法步骤适合目标、精神以及范围。所有此类修改旨在在本文所附权利要求书的范围内。
序列表
<110>库尔生物制药有限公司(Cue Biopharma, Inc.)
罗纳德·D·塞德耳三世(Seidel, Ronald D.)
鲁道夫·J·查帕罗(Chaparro, Rodolfo J.)
约翰·F·罗斯(Ross, John F.)
萨索·切梅尔斯基(Cemerski, Saso)
<120>T细胞调节多肽和其使用方法
<130>CUEB-139WO
<150>US 63/163,265
<151>2021-03-19
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<220>
<223>合成序列
<400>23
Gly Ala Val Gly Val Gly Lys Ser Ala Leu
1 5 10
<210>24
<211>9
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>24
Ala Val Gly Val Gly Lys Ser Ala Leu
1 5
<210>25
<211>9
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>25
Tyr Lys Leu Val Val Val Gly Ala Val
1 5
<210>26
<211>9
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>26
Ala Arg Gly Val Gly Lys Ser Ala Leu
1 5
<210>27
<211>10
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>27
Gly Ala Arg Gly Val Gly Lys Ser Ala Leu
1 5 10
<210>28
<211>10
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>28
Glu Tyr Lys Leu Val Val Val Gly Ala Arg
1 5 10
<210>29
<211>10
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>29
Arg Gly Val Gly Lys Ser Ala Leu Thr Ile
1 5 10
<210>30
<211>9
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>30
Leu Val Val Val Gly Ala Arg Gly Val
1 5
<210>31
<211>10
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>31
Gly Ala Asp Gly Val Gly Lys Ser Ala Leu
1 5 10
<210>32
<211>9
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>32
Ala Cys Gly Val Gly Lys Ser Ala Leu
1 5
<210>33
<211>10
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>33
Gly Ala Cys Gly Val Gly Lys Ser Ala Leu
1 5 10
<210>34
<211>9
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>34
Val Val Gly Ala Val Gly Val Gly Lys
1 5
<210>35
<211>10
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>35
Val Val Val Gly Ala Val Gly Val Gly Lys
1 5 10
<210>36
<211>9
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>36
Val Gly Ala Val Gly Val Gly Lys Ser
1 5
<210>37
<211>10
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>37
Val Gly Ala Val Gly Val Gly Lys Ser Ala
1 5 10
<210>38
<211>10
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>38
Ala Val Gly Val Gly Lys Ser Ala Leu Thr
1 5 10
<210>39
<211>9
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>39
Gly Ala Val Gly Val Gly Lys Ser Ala
1 5
<210>40
<211>10
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>40
Leu Val Val Val Gly Ala Val Gly Val Gly
1 5 10
<210>41
<211>9
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>41
Lys Leu Val Val Val Gly Ala Val Gly
1 5
<210>42
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>42
Ala Ile Thr Arg Lys Met Ala Ala Thr
1 5
<210>43
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>43
Ala Tyr Thr Lys Lys Ala Pro Gln Leu
1 5
<210>44
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>44
Leu Leu Asn Gln His Ala Cys Ala Val
1 5
<210>45
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>45
Lys Leu Val Leu Asp Val Ala His Val
1 5
<210>46
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>46
Phe Met Asn Lys Phe Ile Tyr Glu Ile
1 5
<210>47
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>47
Ser Ile Pro Leu Phe Gln Val Pro Glu
1 5
<210>48
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>48
Leu Leu Asn Phe Thr Glu Ser Arg Thr
1 5
<210>49
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>49
Phe Val Gln Glu Ala Thr Tyr Lys Phe
1 5
<210>50
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>50
Ala Thr Tyr Lys Glu Val Ser Lys Met
1 5
<210>51
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>51
Lys Glu Val Ser Lys Met Val Lys Asp
1 5
<210>52
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>52
Arg His Asn Cys Phe Leu Ala His Lys
1 5
<210>53
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>53
Ala Thr Ala Ala Thr Cys Cys Gln Leu
1 5
<210>54
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>54
Tyr Ile Gln Glu Ser Gln Ala Leu Ala
1 5
<210>55
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>55
Gln Leu Thr Ser Ser Glu Leu Met Ala Ile
1 5 10
<210>56
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>56
Lys Leu Ser Gln Lys Phe Thr Lys Val
1 5
<210>57
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>57
Lys Glu Leu Arg Glu Ser Ser Leu Leu
1 5
<210>58
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>58
Ser Leu Val Val Asp Glu Thr Tyr Val
1 5
<210>59
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>59
Ile Leu Leu Trp Ala Ala Arg Tyr Asp
1 5
<210>60
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>60
Lys Ile Ile Pro Ser Cys Cys Lys Ala
1 5
<210>61
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>61
Cys Arg Gly Asp Val Leu Asp Cys Leu
1 5
<210>62
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>62
Gln Gln Asp Thr Leu Ser Asn Lys Ile
1 5
<210>63
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>63
Thr Met Lys Gln Glu Phe Leu Ile Asn Leu
1 5 10
<210>64
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>64
Asn Leu Val Lys Gln Lys Pro Gln Ile
1 5
<210>65
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>65
Ala Val Ile Ala Asp Phe Ser Gly Leu
1 5
<210>66
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>66
Leu Leu Ala Cys Gly Glu Gly Ala Ala
1 5
<210>67
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>67
Leu Ala Cys Gly Glu Gly Ala Ala Asp
1 5
<210>68
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>68
Lys Ala Pro Gln Leu Thr Ser Ser Glu Leu
1 5 10
<210>69
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>69
Tyr Ile Cys Ser Gln Gln Asp Thr Leu
1 5
<210>70
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>70
Thr Glu Cys Cys Lys Leu Thr Thr Leu
1 5
<210>71
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>71
Cys Thr Ala Glu Ile Ser Leu Ala Asp Leu
1 5 10
<210>72
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>72
Val Thr Lys Glu Leu Arg Glu Ser Ser Leu
1 5 10
<210>73
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>73
Ile Met Ser Tyr Ile Cys Ser Gln Gln Asp
1 5 10
<210>74
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>74
Thr Arg Thr Phe Gln Ala Ile Thr Val
1 5
<210>75
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>75
Phe Gln Lys Leu Gly Glu Tyr Tyr Leu
1 5
<210>76
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>76
Arg Val Ala Lys Gly Tyr Gln Glu Leu
1 5
<210>77
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>77
Ser Tyr Gln Cys Thr Ala Glu Ile Ser Leu
1 5 10
<210>78
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>78
Lys Gln Glu Phe Leu Ile Asn Leu Val
1 5
<210>79
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>79
Met Lys Trp Val Glu Ser Ile Phe Leu
1 5
<210>80
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>80
Pro Val Asn Pro Gly Val Gly Gln Cys
1 5
<210>81
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>81
Ala Ala Asp Ile Ile Ile Gly His Leu
1 5
<210>82
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>82
Gln Val Pro Glu Pro Val Thr Ser Cys
1 5
<210>83
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>83
Thr Thr Leu Glu Arg Gly Gln Cys Ile Ile
1 5 10
<210>84
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>84
Lys Met Ala Ala Thr Ala Ala Thr Cys
1 5
<210>85
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>85
Gln Ala Gln Gly Val Ala Leu Gln Thr Met
1 5 10
<210>86
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>86
Phe Gln Ala Ile Thr Val Thr Lys Leu
1 5
<210>87
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>87
Leu Leu Glu Lys Cys Phe Gln Thr Glu
1 5
<210>88
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>88
Val Ala Tyr Thr Lys Lys Ala Pro Gln
1 5
<210>89
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>89
Lys Tyr Ile Gln Glu Ser Gln Ala Leu
1 5
<210>90
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>90
Gly Val Ala Leu Gln Thr Met Lys Gln
1 5
<210>91
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>91
Gly Gln Glu Gln Glu Val Cys Phe Ala
1 5
<210>92
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>92
Ser Glu Glu Gly Arg His Asn Cys Phe Leu
1 5 10
<210>93
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>93
Arg His Pro Phe Leu Tyr Ala Pro Thr Ile
1 5 10
<210>94
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>94
Thr Glu Ile Gln Lys Leu Val Leu Asp Val
1 5 10
<210>95
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>95
Arg Arg His Pro Gln Leu Ala Val Ser Val
1 5 10
<210>96
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>96
Gly Glu Tyr Tyr Leu Gln Asn Ala Phe Leu
1 5 10
<210>97
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>97
Asn Arg Arg Pro Cys Phe Ser Ser Leu Val
1 5 10
<210>98
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>98
Leu Gln Thr Met Lys Gln Glu Phe Leu Ile
1 5 10
<210>99
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>99
Ile Ala Asp Phe Ser Gly Leu Leu Glu Lys
1 5 10
<210>100
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>100
Gly Leu Leu Glu Lys Cys Cys Gln Gly Gln
1 5 10
<210>101
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>101
Thr Leu Ser Asn Lys Ile Thr Glu Cys
1 5
<210>102
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>102
Leu Gln Asp Gly Glu Lys Ile Met Ser Tyr
1 5 10
<210>103
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>103
Gly Leu Phe Gln Lys Leu Gly Asx Tyr
1 5
<210>104
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>104
Asn Glu Tyr Gly Ile Ala Ser Ile Leu Asp
1 5 10
<210>105
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>105
Lys Met Val Lys Asp Ala Leu Thr Ala Ile
1 5 10
<210>106
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>106
Phe Leu Ala Ser Phe Val His Glu Tyr
1 5
<210>107
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>107
Ala Gln Phe Val Gln Glu Ala Thr Tyr
1 5
<210>108
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>108
Glu Tyr Tyr Leu Gln Asn Ala Phe Leu
1 5
<210>109
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>109
Glu Tyr Ser Arg Arg His Pro Gln Leu
1 5
<210>110
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>110
Ala Tyr Glu Glu Asp Arg Glu Thr Phe
1 5
<210>111
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>111
Ser Tyr Ala Asn Arg Arg Pro Cys Phe
1 5
<210>112
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>112
Cys Phe Ala Glu Glu Gly Gln Lys Leu
1 5
<210>113
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>113
Arg Ser Cys Gly Leu Phe Gln Lys Leu
1 5
<210>114
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>114
Ile Phe Leu Ile Phe Leu Leu Asn Phe
1 5
<210>115
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>115
Lys Pro Glu Gly Leu Ser Pro Asn Leu
1 5
<210>116
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>116
Gly Leu Ser Pro Asn Leu Asn Arg Phe Leu
1 5 10
<210>117
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>117
Cys Met Thr Trp Asn Gln Met Asn Leu Gly Ala Thr Leu Lys Gly
1 5 1015
<210>118
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>118
Trp Asn Gln Met Asn Leu Gly Ala Thr Leu Lys Gly Val Ala Ala
1 5 1015
<210>119
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>119
Cys Met Thr Trp Asn Tyr Met Asn Leu Gly Ala Thr Leu Lys Gly
1 5 1015
<210>120
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>120
Trp Asn Tyr Met Asn Leu Gly Ala Thr Leu Lys Gly Val Ala Ala
1 5 1015
<210>121
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>121
Met Thr Trp Asn Gln Met Asn Leu Gly Ala Thr Leu Lys Gly Val
1 5 1015
<210>122
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>122
Thr Trp Asn Gln Met Asn Leu Gly Ala Thr Leu Lys Gly Val Ala
1 5 1015
<210>123
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>123
Cys Met Thr Trp Asn Leu Met Asn Leu Gly Ala Thr Leu Lys Gly
1 5 1015
<210>124
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>124
Met Thr Trp Asn Leu Met Asn Leu Gly Ala Thr Leu Lys Gly Val
1 5 1015
<210>125
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>125
Thr Trp Asn Leu Met Asn Leu Gly Ala Thr Leu Lys Gly Val Ala
1 5 1015
<210>126
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>126
Trp Asn Leu Met Asn Leu Gly Ala Thr Leu Lys Gly Val Ala Ala
1 5 1015
<210>127
<211>8
<212>PRT
<213>智人(Homo sapiens)
<400>127
Met Asn Leu Gly Ala Thr Leu Lys
1 5
<210>128
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>128
Met Thr Trp Asn Tyr Met Asn Leu Gly Ala Thr Leu Lys Gly Val
1 5 1015
<210>129
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>129
Thr Trp Asn Tyr Met Asn Leu Gly Ala Thr Leu Lys Gly Val Ala
1 5 1015
<210>130
<211>17
<212>PRT
<213>智人(Homo sapiens)
<400>130
Cys Met Thr Trp Asn Gln Met Asn Leu Gly Ala Thr Leu Lys Gly Val
1 5 1015
Ala
<210>131
<211>17
<212>PRT
<213>智人(Homo sapiens)
<400>131
Cys Met Thr Trp Asn Leu Met Asn Leu Gly Ala Thr Leu Lys Gly Val
1 5 1015
Ala
<210>132
<211>17
<212>PRT
<213>智人(Homo sapiens)
<400>132
Cys Met Thr Trp Asn Tyr Met Asn Leu Gly Ala Thr Leu Lys Gly Val
1 5 1015
Ala
<210>133
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>133
Gly Tyr Leu Arg Asn Pro Thr Ala Cys
1 5
<210>134
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>134
Gly Ala Leu Arg Asn Pro Thr Ala Leu
1 5
<210>135
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>135
Tyr Ala Leu Arg Asn Pro Thr Ala Cys
1 5
<210>136
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>136
Gly Leu Leu Arg Asn Pro Thr Ala Cys
1 5
<210>137
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>137
Arg Tyr Arg Pro His Pro Gly Ala Leu
1 5
<210>138
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>138
Tyr Gln Arg Pro His Pro Gly Ala Leu
1 5
<210>139
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>139
Arg Leu Arg Pro His Pro Gly Ala Leu
1 5
<210>140
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>140
Arg Ile Arg Pro His Pro Gly Ala Leu
1 5
<210>141
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>141
Gln Phe Pro Asn His Ser Phe Lys His Glu Asp Pro Met Gly Gln
1 5 1015
<210>142
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>142
His Ser Phe Lys His Glu Asp Pro Tyr
1 5
<210>143
<211>13
<212>PRT
<213>智人(Homo sapiens)
<400>143
Gln Phe Pro Asn His Ser Phe Lys His Glu Asp Pro Met
1 5 10
<210>144
<211>13
<212>PRT
<213>智人(Homo sapiens)
<400>144
Gln Phe Pro Asn His Ser Phe Lys His Glu Asp Pro Tyr
1 5 10
<210>145
<211>13
<212>PRT
<213>智人(Homo sapiens)
<400>145
Lys Arg Pro Phe Met Cys Ala Tyr Pro Gly Cys Asn Lys
1 5 10
<210>146
<211>13
<212>PRT
<213>智人(Homo sapiens)
<400>146
Lys Arg Pro Phe Met Cys Ala Tyr Pro Gly Cys Tyr Lys
1 5 10
<210>147
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>147
Phe Met Cys Ala Tyr Pro Gly Cys Tyr
1 5
<210>148
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>148
Phe Met Cys Ala Tyr Pro Gly Cys Lys
1 5
<210>149
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>149
Lys Arg Pro Phe Met Cys Ala Tyr Pro Gly Cys Asn Lys Arg Tyr
1 5 1015
<210>150
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>150
Ser Glu Lys Arg Pro Phe Met Cys Ala Tyr Pro Gly Cys Asn Lys
1 5 1015
<210>151
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>151
Lys Arg Pro Phe Met Cys Ala Tyr Pro Gly Cys Tyr Lys Arg Tyr
1 5 1015
<210>152
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>152
Asn Leu Met Asn Leu Gly Ala Thr Leu
1 5
<210>153
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>153
Val Leu Asp Phe Ala Pro Pro Gly Ala
1 5
<210>154
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>154
Arg Met Phe Pro Asn Ala Pro Tyr Leu
1 5
<210>155
<211>8
<212>PRT
<213>智人(Homo sapiens)
<400>155
Cys Met Thr Trp Asn Gln Met Asn
1 5
<210>156
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>156
Cys Tyr Thr Trp Asn Gln Met Asn Leu
1 5
<210>157
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>157
Asn Tyr Met Asn Leu Gly Ala Thr Leu
1 5
<210>158
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>158
Tyr Met Phe Pro Asn Ala Pro Tyr Leu
1 5
<210>159
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>159
Ser Leu Gly Glu Gln Gln Tyr Ser Val
1 5
<210>160
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>160
Cys Met Thr Trp Asn Gln Met Asn Leu
1 5
<210>161
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>161
Asn Gln Met Asn Leu Gly Ala Thr Leu
1 5
<210>162
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>162
Lys Leu Pro Gln Leu Cys Thr Glu Leu
1 5
<210>163
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>163
Leu Gln Thr Thr Ile His Asp Ile Ile
1 5
<210>164
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>164
Val Tyr Asp Phe Ala Phe Arg Asp Leu
1 5
<210>165
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>165
Phe Ala Phe Arg Asp Leu Cys Ile Val
1 5
<210>166
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>166
Lys Phe Tyr Ser Lys Ile Ser Glu Tyr
1 5
<210>167
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>167
Ile Ser Glu Tyr Arg His Tyr Cys Tyr
1 5
<210>168
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>168
Thr Leu His Glu Tyr Met Leu Asp Leu
1 5
<210>169
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>169
Tyr Met Leu Asp Leu Gln Pro Glu Thr
1 5
<210>170
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>170
Gln Ala Glu Pro Asp Arg Ala His Tyr
1 5
<210>171
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>171
Arg Ala His Tyr Asn Ile Val Thr Phe
1 5
<210>172
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>172
Cys Asp Ser Thr Leu Arg Leu Cys Val
1 5
<210>173
<211>10
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>173
Leu Cys Val Gln Ser Thr His Val Asp Ile
1 5 10
<210>174
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>174
Leu Leu Met Gly Thr Leu Gly Ile Val
1 5
<210>175
<211>8
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>175
Thr Leu Gly Ile Val Cys Pro Ile
1 5
<210>176
<211>12
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>176
Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile
1 5 10
<210>177
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>177
Cys Tyr Ser Leu Tyr Gly Thr Thr Leu
1 5
<210>178
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>178
Glu Tyr Arg His Tyr Cys Tyr Ser Leu
1 5
<210>179
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>179
Asp Pro Gln Glu Arg Pro Arg Lys Leu
1 5
<210>180
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>180
His Tyr Cys Tyr Ser Leu Tyr Gly Thr
1 5
<210>181
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>181
Asp Phe Ala Phe Arg Asp Leu Cys Ile
1 5
<210>182
<211>10
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>182
Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr
1 5 10
<210>183
<211>10
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>183
His Tyr Cys Tyr Ser Leu Tyr Gly Thr Thr
1 5 10
<210>184
<211>10
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>184
Glu Val Tyr Asp Phe Ala Phe Arg Asp Leu
1 5 10
<210>185
<211>10
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>185
Glu Tyr Arg His Tyr Cys Tyr Ser Leu Tyr
1 5 10
<210>186
<211>10
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>186
Val Tyr Asp Phe Ala Phe Arg Asp Leu Cys
1 5 10
<210>187
<211>10
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>187
Tyr Cys Tyr Ser Ile Tyr Gly Thr Thr Leu
1 5 10
<210>188
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>188
Val Tyr Cys Lys Thr Val Leu Glu Leu
1 5
<210>189
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>189
Val Tyr Gly Asp Thr Leu Glu Lys Leu
1 5
<210>190
<211>10
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>190
Leu Thr Asn Thr Gly Leu Tyr Asn Leu Leu
1 5 10
<210>191
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>191
Asp Leu Gln Pro Glu Thr Thr Asp Leu
1 5
<210>192
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>192
Gly Thr Leu Gly Ile Val Cys Pro Ile
1 5
<210>193
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>193
Glu Pro Asp Arg Ala His Tyr Asn Ile
1 5
<210>194
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>194
Gln Leu Phe Leu Asn Thr Leu Ser Phe
1 5
<210>195
<211>9
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>195
Phe Gln Gln Leu Phe Leu Asn Thr Leu
1 5
<210>196
<211>10
<212>PRT
<213>人乳头瘤病毒(Human papilloma virus)
<400>196
Ala Phe Gln Gln Leu Phe Leu Asn Thr Leu
1 5 10
<210>197
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>197
Ser Thr Ala Pro Pro Ala His Gly Val
1 5
<210>198
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>198
Ser Thr Ala Pro Pro Val His Asn Val
1 5
<210>199
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>199
Ser Leu Ala Pro Pro Val His Asn Val
1 5
<210>200
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>200
Ser Leu Ala Pro Pro Ala His Gly Val
1 5
<210>201
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>201
Ser Ala Pro Asp Thr Arg Pro Ala Pro
1 5
<210>202
<211>20
<212>PRT
<213>智人(Homo sapiens)
<400>202
Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro
1 5 1015
Pro Ala His Gly
20
<210>203
<211>20
<212>PRT
<213>智人(Homo sapiens)
<400>203
Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly
1 5 1015
Val Thr Ser Ala
20
<210>204
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>204
Leu Leu Leu Leu Thr Val Leu Thr Val
1 5
<210>205
<211>317
<212>PRT
<213>智人(Homo sapiens)
<400>205
Met Ser Ser Glu Gln Lys Ser Gln His Cys Lys Pro Glu Glu Gly Val
1 5 1015
Glu Ala Gln Glu Glu Ala Leu Gly Leu Val Gly Ala Gln Ala Pro Thr
202530
Thr Glu Glu Gln Glu Ala Ala Val Ser Ser Ser Ser Pro Leu Val Pro
354045
Gly Thr Leu Glu Glu Val Pro Ala Ala Glu Ser Ala Gly Pro Pro Gln
505560
Ser Pro Gln Gly Ala Ser Ala Leu Pro Thr Thr Ile Ser Phe Thr Cys
65707580
Trp Arg Gln Pro Asn Glu Gly Ser Ser Ser Gln Glu Glu Glu Gly Pro
859095
Ser Thr Ser Pro Asp Ala Glu Ser Leu Phe Arg Glu Ala Leu Ser Asn
100 105 110
Lys Val Asp Glu Leu Ala His Phe Leu Leu Arg Lys Tyr Arg Ala Lys
115 120 125
Glu Leu Val Thr Lys Ala Glu Met Leu Glu Arg Val Ile Lys Asn Tyr
130 135 140
Lys Arg Cys Phe Pro Val Ile Phe Gly Lys Ala Ser Glu Ser Leu Lys
145 150 155 160
Met Ile Phe Gly Ile Asp Val Lys Glu Val Asp Pro Ala Ser Asn Thr
165 170 175
Tyr Thr Leu Val Thr Cys Leu Gly Leu Ser Tyr Asp Gly Leu Leu Gly
180 185 190
Asn Asn Gln Ile Phe Pro Lys Thr Gly Leu Leu Ile Ile Val Leu Gly
195 200 205
Thr Ile Ala Met Glu Gly Asp Ser Ala Ser Glu Glu Glu Ile Trp Glu
210 215 220
Glu Leu Gly Val Met Gly Val Tyr Asp Gly Arg Glu His Thr Val Tyr
225 230 235 240
Gly Glu Pro Arg Lys Leu Leu Thr Gln Asp Trp Val Gln Glu Asn Tyr
245 250 255
Leu Glu Tyr Arg Gln Val Pro Gly Ser Asn Pro Ala Arg Tyr Glu Phe
260 265 270
Leu Trp Gly Pro Arg Ala Leu Ala Glu Thr Ser Tyr Val Lys Val Leu
275 280 285
Glu His Val Val Arg Val Asn Ala Arg Val Arg Ile Ala Tyr Pro Ser
290 295 300
Leu Arg Glu Ala Ala Leu Leu Glu Glu Glu Glu Gly Val
305 310 315
<210>206
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>206
Gly Val Tyr Asp Gly Arg Glu His Thr Val
1 5 10
<210>207
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>207
Asn Tyr Lys Arg Cys Phe Pro Val Ile
1 5
<210>208
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>208
Glu Val Asp Pro Ala Ser Asn Thr Tyr
1 5
<210>209
<211>8
<212>PRT
<213>智人(Homo sapiens)
<400>209
Ser Glu Ser Leu Lys Met Ile Phe
1 5
<210>210
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>210
Ser Glu Ser Leu Ile Cys Met Ile Phe
1 5
<210>211
<211>180
<212>PRT
<213>智人(Homo sapiens)
<400>211
Met Gln Ala Glu Gly Arg Gly Thr Gly Gly Ser Thr Gly Asp Ala Asp
1 5 1015
Gly Pro Gly Gly Pro Gly Ile Pro Asp Gly Pro Gly Gly Asn Ala Gly
202530
Gly Pro Gly Glu Ala Gly Ala Thr Gly Gly Arg Gly Pro Arg Gly Ala
354045
Gly Ala Ala Arg Ala Ser Gly Pro Gly Gly Gly Ala Pro Arg Gly Pro
505560
His Gly Gly Ala Ala Ser Gly Leu Asn Gly Cys Cys Arg Cys Gly Ala
65707580
Arg Gly Pro Glu Ser Arg Leu Leu Glu Phe Tyr Leu Ala Met Pro Phe
859095
Ala Thr Pro Met Glu Ala Glu Leu Ala Arg Arg Ser Leu Ala Gln Asp
100 105 110
Ala Pro Pro Leu Pro Val Pro Gly Val Leu Leu Lys Glu Phe Thr Val
115 120 125
Ser Gly Asn Ile Leu Thr Ile Arg Leu Thr Ala Ala Asp His Arg Gln
130 135 140
Leu Gln Leu Ser Ile Ser Ser Cys Leu Gln Gln Leu Ser Leu Leu Met
145 150 155 160
Trp Ile Thr Gln Cys Phe Leu Pro Val Phe Leu Ala Gln Pro Pro Ser
165 170 175
Gly Gln Arg Arg
180
<210>212
<211>11
<212>PRT
<213>智人(Homo sapiens)
<400>212
Ser Leu Leu Met Trp Ile Thr Gln Cys Phe Leu
1 5 10
<210>213
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>213
Ser Leu Leu Met Trp Ile Thr Gln Cys
1 5
<210>214
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>214
Gln Leu Ser Leu Leu Met Trp Ile Thr
1 5
<210>215
<211>14
<212>PRT
<213>智人(Homo sapiens)
<400>215
Ser Leu Leu Met Trp Ile Thr Gln Cys Phe Leu Pro Val Phe
1 5 10
<210>216
<211>11
<212>PRT
<213>智人(Homo sapiens)
<400>216
Met Leu Met Ala Gln Glu Ala Leu Ala Phe Leu
1 5 10
<210>217
<211>11
<212>PRT
<213>智人(Homo sapiens)
<400>217
Tyr Leu Ala Met Pro Phe Ala Thr Pro Met Glu
1 5 10
<210>218
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>218
Ala Ser Gly Pro Gly Gly Gly Ala Pro Arg
1 5 10
<210>219
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>219
Leu Ala Ala Gln Glu Arg Arg Val Pro Arg
1 5 10
<210>220
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>220
Thr Val Ser Gly Asn Ile Leu Thr Ile Arg
1 5 10
<210>221
<211>13
<212>PRT
<213>智人(Homo sapiens)
<400>221
Ala Pro Arg Gly Pro His Gly Gly Ala Ala Ser Gly Leu
1 5 10
<210>222
<211>11
<212>PRT
<213>智人(Homo sapiens)
<400>222
Met Pro Phe Ala Thr Pro Met Glu Ala Glu Leu
1 5 10
<210>223
<211>12
<212>PRT
<213>智人(Homo sapiens)
<400>223
Lys Glu Phe Thr Val Ser Gly Asn Leu Leu Thr Ile
1 5 10
<210>224
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>224
Met Pro Phe Ala Thr Pro Met Glu Ala
1 5
<210>225
<211>11
<212>PRT
<213>智人(Homo sapiens)
<400>225
Phe Ala Thr Pro Met Glu Ala Glu Leu Ala Arg
1 5 10
<210>226
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>226
Leu Ala Met Pro Phe Ala Thr Pro Met
1 5
<210>227
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>227
Ala Arg Gly Pro Glu Ser Arg Leu Leu
1 5
<210>228
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>228
Glu Leu Thr Leu Gly Glu Phe Leu Lys Leu
1 5 10
<210>229
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>229
Thr Leu Gly Glu Phe Leu Lys Leu Asp Arg Glu Arg Ala Lys Asn
1 5 1015
<210>230
<211>6
<212>PRT
<213>智人(Homo sapiens)
<400>230
Gln Met Phe Phe Cys Phe
1 5
<210>231
<211>15
<212>PRT
<213>智人(Homo sapiens)
<400>231
Asp Leu Ala Gln Met Phe Phe Cys Phe Lys Glu Leu Glu Gly Trp
1 5 1015
<210>232
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>232
Ala Gln Met Phe Phe Cys Phe Lys Glu Leu
1 5 10
<210>233
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>233
Gln Met Phe Phe Cys Phe Lys Glu Leu
1 5
<210>234
<211>622
<212>PRT
<213>智人(Homo sapiens)
<400>234
Met Ala Leu Pro Thr Ala Arg Pro Leu Leu Gly Ser Cys Gly Thr Pro
1 5 1015
Ala Leu Gly Ser Leu Leu Phe Leu Leu Phe Ser Leu Gly Trp Val Gln
202530
Pro Ser Arg Thr Leu Ala Gly Glu Thr Gly Gln Glu Ala Ala Pro Leu
354045
Asp Gly Val Leu Ala Asn Pro Pro Asn Ile Ser Ser Leu Ser Pro Arg
505560
Gln Leu Leu Gly Phe Pro Cys Ala Glu Val Ser Gly Leu Ser Thr Glu
65707580
Arg Val Arg Glu Leu Ala Val Ala Leu Ala Gln Lys Asn Val Lys Leu
859095
Ser Thr Glu Gln Leu Arg Cys Leu Ala His Arg Leu Ser Glu Pro Pro
100 105 110
Glu Asp Leu Asp Ala Leu Pro Leu Asp Leu Leu Leu Phe Leu Asn Pro
115 120 125
Asp Ala Phe Ser Gly Pro Gln Ala Cys Thr Arg Phe Phe Ser Arg Ile
130 135 140
Thr Lys Ala Asn Val Asp Leu Leu Pro Arg Gly Ala Pro Glu Arg Gln
145 150 155 160
Arg Leu Leu Pro Ala Ala Leu Ala Cys Trp Gly Val Arg Gly Ser Leu
165 170 175
Leu Ser Glu Ala Asp Val Arg Ala Leu Gly Gly Leu Ala Cys Asp Leu
180 185 190
Pro Gly Arg Phe Val Ala Glu Ser Ala Glu Val Leu Leu Pro Arg Leu
195 200 205
Val Ser Cys Pro Gly Pro Leu Asp Gln Asp Gln Gln Glu Ala Ala Arg
210 215 220
Ala Ala Leu Gln Gly Gly Gly Pro Pro Tyr Gly Pro Pro Ser Thr Trp
225 230 235 240
Ser Val Ser Thr Met Asp Ala Leu Arg Gly Leu Leu Pro Val Leu Gly
245 250 255
Gln Pro Ile Ile Arg Ser Ile Pro Gln Gly Ile Val Ala Ala Trp Arg
260 265 270
Gln Arg Ser Ser Arg Asp Pro Ser Trp Arg Gln Pro Glu Arg Thr Ile
275 280 285
Leu Arg Pro Arg Phe Arg Arg Glu Val Glu Lys Thr Ala Cys Pro Ser
290 295 300
Gly Lys Lys Ala Arg Glu Ile Asp Glu Ser Leu Ile Phe Tyr Lys Lys
305 310 315 320
Trp Glu Leu Glu Ala Cys Val Asp Ala Ala Leu Leu Ala Thr Gln Met
325 330 335
Asp Arg Val Asn Ala Ile Pro Phe Thr Tyr Glu Gln Leu Asp Val Leu
340 345 350
Lys His Lys Leu Asp Glu Leu Tyr Pro Gln Gly Tyr Pro Glu Ser Val
355 360 365
Ile Gln His Leu Gly Tyr Leu Phe Leu Lys Met Ser Pro Glu Asp Ile
370 375 380
Arg Lys Trp Asn Val Thr Ser Leu Glu Thr Leu Lys Ala Leu Leu Glu
385 390 395 400
Val Asn Lys Gly His Glu Met Ser Pro Gln Val Ala Thr Leu Ile Asp
405 410 415
Arg Phe Val Lys Gly Arg Gly Gln Leu Asp Lys Asp Thr Leu Asp Thr
420 425 430
Leu Thr Ala Phe Tyr Pro Gly Tyr Leu Cys Ser Leu Ser Pro Glu Glu
435 440 445
Leu Ser Ser Val Pro Pro Ser Ser Ile Trp Ala Val Arg Pro Gln Asp
450 455 460
Leu Asp Thr Cys Asp Pro Arg Gln Leu Asp Val Leu Tyr Pro Lys Ala
465 470 475 480
Arg Leu Ala Phe Gln Asn Met Asn Gly Ser Glu Tyr Phe Val Lys Ile
485 490 495
Gln Ser Phe Leu Gly Gly Ala Pro Thr Glu Asp Leu Lys Ala Leu Ser
500 505 510
Gln Gln Asn Val Ser Met Asp Leu Ala Thr Phe Met Lys Leu Arg Thr
515 520 525
Asp Ala Val Leu Pro Leu Thr Val Ala Glu Val Gln Lys Leu Leu Gly
530 535 540
Pro His Val Glu Gly Leu Lys Ala Glu Glu Arg His Arg Pro Val Arg
545 550 555 560
Asp Trp Ile Leu Arg Gln Arg Gln Asp Asp Leu Asp Thr Leu Gly Leu
565 570 575
Gly Leu Gln Gly Gly Ile Pro Asn Gly Tyr Leu Val Leu Asp Leu Ser
580 585 590
Met Gln Glu Ala Leu Ser Gly Thr Pro Cys Leu Leu Gly Pro Gly Pro
595 600 605
Val Leu Thr Val Leu Ala Leu Leu Leu Ala Ser Thr Leu Ala
610 615 620
<210>235
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>235
Ser Leu Leu Phe Leu Leu Phe Ser Leu
1 5
<210>236
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>236
Val Leu Pro Leu Thr Val Ala Glu Val
1 5
<210>237
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>237
Glu Leu Ala Val Ala Leu Ala Gln Lys
1 5
<210>238
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>238
Ala Leu Gln Gly Gly Gly Pro Pro Tyr
1 5
<210>239
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>239
Phe Tyr Pro Gly Tyr Leu Cys Ser Leu
1 5
<210>240
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>240
Leu Tyr Pro Lys Ala Arg Leu Ala Phe
1 5
<210>241
<211>118
<212>PRT
<213>智人(Homo sapiens)
<400>241
Met Pro Arg Glu Asp Ala His Phe Ile Tyr Gly Tyr Pro Lys Lys Gly
1 5 1015
His Gly His Ser Tyr Thr Thr Ala Glu Glu Ala Ala Gly Ile Gly Ile
202530
Leu Thr Val Ile Leu Gly Val Leu Leu Leu Ile Gly Cys Trp Tyr Cys
354045
Arg Arg Arg Asn Gly Tyr Arg Ala Leu Met Asp Lys Ser Leu His Val
505560
Gly Thr Gln Cys Ala Leu Thr Arg Arg Cys Pro Gln Glu Gly Phe Asp
65707580
His Arg Asp Ser Lys Val Ser Leu Gln Glu Lys Asn Cys Glu Pro Val
859095
Val Pro Asn Ala Pro Pro Ala Tyr Glu Lys Leu Ser Ala Glu Gln Ser
100 105 110
Pro Pro Pro Tyr Ser Pro
115
<210>242
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>242
Glu Leu Ala Gly Ile Gly Ile Leu Thr Val
1 5 10
<210>243
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>243
Val Met Ala Pro Arg Thr Leu Phe Leu
1 5
<210>244
<211>9
<212>PRT
<213>流感病毒(Influenza virus)
<400>244
Gly Ile Leu Gly Phe Val Phe Thr Leu
1 5
<210>245
<211>9
<212>PRT
<213>爱泼斯坦巴尔病毒(Epstein-Barr virus)
<400>245
Ile Val Thr Asp Phe Ser Val Ile Lys
1 5
<210>246
<211>10
<212>PRT
<213>爱泼斯坦巴尔病毒(Epstein-Barr virus)
<400>246
Ala Val Phe Asp Arg Lys Ser Asp Ala Lys
1 5 10
<210>247
<211>9
<212>PRT
<213>巨细胞病毒(Cytomegalovirus)
<400>247
Asn Leu Val Pro Met Val Ala Thr Val
1 5
<210>248
<211>9
<212>PRT
<213>巨细胞病毒(Cytomegalovirus)
<400>248
Ala Thr Val Gln Gly Gln Asn Leu Lys
1 5
<210>249
<211>9
<212>PRT
<213>巨细胞病毒(Cytomegalovirus)
<400>249
Val Met Ala Pro Arg Thr Leu Ile Leu
1 5
<210>250
<211>8
<212>PRT
<213>SARS-CoV-2
<400>250
Asn Leu Thr Thr Arg Thr Gln Leu
1 5
<210>251
<211>9
<212>PRT
<213>SARS-CoV-2
<400>251
Leu Pro Pro Ala Tyr Thr Asn Ser Phe
1 5
<210>252
<211>9
<212>PRT
<213>SARS-CoV-2
<400>252
Lys Val Phe Arg Ser Ser Val Leu His
1 5
<210>253
<211>9
<212>PRT
<213>SARS-CoV-2
<400>253
Leu Pro Phe Phe Ser Asn Val Thr Trp
1 5
<210>254
<211>9
<212>PRT
<213>SARS-CoV-2
<400>254
Pro Phe Phe Ser Asn Val Thr Trp Phe
1 5
<210>255
<211>9
<212>PRT
<213>SARS-CoV-2
<400>255
Arg Phe Asp Asn Pro Val Leu Pro Phe
1 5
<210>256
<211>9
<212>PRT
<213>SARS-CoV-2
<400>256
Leu Pro Phe Asn Asp Gly Val Tyr Phe
1 5
<210>257
<211>9
<212>PRT
<213>SARS-CoV-2
<400>257
Gly Val Tyr Phe Ala Ser Thr Glu Lys
1 5
<210>258
<211>10
<212>PRT
<213>SARS-CoV-2
<400>258
Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp
1 5 10
<210>259
<211>9
<212>PRT
<213>SARS-CoV-2
<400>259
Thr Leu Asp Ser Lys Thr Gln Ser Leu
1 5
<210>260
<211>9
<212>PRT
<213>SARS-CoV-2
<400>260
Gly Val Tyr Tyr His Lys Asn Asn Lys
1 5
<210>261
<211>9
<212>PRT
<213>SARS-CoV-2
<400>261
Tyr Tyr His Lys Asn Asn Lys Ser Trp
1 5
<210>262
<211>10
<212>PRT
<213>SARS-CoV-2
<400>262
Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe
1 5 10
<210>263
<211>9
<212>PRT
<213>SARS-CoV-2
<400>263
Phe Glu Tyr Val Ser Gln Pro Phe Leu
1 5
<210>264
<211>9
<212>PRT
<213>SARS-CoV-2
<400>264
Glu Tyr Val Ser Gln Pro Phe Leu Met
1 5
<210>265
<211>9
<212>PRT
<213>SARS-CoV-2
<400>265
Phe Val Phe Lys Asn Ile Asp Gly Tyr
1 5
<210>266
<211>9
<212>PRT
<213>SARS-CoV-2
<400>266
Thr Pro Ile Asn Leu Val Arg Asp Leu
1 5
<210>267
<211>8
<212>PRT
<213>SARS-CoV-2
<400>267
Leu Pro Gln Gly Phe Ser Ala Leu
1 5
<210>268
<211>10
<212>PRT
<213>SARS-CoV-2
<400>268
Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe
1 5 10
<210>269
<211>9
<212>PRT
<213>SARS-CoV-2
<400>269
Ile Asn Ile Thr Arg Phe Gln Thr Leu
1 5
<210>270
<211>9
<212>PRT
<213>SARS-CoV-2
<400>270
Leu Leu Ala Leu His Arg Ser Tyr Leu
1 5
<210>271
<211>9
<212>PRT
<213>SARS-CoV-2
<400>271
Trp Thr Ala Gly Ala Ala Ala Tyr Tyr
1 5
<210>272
<211>11
<212>PRT
<213>SARS-CoV-2
<400>272
Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr Phe
1 5 10
<210>273
<211>9
<212>PRT
<213>SARS-CoV-2
<400>273
Tyr Leu Gln Pro Arg Thr Phe Leu Leu
1 5
<210>274
<211>8
<212>PRT
<213>SARS-CoV-2
<400>274
Tyr Leu Gln Pro Arg Thr Phe Leu
1 5
<210>275
<211>10
<212>PRT
<213>SARS-CoV-2
<400>275
Ser Glu Thr Lys Cys Thr Leu Lys Ser Phe
1 5 10
<210>276
<211>9
<212>PRT
<213>SARS-CoV-2
<400>276
Thr Leu Lys Ser Phe Thr Val Glu Lys
1 5
<210>277
<211>9
<212>PRT
<213>SARS-CoV-2
<400>277
Gln Pro Thr Glu Ser Ile Val Arg Phe
1 5
<210>278
<211>11
<212>PRT
<213>SARS-CoV-2
<400>278
Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe
1 5 10
<210>279
<211>9
<212>PRT
<213>SARS-CoV-2
<400>279
Gly Glu Val Phe Asn Ala Thr Arg Phe
1 5
<210>280
<211>9
<212>PRT
<213>SARS-CoV-2
<400>280
Asn Ala Thr Arg Phe Ala Ser Val Tyr
1 5
<210>281
<211>10
<212>PRT
<213>SARS-CoV-2
<400>281
Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe
1 5 10
<210>282
<211>9
<212>PRT
<213>SARS-CoV-2
<400>282
Asn Ser Ala Ser Phe Ser Thr Phe Lys
1 5
<210>283
<211>10
<212>PRT
<213>SARS-CoV-2
<400>283
Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys
1 5 10
<210>284
<211>9
<212>PRT
<213>SARS-CoV-2
<400>284
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu
1 5
<210>285
<211>9
<212>PRT
<213>SARS-CoV-2
<400>285
Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe
1 5
<210>286
<211>9
<212>PRT
<213>SARS-CoV-2
<400>286
Arg Leu Phe Arg Lys Ser Asn Leu Lys
1 5
<210>287
<211>11
<212>PRT
<213>SARS-CoV-2
<400>287
Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile
1 5 10
<210>288
<211>9
<212>PRT
<213>SARS-CoV-2
<400>288
Tyr Phe Pro Leu Gln Ser Tyr Gly Phe
1 5
<210>289
<211>8
<212>PRT
<213>SARS-CoV-2
<400>289
Gln Pro Tyr Arg Val Val Val Leu
1 5
<210>290
<211>9
<212>PRT
<213>SARS-CoV-2
<400>290
Pro Tyr Arg Val Val Val Leu Ser Phe
1 5
<210>291
<211>9
<212>PRT
<213>SARS-CoV-2
<400>291
Gly Pro Lys Lys Ser Thr Asn Leu Val
1 5
<210>292
<211>9
<212>PRT
<213>SARS-CoV-2
<400>292
Thr Ser Asn Gln Val Ala Val Leu Tyr
1 5
<210>293
<211>9
<212>PRT
<213>SARS-CoV-2
<400>293
Val Tyr Ser Thr Gly Ser Asn Val Phe
1 5
<210>294
<211>8
<212>PRT
<213>SARS-CoV-2
<400>294
Ala Glu His Val Asn Asn Ser Tyr
1 5
<210>295
<211>11
<212>PRT
<213>SARS-CoV-2
<400>295
Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr
1 5 10
<210>296
<211>9
<212>PRT
<213>SARS-CoV-2
<400>296
Ser Pro Arg Arg Ala Arg Ser Val Ala
1 5
<210>297
<211>9
<212>PRT
<213>SARS-CoV-2
<400>297
Val Ala Ser Gln Ser Ile Ile Ala Tyr
1 5
<210>298
<211>9
<212>PRT
<213>SARS-CoV-2
<400>298
Ser Ile Ile Ala Tyr Thr Met Ser Leu
1 5
<210>299
<211>9
<212>PRT
<213>SARS-CoV-2
<400>299
Leu Gly Ala Glu Asn Ser Val Ala Tyr
1 5
<210>300
<211>13
<212>PRT
<213>SARS-CoV-2
<400>300
Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe
1 5 10
<210>301
<211>9
<212>PRT
<213>SARS-CoV-2
<400>301
Ile Pro Thr Asn Phe Thr Ile Ser Val
1 5
<210>302
<211>10
<212>PRT
<213>SARS-CoV-2
<400>302
Thr Glu Ile Leu Pro Val Ser Met Thr Lys
1 5 10
<210>303
<211>11
<212>PRT
<213>SARS-CoV-2
<400>303
Gln Glu Val Phe Ala Gln Val Lys Gln Ile Tyr
1 5 10
<210>304
<211>10
<212>PRT
<213>SARS-CoV-2
<400>304
Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys
1 5 10
<210>305
<211>10
<212>PRT
<213>SARS-CoV-2
<400>305
Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe
1 5 10
<210>306
<211>9
<212>PRT
<213>SARS-CoV-2
<400>306
Leu Leu Phe Asn Lys Val Thr Leu Ala
1 5
<210>307
<211>9
<212>PRT
<213>SARS-CoV-2
<400>307
Thr Leu Ala Asp Ala Gly Phe Ile Lys
1 5
<210>308
<211>10
<212>PRT
<213>SARS-CoV-2
<400>308
Leu Ala Asp Ala Gly Phe Ile Lys Gln Tyr
1 5 10
<210>309
<211>9
<212>PRT
<213>SARS-CoV-2
<400>309
Ala Asp Ala Gly Phe Ile Lys Gln Tyr
1 5
<210>310
<211>14
<212>PRT
<213>SARS-CoV-2
<400>310
Val Leu Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr
1 5 10
<210>311
<211>9
<212>PRT
<213>SARS-CoV-2
<400>311
Ile Pro Phe Ala Met Gln Met Ala Tyr
1 5
<210>312
<211>9
<212>PRT
<213>SARS-CoV-2
<400>312
Ser Ser Thr Ala Ser Ala Leu Gly Lys
1 5
<210>313
<211>9
<212>PRT
<213>SARS-CoV-2
<400>313
Val Leu Asn Asp Ile Leu Ser Arg Leu
1 5
<210>314
<211>9
<212>PRT
<213>SARS-CoV-2
<400>314
Arg Leu Asp Lys Val Glu Ala Glu Val
1 5
<210>315
<211>10
<212>PRT
<213>SARS-CoV-2
<400>315
Val Glu Ala Glu Val Gln Ile Asp Arg Leu
1 5 10
<210>316
<211>9
<212>PRT
<213>SARS-CoV-2
<400>316
Ala Glu Val Gln Ile Asp Arg Leu Ile
1 5
<210>317
<211>9
<212>PRT
<213>SARS-CoV-2
<400>317
Leu Ile Thr Gly Arg Leu Gln Ser Leu
1 5
<210>318
<211>9
<212>PRT
<213>SARS-CoV-2
<400>318
Arg Leu Gln Ser Leu Gln Thr Tyr Val
1 5
<210>319
<211>9
<212>PRT
<213>SARS-CoV-2
<400>319
Ala Glu Ile Arg Ala Ser Ala Asn Leu
1 5
<210>320
<211>9
<212>PRT
<213>SARS-CoV-2
<400>320
Ala Ser Ala Asn Leu Ala Ala Thr Lys
1 5
<210>321
<211>9
<212>PRT
<213>SARS-CoV-2
<400>321
His Leu Met Ser Phe Pro Gln Ser Ala
1 5
<210>322
<211>11
<212>PRT
<213>SARS-CoV-2
<400>322
Phe Pro Gln Ser Ala Pro His Gly Val Val Phe
1 5 10
<210>323
<211>8
<212>PRT
<213>SARS-CoV-2
<400>323
Ala Pro His Gly Val Val Phe Leu
1 5
<210>324
<211>9
<212>PRT
<213>SARS-CoV-2
<400>324
Val Thr Tyr Val Pro Ala Gln Glu Lys
1 5
<210>325
<211>10
<212>PRT
<213>SARS-CoV-2
<400>325
Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe
1 5 10
<210>326
<211>12
<212>PRT
<213>SARS-CoV-2
<400>326
Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp
1 5 10
<210>327
<211>9
<212>PRT
<213>SARS-CoV-2
<400>327
Gly Thr His Trp Phe Val Thr Gln Arg
1 5
<210>328
<211>14
<212>PRT
<213>SARS-CoV-2
<400>328
Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys
1 5 10
<210>329
<211>9
<212>PRT
<213>SARS-CoV-2
<400>329
Lys Glu Ile Asp Arg Leu Asn Glu Val
1 5
<210>330
<211>12
<212>PRT
<213>SARS-CoV-2
<400>330
Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp
1 5 10
<210>331
<211>9
<212>PRT
<213>SARS-CoV-2
<400>331
Tyr Glu Gln Tyr Ile Lys Trp Pro Trp
1 5
<210>332
<211>9
<212>PRT
<213>SARS-CoV-2
<400>332
Gln Tyr Ile Lys Trp Pro Trp Tyr Ile
1 5
<210>333
<211>9
<212>PRT
<213>SARS-CoV-2
<400>333
Phe Ile Ala Gly Leu Ile Ala Ile Val
1 5
<210>334
<211>10
<212>PRT
<213>SARS-CoV-2
<400>334
Ser Glu Pro Val Leu Lys Gly Val Lys Leu
1 5 10
<210>335
<211>9
<212>PRT
<213>SARS-CoV-2
<400>335
Gly Thr Ile Thr Val Glu Glu Leu Lys
1 5
<210>336
<211>10
<212>PRT
<213>SARS-CoV-2
<400>336
Glu Glu Leu Lys Lys Leu Leu Glu Gln Trp
1 5 10
<210>337
<211>9
<212>PRT
<213>SARS-CoV-2
<400>337
Lys Leu Leu Glu Gln Trp Asn Leu Val
1 5
<210>338
<211>9
<212>PRT
<213>SARS-CoV-2
<400>338
Phe Ala Tyr Ala Asn Arg Asn Arg Phe
1 5
<210>339
<211>9
<212>PRT
<213>SARS-CoV-2
<400>339
Tyr Ala Asn Arg Asn Arg Phe Leu Tyr
1 5
<210>340
<211>10
<212>PRT
<213>SARS-CoV-2
<400>340
Ser Tyr Phe Ile Ala Ser Phe Arg Leu Phe
1 5 10
<210>341
<211>9
<212>PRT
<213>SARS-CoV-2
<400>341
Arg Leu Phe Ala Arg Thr Arg Ser Met
1 5
<210>342
<211>8
<212>PRT
<213>SARS-CoV-2
<400>342
Val Pro Leu His Gly Thr Ile Leu
1 5
<210>343
<211>10
<212>PRT
<213>SARS-CoV-2
<400>343
Ser Glu Leu Val Ile Gly Ala Val Ile Leu
1 5 10
<210>344
<211>9
<212>PRT
<213>SARS-CoV-2
<400>344
His Leu Arg Ile Ala Gly His His Leu
1 5
<210>345
<211>9
<212>PRT
<213>SARS-CoV-2
<400>345
Arg Ile Ala Gly His His Leu Gly Arg
1 5
<210>346
<211>11
<212>PRT
<213>SARS-CoV-2
<400>346
Lys Glu Ile Thr Val Ala Thr Ser Arg Thr Leu
1 5 10
<210>347
<211>10
<212>PRT
<213>SARS-CoV-2
<400>347
Ala Thr Ser Arg Thr Leu Ser Tyr Tyr Lys
1 5 10
<210>348
<211>14
<212>PRT
<213>SARS-CoV-2
<400>348
Ala Ser Gln Arg Val Ala Gly Asp Ser Gly Phe Ala Ala Tyr
1 5 10
<210>349
<211>10
<212>PRT
<213>SARS-CoV-2
<400>349
Val Ala Gly Asp Ser Gly Phe Ala Ala Tyr
1 5 10
<210>350
<211>9
<212>PRT
<213>SARS-CoV-2
<400>350
Leu Pro Asn Asn Thr Ala Ser Trp Phe
1 5
<210>351
<211>10
<212>PRT
<213>SARS-CoV-2
<400>351
Lys Phe Pro Arg Gly Gln Gly Val Pro Ile
1 5 10
<210>352
<211>13
<212>PRT
<213>SARS-CoV-2
<400>352
Asn Thr Asn Ser Ser Pro Asp Asp Gln Ile Gly Tyr Tyr
1 5 10
<210>353
<211>9
<212>PRT
<213>SARS-CoV-2
<400>353
Ser Pro Arg Trp Tyr Phe Tyr Tyr Leu
1 5
<210>354
<211>9
<212>PRT
<213>SARS-CoV-2
<400>354
Leu Leu Leu Asp Arg Leu Asn Gln Leu
1 5
<210>355
<211>9
<212>PRT
<213>SARS-CoV-2
<400>355
Lys Ala Tyr Asn Val Thr Gln Ala Phe
1 5
<210>356
<211>13
<212>PRT
<213>SARS-CoV-2
<400>356
Gln Glu Leu Ile Arg Gln Gly Thr Asp Tyr Lys His Trp
1 5 10
<210>357
<211>9
<212>PRT
<213>SARS-CoV-2
<400>357
Ala Ser Ala Phe Phe Gly Met Ser Arg
1 5
<210>358
<211>13
<212>PRT
<213>SARS-CoV-2
<400>358
Ser Arg Ile Gly Met Glu Val Thr Pro Ser Gly Thr Trp
1 5 10
<210>359
<211>11
<212>PRT
<213>SARS-CoV-2
<400>359
Gly Met Glu Val Thr Pro Ser Gly Thr Trp Leu
1 5 10
<210>360
<211>9
<212>PRT
<213>SARS-CoV-2
<400>360
Thr Pro Ser Gly Thr Trp Leu Thr Tyr
1 5
<210>361
<211>11
<212>PRT
<213>SARS-CoV-2
<400>361
Ala Tyr Lys Thr Phe Pro Pro Thr Glu Pro Lys
1 5 10
<210>362
<211>9
<212>PRT
<213>SARS-CoV-2
<400>362
Leu Pro Ala Ala Asp Leu Asp Asp Phe
1 5
<210>363
<211>5
<212>PRT
<213>智人(Homo sapiens)
<400>363
Gly Thr Leu Arg Gly
1 5
<210>364
<211>5
<212>PRT
<213>智人(Homo sapiens)
<400>364
Tyr Asn Gln Ser Glu
1 5
<210>365
<211>5
<212>PRT
<213>智人(Homo sapiens)
<400>365
Thr Ala Ala Asp Met
1 5
<210>366
<211>5
<212>PRT
<213>智人(Homo sapiens)
<400>366
Ala Gln Thr Thr Lys
1 5
<210>367
<211>5
<212>PRT
<213>智人(Homo sapiens)
<400>367
Val Glu Thr Arg Pro
1 5
<210>368
<211>5
<212>PRT
<213>智人(Homo sapiens)
<400>368
Gly Asp Gly Thr Phe
1 5
<210>369
<211>5
<212>PRT
<213>智人(Homo sapiens)
<400>369
Arg Asn Leu Arg Gly
1 5
<210>370
<211>5
<212>PRT
<213>智人(Homo sapiens)
<400>370
Thr Ala Ala Asp Thr
1 5
<210>371
<211>5
<212>PRT
<213>智人(Homo sapiens)
<400>371
Ala Gln Ile Thr Gln
1 5
<210>372
<211>5
<212>PRT
<213>智人(Homo sapiens)
<400>372
Gly Asp Arg Thr Phe
1 5
<210>373
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>373
Gly Ser His Ser Met Arg Tyr Phe Phe Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gly Glu Thr
505560
Arg Lys Val Lys Ala His Ser Gln Thr His Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Cys Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Val Gln
859095
Arg Met Tyr Gly Cys Asp Val Gly Ser Asp Trp Arg Phe Leu Arg Gly
100 105 110
Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Thr Thr Lys
130 135 140
His Lys Trp Glu Ala Ala His Val Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Ala Pro Lys Thr His Met Thr His His
180 185 190
Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Gln Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>374
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>374
Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu Thr
505560
Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile Gln
859095
Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Lys
130 135 140
Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>375
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>375
Gly Ser His Ser Met Arg Tyr Phe Ser Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Glu Glu Thr
505560
Gly Lys Val Lys Ala His Ser Gln Thr Asp Arg Glu Asn Leu Arg Ile
65707580
Ala Leu Arg Cys Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Met Met Phe Gly Cys Asp Val Gly Ser Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Lys
130 135 140
Arg Lys Trp Glu Ala Ala His Val Ala Glu Gln Gln Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Asp Gly Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>376
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>376
Gly Ser His Ser Met Arg Tyr Phe Thr Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Asn Thr
505560
Arg Asn Val Lys Ala His Ser Gln Ile Asp Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Cys Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Ile Gln
859095
Met Met Tyr Gly Cys Asp Val Gly Ser Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Gln Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Val Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ser Val Val Val Pro Ser Gly Gln Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>377
<211>276
<212>PRT
<213>智人(Homo sapiens)
<400>377
Gly Ser His Ser Met Arg Tyr Phe Phe Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Lys Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu Thr
505560
Arg Asn Met Lys Ala His Ser Gln Thr Asp Arg Ala Asn Leu Gly Thr
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile Gln
859095
Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Lys
130 135 140
Arg Lys Trp Glu Ala Val His Ala Ala Glu Gln Arg Arg Val Tyr Leu
145 150 155 160
Glu Gly Arg Cys Val Asp Gly Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Leu
275
<210>378
<211>276
<212>PRT
<213>智人(Homo sapiens)
<400>378
Gly Ser His Ser Met Arg Tyr Phe Phe Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu Thr
505560
Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Ile Gln
859095
Ile Met Tyr Gly Cys Asp Val Gly Ser Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Lys
130 135 140
Arg Lys Trp Glu Ala Ala His Glu Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Asp Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Leu
275
<210>379
<211>276
<212>PRT
<213>智人(Homo sapiens)
<400>379
Gly Ser His Ser Met Arg Tyr Phe Ser Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Glu Glu Thr
505560
Gly Lys Val Lys Ala His Ser Gln Thr Asp Arg Glu Asn Leu Arg Ile
65707580
Ala Leu Arg Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Met Met Phe Gly Cys Asp Val Gly Ser Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Val Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Asp Gly Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>380
<211>276
<212>PRT
<213>智人(Homo sapiens)
<400>380
Gly Ser His Ser Met Arg Tyr Phe Ser Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Glu Glu Thr
505560
Gly Lys Val Lys Ala Gln Ser Gln Thr Asp Arg Glu Asn Leu Arg Ile
65707580
Ala Leu Arg Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Met Met Phe Gly Cys Asp Val Gly Ser Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Lys
130 135 140
Arg Lys Trp Glu Ala Ala His Val Ala Glu Gln Gln Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Asp Gly Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>381
<211>276
<212>PRT
<213>智人(Homo sapiens)
<400>381
Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Asn Thr
505560
Arg Lys Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile Gln
859095
Arg Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Gln Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Thr Ala His Glu Ala Glu Gln Trp Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Ala Pro Lys Thr His Met Thr His His
180 185 190
Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ser Val Val Val Pro Ser Gly Gln Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>382
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>382
Gly Ser His Ser Leu Lys Tyr Phe His Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Asn Asp Ala Ala Ser Pro Arg Met Val Pro Arg
354045
Ala Pro Trp Met Glu Gln Glu Gly Ser Glu Tyr Trp Asp Arg Glu Thr
505560
Arg Ser Ala Arg Asp Thr Ala Gln Ile Phe Arg Val Asn Leu Arg Thr
65707580
Leu Arg Gly Cys Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Trp Met His Gly Cys Glu Leu Gly Pro Asp Arg Arg Phe Leu Arg Gly
100 105 110
Tyr Glu Gln Phe Ala Tyr Asp Gly Lys Asp Tyr Leu Thr Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Val Asp Thr Ala Ala Gln Ile Ser Glu
130 135 140
Gln Lys Ser Asn Asp Ala Ser Glu Ala Glu His Gln Arg Ala Tyr Leu
145 150 155 160
Glu Asp Thr Cys Val Glu Trp Leu His Lys Tyr Leu Glu Lys Gly Lys
165 170 175
Glu Thr Leu Leu His Leu Glu Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Gln Asp Gly Glu Gly His
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Val Thr Leu
260 265 270
Arg Trp Lys
275
<210>383
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>383
Gly Ser His Ser Leu Lys Tyr Phe His Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Asn Asp Ala Ala Ser Pro Arg Met Val Pro Arg
354045
Ala Pro Trp Met Glu Gln Glu Gly Ser Glu Tyr Trp Asp Arg Glu Thr
505560
Arg Ser Ala Arg Asp Thr Ala Gln Ile Phe Arg Val Asn Leu Arg Thr
65707580
Leu Arg Gly Cys Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Trp Met His Gly Cys Glu Leu Gly Pro Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Glu Gln Phe Ala Tyr Asp Gly Lys Asp Tyr Leu Thr Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Val Asp Thr Ala Ala Gln Ile Ser Glu
130 135 140
Gln Lys Ser Asn Asp Ala Ser Glu Ala Glu His Gln Arg Ala Tyr Leu
145 150 155 160
Glu Asp Thr Cys Val Glu Trp Leu His Lys Tyr Leu Glu Lys Gly Lys
165 170 175
Glu Thr Leu Leu His Leu Glu Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Gln Asp Gly Glu Gly His
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Val Thr Leu
260 265 270
Arg Trp Lys
275
<210>384
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>384
Gly Ser His Ser Met Arg Tyr Phe Ser Ala Ala Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Met Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ser Ala Cys Pro Arg Met Glu Pro Arg
354045
Ala Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Glu Glu Glu Thr
505560
Arg Asn Thr Lys Ala His Ala Gln Thr Asp Arg Met Asn Leu Gln Thr
65707580
Leu Arg Gly Cys Tyr Asn Gln Ser Glu Ala Ser Ser His Thr Leu Gln
859095
Trp Met Ile Gly Cys Asp Leu Gly Ser Asp Gly Arg Leu Leu Arg Gly
100 105 110
Tyr Glu Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Leu Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Ser Lys
130 135 140
Arg Lys Cys Glu Ala Ala Asn Val Ala Glu Gln Arg Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu His Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Met Leu Gln Arg Ala Asp Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Val Phe Asp Tyr Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Ile Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Val Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Leu Met Leu
260 265 270
Arg Trp Lys
275
<210>385
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>385
Gly Ser His Ser Met Arg Tyr Phe Ser Ala Ala Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Met Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ser Ala Cys Pro Arg Met Glu Pro Arg
354045
Ala Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Glu Glu Glu Thr
505560
Arg Asn Thr Lys Ala His Ala Gln Thr Asp Arg Met Asn Leu Gln Thr
65707580
Leu Arg Gly Cys Tyr Asn Gln Ser Glu Ala Ser Ser His Thr Leu Gln
859095
Trp Met Ile Gly Cys Asp Leu Gly Ser Asp Gly Arg Leu Ile Arg Gly
100 105 110
Tyr Glu Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Leu Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Ser Lys
130 135 140
Arg Lys Cys Glu Ala Ala Asn Val Ala Glu Gln Arg Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu His Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Met Leu Gln Arg Ala Asp Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Val Phe Asp Tyr Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Ile Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Val Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Leu Met Leu
260 265 270
Arg Trp Lys
275
<210>386
<211>133
<212>PRT
<213>智人(Homo sapiens)
<400>386
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala
1 5 1015
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
202530
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
354045
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
505560
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65707580
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
859095
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210>387
<211>133
<212>PRT
<213>智人(Homo sapiens)
<400>387
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala
1 5 1015
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
202530
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
354045
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
505560
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65707580
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
859095
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210>388
<211>133
<212>PRT
<213>智人(Homo sapiens)
<400>388
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Thr
1 5 1015
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
202530
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
354045
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
505560
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65707580
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
859095
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210>389
<211>219
<212>PRT
<213>智人(Homo sapiens)
<400>389
Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr Gly Ser
1 5 1015
Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu Asp Leu
202530
Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile Ile Gln
354045
Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser Tyr Arg
505560
Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn Ala Ala
65707580
Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr Arg Cys
859095
Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val Lys Val
100 105 110
Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val Asp Pro
115 120 125
Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr Pro Lys
130 135 140
Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser Gly Lys
145 150 155 160
Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn Val Thr
165 170 175
Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr Cys Thr
180 185 190
Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu Val Ile
195 200 205
Pro Gly Asn Ile Leu Asn Val Ser Ile Lys Ile
210 215
<210>390
<211>167
<212>PRT
<213>智人(Homo sapiens)
<400>390
Asp Pro Ala Gly Leu Leu Asp Leu Arg Gln Gly Met Phe Ala Gln Leu
1 5 1015
Val Ala Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser
202530
Asp Pro Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys
354045
Glu Asp Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val
505560
Phe Phe Gln Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly
65707580
Ser Val Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly
859095
Ala Ala Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu
100 105 110
Ala Arg Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser
115 120 125
Ala Gly Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg
130 135 140
His Ala Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg
145 150 155 160
Val Thr Pro Glu Ile Pro Ala
165
<210>391
<211>240
<212>PRT
<213>智人(Homo sapiens)
<400>391
Gln Glu Lys Glu Val Arg Ala Met Val Gly Ser Asp Val Glu Leu Ser
1 5 1015
Cys Ala Cys Pro Glu Gly Ser Arg Phe Asp Leu Asn Asp Val Tyr Val
202530
Tyr Trp Gln Thr Ser Glu Ser Lys Thr Val Val Thr Tyr His Ile Pro
354045
Gln Asn Ser Ser Leu Glu Asn Val Asp Ser Arg Tyr Arg Asn Arg Ala
505560
Leu Met Ser Pro Ala Gly Met Leu Arg Gly Asp Phe Ser Leu Arg Leu
65707580
Phe Asn Val Thr Pro Gln Asp Glu Gln Lys Phe His Cys Leu Val Leu
859095
Ser Gln Ser Leu Gly Phe Gln Glu Val Leu Ser Val Glu Val Thr Leu
100 105 110
His Val Ala Ala Asn Phe Ser Val Pro Val Val Ser Ala Pro His Ser
115 120 125
Pro Ser Gln Asp Glu Leu Thr Phe Thr Cys Thr Ser Ile Asn Gly Tyr
130 135 140
Pro Arg Pro Asn Val Tyr Trp Ile Asn Lys Thr Asp Asn Ser Leu Leu
145 150 155 160
Asp Gln Ala Leu Gln Asn Asp Thr Val Phe Leu Asn Met Arg Gly Leu
165 170 175
Tyr Asp Val Val Ser Val Leu Arg Ile Ala Arg Thr Pro Ser Val Asn
180 185 190
Ile Gly Cys Cys Ile Glu Asn Val Leu Leu Gln Gln Asn Leu Thr Val
195 200 205
Gly Ser Gln Thr Gly Asn Asp Ile Gly Glu Arg Asp Lys Ile Thr Glu
210 215 220
Asn Pro Val Ser Thr Gly Glu Lys Asn Ala Ala Thr Trp Ser Ile Leu
225 230 235 240
<210>392
<211>134
<212>PRT
<213>智人(Homo sapiens)
<400>392
Leu Gln Val Ser His Arg Tyr Pro Arg Ile Gln Ser Ile Lys Val Gln
1 5 1015
Phe Thr Glu Tyr Lys Lys Glu Lys Gly Phe Ile Leu Thr Ser Gln Lys
202530
Glu Asp Glu Ile Met Lys Val Gln Asn Asn Ser Val Ile Ile Asn Cys
354045
Asp Gly Phe Tyr Leu Ile Ser Leu Lys Gly Tyr Phe Ser Gln Glu Val
505560
Asn Ile Ser Leu His Tyr Gln Lys Asp Glu Glu Pro Leu Phe Gln Leu
65707580
Lys Lys Val Arg Ser Val Asn Ser Leu Met Val Ala Ser Leu Thr Tyr
859095
Lys Asp Lys Val Tyr Leu Asn Val Thr Thr Asp Asn Thr Ser Leu Asp
100 105 110
Asp Phe His Val Asn Gly Gly Glu Leu Ile Leu Ile His Gln Asn Pro
115 120 125
Gly Glu Phe Cys Val Leu
130
<210>393
<211>201
<212>PRT
<213>智人(Homo sapiens)
<400>393
Leu Phe Thr Val Thr Val Pro Lys Glu Leu Tyr Ile Ile Glu His Gly
1 5 1015
Ser Asn Val Thr Leu Glu Cys Asn Phe Asp Thr Gly Ser His Val Asn
202530
Leu Gly Ala Ile Thr Ala Ser Leu Gln Lys Val Glu Asn Asp Thr Ser
354045
Pro His Arg Glu Arg Ala Thr Leu Leu Glu Glu Gln Leu Pro Leu Gly
505560
Lys Ala Ser Phe His Ile Pro Gln Val Gln Val Arg Asp Glu Gly Gln
65707580
Tyr Gln Cys Ile Ile Ile Tyr Gly Val Ala Trp Asp Tyr Lys Tyr Leu
859095
Thr Leu Lys Val Lys Ala Ser Tyr Arg Lys Ile Asn Thr His Ile Leu
100 105 110
Lys Val Pro Glu Thr Asp Glu Val Glu Leu Thr Cys Gln Ala Thr Gly
115 120 125
Tyr Pro Leu Ala Glu Val Ser Trp Pro Asn Val Ser Val Pro Ala Asn
130 135 140
Thr Ser His Ser Arg Thr Pro Glu Gly Leu Tyr Gln Val Thr Ser Val
145 150 155 160
Leu Arg Leu Lys Pro Pro Pro Gly Arg Asn Phe Ser Cys Val Phe Trp
165 170 175
Asn Thr His Val Arg Glu Leu Thr Leu Ala Ser Ile Asp Leu Gln Ser
180 185 190
Gln Met Glu Pro Arg Thr His Pro Thr
195 200
<210>394
<211>208
<212>PRT
<213>智人(Homo sapiens)
<400>394
Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu Ser Cys
1 5 1015
Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile Tyr Trp
202530
Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp Met Asn
354045
Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr Asn Asn
505560
Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly Thr Tyr
65707580
Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg Glu His
859095
Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr Pro Ser
100 105 110
Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile Ile Cys
115 120 125
Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu Glu Asn
130 135 140
Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp Pro Glu
145 150 155 160
Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met Thr Thr
165 170 175
Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg Val Asn
180 185 190
Gln Thr Phe Asn Trp Asn Thr Thr Lys Gln Glu His Phe Pro Asp Asn
195 200 205
<210>395
<211>224
<212>PRT
<213>智人(Homo sapiens)
<400>395
Ala Pro Leu Lys Ile Gln Ala Tyr Phe Asn Glu Thr Ala Asp Leu Pro
1 5 1015
Cys Gln Phe Ala Asn Ser Gln Asn Gln Ser Leu Ser Glu Leu Val Val
202530
Phe Trp Gln Asp Gln Glu Asn Leu Val Leu Asn Glu Val Tyr Leu Gly
354045
Lys Glu Lys Phe Asp Ser Val His Ser Lys Tyr Met Asn Arg Thr Ser
505560
Phe Asp Ser Asp Ser Trp Thr Leu Arg Leu His Asn Leu Gln Ile Lys
65707580
Asp Lys Gly Leu Tyr Gln Cys Ile Ile His His Lys Lys Pro Thr Gly
859095
Met Ile Arg Ile His Gln Met Asn Ser Glu Leu Ser Val Leu Ala Asn
100 105 110
Phe Ser Gln Pro Glu Ile Val Pro Ile Ser Asn Ile Thr Glu Asn Val
115 120 125
Tyr Ile Asn Leu Thr Cys Ser Ser Ile His Gly Tyr Pro Glu Pro Lys
130 135 140
Lys Met Ser Val Leu Leu Arg Thr Lys Asn Ser Thr Ile Glu Tyr Asp
145 150 155 160
Gly Ile Met Gln Lys Ser Gln Asp Asn Val Thr Glu Leu Tyr Asp Val
165 170 175
Ser Ile Ser Leu Ser Val Ser Phe Pro Asp Val Thr Ser Asn Met Thr
180 185 190
Ile Phe Cys Ile Leu Glu Thr Asp Lys Thr Arg Leu Leu Ser Ser Pro
195 200 205
Phe Ser Ile Glu Leu Glu Asp Pro Gln Pro Pro Pro Asp His Ile Pro
210 215 220
<210>396
<211>179
<212>PRT
<213>智人(Homo sapiens)
<400>396
Gln Leu Phe His Leu Gln Lys Glu Leu Ala Glu Leu Arg Glu Ser Thr
1 5 1015
Ser Gln Met His Thr Ala Ser Ser Leu Glu Lys Gln Ile Gly His Pro
202530
Ser Pro Pro Pro Glu Lys Lys Glu Leu Arg Lys Val Ala His Leu Thr
354045
Gly Lys Ser Asn Ser Arg Ser Met Pro Leu Glu Trp Glu Asp Thr Tyr
505560
Gly Ile Val Leu Leu Ser Gly Val Lys Tyr Lys Lys Gly Gly Leu Val
65707580
Ile Asn Glu Thr Gly Leu Tyr Phe Val Tyr Ser Lys Val Tyr Phe Arg
859095
Gly Gln Ser Cys Asn Asn Leu Pro Leu Ser His Lys Val Tyr Met Arg
100 105 110
Asn Ser Lys Tyr Pro Gln Asp Leu Val Met Met Glu Gly Lys Met Met
115 120 125
Ser Tyr Cys Thr Thr Gly Gln Met Trp Ala Arg Ser Ser Tyr Leu Gly
130 135 140
Ala Val Phe Asn Leu Thr Ser Ala Asp His Leu Tyr Val Asn Val Ser
145 150 155 160
Glu Leu Ser Leu Val Asn Phe Glu Glu Ser Gln Thr Phe Phe Gly Leu
165 170 175
Tyr Lys Leu
<210>397
<211>223
<212>PRT
<213>智人(Homo sapiens)
<400>397
Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser
1 5 1015
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
202530
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
354045
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
505560
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
65707580
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
859095
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
100 105 110
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
115 120 125
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
130 135 140
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
145 150 155 160
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
165 170 175
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
180 185 190
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
195 200 205
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
210 215 220
<210>398
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>398
Gly Ser Gly Gly Ser
1 5
<210>399
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>399
Gly Gly Gly Gly Ser
1 5
<210>400
<211>4
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>400
Gly Gly Gly Ser
1
<210>401
<211>4
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>401
Gly Gly Ser Gly
1
<210>402
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>402
Gly Gly Ser Gly Gly
1 5
<210>403
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>403
Gly Ser Gly Ser Gly
1 5
<210>404
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>404
Gly Ser Gly Gly Gly
1 5
<210>405
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>405
Gly Gly Gly Ser Gly
1 5
<210>406
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>406
Gly Ser Ser Ser Gly
1 5
<210>407
<211>10
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>407
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210>408
<211>15
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>408
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 1015
<210>409
<211>20
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>409
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 1015
Gly Gly Gly Ser
20
<210>410
<211>35
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>410
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 1015
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
202530
Gly Gly Ser
35
<210>411
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>411
Ala Ala Ala Gly Gly
1 5
<210>412
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>412
Glu Ala Ala Ala Lys
1 5
<210>413
<211>6
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>413
Ala Glu Ala Ala Ala Lys
1 5
<210>414
<211>7
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>414
Ala Glu Ala Ala Ala Lys Ala
1 5
<210>415
<211>16
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>415
Ala Glu Ala Ala Ala Lys Ala Leu Glu Ala Glu Ala Ala Ala Lys Ala
1 5 1015
<210>416
<211>10
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>416
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10
<210>417
<211>15
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>417
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 1015
<210>418
<211>46
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>418
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 1015
Glu Ala Ala Ala Lys Ala Leu Glu Ala Glu Ala Ala Ala Lys Glu Ala
202530
Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala
354045
<210>419
<211>12
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>419
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala
1 5 10
<210>420
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>420
Pro Ala Pro Ala Pro
1 5
<210>421
<211>8
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>421
Ala Pro Ala Pro Ala Pro Ala Pro
1 5
<210>422
<211>12
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>422
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 10
<210>423
<211>16
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>423
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 1015
<210>424
<211>20
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>424
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 1015
Ala Pro Ala Pro
20
<210>425
<211>4
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>425
Lys Pro Lys Pro
1
<210>426
<211>8
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>426
Lys Pro Lys Pro Lys Pro Lys Pro
1 5
<210>427
<211>12
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>427
Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro
1 5 10
<210>428
<211>16
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>428
Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro
1 5 1015
<210>429
<211>20
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>429
Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro
1 5 1015
Lys Pro Lys Pro
20
<210>430
<211>4
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>430
Glu Pro Glu Pro
1
<210>431
<211>8
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>431
Glu Pro Glu Pro Glu Pro Glu Pro
1 5
<210>432
<211>12
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>432
Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro
1 5 10
<210>433
<211>16
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>433
Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro
1 5 1015
<210>434
<211>20
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>434
Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro
1 5 1015
Glu Pro Glu Pro
20
<210>435
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>435
Gly Cys Gly Gly Ser
1 5
<210>436
<211>55
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(6)..(55)
<223>在位置6至55的Gly Gly Gly Gly Ser的各拷贝存在或不存在,使得Gly GlyGl Gly Ser的拷贝数在1至10范围内。
<400>436
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 1015
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
202530
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
354045
Gly Ser Gly Gly Gly Gly Ser
5055
<210>437
<211>15
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>437
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 1015
<210>438
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>438
Cys Gly Gly Gly Ser
1 5
<210>439
<211>55
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(6)..(55)
<223>在位置6至55的Gly Gly Gly Gly Ser的各拷贝存在或不存在,使得Gly GlyGl Gly Ser的拷贝数在1至10范围内。
<400>439
Cys Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 1015
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
202530
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
354045
Gly Ser Gly Gly Gly Gly Ser
5055
<210>440
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>440
Gly Gly Cys Gly Ser
1 5
<210>441
<211>55
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(6)..(55)
<223>在位置6至55的Gly Gly Gly Gly Ser的各拷贝存在或不存在,使得Gly GlyGl Gly Ser的拷贝数在1至10范围内。
<400>441
Gly Gly Cys Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 1015
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
202530
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
354045
Gly Ser Gly Gly Gly Gly Ser
5055
<210>442
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>442
Gly Gly Gly Cys Ser
1 5
<210>443
<211>55
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(6)..(55)
<223>在位置6至55的Gly Gly Gly Gly Ser的各拷贝存在或不存在,使得Gly GlyGl Gly Ser的拷贝数在1至10范围内。
<400>443
Gly Gly Gly Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 1015
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
202530
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
354045
Gly Ser Gly Gly Gly Gly Ser
5055
<210>444
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>444
Gly Gly Gly Gly Cys
1 5
<210>445
<211>55
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(6)..(55)
<223>在位置6至55的Gly Gly Gly Gly Ser的各拷贝存在或不存在,使得Gly GlyGl Gly Ser的拷贝数在1至10范围内。
<400>445
Gly Gly Gly Gly Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 1015
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
202530
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
354045
Gly Ser Gly Gly Gly Gly Ser
5055
<210>446
<211>5
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(4)..(4)
<223>其中Xaa为除脯氨酸外的氨基酸
<400>446
Val Pro Gly Xaa Gly
1 5
<210>4
<211>55
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(50)
<223>在位置1至50的Gly Gly Gly Gly Ser的各拷贝存在或不存在,使得Gly GlyGl Gly Ser的拷贝数在1至10范围内。
<400>447
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 1015
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
202530
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
354045
Gly Ser Gly Cys Gly Gly Ser
5055
<210>448
<211>99
<212>PRT
<213>智人(Homo sapiens)
<400>448
Ile Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg His Pro Ala Glu
1 5 1015
Asn Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro
202530
Ser Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys
354045
Val Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu
505560
Leu Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys
65707580
Arg Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp
859095
Arg Asp Met
<210>449
<211>99
<212>PRT
<213>智人(Homo sapiens)
<400>449
Ile Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu
1 5 1015
Asn Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro
202530
Ser Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys
354045
Val Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu
505560
Leu Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys
65707580
Arg Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp
859095
Arg Asp Met
<210>450
<211>227
<212>PRT
<213>智人(Homo sapiens)
<400>450
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 1015
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
202530
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
354045
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
505560
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65707580
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
859095
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210>451
<211>227
<212>PRT
<213>智人(Homo sapiens)
<400>451
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 1015
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
202530
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
354045
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
505560
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65707580
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
859095
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210>452
<211>227
<212>PRT
<213>智人(Homo sapiens)
<400>452
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 1015
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
202530
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
354045
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
505560
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65707580
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
859095
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210>453
<211>227
<212>PRT
<213>智人(Homo sapiens)
<400>453
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 1015
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
202530
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
354045
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
505560
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65707580
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
859095
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210>454
<211>227
<212>PRT
<213>智人(Homo sapiens)
<400>454
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly
1 5 1015
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
202530
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
354045
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
505560
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65707580
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
859095
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210>455
<211>227
<212>PRT
<213>智人(Homo sapiens)
<400>455
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 1015
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
202530
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
354045
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
505560
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr
65707580
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
859095
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210>456
<211>325
<212>PRT
<213>智人(Homo sapiens)
<400>456
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser
1 5 1015
Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
202530
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
354045
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
505560
Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr
65707580
Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr
859095
Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro
100 105 110
Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
115 120 125
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
130 135 140
Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
145 150 155 160
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
165 170 175
Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu
180 185 190
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala
195 200 205
Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro
210 215 220
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
225 230 235 240
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
245 250 255
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
260 265 270
Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
275 280 285
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
290 295 300
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
305 310 315 320
Leu Ser Pro Gly Lys
325
<210>457
<211>246
<212>PRT
<213>智人(Homo sapiens)
<400>457
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Leu Lys Thr
1 5 1015
Pro Leu Gly Asp Thr Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
202530
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
354045
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
505560
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
65707580
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
859095
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
100 105 110
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
115 120 125
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
130 135 140
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
145 150 155 160
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
165 170 175
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
180 185 190
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
195 200 205
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
210 215 220
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
225 230 235 240
Ser Leu Ser Pro Gly Lys
245
<210>458
<211>383
<212>PRT
<213>智人(Homo sapiens)
<400>458
Pro Thr Lys Ala Pro Asp Val Phe Pro Ile Ile Ser Gly Cys Arg His
1 5 1015
Pro Lys Asp Asn Ser Pro Val Val Leu Ala Cys Leu Ile Thr Gly Tyr
202530
His Pro Thr Ser Val Thr Val Thr Trp Tyr Met Gly Thr Gln Ser Gln
354045
Pro Gln Arg Thr Phe Pro Glu Ile Gln Arg Arg Asp Ser Tyr Tyr Met
505560
Thr Ser Ser Gln Leu Ser Thr Pro Leu Gln Gln Trp Arg Gln Gly Glu
65707580
Tyr Lys Cys Val Val Gln His Thr Ala Ser Lys Ser Lys Lys Glu Ile
859095
Phe Arg Trp Pro Glu Ser Pro Lys Ala Gln Ala Ser Ser Val Pro Thr
100 105 110
Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Pro
115 120 125
Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys Glu
130 135 140
Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys
145 150 155 160
Pro Ser His Thr Gln Pro Leu Gly Val Tyr Leu Leu Thr Pro Ala Val
165 170 175
Gln Asp Leu Trp Leu Arg Asp Lys Ala Thr Phe Thr Cys Phe Val Val
180 185 190
Gly Ser Asp Leu Lys Asp Ala His Leu Thr Trp Glu Val Ala Gly Lys
195 200 205
Val Pro Thr Gly Gly Val Glu Glu Gly Leu Leu Glu Arg His Ser Asn
210 215 220
Gly Ser Gln Ser Gln His Ser Arg Leu Thr Leu Pro Arg Ser Leu Trp
225 230 235 240
Asn Ala Gly Thr Ser Val Thr Cys Thr Leu Asn His Pro Ser Leu Pro
245 250 255
Pro Gln Arg Leu Met Ala Leu Arg Glu Pro Ala Ala Gln Ala Pro Val
260 265 270
Lys Leu Ser Leu Asn Leu Leu Ala Ser Ser Asp Pro Pro Glu Ala Ala
275 280 285
Ser Trp Leu Leu Cys Glu Val Ser Gly Phe Ser Pro Pro Asn Ile Leu
290 295 300
Leu Met Trp Leu Glu Asp Gln Arg Glu Val Asn Thr Ser Gly Phe Ala
305 310 315 320
Pro Ala Arg Pro Pro Pro Gln Pro Arg Ser Thr Thr Phe Trp Ala Trp
325 330 335
Ser Val Leu Arg Val Pro Ala Pro Pro Ser Pro Gln Pro Ala Thr Tyr
340 345 350
Thr Cys Val Val Ser His Glu Asp Ser Arg Thr Leu Leu Asn Ala Ser
355 360 365
Arg Ser Leu Glu Val Ser Tyr Val Thr Asp His Gly Pro Met Lys
370 375 380
<210>459
<211>276
<212>PRT
<213>智人(Homo sapiens)
<400>459
Val Thr Ser Thr Leu Thr Ile Lys Glx Ser Asp Trp Leu Gly Glu Ser
1 5 1015
Met Phe Thr Cys Arg Val Asp His Arg Gly Leu Thr Phe Gln Gln Asn
202530
Ala Ser Ser Met Cys Val Pro Asp Gln Asp Thr Ala Ile Arg Val Phe
354045
Ala Ile Pro Pro Ser Phe Ala Ser Ile Phe Leu Thr Lys Ser Thr Lys
505560
Leu Thr Cys Leu Val Thr Asp Leu Thr Thr Tyr Asx Ser Val Thr Ile
65707580
Ser Trp Thr Arg Glu Glu Asn Gly Ala Val Lys Thr His Thr Asn Ile
859095
Ser Glu Ser His Pro Asn Ala Thr Phe Ser Ala Val Gly Glu Ala Ser
100 105 110
Ile Cys Glu Asp Asx Asp Trp Ser Gly Glu Arg Phe Thr Cys Thr Val
115 120 125
Thr His Thr Asp Leu Pro Ser Pro Leu Lys Gln Thr Ile Ser Arg Pro
130 135 140
Lys Gly Val Ala Leu His Arg Pro Asx Val Tyr Leu Leu Pro Pro Ala
145 150 155 160
Arg Glx Glx Leu Asn Leu Arg Glu Ser Ala Thr Ile Thr Cys Leu Val
165 170 175
Thr Gly Phe Ser Pro Ala Asp Val Phe Val Glu Trp Met Gln Arg Gly
180 185 190
Glu Pro Leu Ser Pro Gln Lys Tyr Val Thr Ser Ala Pro Met Pro Glu
195 200 205
Pro Gln Ala Pro Gly Arg Tyr Phe Ala His Ser Ile Leu Thr Val Ser
210 215 220
Glu Glu Glu Trp Asn Thr Gly Gly Thr Tyr Thr Cys Val Val Ala His
225 230 235 240
Glu Ala Leu Pro Asn Arg Val Thr Glu Arg Thr Val Asp Lys Ser Thr
245 250 255
Gly Lys Pro Thr Leu Tyr Asn Val Ser Leu Val Met Ser Asp Thr Ala
260 265 270
Gly Thr Cys Tyr
275
<210>460
<211>353
<212>PRT
<213>智人(Homo sapiens)
<400>460
Ala Ser Pro Thr Ser Pro Lys Val Phe Pro Leu Ser Leu Cys Ser Thr
1 5 1015
Gln Pro Asp Gly Asn Val Val Ile Ala Cys Leu Val Gln Gly Phe Phe
202530
Pro Gln Glu Pro Leu Ser Val Thr Trp Ser Glu Ser Gly Gln Gly Val
354045
Thr Ala Arg Asn Phe Pro Pro Ser Gln Asp Ala Ser Gly Asp Leu Tyr
505560
Thr Thr Ser Ser Gln Leu Thr Leu Pro Ala Thr Gln Cys Leu Ala Gly
65707580
Lys Ser Val Thr Cys His Val Lys His Tyr Thr Asn Pro Ser Gln Asp
859095
Val Thr Val Pro Cys Pro Val Pro Ser Thr Pro Pro Thr Pro Ser Pro
100 105 110
Ser Thr Pro Pro Thr Pro Ser Pro Ser Cys Cys His Pro Arg Leu Ser
115 120 125
Leu His Arg Pro Ala Leu Glu Asp Leu Leu Leu Gly Ser Glu Ala Asn
130 135 140
Leu Thr Cys Thr Leu Thr Gly Leu Arg Asp Ala Ser Gly Val Thr Phe
145 150 155 160
Thr Trp Thr Pro Ser Ser Gly Lys Ser Ala Val Gln Gly Pro Pro Glu
165 170 175
Arg Asp Leu Cys Gly Cys Tyr Ser Val Ser Ser Val Leu Pro Gly Cys
180 185 190
Ala Glu Pro Trp Asn His Gly Lys Thr Phe Thr Cys Thr Ala Ala Tyr
195 200 205
Pro Glu Ser Lys Thr Pro Leu Thr Ala Thr Leu Ser Lys Ser Gly Asn
210 215 220
Thr Phe Arg Pro Glu Val His Leu Leu Pro Pro Pro Ser Glu Glu Leu
225 230 235 240
Ala Leu Asn Glu Leu Val Thr Leu Thr Cys Leu Ala Arg Gly Phe Ser
245 250 255
Pro Lys Asp Val Leu Val Arg Trp Leu Gln Gly Ser Gln Glu Leu Pro
260 265 270
Arg Glu Lys Tyr Leu Thr Trp Ala Ser Arg Gln Glu Pro Ser Gln Gly
275 280 285
Thr Thr Thr Phe Ala Val Thr Ser Ile Leu Arg Val Ala Ala Glu Asp
290 295 300
Trp Lys Lys Gly Asp Thr Phe Ser Cys Met Val Gly His Glu Ala Leu
305 310 315 320
Pro Leu Ala Phe Thr Gln Lys Thr Ile Asp Arg Leu Ala Gly Lys Pro
325 330 335
Thr His Val Asn Val Ser Val Val Met Ala Glu Val Asp Gly Thr Cys
340 345 350
Tyr
<210>461
<211>222
<212>PRT
<213>智人(Homo sapiens)
<400>461
Ala Asp Pro Cys Asp Ser Asn Pro Arg Gly Val Ser Ala Tyr Leu Ser
1 5 1015
Arg Pro Ser Pro Phe Asp Leu Phe Ile Arg Lys Ser Pro Thr Ile Thr
202530
Cys Leu Val Val Asp Leu Ala Pro Ser Lys Gly Thr Val Asn Leu Thr
354045
Trp Ser Arg Ala Ser Gly Lys Pro Val Asn His Ser Thr Arg Lys Glu
505560
Glu Lys Gln Arg Asn Gly Thr Leu Thr Val Thr Ser Thr Leu Pro Val
65707580
Gly Thr Arg Asp Trp Ile Glu Gly Glu Thr Tyr Gln Cys Arg Val Thr
859095
His Pro His Leu Pro Arg Ala Leu Met Arg Ser Thr Thr Lys Thr Ser
100 105 110
Gly Pro Arg Ala Ala Pro Glu Val Tyr Ala Phe Ala Thr Pro Glu Trp
115 120 125
Pro Gly Ser Arg Asp Lys Arg Thr Leu Ala Cys Leu Ile Gln Asn Phe
130 135 140
Met Pro Glu Asp Ile Ser Val Gln Trp Leu His Asn Glu Val Gln Leu
145 150 155 160
Pro Asp Ala Arg His Ser Thr Thr Gln Pro Arg Lys Thr Lys Gly Ser
165 170 175
Gly Phe Phe Val Phe Ser Arg Leu Glu Val Thr Arg Ala Glu Trp Glu
180 185 190
Gln Lys Asp Glu Phe Ile Cys Arg Ala Val His Glu Ala Ala Ser Pro
195 200 205
Ser Gln Thr Val Gln Arg Ala Val Ser Val Asn Pro Gly Lys
210 215 220
<210>462
<211>327
<212>PRT
<213>智人(Homo sapiens)
<400>462
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 1015
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
202530
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
354045
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
505560
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65707580
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
859095
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210>463
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>463
Gly Ser His Ser Met Arg Tyr Phe Phe Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gly Glu Thr
505560
Arg Lys Val Lys Ala His Ser Gln Thr His Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Val Gln
859095
Arg Met Tyr Gly Cys Asp Val Gly Ser Asp Trp Arg Phe Leu Arg Gly
100 105 110
Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Thr Thr Lys
130 135 140
His Lys Trp Glu Ala Ala His Val Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Ala Pro Lys Thr His Met Thr His His
180 185 190
Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Gln Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>464
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>464
Gly Ser His Ser Met Arg Tyr Phe Phe Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gly Glu Thr
505560
Arg Lys Val Lys Ala His Ser Gln Thr His Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Ala Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Val Gln
859095
Arg Met Tyr Gly Cys Asp Val Gly Ser Asp Trp Arg Phe Leu Arg Gly
100 105 110
Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Thr Thr Lys
130 135 140
His Lys Trp Glu Ala Ala His Val Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Ala Pro Lys Thr His Met Thr His His
180 185 190
Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Gln Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>465
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>465
Gly Ser His Ser Met Arg Tyr Phe Phe Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gly Glu Thr
505560
Arg Lys Val Lys Ala His Ser Gln Thr His Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Ala Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Val Gln
859095
Arg Met Tyr Gly Cys Asp Val Gly Ser Asp Trp Arg Phe Leu Arg Gly
100 105 110
Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Thr Thr Lys
130 135 140
His Lys Trp Glu Ala Ala His Val Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Ala Pro Lys Thr His Met Thr His His
180 185 190
Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Gln Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>466
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>466
Gly Ser His Ser Met Arg Tyr Phe Phe Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gly Glu Thr
505560
Arg Lys Val Lys Ala His Ser Gln Thr His Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Cys Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Val Gln
859095
Arg Met Tyr Gly Cys Asp Val Gly Ser Asp Trp Arg Phe Leu Arg Gly
100 105 110
Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Cys Ala Gln Thr Thr Lys
130 135 140
His Lys Trp Glu Ala Ala His Val Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Ala Pro Lys Thr His Met Thr His His
180 185 190
Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Gln Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>467
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>467
Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu Thr
505560
Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile Gln
859095
Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Lys
130 135 140
Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>468
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>468
Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu Thr
505560
Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Ala Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile Gln
859095
Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Lys
130 135 140
Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>469
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>469
Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu Thr
505560
Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Ala Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile Gln
859095
Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Lys
130 135 140
Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>470
<211>274
<212>PRT
<213>智人(Homo sapiens)
<400>470
Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu Thr
505560
Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile Gln
859095
Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Cys Ala Gln Ile Thr Lys
130 135 140
Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp
<210>471
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>471
Gly Ser His Ser Met Arg Tyr Phe Ser Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Glu Glu Thr
505560
Gly Lys Val Lys Ala His Ser Gln Thr Asp Arg Glu Asn Leu Arg Ile
65707580
Ala Leu Arg Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Met Met Phe Gly Cys Asp Val Gly Ser Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Lys
130 135 140
Arg Lys Trp Glu Ala Ala His Val Ala Glu Gln Gln Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Asp Gly Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>472
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>472
Gly Ser His Ser Met Arg Tyr Phe Ser Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Glu Glu Thr
505560
Gly Lys Val Lys Ala His Ser Gln Thr Asp Arg Glu Asn Leu Arg Ile
65707580
Ala Leu Arg Ala Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Met Met Phe Gly Cys Asp Val Gly Ser Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Lys
130 135 140
Arg Lys Trp Glu Ala Ala His Val Ala Glu Gln Gln Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Asp Gly Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>473
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>473
Gly Ser His Ser Met Arg Tyr Phe Ser Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Glu Glu Thr
505560
Gly Lys Val Lys Ala His Ser Gln Thr Asp Arg Glu Asn Leu Arg Ile
65707580
Ala Leu Arg Ala Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Met Met Phe Gly Cys Asp Val Gly Ser Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Lys
130 135 140
Arg Lys Trp Glu Ala Ala His Val Ala Glu Gln Gln Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Asp Gly Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>474
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>474
Gly Ser His Ser Met Arg Tyr Phe Ser Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Glu Glu Thr
505560
Gly Lys Val Lys Ala His Ser Gln Thr Asp Arg Glu Asn Leu Arg Ile
65707580
Ala Leu Arg Cys Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Met Met Phe Gly Cys Asp Val Gly Ser Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Cys Ala Gln Ile Thr Lys
130 135 140
Arg Lys Trp Glu Ala Ala His Val Ala Glu Gln Gln Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Asp Gly Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>475
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>475
Gly Ser His Ser Met Arg Tyr Phe Thr Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Asn Thr
505560
Arg Asn Val Lys Ala His Ser Gln Ile Asp Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Ile Gln
859095
Met Met Tyr Gly Cys Asp Val Gly Ser Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Gln Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Val Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ser Val Val Val Pro Ser Gly Gln Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>476
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>476
Gly Ser His Ser Met Arg Tyr Phe Thr Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Asn Thr
505560
Arg Asn Val Lys Ala His Ser Gln Ile Asp Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Ala Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Ile Gln
859095
Met Met Tyr Gly Cys Asp Val Gly Ser Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Gln Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Val Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ser Val Val Val Pro Ser Gly Gln Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>477
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>477
Gly Ser His Ser Met Arg Tyr Phe Thr Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Asn Thr
505560
Arg Asn Val Lys Ala His Ser Gln Ile Asp Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Ala Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Ile Gln
859095
Met Met Tyr Gly Cys Asp Val Gly Ser Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Gln Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Val Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ser Val Val Val Pro Ser Gly Gln Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>478
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>478
Gly Ser His Ser Met Arg Tyr Phe Thr Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Asn Thr
505560
Arg Asn Val Lys Ala His Ser Gln Ile Asp Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Cys Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Ile Gln
859095
Met Met Tyr Gly Cys Asp Val Gly Ser Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Gln Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Cys Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Val Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ser Val Val Val Pro Ser Gly Gln Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu
275
<210>479
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(9)..(9)
<223>Xaa为苯丙氨酸、酪氨酸、丝氨酸或苏氨酸
<220>
<221>变体
<222>(44)..(44)
<223>Xaa为赖氨酸或精氨酸
<220>
<221>变体
<222>(62)..(62)
<223>Xaa为谷氨酰胺、甘氨酸、谷氨酸或精氨酸
<220>
<221>变体
<222>(63)..(63)
<223>Xaa为天冬酰胺或谷氨酸
<220>
<221>变体
<222>(65)..(65)
<223>Xaa为精氨酸或甘氨酸
<220>
<221>变体
<222>(66)..(66)
<223>Xaa为天冬酰胺或赖氨酸
<220>
<221>变体
<222>(67)..(67)
<223>Xaa为甲硫氨酸或缬氨酸
<220>
<221>变体
<222>(70)..(70)
<223>Xaa为组氨酸或谷氨酰胺
<220>
<221>变体
<222>(73)..(73)
<223>Xaa为苏氨酸或异亮氨酸
<220>
<221>变体
<222>(74)..(74)
<223>Xaa为天冬氨酸或组氨酸
<220>
<221>变体
<222>(76)..(76)
<223>Xaa为丙氨酸、缬氨酸或谷氨酸
<220>
<221>变体
<222>(77)..(77)
<223>Xaa为天冬酰胺或天冬氨酸
<220>
<221>变体
<222>(79)..(79)
<223>Xaa为甘氨酸或精氨酸
<220>
<221>变体
<222>(80)..(80)
<223>Xaa为苏氨酸或精氨酸
<220>
<221>变体
<222>(81)..(81)
<223>Xaa为亮氨酸或丙氨酸
<220>
<221>变体
<222>(82)..(82)
<223>Xaa为精氨酸或亮氨酸
<220>
<221>变体
<222>(83)..(83)
<223>Xaa为甘氨酸或精氨酸
<220>
<221>变体
<222>(90)..(90)
<223>Xaa为丙氨酸或天冬氨酸
<220>
<221>变体
<222>(95)..(95)
<223>Xaa为异亮氨酸、亮氨酸或缬氨酸
<220>
<221>变体
<222>(97)..(97)
<223>Xaa为异亮氨酸、精氨酸或甲硫氨酸
<220>
<221>变体
<222>(99)..(99)
<223>Xaa为苯丙氨酸或酪氨酸
<220>
<221>变体
<222>(105)..(105)
<223>Xaa为丝氨酸或脯氨酸
<220>
<221>变体
<222>(107)..(107)
<223>Xaa为色氨酸或甘氨酸
<220>
<221>变体
<222>(114)..(114)
<223>Xaa为精氨酸、组氨酸或谷氨酰胺
<220>
<221>变体
<222>(116)..(116)
<223>Xaa为天冬氨酸或酪氨酸
<220>
<221>变体
<222>(127)..(127)
<223>Xaa为天冬酰胺或赖氨酸
<220>
<221>变体
<222>(142)..(142)
<223>Xaa为苏氨酸或异亮氨酸
<220>
<221>变体
<222>(144)..(144)
<223>Xaa为赖氨酸或谷氨酰胺
<220>
<221>变体
<222>(145)..(145)
<223>Xaa为精氨酸或组氨酸
<220>
<221>变体
<222>(149)..(149)
<223>Xaa为丙氨酸或苏氨酸
<220>
<221>变体
<222>(150)..(150)
<223>Xaa为丙氨酸或缬氨酸
<220>
<221>变体
<222>(151)..(151)
<223>Xaa为组氨酸或精氨酸
<220>
<221>变体
<222>(156)..(156)
<223>Xaa为精氨酸、亮氨酸、谷氨酰胺或色氨酸
<220>
<221>变体
<222>(158)..(158)
<223>Xaa为缬氨酸或丙氨酸
<220>
<221>变体
<222>(161)..(161)
<223>Xaa为天冬氨酸或谷氨酸
<220>
<221>变体
<222>(163)..(163)
<223>Xaa为精氨酸或苏氨酸
<220>
<221>变体
<222>(166)..(166)
<223>Xaa为天冬氨酸或谷氨酸
<220>
<221>变体
<222>(167)..(167)
<223>Xaa为色氨酸或甘氨酸
<220>
<221>变体
<222>(184)..(184)
<223>Xaa为脯氨酸或丙氨酸
<220>
<221>变体
<222>(193)..(193)
<223>Xaa为脯氨酸或丙氨酸
<220>
<221>变体
<222>(194)..(194)
<223>Xaa为缬氨酸或异亮氨酸
<220>
<221>变体
<222>(207)..(207)
<223>Xaa为丝氨酸或甘氨酸
<220>
<221>变体
<222>(246)..(246)
<223>Xaa为丙氨酸或丝氨酸
<220>
<221>变体
<222>(253)..(253)
<223>Xaa为谷氨酰胺或谷氨酸
<220>
<221>变体
<222>(276)..(276)
<223>Xaa为脯氨酸或亮氨酸
<400>479
Gly Ser His Ser Met Arg Tyr Phe Xaa Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Xaa Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Xaa Xaa Thr
505560
Xaa Xaa Xaa Lys Ala Xaa Ser Gln Xaa Xaa Arg Xaa Xaa Leu Xaa Xaa
65707580
Xaa Xaa Xaa Tyr Tyr Asn Gln Ser Glu Xaa Gly Ser His Thr Xaa Gln
859095
Xaa Met Xaa Gly Cys Asp Val Gly Xaa Asp Xaa Arg Phe Leu Arg Gly
100 105 110
Tyr Xaa Gln Xaa Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Xaa Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Xaa Thr Xaa
130 135 140
Xaa Lys Trp Glu Xaa Xaa Xaa Glu Ala Glu Gln Xaa Arg Xaa Tyr Leu
145 150 155 160
Xaa Gly Xaa Cys Val Xaa Xaa Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Xaa Pro Lys Thr His Met Thr His His
180 185 190
Xaa Xaa Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Xaa Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Xaa Val Val Val Pro Ser Gly Xaa Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Xaa
275
<210>480
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>480
Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Pro Arg Glu Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Asn Thr
505560
Gln Ile Tyr Lys Ala Gln Ala Gln Thr Asp Arg Glu Ser Leu Arg Asn
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Ser Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
His Asp Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Glu Ala Glu Gln Arg Arg Ala Tyr Leu
145 150 155 160
Glu Gly Glu Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Asp Lys Leu Glu Arg Ala Asp Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Arg Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>481
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>481
Gly Ser His Ser Met Arg Tyr Phe Asp Thr Ala Met Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Pro Arg Glu Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Asn Thr
505560
Gln Ile Phe Lys Thr Asn Thr Gln Thr Asp Arg Glu Ser Leu Arg Asn
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Ser Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
His Asn Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Val Ala Glu Gln Asp Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Asp Thr Leu Glu Arg Ala Asp Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Arg Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>482
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>482
Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ala Met Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Pro Arg Met Ala Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Asn Thr
505560
Gln Ile Ser Lys Thr Asn Thr Gln Thr Tyr Arg Glu Ser Leu Arg Asn
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Ile Ile Gln
859095
Arg Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
Tyr Asp Gln Ser Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Ser Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Glu Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Leu Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Ala Asp Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Arg Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>483
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>483
Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Pro Arg Glu Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Asn Thr
505560
Gln Ile Cys Lys Thr Asn Thr Gln Thr Tyr Arg Glu Asn Leu Arg Thr
65707580
Ala Leu Arg Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Arg Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
His Asn Gln Phe Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Ser Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Val Ala Glu Gln Leu Arg Thr Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Ala Asp Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Arg Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>484
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>484
Gly Ser His Ser Met Arg Tyr Phe His Thr Ala Met Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Thr Val Gly Tyr Val Asp Asp Thr Leu
202530
Phe Val Arg Phe Asp Ser Asp Ala Thr Ser Pro Arg Lys Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Glu Thr
505560
Gln Ile Ser Lys Thr Asn Thr Gln Thr Tyr Arg Glu Ser Leu Arg Asn
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Arg Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
His Asn Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Ser Gln
130 135 140
Arg Lys Leu Glu Ala Ala Arg Val Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Glu Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Asp Lys Leu Glu Arg Ala Asp Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Arg Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>485
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>485
Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ala Met Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Pro Arg Met Ala Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Glu Thr
505560
Gln Lys Tyr Lys Arg Gln Ala Gln Thr Asp Arg Val Ser Leu Arg Asn
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Arg Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
His Asp Gln Ser Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Ser Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Glu Ala Glu Gln Trp Arg Ala Tyr Leu
145 150 155 160
Glu Gly Leu Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Ala Asp Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Arg Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>486
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>486
Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ala Met Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Pro Arg Thr Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Asn Thr
505560
Gln Ile Phe Lys Thr Asn Thr Gln Thr Tyr Arg Glu Asn Leu Arg Ile
65707580
Ala Leu Arg Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Ile Ile Gln
859095
Arg Met Tyr Gly Cys Asp Leu Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
His Asp Gln Ser Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Ser Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Val Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Leu Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Ala Asp Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Arg Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>487
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(9)..(9)
<223>Xaa为组氨酸、酪氨酸或天冬氨酸
<220>
<221>变体
<222>(11)..(11)
<223>Xaa为丙氨酸或丝氨酸
<220>
<221>变体
<222>(12)..(12)
<223>Xaa为甲硫氨酸或缬氨酸
<220>
<221>变体
<222>(24)..(24)
<223>Xaa为丙氨酸、丝氨酸或苏氨酸
<220>
<221>变体
<222>(32)..(32)
<223>Xaa为谷氨酰胺或亮氨酸
<220>
<221>变体
<222>(41)..(41)
<223>Xaa为丙氨酸或苏氨酸
<220>
<221>变体
<222>(45)..(45)
<223>Xaa为谷氨酸、甲硫氨酸、赖氨酸或苏氨酸
<220>
<221>变体
<222>(46)..(46)
<223>Xaa为丙氨酸或苏氨酸
<220>
<221>变体
<222>(63)..(63)
<223>Xaa为谷氨酸或天冬酰胺
<220>
<221>变体
<222>(66)..(66)
<223>Xaa为异亮氨酸或赖氨酸
<220>
<221>变体
<222>(67)..(67)
<223>Xaa为酪氨酸、苯丙氨酸、丝氨酸或胱氨酸
<220>
<221>变体
<222>(70)..(70)
<223>Xaa为天冬酰胺或谷氨酰胺
<220>
<221>变体
<222>(71)..(71)
<223>Xaa为丙氨酸或苏氨酸
<220>
<221>变体
<222>(74)..(74)
<223>Xaa为天冬氨酸或酪氨酸
<220>
<221>变体
<222>(76)..(76)
<223>Xaa为谷氨酸或缬氨酸
<220>
<221>变体
<222>(77)..(77)
<223>Xaa为丝氨酸或天冬酰胺
<220>
<221>变体
<222>(80)..(80)
<223>Xaa为苏氨酸、天冬酰胺或异亮氨酸
<220>
<221>变体
<222>(81)..(81)
<223>Xaa为丙氨酸或亮氨酸
<220>
<221>变体
<222>(82)..(82)
<223>Xaa为亮氨酸或精氨酸
<220>
<221>变体
<222>(83)..(83)
<223>Xaa为精氨酸或甘氨酸
<220>
<221>变体
<222>(94)..(94)
<223>Xaa为苏氨酸或异亮氨酸
<220>
<221>变体
<222>(95)..(95)
<223>Xaa为亮氨酸或异亮氨酸
<220>
<221>变体
<222>(97)..(97)
<223>Xaa为精氨酸或丝氨酸
<220>
<221>变体
<222>(131)..(131)
<223>Xaa为精氨酸或丝氨酸
<220>
<221>变体
<222>(143)..(143)
<223>Xaa为Ser或Thr
<220>
<221>变体
<222>(147)..(147)
<223>Xaa为Leu或Trp
<220>
<221>变体
<222>(152)..(152)
<223>Xaa为Glu或Val
<220>
<221>变体
<222>(156)..(156)
<223>Xaa为Arg、Asp或Leu
<220>
<221>变体
<222>(158)..(158)
<223>Xaa为Ala或Thr
<220>
<221>变体
<222>(163)..(163)
<223>Xaa为亮氨酸、谷氨酸或苏氨酸
<220>
<221>变体
<222>(177)..(177)
<223>Xaa为谷氨酸或天冬氨酸
<220>
<221>变体
<222>(178)..(178)
<223>Xaa为赖氨酸或苏氨酸
<220>
<221>变体
<222>(180)..(180)
<223>Xaa为谷氨酸或谷氨酰胺
<220>
<221>变体
<222>(194)..(194)
<223>Xaa为异亮氨酸或缬氨酸
<400>487
Gly Ser His Ser Met Arg Tyr Phe Xaa Thr Xaa Xaa Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Xaa Val Gly Tyr Val Asp Asp Thr Xaa
202530
Phe Val Arg Phe Asp Ser Asp Ala Xaa Ser Pro Arg Xaa Xaa Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Xaa Thr
505560
Gln Xaa Xaa Lys Thr Xaa Xaa Thr Gln Xaa Tyr Xaa Xaa Asn Leu Xaa
65707580
Xaa Xaa Xaa Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Xaa Xaa Gln
859095
Xaa Met Tyr Gly Cys Asp Leu Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
His Asp Gln Ser Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Xaa Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Xaa Gln
130 135 140
Arg Lys Xaa Glu Ala Ala Arg Xaa Ala Glu Gln Xaa Arg Xaa Tyr Leu
145 150 155 160
Glu Gly Xaa Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Xaa Xaa Leu Xaa Arg Ala Asp Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Xaa Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Arg Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>488
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>488
Cys Ser His Ser Met Lys Tyr Phe Phe Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Pro Arg Gly Glu Pro Arg
354045
Ala Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Glu Thr
505560
Gln Lys Tyr Lys Arg Gln Ala Gln Thr Asp Arg Val Ser Leu Arg Asn
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Trp Met Cys Gly Cys Asp Leu Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
Tyr Asp Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Glu Ala Glu Gln Arg Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Ala Glu His Pro Lys Thr His Val Thr His His
180 185 190
Pro Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Trp Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Met Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>489
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>489
Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ala Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro His Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Pro Arg Gly Glu Pro Arg
354045
Ala Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Glu Thr
505560
Gln Lys Tyr Lys Arg Gln Ala Gln Thr Asp Arg Val Ser Leu Arg Asn
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Arg Ser His Ile Ile Gln
859095
Arg Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
Tyr Asp Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Glu Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Leu Cys Val Glu Trp Leu Arg Arg Tyr Leu Lys Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Ala Glu His Pro Lys Thr His Val Thr His His
180 185 190
Pro Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Trp Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>490
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>490
Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ala Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro His Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Pro Arg Gly Glu Pro Arg
354045
Ala Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Glu Thr
505560
Gln Lys Tyr Lys Arg Gln Ala Gln Thr Asp Arg Val Ser Leu Arg Asn
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Ile Ile Gln
859095
Arg Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
Tyr Asp Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Glu Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Leu Cys Val Glu Trp Leu Arg Arg Tyr Leu Lys Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Ala Glu His Pro Lys Thr His Val Thr His His
180 185 190
Pro Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Trp Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>491
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>491
Gly Ser His Ser Met Arg Tyr Phe Ser Thr Ser Val Ser Trp Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Pro Arg Gly Glu Pro Arg
354045
Glu Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Glu Thr
505560
Gln Lys Tyr Lys Arg Gln Ala Gln Ala Asp Arg Val Asn Leu Arg Lys
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Leu Gln
859095
Arg Met Phe Gly Cys Asp Leu Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
Tyr Asn Gln Phe Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Glu Ala Glu Gln Arg Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Ala Glu His Pro Lys Thr His Val Thr His His
180 185 190
Pro Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Trp Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Leu Thr Leu
260 265 270
Arg Trp Lys Pro
275
<210>492
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>492
Cys Ser His Ser Met Arg Tyr Phe Asp Thr Ala Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Pro Arg Gly Glu Pro Arg
354045
Ala Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Glu Thr
505560
Gln Lys Tyr Lys Arg Gln Ala Gln Ala Asp Arg Val Asn Leu Arg Lys
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Leu Gln
859095
Trp Met Tyr Gly Cys Asp Leu Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
Tyr Asp Gln Ser Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Glu Ala Glu Gln Trp Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Ala Glu His Pro Lys Thr His Val Thr His His
180 185 190
Pro Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>493
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>493
Cys Ser His Ser Met Arg Tyr Phe Asp Thr Ala Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Pro Arg Gly Glu Pro Arg
354045
Ala Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Glu Thr
505560
Gln Asn Tyr Lys Arg Gln Ala Gln Ala Asp Arg Val Ser Leu Arg Asn
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Leu Gln
859095
Arg Met Tyr Gly Cys Asp Leu Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
Tyr Asp Gln Ser Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Leu Glu Ala Ala Arg Ala Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Ala Glu Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Leu Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Gln Glu Gln Arg
245 250 255
Tyr Thr Cys His Met Gln His Glu Gly Leu Gln Glu Pro Leu Thr Leu
260 265 270
Ser Trp Glu Pro
275
<210>494
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>494
Cys Ser His Ser Met Arg Tyr Phe Asp Thr Ala Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Pro Arg Gly Glu Pro Arg
354045
Ala Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Glu Thr
505560
Gln Lys Tyr Lys Arg Gln Ala Gln Ala Asp Arg Val Ser Leu Arg Asn
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Leu Gln
859095
Arg Met Ser Gly Cys Asp Leu Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
Tyr Asp Gln Ser Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Leu Glu Ala Ala Arg Ala Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Ala Glu Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Leu Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Gln Glu Gln Arg
245 250 255
Tyr Thr Cys His Met Gln His Glu Gly Leu Gln Glu Pro Leu Thr Leu
260 265 270
Ser Trp Glu Pro
275
<210>495
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>495
Cys Ser His Ser Met Arg Tyr Phe Tyr Thr Ala Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Gln Phe Asp Ser Asp Ala Ala Ser Pro Arg Gly Glu Pro Arg
354045
Ala Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Glu Thr
505560
Gln Lys Tyr Lys Arg Gln Ala Gln Thr Asp Arg Val Ser Leu Arg Asn
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Arg Met Tyr Gly Cys Asp Leu Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
Tyr Asn Gln Phe Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Thr Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Lys Thr Leu Gln Arg Ala Glu His Pro Lys Thr His Val Thr His His
180 185 190
Pro Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Leu Thr Leu
260 265 270
Arg Trp Gly Pro
275
<210>496
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>496
Cys Ser His Ser Met Arg Tyr Phe Tyr Thr Ala Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro His Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Pro Arg Gly Glu Pro Arg
354045
Ala Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Glu Thr
505560
Gln Asn Tyr Lys Arg Gln Ala Gln Thr Asp Arg Val Asn Leu Arg Lys
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Ile Ile Gln
859095
Arg Met Tyr Gly Cys Asp Leu Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
His Asp Gln Leu Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Glu Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Ala Glu His Pro Lys Thr His Val Thr His His
180 185 190
Pro Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>497
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(1)
<223>Xaa为半胱氨酸或甘氨酸
<220>
<221>变体
<222>(6)..(6)
<223>Xaa为精氨酸或赖氨酸
<220>
<221>变体
<222>(9)..(9)
<223>Xaa为苯丙氨酸、酪氨酸、丝氨酸或天冬氨酸
<220>
<221>变体
<222>(14)..(14)
<223>Xaa为精氨酸或色氨酸
<220>
<221>变体
<222>(21)..(21)
<223>Xaa为组氨酸或精氨酸
<220>
<221>变体
<222>(24)..(24)
<223>Xaa为丙氨酸或丝氨酸
<220>
<221>变体
<222>(35)..(35)
<223>Xaa为谷氨酰胺或精氨酸
<220>
<221>变体
<222>(49)..(49)
<223>Xaa为丙氨酸或精氨酸
<220>
<221>变体
<222>(66)..(66)
<223>Xaa为天冬酰胺或赖氨酸
<220>
<221>变体
<222>(73)..(73)
<223>Xaa为苏氨酸或丙氨酸
<220>
<221>变体
<222>(77)..(77)
<223>Xaa为丝氨酸或天冬酰胺
<220>
<221>变体
<222>(80)..(80)
<223>Xaa为天冬酰胺或赖氨酸
<220>
<221>变体
<222>(90)..(90)
<223>Xaa为丙氨酸或天冬氨酸
<220>
<221>变体
<222>(91)..(91)
<223>Xaa为甘氨酸或精氨酸
<220>
<221>变体
<222>(94)..(94)
<223>Xaa为苏氨酸或异亮氨酸
<220>
<221>变体
<222>(95)..(95)
<223>Xaa为亮氨酸或异亮氨酸
<220>
<221>变体
<222>(97)..(97)
<223>Xaa为色氨酸或精氨酸
<220>
<221>变体
<222>(99)..(99)
<223>Xaa为半胱氨酸、酪氨酸、苯丙氨酸或丝氨酸
<220>
<221>变体
<222>(103)..(103)
<223>Xaa为亮氨酸或缬氨酸
<220>
<221>变体
<222>(113)..(113)
<223>Xaa为酪氨酸或组氨酸
<220>
<221>变体
<222>(114)..(114)
<223>Xaa为天冬氨酸或天冬酰胺
<220>
<221>变体
<222>(116)..(116)
<223>Xaa为酪氨酸、苯丙氨酸、丝氨酸或亮氨酸
<220>
<221>变体
<222>(147)..(147)
<223>Xaa为亮氨酸或色氨酸
<220>
<221>变体
<222>(152)..(152)
<223>Xaa为谷氨酸、丙氨酸或苏氨酸
<220>
<221>变体
<222>(156)..(156)
<223>Xaa为精氨酸、亮氨酸或色氨酸
<220>
<221>变体
<222>(163)..(163)
<223>Xaa为亮氨酸或苏氨酸
<220>
<221>变体
<222>(173)..(173)
<223>Xaa为谷氨酸或赖氨酸
<220>
<221>变体
<222>(177)..(177)
<223>Xaa为谷氨酸或赖氨酸
<220>
<221>变体
<222>(184)..(184)
<223>Xaa为组氨酸或脯氨酸
<220>
<221>变体
<222>(194)..(194)
<223>Xaa为精氨酸或缬氨酸
<220>
<221>变体
<222>(219)..(219)
<223>Xaa为色氨酸或精氨酸
<220>
<221>变体
<222>(248)..(248)
<223>Xaa为缬氨酸或甲硫氨酸
<220>
<221>变体
<222>(253)..(253)
<223>Xaa为谷氨酸或赖氨酸
<220>
<221>变体
<222>(261)..(261)
<223>Xaa为甲硫氨酸或缬氨酸
<220>
<221>变体
<222>(267)..(267)
<223>Xaa为脯氨酸或谷氨酰胺
<220>
<221>变体
<222>(273)..(273)
<223>Xaa为精氨酸或丝氨酸
<220>
<221>变体
<222>(275)..(275)
<223>Xaa为脯氨酸或甘氨酸
<400>497
Xaa Ser His Ser Met Xaa Tyr Phe Xaa Thr Ala Val Ser Xaa Pro Gly
1 5 1015
Arg Gly Glu Pro Xaa Phe Ile Xaa Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Xaa Phe Asp Ser Asp Ala Ala Ser Pro Arg Gly Glu Pro Arg
354045
Xaa Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Glu Thr
505560
Gln Xaa Tyr Lys Arg Gln Ala Gln Xaa Asp Arg Val Xaa Leu Arg Xaa
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Xaa Xaa Ser His Xaa Xaa Gln
859095
Xaa Met Xaa Gly Cys Asp Xaa Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
Xaa Xaa Gln Xaa Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Xaa Glu Ala Ala Arg Xaa Ala Glu Gln Xaa Arg Ala Tyr Leu
145 150 155 160
Glu Gly Xaa Cys Val Glu Trp Leu Arg Arg Tyr Leu Xaa Asn Gly Lys
165 170 175
Xaa Thr Leu Gln Arg Ala Glu Xaa Pro Lys Thr His Val Thr His His
180 185 190
Pro Xaa Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Xaa Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Xaa Val Pro Ser Gly Xaa Glu Gln Arg
245 250 255
Tyr Thr Cys His Xaa Gln His Glu Gly Leu Xaa Glu Pro Leu Thr Leu
260 265 270
Xaa Trp Xaa Pro
275
<210>498
<211>284
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(89)..(89)
<223>Xaa为Lys或Glu
<220>
<221>变体
<222>(107)..(107)
<223>Xaa为Arg或Gly
<220>
<221>变体
<222>(157)..(157)
<223>Xaa为Arg或Gly
<220>
<221>变体
<222>(158)..(158)
<223>Xaa为Ala或Val
<220>
<221>变体
<222>(255)..(255)
<223>Xaa为Gln或Pro
<220>
<221>变体
<222>(267)..(267)
<223>Xaa为Pro或Ser
<400>498
Gly Ser His Ser Leu Lys Tyr Phe His Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Asn Asp Ala Ala Ser Pro Arg Met Val Pro Arg
354045
Ala Pro Trp Met Glu Gln Glu Gly Ser Glu Tyr Trp Asp Arg Glu Thr
505560
Arg Ser Ala Arg Asp Thr Ala Gln Ile Phe Arg Val Asn Leu Arg Thr
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Xaa Ala Gly Ser His Thr Leu Gln
859095
Trp Met His Gly Cys Glu Leu Gly Pro Asp Xaa Arg Phe Leu Arg Gly
100 105 110
Tyr Glu Gln Phe Ala Tyr Asp Gly Lys Asp Tyr Leu Thr Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Val Asp Thr Ala Ala Gln Ile Ser Glu
130 135 140
Gln Lys Ser Asn Asp Ala Ser Glu Ala Glu His Gln Xaa Xaa Tyr Leu
145 150 155 160
Glu Asp Thr Cys Val Glu Trp Leu His Lys Tyr Leu Glu Lys Gly Lys
165 170 175
Glu Thr Leu Leu His Leu Glu Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Gln Asp Gly Glu Gly His
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Xaa Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Xaa Glu Pro Val Thr Leu
260 265 270
Arg Trp Lys Pro Ala Ser Gln Pro Thr Ile Pro Ile
275 280
<210>499
<211>284
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(7)..(7)
<223>Xaa为Tyr或Phe
<220>
<221>变体
<222>(50)..(50)
<223>Xaa为Pro或Gln
<220>
<221>变体
<222>(251)..(251)
<223>Xaa为Ser或Pro
<220>
<221>变体
<222>(278)..(278)
<223>Xaa为Pro或Leu
<400>499
Gly Ser His Ser Leu Arg Xaa Phe Ser Thr Ala Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Tyr Ile Ala Val Glu Tyr Val Asp Asp Thr Gln
202530
Phe Leu Arg Phe Asp Ser Asp Ala Ala Ile Pro Arg Met Glu Pro Arg
354045
Glu Xaa Trp Val Glu Gln Glu Gly Pro Gln Tyr Trp Glu Trp Thr Thr
505560
Gly Tyr Ala Lys Ala Asn Ala Gln Thr Asp Arg Val Ala Leu Arg Asn
65707580
Leu Leu Arg Arg Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Gly Met Asn Gly Cys Asp Met Gly Pro Asp Gly Arg Leu Leu Arg Gly
100 105 110
Tyr His Gln His Ala Tyr Asp Gly Lys Asp Tyr Ile Ser Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Val Ala Gln Ile Thr Gln
130 135 140
Arg Phe Tyr Glu Ala Glu Glu Tyr Ala Glu Glu Phe Arg Thr Tyr Leu
145 150 155 160
Glu Gly Glu Cys Leu Glu Leu Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Ala Asp Pro Pro Lys Ala His Val Ala His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Glu Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Xaa Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Gln Pro Leu Ile Leu
260 265 270
Arg Trp Glu Gln Ser Xaa Gln Pro Thr Ile Pro Ile
275 280
<210>500
<211>284
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(13)..(13)
<223>Xaa为Ser或Phe
<220>
<221>变体
<222>(27)..(27)
<223>Xaa为Tyr或His
<220>
<221>变体
<222>(31)..(31)
<223>Xaa为Thr、Ser或Met
<220>
<221>变体
<222>(34)..(34)
<223>Xaa为Leu或Val
<220>
<221>变体
<222>(54)..(54)
<223>Xaa为Gln或Arg
<220>
<221>变体
<222>(81)..(81)
<223>Xaa为Pro或Leu
<220>
<221>变体
<222>(100)..(100)
<223>Xaa为Gly或Asp
<220>
<221>变体
<222>(104)..(104)
<223>Xaa为Gly或Val
<220>
<221>变体
<222>(105)..(105)
<223>Xaa为Ser或Cys
<220>
<221>变体
<222>(110)..(110)
<223>Xaa为Leu或Ile
<220>
<221>变体
<222>(159)..(159)
<223>Xaa为Tyr或His
<220>
<221>变体
<222>(169)..(169)
<223>Xaa为His或Arg
<220>
<221>变体
<222>(171)..(171)
<223>Xaa为Tyr或His
<220>
<221>变体
<222>(178)..(178)
<223>Xaa为Met或Thr
<220>
<221>变体
<222>(185)..(185)
<223>Xaa为Pro或Ala
<220>
<221>变体
<222>(219)..(219)
<223>Xaa为Arg、Trp或Gln
<220>
<221>变体
<222>(258)..(258)
<223>Xaa为Thr或Met
<220>
<221>变体
<222>(275)..(275)
<223>Xaa为Lys或Glu
<400>500
Gly Ser His Ser Met Arg Tyr Phe Ser Ala Ala Val Xaa Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Met Gly Xaa Val Asp Asp Xaa Gln
202530
Phe Xaa Arg Phe Asp Ser Asp Ser Ala Cys Pro Arg Met Glu Pro Arg
354045
Ala Pro Trp Val Glu Xaa Glu Gly Pro Glu Tyr Trp Glu Glu Glu Thr
505560
Arg Asn Thr Lys Ala His Ala Gln Thr Asp Arg Met Asn Leu Gln Thr
65707580
Xaa Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Ser Ser His Thr Leu Gln
859095
Trp Met Ile Xaa Cys Asp Leu Xaa Xaa Asp Gly Arg Leu Xaa Arg Gly
100 105 110
Tyr Glu Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Leu Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Ser Lys
130 135 140
Arg Lys Cys Glu Ala Ala Asn Val Ala Glu Gln Arg Arg Ala Xaa Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Xaa Arg Xaa Leu Glu Asn Gly Lys
165 170 175
Glu Xaa Leu Gln Arg Ala Asp Pro Xaa Lys Thr His Val Thr His His
180 185 190
Pro Val Phe Asp Tyr Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Ile Leu Thr Trp Gln Xaa Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Val Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Xaa Cys His Val Gln His Glu Gly Leu Pro Glu Pro Leu Met Leu
260 265 270
Arg Trp Xaa Gln Ser Ser Leu Pro Thr Ile Pro Ile
275 280
<210>501
<211>609
<212>PRT
<213>智人(Homo sapiens)
<400>501
Met Lys Trp Val Glu Ser Ile Phe Leu Ile Phe Leu Leu Asn Phe Thr
1 5 1015
Glu Ser Arg Thr Leu His Arg Asn Glu Tyr Gly Ile Ala Ser Ile Leu
202530
Asp Ser Tyr Gln Cys Thr Ala Glu Ile Ser Leu Ala Asp Leu Ala Thr
354045
Ile Phe Phe Ala Gln Phe Val Gln Glu Ala Thr Tyr Lys Glu Val Ser
505560
Lys Met Val Lys Asp Ala Leu Thr Ala Ile Glu Lys Pro Thr Gly Asp
65707580
Glu Gln Ser Ser Gly Cys Leu Glu Asn Gln Leu Pro Ala Phe Leu Glu
859095
Glu Leu Cys His Glu Lys Glu Ile Leu Glu Lys Tyr Gly His Ser Asp
100 105 110
Cys Cys Ser Gln Ser Glu Glu Gly Arg His Asn Cys Phe Leu Ala His
115 120 125
Lys Lys Pro Thr Pro Ala Ser Ile Pro Leu Phe Gln Val Pro Glu Pro
130 135 140
Val Thr Ser Cys Glu Ala Tyr Glu Glu Asp Arg Glu Thr Phe Met Asn
145 150 155 160
Lys Phe Ile Tyr Glu Ile Ala Arg Arg His Pro Phe Leu Tyr Ala Pro
165 170 175
Thr Ile Leu Leu Trp Ala Ala Arg Tyr Asp Lys Ile Ile Pro Ser Cys
180 185 190
Cys Lys Ala Glu Asn Ala Val Glu Cys Phe Gln Thr Lys Ala Ala Thr
195 200 205
Val Thr Lys Glu Leu Arg Glu Ser Ser Leu Leu Asn Gln His Ala Cys
210 215 220
Ala Val Met Lys Asn Phe Gly Thr Arg Thr Phe Gln Ala Ile Thr Val
225 230 235 240
Thr Lys Leu Ser Gln Lys Phe Thr Lys Val Asn Phe Thr Glu Ile Gln
245 250 255
Lys Leu Val Leu Asp Val Ala His Val His Glu His Cys Cys Arg Gly
260 265 270
Asp Val Leu Asp Cys Leu Gln Asp Gly Glu Lys Ile Met Ser Tyr Ile
275 280 285
Cys Ser Gln Gln Asp Thr Leu Ser Asn Lys Ile Thr Glu Cys Cys Lys
290 295 300
Leu Thr Thr Leu Glu Arg Gly Gln Cys Ile Ile His Ala Glu Asn Asp
305 310 315 320
Glu Lys Pro Glu Gly Leu Ser Pro Asn Leu Asn Arg Phe Leu Gly Asp
325 330 335
Arg Asp Phe Asn Gln Phe Ser Ser Gly Glu Lys Asn Ile Phe Leu Ala
340 345 350
Ser Phe Val His Glu Tyr Ser Arg Arg His Pro Gln Leu Ala Val Ser
355 360 365
Val Ile Leu Arg Val Ala Lys Gly Tyr Gln Glu Leu Leu Glu Lys Cys
370 375 380
Phe Gln Thr Glu Asn Pro Leu Glu Cys Gln Asp Lys Gly Glu Glu Glu
385 390 395 400
Leu Gln Lys Tyr Ile Gln Glu Ser Gln Ala Leu Ala Lys Arg Ser Cys
405 410 415
Gly Leu Phe Gln Lys Leu Gly Glu Tyr Tyr Leu Gln Asn Ala Phe Leu
420 425 430
Val Ala Tyr Thr Lys Lys Ala Pro Gln Leu Thr Ser Ser Glu Leu Met
435 440 445
Ala Ile Thr Arg Lys Met Ala Ala Thr Ala Ala Thr Cys Cys Gln Leu
450 455 460
Ser Glu Asp Lys Leu Leu Ala Cys Gly Glu Gly Ala Ala Asp Ile Ile
465 470 475 480
Ile Gly His Leu Cys Ile Arg His Glu Met Thr Pro Val Asn Pro Gly
485 490 495
Val Gly Gln Cys Cys Thr Ser Ser Tyr Ala Asn Arg Arg Pro Cys Phe
500 505 510
Ser Ser Leu Val Val Asp Glu Thr Tyr Val Pro Pro Ala Phe Ser Asp
515 520 525
Asp Lys Phe Ile Phe His Lys Asp Leu Cys Gln Ala Gln Gly Val Ala
530 535 540
Leu Gln Thr Met Lys Gln Glu Phe Leu Ile Asn Leu Val Lys Gln Lys
545 550 555 560
Pro Gln Ile Thr Glu Glu Gln Leu Glu Ala Val Ile Ala Asp Phe Ser
565 570 575
Gly Leu Leu Glu Lys Cys Cys Gln Gly Gln Glu Gln Glu Val Cys Phe
580 585 590
Ala Glu Glu Gly Gln Lys Leu Ile Ser Lys Thr Arg Ala Ala Leu Gly
595 600 605
Val
<210>502
<211>502
<212>PRT
<213>智人(Homo sapiens)
<400>502
Met Asp Phe Leu Leu Leu Gln Asp Pro Ala Ser Thr Cys Val Pro Glu
1 5 1015
Pro Ala Ser Gln His Thr Leu Arg Ser Gly Pro Gly Cys Leu Gln Gln
202530
Pro Glu Gln Gln Gly Val Arg Asp Pro Gly Gly Ile Trp Ala Lys Leu
354045
Gly Ala Ala Glu Ala Ser Ala Glu Arg Leu Gln Gly Arg Arg Ser Arg
505560
Gly Ala Ser Gly Ser Glu Pro Gln Gln Met Gly Ser Asp Val Arg Asp
65707580
Leu Asn Ala Leu Leu Pro Ala Val Pro Ser Leu Gly Gly Gly Gly Gly
859095
Cys Ala Leu Pro Val Ser Gly Ala Ala Gln Trp Ala Pro Val Leu Asp
100 105 110
Phe Ala Pro Pro Gly Ala Ser Ala Tyr Gly Ser Leu Gly Gly Pro Ala
115 120 125
Pro Pro Pro Ala Pro Pro Pro Pro Pro Pro Pro Pro Pro His Ser Phe
130 135 140
Ile Lys Gln Glu Pro Ser Trp Gly Gly Ala Glu Pro His Glu Glu Gln
145 150 155 160
Cys Leu Ser Ala Phe Thr Val His Phe Ser Gly Gln Phe Thr Gly Thr
165 170 175
Ala Gly Ala Cys Arg Tyr Gly Pro Phe Gly Pro Pro Pro Pro Ser Gln
180 185 190
Ala Ser Ser Gly Gln Ala Arg Met Phe Pro Asn Ala Pro Tyr Leu Pro
195 200 205
Ser Cys Leu Glu Ser Gln Pro Ala Ile Arg Asn Gln Gly Tyr Ser Thr
210 215 220
Val Thr Phe Asp Gly Thr Pro Ser Tyr Gly His Thr Pro Ser His His
225 230 235 240
Ala Ala Gln Phe Pro Asn His Ser Phe Lys His Glu Asp Pro Met Gly
245 250 255
Gln Gln Gly Ser Leu Gly Glu Gln Gln Tyr Ser Val Pro Pro Pro Val
260 265 270
Tyr Gly Cys His Thr Pro Thr Asp Ser Cys Thr Gly Ser Gln Ala Leu
275 280 285
Leu Leu Arg Thr Pro Tyr Ser Ser Asp Asn Leu Tyr Gln Met Thr Ser
290 295 300
Gln Leu Glu Cys Met Thr Trp Asn Gln Met Asn Leu Gly Ala Thr Leu
305 310 315 320
Lys Gly His Ser Thr Gly Tyr Glu Ser Asp Asn His Thr Thr Pro Ile
325 330 335
Leu Cys Gly Ala Gln Tyr Arg Ile His Thr His Gly Val Phe Arg Gly
340 345 350
Ile Gln Asp Val Arg Arg Val Pro Gly Val Ala Pro Thr Leu Val Arg
355 360 365
Ser Ala Ser Glu Thr Ser Glu Lys Arg Pro Phe Met Cys Ala Tyr Pro
370 375 380
Gly Cys Asn Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met His Ser
385 390 395 400
Arg Lys His Thr Gly Glu Lys Pro Tyr Gln Cys Asp Phe Lys Asp Cys
405 410 415
Glu Arg Arg Phe Ser Arg Ser Asp Gln Leu Lys Arg His Gln Arg Arg
420 425 430
His Thr Gly Val Lys Pro Phe Gln Cys Lys Thr Cys Gln Arg Lys Phe
435 440 445
Ser Arg Ser Asp His Leu Lys Thr His Thr Arg Thr His Thr Gly Glu
450 455 460
Lys Pro Phe Ser Cys Arg Trp Pro Ser Cys Gln Lys Lys Phe Ala Arg
465 470 475 480
Ser Asp Glu Leu Val Arg His His Asn Met His Gln Arg Asn Met Thr
485 490 495
Lys Leu Gln Leu Ala Leu
500
<210>503
<211>519
<212>PRT
<213>智人(Homo sapiens)
<400>503
Met Asp Phe Leu Leu Leu Gln Asp Pro Ala Ser Thr Cys Val Pro Glu
1 5 1015
Pro Ala Ser Gln His Thr Leu Arg Ser Gly Pro Gly Cys Leu Gln Gln
202530
Pro Glu Gln Gln Gly Val Arg Asp Pro Gly Gly Ile Trp Ala Lys Leu
354045
Gly Ala Ala Glu Ala Ser Ala Glu Arg Leu Gln Gly Arg Arg Ser Arg
505560
Gly Ala Ser Gly Ser Glu Pro Gln Gln Met Gly Ser Asp Val Arg Asp
65707580
Leu Asn Ala Leu Leu Pro Ala Val Pro Ser Leu Gly Gly Gly Gly Gly
859095
Cys Ala Leu Pro Val Ser Gly Ala Ala Gln Trp Ala Pro Val Leu Asp
100 105 110
Phe Ala Pro Pro Gly Ala Ser Ala Tyr Gly Ser Leu Gly Gly Pro Ala
115 120 125
Pro Pro Pro Ala Pro Pro Pro Pro Pro Pro Pro Pro Pro His Ser Phe
130 135 140
Ile Lys Gln Glu Pro Ser Trp Gly Gly Ala Glu Pro His Glu Glu Gln
145 150 155 160
Cys Leu Ser Ala Phe Thr Val His Phe Ser Gly Gln Phe Thr Gly Thr
165 170 175
Ala Gly Ala Cys Arg Tyr Gly Pro Phe Gly Pro Pro Pro Pro Ser Gln
180 185 190
Ala Ser Ser Gly Gln Ala Arg Met Phe Pro Asn Ala Pro Tyr Leu Pro
195 200 205
Ser Cys Leu Glu Ser Gln Pro Ala Ile Arg Asn Gln Gly Tyr Ser Thr
210 215 220
Val Thr Phe Asp Gly Thr Pro Ser Tyr Gly His Thr Pro Ser His His
225 230 235 240
Ala Ala Gln Phe Pro Asn His Ser Phe Lys His Glu Asp Pro Met Gly
245 250 255
Gln Gln Gly Ser Leu Gly Glu Gln Gln Tyr Ser Val Pro Pro Pro Val
260 265 270
Tyr Gly Cys His Thr Pro Thr Asp Ser Cys Thr Gly Ser Gln Ala Leu
275 280 285
Leu Leu Arg Thr Pro Tyr Ser Ser Asp Asn Leu Tyr Gln Met Thr Ser
290 295 300
Gln Leu Glu Cys Met Thr Trp Asn Gln Met Asn Leu Gly Ala Thr Leu
305 310 315 320
Lys Gly Val Ala Ala Gly Ser Ser Ser Ser Val Lys Trp Thr Glu Gly
325 330 335
Gln Ser Asn His Ser Thr Gly Tyr Glu Ser Asp Asn His Thr Thr Pro
340 345 350
Ile Leu Cys Gly Ala Gln Tyr Arg Ile His Thr His Gly Val Phe Arg
355 360 365
Gly Ile Gln Asp Val Arg Arg Val Pro Gly Val Ala Pro Thr Leu Val
370 375 380
Arg Ser Ala Ser Glu Thr Ser Glu Lys Arg Pro Phe Met Cys Ala Tyr
385 390 395 400
Pro Gly Cys Asn Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met His
405 410 415
Ser Arg Lys His Thr Gly Glu Lys Pro Tyr Gln Cys Asp Phe Lys Asp
420 425 430
Cys Glu Arg Arg Phe Ser Arg Ser Asp Gln Leu Lys Arg His Gln Arg
435 440 445
Arg His Thr Gly Val Lys Pro Phe Gln Cys Lys Thr Cys Gln Arg Lys
450 455 460
Phe Ser Arg Ser Asp His Leu Lys Thr His Thr Arg Thr His Thr Gly
465 470 475 480
Glu Lys Pro Phe Ser Cys Arg Trp Pro Ser Cys Gln Lys Lys Phe Ala
485 490 495
Arg Ser Asp Glu Leu Val Arg His His Asn Met His Gln Arg Asn Met
500 505 510
Thr Lys Leu Gln Leu Ala Leu
515
<210>504
<211>522
<212>PRT
<213>智人(Homo sapiens)
<400>504
Met Asp Phe Leu Leu Leu Gln Asp Pro Ala Ser Thr Cys Val Pro Glu
1 5 1015
Pro Ala Ser Gln His Thr Leu Arg Ser Gly Pro Gly Cys Leu Gln Gln
202530
Pro Glu Gln Gln Gly Val Arg Asp Pro Gly Gly Ile Trp Ala Lys Leu
354045
Gly Ala Ala Glu Ala Ser Ala Glu Arg Leu Gln Gly Arg Arg Ser Arg
505560
Gly Ala Ser Gly Ser Glu Pro Gln Gln Met Gly Ser Asp Val Arg Asp
65707580
Leu Asn Ala Leu Leu Pro Ala Val Pro Ser Leu Gly Gly Gly Gly Gly
859095
Cys Ala Leu Pro Val Ser Gly Ala Ala Gln Trp Ala Pro Val Leu Asp
100 105 110
Phe Ala Pro Pro Gly Ala Ser Ala Tyr Gly Ser Leu Gly Gly Pro Ala
115 120 125
Pro Pro Pro Ala Pro Pro Pro Pro Pro Pro Pro Pro Pro His Ser Phe
130 135 140
Ile Lys Gln Glu Pro Ser Trp Gly Gly Ala Glu Pro His Glu Glu Gln
145 150 155 160
Cys Leu Ser Ala Phe Thr Val His Phe Ser Gly Gln Phe Thr Gly Thr
165 170 175
Ala Gly Ala Cys Arg Tyr Gly Pro Phe Gly Pro Pro Pro Pro Ser Gln
180 185 190
Ala Ser Ser Gly Gln Ala Arg Met Phe Pro Asn Ala Pro Tyr Leu Pro
195 200 205
Ser Cys Leu Glu Ser Gln Pro Ala Ile Arg Asn Gln Gly Tyr Ser Thr
210 215 220
Val Thr Phe Asp Gly Thr Pro Ser Tyr Gly His Thr Pro Ser His His
225 230 235 240
Ala Ala Gln Phe Pro Asn His Ser Phe Lys His Glu Asp Pro Met Gly
245 250 255
Gln Gln Gly Ser Leu Gly Glu Gln Gln Tyr Ser Val Pro Pro Pro Val
260 265 270
Tyr Gly Cys His Thr Pro Thr Asp Ser Cys Thr Gly Ser Gln Ala Leu
275 280 285
Leu Leu Arg Thr Pro Tyr Ser Ser Asp Asn Leu Tyr Gln Met Thr Ser
290 295 300
Gln Leu Glu Cys Met Thr Trp Asn Gln Met Asn Leu Gly Ala Thr Leu
305 310 315 320
Lys Gly Val Ala Ala Gly Ser Ser Ser Ser Val Lys Trp Thr Glu Gly
325 330 335
Gln Ser Asn His Ser Thr Gly Tyr Glu Ser Asp Asn His Thr Thr Pro
340 345 350
Ile Leu Cys Gly Ala Gln Tyr Arg Ile His Thr His Gly Val Phe Arg
355 360 365
Gly Ile Gln Asp Val Arg Arg Val Pro Gly Val Ala Pro Thr Leu Val
370 375 380
Arg Ser Ala Ser Glu Thr Ser Glu Lys Arg Pro Phe Met Cys Ala Tyr
385 390 395 400
Pro Gly Cys Asn Lys Arg Tyr Phe Lys Leu Ser His Leu Gln Met His
405 410 415
Ser Arg Lys His Thr Gly Glu Lys Pro Tyr Gln Cys Asp Phe Lys Asp
420 425 430
Cys Glu Arg Arg Phe Ser Arg Ser Asp Gln Leu Lys Arg His Gln Arg
435 440 445
Arg His Thr Gly Val Lys Pro Phe Gln Cys Lys Thr Cys Gln Arg Lys
450 455 460
Phe Ser Arg Ser Asp His Leu Lys Thr His Thr Arg Thr His Thr Gly
465 470 475 480
Lys Thr Ser Glu Lys Pro Phe Ser Cys Arg Trp Pro Ser Cys Gln Lys
485 490 495
Lys Phe Ala Arg Ser Asp Glu Leu Val Arg His His Asn Met His Gln
500 505 510
Arg Asn Met Thr Lys Leu Gln Leu Ala Leu
515 520
<210>505
<211>302
<212>PRT
<213>智人(Homo sapiens)
<400>505
Met Glu Lys Gly Tyr Ser Thr Val Thr Phe Asp Gly Thr Pro Ser Tyr
1 5 1015
Gly His Thr Pro Ser His His Ala Ala Gln Phe Pro Asn His Ser Phe
202530
Lys His Glu Asp Pro Met Gly Gln Gln Gly Ser Leu Gly Glu Gln Gln
354045
Tyr Ser Val Pro Pro Pro Val Tyr Gly Cys His Thr Pro Thr Asp Ser
505560
Cys Thr Gly Ser Gln Ala Leu Leu Leu Arg Thr Pro Tyr Ser Ser Asp
65707580
Asn Leu Tyr Gln Met Thr Ser Gln Leu Glu Cys Met Thr Trp Asn Gln
859095
Met Asn Leu Gly Ala Thr Leu Lys Gly Val Ala Ala Gly Ser Ser Ser
100 105 110
Ser Val Lys Trp Thr Glu Gly Gln Ser Asn His Ser Thr Gly Tyr Glu
115 120 125
Ser Asp Asn His Thr Thr Pro Ile Leu Cys Gly Ala Gln Tyr Arg Ile
130 135 140
His Thr His Gly Val Phe Arg Gly Ile Gln Asp Val Arg Arg Val Pro
145 150 155 160
Gly Val Ala Pro Thr Leu Val Arg Ser Ala Ser Glu Thr Ser Glu Lys
165 170 175
Arg Pro Phe Met Cys Ala Tyr Pro Gly Cys Asn Lys Arg Tyr Phe Lys
180 185 190
Leu Ser His Leu Gln Met His Ser Arg Lys His Thr Gly Glu Lys Pro
195 200 205
Tyr Gln Cys Asp Phe Lys Asp Cys Glu Arg Arg Phe Ser Arg Ser Asp
210 215 220
Gln Leu Lys Arg His Gln Arg Arg His Thr Gly Val Lys Pro Phe Gln
225 230 235 240
Cys Lys Thr Cys Gln Arg Lys Phe Ser Arg Ser Asp His Leu Lys Thr
245 250 255
His Thr Arg Thr His Thr Gly Glu Lys Pro Phe Ser Cys Arg Trp Pro
260 265 270
Ser Cys Gln Lys Lys Phe Ala Arg Ser Asp Glu Leu Val Arg His His
275 280 285
Asn Met His Gln Arg Asn Met Thr Lys Leu Gln Leu Ala Leu
290 295 300
<210>506
<211>288
<212>PRT
<213>智人(Homo sapiens)
<400>506
Met Glu Lys Gly Tyr Ser Thr Val Thr Phe Asp Gly Thr Pro Ser Tyr
1 5 1015
Gly His Thr Pro Ser His His Ala Ala Gln Phe Pro Asn His Ser Phe
202530
Lys His Glu Asp Pro Met Gly Gln Gln Gly Ser Leu Gly Glu Gln Gln
354045
Tyr Ser Val Pro Pro Pro Val Tyr Gly Cys His Thr Pro Thr Asp Ser
505560
Cys Thr Gly Ser Gln Ala Leu Leu Leu Arg Thr Pro Tyr Ser Ser Asp
65707580
Asn Leu Tyr Gln Met Thr Ser Gln Leu Glu Cys Met Thr Trp Asn Gln
859095
Met Asn Leu Gly Ala Thr Leu Lys Gly His Ser Thr Gly Tyr Glu Ser
100 105 110
Asp Asn His Thr Thr Pro Ile Leu Cys Gly Ala Gln Tyr Arg Ile His
115 120 125
Thr His Gly Val Phe Arg Gly Ile Gln Asp Val Arg Arg Val Pro Gly
130 135 140
Val Ala Pro Thr Leu Val Arg Ser Ala Ser Glu Thr Ser Glu Lys Arg
145 150 155 160
Pro Phe Met Cys Ala Tyr Pro Gly Cys Asn Lys Arg Tyr Phe Lys Leu
165 170 175
Ser His Leu Gln Met His Ser Arg Lys His Thr Gly Glu Lys Pro Tyr
180 185 190
Gln Cys Asp Phe Lys Asp Cys Glu Arg Arg Phe Ser Arg Ser Asp Gln
195 200 205
Leu Lys Arg His Gln Arg Arg His Thr Gly Val Lys Pro Phe Gln Cys
210 215 220
Lys Thr Cys Gln Arg Lys Phe Ser Arg Ser Asp His Leu Lys Thr His
225 230 235 240
Thr Arg Thr His Thr Gly Lys Thr Ser Glu Lys Pro Phe Ser Cys Arg
245 250 255
Trp Pro Ser Cys Gln Lys Lys Phe Ala Arg Ser Asp Glu Leu Val Arg
260 265 270
His His Asn Met His Gln Arg Asn Met Thr Lys Leu Gln Leu Ala Leu
275 280 285
<210>507
<211>158
<212>PRT
<213>智人(Homo sapiens)
<400>507
Met His Gln Lys Arg Thr Ala Met Phe Gln Asp Pro Gln Glu Arg Pro
1 5 1015
Arg Lys Leu Pro Gln Leu Cys Thr Glu Leu Gln Thr Thr Ile His Asp
202530
Ile Ile Leu Glu Cys Val Tyr Cys Lys Gln Gln Leu Leu Arg Arg Glu
354045
Val Tyr Asp Phe Ala Phe Arg Asp Leu Cys Ile Val Tyr Arg Asp Gly
505560
Asn Pro Tyr Ala Val Cys Asp Lys Cys Leu Lys Phe Tyr Ser Lys Ile
65707580
Ser Glu Tyr Arg His Tyr Cys Tyr Ser Val Tyr Gly Thr Thr Leu Glu
859095
Gln Gln Tyr Asn Lys Pro Leu Cys Asp Leu Leu Ile Arg Cys Ile Asn
100 105 110
Cys Gln Lys Pro Leu Cys Pro Glu Glu Lys Gln Arg His Leu Asp Lys
115 120 125
Lys Gln Arg Phe His Asn Ile Arg Gly Arg Trp Thr Gly Arg Cys Met
130 135 140
Ser Cys Cys Arg Ser Ser Arg Thr Arg Arg Glu Thr Gln Leu
145 150 155
<210>508
<211>141
<212>PRT
<213>智人(Homo sapiens)
<400>508
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 1015
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Tyr Ser Ser
202530
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
354045
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
505560
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65707580
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser Gln
859095
Lys Pro Tyr Ser Thr Met Ala Asp Pro Ala Gly Thr Asn Gly Glu Glu
100 105 110
Gly Thr Gly Cys Asn Gly Trp Phe Tyr Val Glu Ala Val Val Glu Lys
115 120 125
Lys Thr Gly Asp Ala Ile Ser Asp Asp Glu Asn Glu Asn
130 135 140
<210>509
<211>133
<212>PRT
<213>智人(Homo sapiens)
<400>509
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 1015
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
202530
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
354045
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
505560
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65707580
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
859095
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210>510
<211>272
<212>PRT
<213>智人(Homo sapiens)
<400>510
Met Asp Ser Tyr Leu Leu Met Trp Gly Leu Leu Thr Phe Ile Met Val
1 5 1015
Pro Gly Cys Gln Ala Glu Leu Cys Asp Asp Asp Pro Pro Glu Ile Pro
202530
His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr Met Leu Asn
354045
Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly Ser Leu Tyr
505560
Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp Asn Gln Cys
65707580
Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln Val Thr Pro
859095
Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met Gln Ser Pro
100 105 110
Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys Arg Glu Pro
115 120 125
Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His Phe Val Val
130 135 140
Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg Ala Leu His
145 150 155 160
Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly Lys Thr Arg
165 170 175
Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu Thr Ser Gln
180 185 190
Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly Arg Pro Glu
195 200 205
Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln Ile Gln Thr
210 215 220
Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr Glu Tyr Gln
225 230 235 240
Val Ala Val Ala Gly Cys Val Phe Leu Leu Ile Ser Val Leu Leu Leu
245 250 255
Ser Gly Leu Thr Trp Gln Arg Arg Gln Arg Lys Ser Arg Arg Thr Ile
260 265 270
<210>511
<211>551
<212>PRT
<213>智人(Homo sapiens)
<400>511
Met Ala Ala Pro Ala Leu Ser Trp Arg Leu Pro Leu Leu Ile Leu Leu
1 5 1015
Leu Pro Leu Ala Thr Ser Trp Ala Ser Ala Ala Val Asn Gly Thr Ser
202530
Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala Asn Ile Ser Cys Val Trp
354045
Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser Cys Gln Val His Ala Trp
505560
Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys Glu Leu Leu Pro Val Ser
65707580
Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu Gly Ala Pro Asp Ser Gln
859095
Lys Leu Thr Thr Val Asp Ile Val Thr Leu Arg Val Leu Cys Arg Glu
100 105 110
Gly Val Arg Trp Arg Val Met Ala Ile Gln Asp Phe Lys Pro Phe Glu
115 120 125
Asn Leu Arg Leu Met Ala Pro Ile Ser Leu Gln Val Val His Val Glu
130 135 140
Thr His Arg Cys Asn Ile Ser Trp Glu Ile Ser Gln Ala Ser His Tyr
145 150 155 160
Phe Glu Arg His Leu Glu Phe Glu Ala Arg Thr Leu Ser Pro Gly His
165 170 175
Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu Lys Gln Lys Gln Glu Trp
180 185 190
Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr Gln Tyr Glu Phe Gln Val
195 200 205
Arg Val Lys Pro Leu Gln Gly Glu Phe Thr Thr Trp Ser Pro Trp Ser
210 215 220
Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala Ala Leu Gly Lys Asp Thr
225 230 235 240
Ile Pro Trp Leu Gly His Leu Leu Val Gly Leu Ser Gly Ala Phe Gly
245 250 255
Phe Ile Ile Leu Val Tyr Leu Leu Ile Asn Cys Arg Asn Thr Gly Pro
260 265 270
Trp Leu Lys Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe
275 280 285
Phe Ser Gln Leu Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu
290 295 300
Ser Ser Pro Phe Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro
305 310 315 320
Glu Ile Ser Pro Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu
325 330 335
Leu Leu Gln Gln Asp Lys Val Pro Glu Pro Ala Ser Leu Ser Ser Asn
340 345 350
His Ser Leu Thr Ser Cys Phe Thr Asn Gln Gly Tyr Phe Phe Phe His
355 360 365
Leu Pro Asp Ala Leu Glu Ile Glu Ala Cys Gln Val Tyr Phe Thr Tyr
370 375 380
Asp Pro Tyr Ser Glu Glu Asp Pro Asp Glu Gly Val Ala Gly Ala Pro
385 390 395 400
Thr Gly Ser Ser Pro Gln Pro Leu Gln Pro Leu Ser Gly Glu Asp Asp
405 410 415
Ala Tyr Cys Thr Phe Pro Ser Arg Asp Asp Leu Leu Leu Phe Ser Pro
420 425 430
Ser Leu Leu Gly Gly Pro Ser Pro Pro Ser Thr Ala Pro Gly Gly Ser
435 440 445
Gly Ala Gly Glu Glu Arg Met Pro Pro Ser Leu Gln Glu Arg Val Pro
450 455 460
Arg Asp Trp Asp Pro Gln Pro Leu Gly Pro Pro Thr Pro Gly Val Pro
465 470 475 480
Asp Leu Val Asp Phe Gln Pro Pro Pro Glu Leu Val Leu Arg Glu Ala
485 490 495
Gly Glu Glu Val Pro Asp Ala Gly Pro Arg Glu Gly Val Ser Phe Pro
500 505 510
Trp Ser Arg Pro Pro Gly Gln Gly Glu Phe Arg Ala Leu Asn Ala Arg
515 520 525
Leu Pro Leu Asn Thr Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly
530 535 540
Gln Asp Pro Thr His Leu Val
545 550
<210>512
<211>369
<212>PRT
<213>智人(Homo sapiens)
<400>512
Met Leu Lys Pro Ser Leu Pro Phe Thr Ser Leu Leu Phe Leu Gln Leu
1 5 1015
Pro Leu Leu Gly Val Gly Leu Asn Thr Thr Ile Leu Thr Pro Asn Gly
202530
Asn Glu Asp Thr Thr Ala Asp Phe Phe Leu Thr Thr Met Pro Thr Asp
354045
Ser Leu Ser Val Ser Thr Leu Pro Leu Pro Glu Val Gln Cys Phe Val
505560
Phe Asn Val Glu Tyr Met Asn Cys Thr Trp Asn Ser Ser Ser Glu Pro
65707580
Gln Pro Thr Asn Leu Thr Leu His Tyr Trp Tyr Lys Asn Ser Asp Asn
859095
Asp Lys Val Gln Lys Cys Ser His Tyr Leu Phe Ser Glu Glu Ile Thr
100 105 110
Ser Gly Cys Gln Leu Gln Lys Lys Glu Ile His Leu Tyr Gln Thr Phe
115 120 125
Val Val Gln Leu Gln Asp Pro Arg Glu Pro Arg Arg Gln Ala Thr Gln
130 135 140
Met Leu Lys Leu Gln Asn Leu Val Ile Pro Trp Ala Pro Glu Asn Leu
145 150 155 160
Thr Leu His Lys Leu Ser Glu Ser Gln Leu Glu Leu Asn Trp Asn Asn
165 170 175
Arg Phe Leu Asn His Cys Leu Glu His Leu Val Gln Tyr Arg Thr Asp
180 185 190
Trp Asp His Ser Trp Thr Glu Gln Ser Val Asp Tyr Arg His Lys Phe
195 200 205
Ser Leu Pro Ser Val Asp Gly Gln Lys Arg Tyr Thr Phe Arg Val Arg
210 215 220
Ser Arg Phe Asn Pro Leu Cys Gly Ser Ala Gln His Trp Ser Glu Trp
225 230 235 240
Ser His Pro Ile His Trp Gly Ser Asn Thr Ser Lys Glu Asn Pro Phe
245 250 255
Leu Phe Ala Leu Glu Ala Val Val Ile Ser Val Gly Ser Met Gly Leu
260 265 270
Ile Ile Ser Leu Leu Cys Val Tyr Phe Trp Leu Glu Arg Thr Met Pro
275 280 285
Arg Ile Pro Thr Leu Lys Asn Leu Glu Asp Leu Val Thr Glu Tyr His
290 295 300
Gly Asn Phe Ser Ala Trp Ser Gly Val Ser Lys Gly Leu Ala Glu Ser
305 310 315 320
Leu Gln Pro Asp Tyr Ser Glu Arg Leu Cys Leu Val Ser Glu Ile Pro
325 330 335
Pro Lys Gly Gly Ala Leu Gly Glu Gly Pro Gly Ala Ser Pro Cys Asn
340 345 350
Gln His Ser Pro Tyr Trp Ala Pro Pro Cys Tyr Thr Leu Lys Pro Glu
355 360 365
Thr
<210>513
<211>956
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>513
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser
145 150 155 160
Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr
165 170 175
Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln
180 185 190
Arg Met Glu Pro Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr
195 200 205
Trp Asp Gln Glu Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg
210 215 220
Val Asp Leu Gly Thr Leu Arg Gly Ala Tyr Asn Gln Ser Glu Asp Gly
225 230 235 240
Ser His Thr Ile Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly
245 250 255
Arg Phe Leu Arg Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr
260 265 270
Ile Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala
275 280 285
Ala Gln Ile Thr Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln
290 295 300
Gln Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr
305 310 315 320
Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr
325 330 335
His Met Thr His His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys
340 345 350
Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg
355 360 365
Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro
370 375 380
Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser
385 390 395 400
Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro
405 410 415
Lys Pro Leu Thr Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr
420 425 430
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
435 440 445
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
450 455 460
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
465 470 475 480
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
485 490 495
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
500 505 510
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
515 520 525
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
530 535 540
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
545 550 555 560
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
565 570 575
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
580 585 590
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
595 600 605
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
610 615 620
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
625 630 635 640
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly
645 650 655
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro
660 665 670
Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu
675 680 685
Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro
690 695 700
Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala
705 710 715 720
Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu
725 730 735
Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro
740 745 750
Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly
755 760 765
Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile
770 775 780
Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser
785 790 795 800
Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
805 810 815
Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys
820 825 830
Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu
835 840 845
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
850 855 860
Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
865 870 875 880
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
885 890 895
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
900 905 910
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
915 920 925
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
930 935 940
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
945 950 955
<210>514
<211>959
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>514
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser
145 150 155 160
Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr
165 170 175
Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln
180 185 190
Arg Met Glu Pro Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr
195 200 205
Trp Asp Gln Glu Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg
210 215 220
Val Asp Leu Gly Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly
225 230 235 240
Ser His Thr Ile Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly
245 250 255
Arg Phe Leu Arg Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr
260 265 270
Ile Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala
275 280 285
Ala Gln Ile Thr Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln
290 295 300
Gln Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr
305 310 315 320
Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr
325 330 335
His Met Thr His His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys
340 345 350
Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg
355 360 365
Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro
370 375 380
Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser
385 390 395 400
Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro
405 410 415
Lys Pro Leu Thr Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr
420 425 430
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
435 440 445
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
450 455 460
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
465 470 475 480
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
485 490 495
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
500 505 510
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
515 520 525
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
530 535 540
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
545 550 555 560
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
565 570 575
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
580 585 590
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
595 600 605
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
610 615 620
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
625 630 635 640
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly
645 650 655
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro
660 665 670
Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu
675 680 685
Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro
690 695 700
Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala
705 710 715 720
Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu
725 730 735
Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro
740 745 750
Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly
755 760 765
Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile
770 775 780
Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser
785 790 795 800
Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
805 810 815
Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys
820 825 830
Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu
835 840 845
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
850 855 860
Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
865 870 875 880
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
885 890 895
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
900 905 910
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
915 920 925
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
930 935 940
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Arg Glu Phe
945 950 955
<210>515
<211>936
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>515
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Cys Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser
625 630 635 640
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser
645 650 655
Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln
660 665 670
Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg
675 680 685
Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys
690 695 700
His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu
705 710 715 720
Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile
725 730 735
Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr
740 745 750
Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu
755 760 765
Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly
770 775 780
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
785 790 795 800
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
805 810 815
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
820 825 830
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
835 840 845
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
850 855 860
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
865 870 875 880
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
885 890 895
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
900 905 910
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
915 920 925
Gln Ser Ile Ile Ser Thr Leu Thr
930 935
<210>516
<211>783
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>516
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser
625 630 635 640
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser
645 650 655
Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln
660 665 670
Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg
675 680 685
Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys
690 695 700
His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu
705 710 715 720
Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile
725 730 735
Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr
740 745 750
Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu
755 760 765
Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
770 775 780
<210>517
<211>771
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>517
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Ser Ala Pro
625 630 635 640
Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu
645 650 655
Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro
660 665 670
Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala
675 680 685
Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu
690 695 700
Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro
705 710 715 720
Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly
725 730 735
Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile
740 745 750
Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser
755 760 765
Thr Leu Thr
770
<210>518
<211>929
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>518
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala Pro Ala Pro Ala
625 630 635 640
Pro Ala Pro Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
645 650 655
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
660 665 670
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
675 680 685
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
690 695 700
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
705 710 715 720
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
725 730 735
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
740 745 750
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
755 760 765
Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly
770 775 780
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser
785 790 795 800
Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp
805 810 815
Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu
820 825 830
Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu
835 840 845
Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu
850 855 860
Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp
865 870 875 880
Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu
885 890 895
Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu
900 905 910
Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu
915 920 925
Thr
<210>519
<211>933
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>519
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala Glu Ala Ala Ala
625 630 635 640
Lys Glu Ala Ala Ala Lys Ala Ala Pro Thr Ser Ser Ser Thr Lys Lys
645 650 655
Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu
660 665 670
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
675 680 685
Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
690 695 700
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
705 710 715 720
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
725 730 735
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
740 745 750
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
755 760 765
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly
770 775 780
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
785 790 795 800
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala
805 810 815
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
820 825 830
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
835 840 845
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
850 855 860
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
865 870 875 880
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
885 890 895
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
900 905 910
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
915 920 925
Ile Ser Thr Leu Thr
930
<210>520
<211>936
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>520
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Cys Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser
625 630 635 640
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser
645 650 655
Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln
660 665 670
Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg
675 680 685
Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys
690 695 700
His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu
705 710 715 720
Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile
725 730 735
Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr
740 745 750
Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu
755 760 765
Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly
770 775 780
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
785 790 795 800
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
805 810 815
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
820 825 830
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
835 840 845
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
850 855 860
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
865 870 875 880
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
885 890 895
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
900 905 910
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
915 920 925
Gln Ser Ile Ile Ser Thr Leu Thr
930 935
<210>521
<211>936
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>521
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Cys Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser
625 630 635 640
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser
645 650 655
Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln
660 665 670
Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg
675 680 685
Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys
690 695 700
His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu
705 710 715 720
Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile
725 730 735
Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr
740 745 750
Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu
755 760 765
Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly
770 775 780
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
785 790 795 800
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
805 810 815
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
820 825 830
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
835 840 845
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
850 855 860
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
865 870 875 880
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
885 890 895
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
900 905 910
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
915 920 925
Gln Ser Ile Ile Ser Thr Leu Thr
930 935
<210>522
<211>936
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(301)..(302)
<223>在位置301和302的氨基酸连接至表位。
<400>522
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala
1 5 1015
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
202530
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
354045
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
505560
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65707580
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
859095
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr
145 150 155 160
Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met
165 170 175
Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met
180 185 190
Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His
195 200 205
Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn
210 215 220
Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser
225 230 235 240
Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe
245 250 255
Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn
260 265 270
Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly
275 280 285
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Cys Gly
290 295 300
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile Gln Arg Thr
305 310 315 320
Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn Gly Lys Ser
325 330 335
Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser Asp Ile Glu
340 345 350
Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val Glu His Ser
355 360 365
Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu Tyr Tyr Thr
370 375 380
Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg Val Asn His
385 390 395 400
Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg Asp Met Gly
405 410 415
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser
420 425 430
His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro Gly Arg Gly
435 440 445
Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln Phe Val
450 455 460
Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg Ala Pro
465 470 475 480
Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu Thr Arg Asn
485 490 495
Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly Thr Leu Arg
500 505 510
Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile Gln Ile Met
515 520 525
Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg Gly Tyr Arg
530 535 540
Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu Asp Leu
545 550 555 560
Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Lys Arg Lys
565 570 575
Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr Leu Glu Gly
580 585 590
Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys Glu Thr
595 600 605
Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His Pro Ile
610 615 620
Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro
625 630 635 640
Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln
645 650 655
Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly Thr Phe Gln
660 665 670
Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg Tyr Thr
675 680 685
Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu Arg Trp
690 695 700
Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
705 710 715 720
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
725 730 735
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
740 745 750
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
755 760 765
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
770 775 780
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
785 790 795 800
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
805 810 815
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
820 825 830
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
835 840 845
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
850 855 860
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
865 870 875 880
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
885 890 895
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
900 905 910
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
915 920 925
Lys Ser Leu Ser Leu Ser Pro Gly
930 935
<210>523
<211>956
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>523
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser
145 150 155 160
Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr
165 170 175
Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln
180 185 190
Arg Met Glu Pro Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr
195 200 205
Trp Asp Gln Glu Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg
210 215 220
Val Asp Leu Gly Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly
225 230 235 240
Ser His Thr Ile Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly
245 250 255
Arg Phe Leu Arg Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr
260 265 270
Ile Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Cys
275 280 285
Ala Gln Ile Thr Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln
290 295 300
Gln Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr
305 310 315 320
Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr
325 330 335
His Met Thr His His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys
340 345 350
Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg
355 360 365
Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro
370 375 380
Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser
385 390 395 400
Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro
405 410 415
Lys Pro Leu Thr Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr
420 425 430
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
435 440 445
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
450 455 460
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
465 470 475 480
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
485 490 495
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
500 505 510
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
515 520 525
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
530 535 540
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
545 550 555 560
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
565 570 575
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
580 585 590
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
595 600 605
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
610 615 620
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
625 630 635 640
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly
645 650 655
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro
660 665 670
Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu
675 680 685
Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro
690 695 700
Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala
705 710 715 720
Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu
725 730 735
Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro
740 745 750
Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly
755 760 765
Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile
770 775 780
Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser
785 790 795 800
Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
805 810 815
Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys
820 825 830
Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu
835 840 845
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
850 855 860
Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
865 870 875 880
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
885 890 895
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
900 905 910
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
915 920 925
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
930 935 940
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
945 950 955
<210>524
<211>925
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>524
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala Pro Ala Pro Ala
625 630 635 640
Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu
645 650 655
Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn
660 665 670
Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys
675 680 685
Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro
690 695 700
Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg
705 710 715 720
Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys
725 730 735
Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr
740 745 750
Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile
755 760 765
Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
770 775 780
Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys
785 790 795 800
Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile
805 810 815
Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu
820 825 830
Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu
835 840 845
Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu
850 855 860
Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn
865 870 875 880
Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met
885 890 895
Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg
900 905 910
Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
915 920 925
<210>525
<211>933
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>525
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala Pro Ala Pro Ala
625 630 635 640
Pro Ala Pro Ala Pro Ala Pro Ala Pro Thr Ser Ser Ser Thr Lys Lys
645 650 655
Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu
660 665 670
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
675 680 685
Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
690 695 700
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
705 710 715 720
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
725 730 735
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
740 745 750
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
755 760 765
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly
770 775 780
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
785 790 795 800
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala
805 810 815
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
820 825 830
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
835 840 845
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
850 855 860
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
865 870 875 880
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
885 890 895
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
900 905 910
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
915 920 925
Ile Ser Thr Leu Thr
930
<210>526
<211>937
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>526
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala Pro Ala Pro Ala
625 630 635 640
Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Thr Ser Ser
645 650 655
Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu
660 665 670
Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr
675 680 685
Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu
690 695 700
Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val
705 710 715 720
Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu
725 730 735
Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr
740 745 750
Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe
755 760 765
Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
770 775 780
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
785 790 795 800
Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu
805 810 815
Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile
820 825 830
Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe
835 840 845
Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu
850 855 860
Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys
865 870 875 880
Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile
885 890 895
Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala
900 905 910
Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe
915 920 925
Cys Gln Ser Ile Ile Ser Thr Leu Thr
930 935
<210>527
<211>941
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>527
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala Pro Ala Pro Ala
625 630 635 640
Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala
645 650 655
Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu
660 665 670
Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn
675 680 685
Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys
690 695 700
Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro
705 710 715 720
Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg
725 730 735
Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys
740 745 750
Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr
755 760 765
Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile
770 775 780
Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
785 790 795 800
Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys
805 810 815
Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile
820 825 830
Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu
835 840 845
Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu
850 855 860
Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu
865 870 875 880
Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn
885 890 895
Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met
900 905 910
Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg
915 920 925
Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
930 935 940
<210>528
<211>929
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>528
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Pro Lys Pro Lys
625 630 635 640
Pro Lys Pro Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
645 650 655
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
660 665 670
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
675 680 685
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
690 695 700
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
705 710 715 720
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
725 730 735
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
740 745 750
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
755 760 765
Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly
770 775 780
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser
785 790 795 800
Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp
805 810 815
Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu
820 825 830
Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu
835 840 845
Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu
850 855 860
Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp
865 870 875 880
Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu
885 890 895
Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu
900 905 910
Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu
915 920 925
Thr
<210>529
<211>929
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>529
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Glu Pro Glu Pro Glu
625 630 635 640
Pro Glu Pro Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
645 650 655
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
660 665 670
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
675 680 685
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
690 695 700
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
705 710 715 720
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
725 730 735
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
740 745 750
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
755 760 765
Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly
770 775 780
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser
785 790 795 800
Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp
805 810 815
Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu
820 825 830
Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu
835 840 845
Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu
850 855 860
Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp
865 870 875 880
Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu
885 890 895
Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu
900 905 910
Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu
915 920 925
Thr
<210>530
<211>917
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>530
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala Pro Ala Pro Ala
625 630 635 640
Pro Ala Pro Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
645 650 655
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
660 665 670
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
675 680 685
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
690 695 700
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
705 710 715 720
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
725 730 735
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
740 745 750
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
755 760 765
Gln Ser Ile Ile Ser Thr Leu Thr Ala Pro Ala Pro Ala Pro Ala Pro
770 775 780
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala
785 790 795 800
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
805 810 815
Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
820 825 830
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
835 840 845
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
850 855 860
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
865 870 875 880
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
885 890 895
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
900 905 910
Ile Ser Thr Leu Thr
915
<210>531
<211>931
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>531
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Pro
625 630 635 640
Gly Gly Gly Gly Pro Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln
645 650 655
Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly
660 665 670
Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys
675 680 685
Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu
690 695 700
Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser
705 710 715 720
Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val
725 730 735
Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr
740 745 750
Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr
755 760 765
Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly
770 775 780
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro
785 790 795 800
Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu
805 810 815
Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro
820 825 830
Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala
835 840 845
Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu
850 855 860
Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro
865 870 875 880
Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly
885 890 895
Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile
900 905 910
Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser
915 920 925
Thr Leu Thr
930
<210>532
<211>936
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>532
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Pro
625 630 635 640
Gly Gly Gly Gly Pro Gly Gly Gly Gly Pro Ala Pro Thr Ser Ser Ser
645 650 655
Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln
660 665 670
Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg
675 680 685
Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys
690 695 700
His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu
705 710 715 720
Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile
725 730 735
Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr
740 745 750
Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu
755 760 765
Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly
770 775 780
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
785 790 795 800
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
805 810 815
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
820 825 830
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
835 840 845
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
850 855 860
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
865 870 875 880
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
885 890 895
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
900 905 910
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
915 920 925
Gln Ser Ile Ile Ser Thr Leu Thr
930 935
<210>533
<211>936
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>533
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Phe Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gly Glu
180 185 190
Thr Arg Lys Val Lys Ala His Ser Gln Thr His Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Val
210 215 220
Gln Arg Met Tyr Gly Cys Asp Val Gly Ser Asp Trp Arg Phe Leu Arg
225 230 235 240
Gly Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Cys Ala Gln Thr Thr
260 265 270
Lys His Lys Trp Glu Ala Ala His Val Ala Glu Gln Leu Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Ala Pro Lys Thr His Met Thr His
305 310 315 320
His Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Gln Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser
625 630 635 640
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser
645 650 655
Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln
660 665 670
Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg
675 680 685
Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys
690 695 700
His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu
705 710 715 720
Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile
725 730 735
Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr
740 745 750
Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu
755 760 765
Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly
770 775 780
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
785 790 795 800
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
805 810 815
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
820 825 830
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
835 840 845
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
850 855 860
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
865 870 875 880
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
885 890 895
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
900 905 910
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
915 920 925
Gln Ser Ile Ile Ser Thr Leu Thr
930 935
<210>534
<211>936
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>534
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Phe Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gly Glu
180 185 190
Thr Arg Lys Val Lys Ala His Ser Gln Thr His Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Val
210 215 220
Gln Arg Met Tyr Gly Cys Asp Val Gly Ser Asp Trp Arg Phe Leu Arg
225 230 235 240
Gly Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Thr Thr
260 265 270
Lys His Lys Trp Glu Ala Ala His Val Ala Glu Gln Leu Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Ala Pro Lys Thr His Met Thr His
305 310 315 320
His Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Gln Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser
625 630 635 640
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser
645 650 655
Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln
660 665 670
Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg
675 680 685
Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys
690 695 700
His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu
705 710 715 720
Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile
725 730 735
Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr
740 745 750
Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu
755 760 765
Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly
770 775 780
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
785 790 795 800
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
805 810 815
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
820 825 830
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
835 840 845
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
850 855 860
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
865 870 875 880
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
885 890 895
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
900 905 910
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
915 920 925
Gln Ser Ile Ile Ser Thr Leu Thr
930 935
<210>535
<211>936
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>535
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser
625 630 635 640
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser
645 650 655
Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln
660 665 670
Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg
675 680 685
Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys
690 695 700
His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu
705 710 715 720
Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile
725 730 735
Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr
740 745 750
Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu
755 760 765
Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly
770 775 780
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
785 790 795 800
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
805 810 815
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
820 825 830
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
835 840 845
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
850 855 860
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
865 870 875 880
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
885 890 895
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
900 905 910
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
915 920 925
Gln Ser Ile Ile Ser Thr Leu Thr
930 935
<210>536
<211>956
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<400>536
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser
145 150 155 160
Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr
165 170 175
Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln
180 185 190
Arg Met Glu Pro Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr
195 200 205
Trp Asp Gln Glu Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg
210 215 220
Val Asp Leu Gly Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly
225 230 235 240
Ser His Thr Ile Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly
245 250 255
Arg Phe Leu Arg Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr
260 265 270
Ile Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala
275 280 285
Ala Gln Ile Thr Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln
290 295 300
Gln Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr
305 310 315 320
Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr
325 330 335
His Met Thr His His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys
340 345 350
Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg
355 360 365
Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro
370 375 380
Cys Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser
385 390 395 400
Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro
405 410 415
Lys Pro Leu Thr Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr
420 425 430
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
435 440 445
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
450 455 460
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
465 470 475 480
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
485 490 495
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
500 505 510
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
515 520 525
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
530 535 540
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
545 550 555 560
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
565 570 575
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
580 585 590
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
595 600 605
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
610 615 620
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
625 630 635 640
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly
645 650 655
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro
660 665 670
Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu
675 680 685
Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro
690 695 700
Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala
705 710 715 720
Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu
725 730 735
Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro
740 745 750
Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly
755 760 765
Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile
770 775 780
Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser
785 790 795 800
Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
805 810 815
Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys
820 825 830
Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu
835 840 845
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
850 855 860
Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
865 870 875 880
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
885 890 895
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
900 905 910
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
915 920 925
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
930 935 940
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
945 950 955
<210>537
<211>945
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>537
Asn Leu Val Pro Met Val Ala Thr Val Gly Cys Gly Gly Ser Gly Gly
1 5 1015
Gly Gly Ser Gly Gly Gly Gly Ser Ile Gln Arg Thr Pro Lys Ile Gln
202530
Val Tyr Ser Cys His Pro Ala Glu Asn Gly Lys Ser Asn Phe Leu Asn
354045
Cys Tyr Val Ser Gly Phe His Pro Ser Asp Ile Glu Val Asp Leu Leu
505560
Lys Asn Gly Glu Arg Ile Glu Lys Val Glu His Ser Asp Leu Ser Phe
65707580
Ser Lys Asp Trp Ser Phe Tyr Leu Leu Tyr Tyr Thr Glu Phe Thr Pro
859095
Thr Glu Lys Asp Glu Tyr Ala Cys Arg Val Asn His Val Thr Leu Ser
100 105 110
Gln Pro Lys Ile Val Lys Trp Asp Arg Asp Met Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser His Ser Met Arg
130 135 140
Tyr Phe Phe Thr Ser Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe
145 150 155 160
Ile Ala Val Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser
165 170 175
Asp Ala Ala Ser Gln Arg Met Glu Pro Arg Ala Pro Trp Ile Glu Gln
180 185 190
Glu Gly Pro Glu Tyr Trp Asp Gly Glu Thr Arg Lys Val Lys Ala His
195 200 205
Ser Gln Thr His Arg Val Asp Leu Gly Thr Leu Arg Gly Cys Tyr Asn
210 215 220
Gln Ser Glu Ala Gly Ser His Thr Val Gln Arg Met Tyr Gly Cys Asp
225 230 235 240
Val Gly Ser Asp Trp Arg Phe Leu Arg Gly Tyr His Gln Tyr Ala Tyr
245 250 255
Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu Asp Leu Arg Ser Trp Thr
260 265 270
Ala Ala Asp Met Ala Ala Gln Thr Thr Lys His Lys Trp Glu Ala Ala
275 280 285
His Val Ala Glu Gln Leu Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu
290 295 300
Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Thr
305 310 315 320
Asp Ala Pro Lys Thr His Met Thr His His Ala Val Ser Asp His Glu
325 330 335
Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe Tyr Pro Ala Glu Ile Thr
340 345 350
Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu
355 360 365
Val Glu Thr Arg Pro Cys Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala
370 375 380
Val Val Val Pro Ser Gly Gln Glu Gln Arg Tyr Thr Cys His Val Gln
385 390 395 400
His Glu Gly Leu Pro Lys Pro Leu Thr Leu Arg Trp Glu Ala Ala Ala
405 410 415
Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
420 425 430
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
435 440 445
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
450 455 460
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
465 470 475 480
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
485 490 495
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
500 505 510
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
515 520 525
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
530 535 540
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
545 550 555 560
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
565 570 575
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
580 585 590
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
595 600 605
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
610 615 620
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
625 630 635 640
Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
645 650 655
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
660 665 670
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
675 680 685
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
690 695 700
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
705 710 715 720
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
725 730 735
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
740 745 750
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
755 760 765
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
770 775 780
Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly
785 790 795 800
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser
805 810 815
Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp
820 825 830
Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu
835 840 845
Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu
850 855 860
Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu
865 870 875 880
Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp
885 890 895
Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu
900 905 910
Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu
915 920 925
Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu
930 935 940
Thr
945
<210>538
<211>945
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>538
Ala Thr Val Gln Gly Gln Asn Leu Lys Gly Cys Gly Gly Ser Gly Gly
1 5 1015
Gly Gly Ser Gly Gly Gly Gly Ser Ile Gln Arg Thr Pro Lys Ile Gln
202530
Val Tyr Ser Cys His Pro Ala Glu Asn Gly Lys Ser Asn Phe Leu Asn
354045
Cys Tyr Val Ser Gly Phe His Pro Ser Asp Ile Glu Val Asp Leu Leu
505560
Lys Asn Gly Glu Arg Ile Glu Lys Val Glu His Ser Asp Leu Ser Phe
65707580
Ser Lys Asp Trp Ser Phe Tyr Leu Leu Tyr Tyr Thr Glu Phe Thr Pro
859095
Thr Glu Lys Asp Glu Tyr Ala Cys Arg Val Asn His Val Thr Leu Ser
100 105 110
Gln Pro Lys Ile Val Lys Trp Asp Arg Asp Met Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser His Ser Met Arg
130 135 140
Tyr Phe Tyr Thr Ser Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe
145 150 155 160
Ile Ala Val Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser
165 170 175
Asp Ala Ala Ser Gln Arg Met Glu Pro Arg Ala Pro Trp Ile Glu Gln
180 185 190
Glu Gly Pro Glu Tyr Trp Asp Gln Glu Thr Arg Asn Val Lys Ala Gln
195 200 205
Ser Gln Thr Asp Arg Val Asp Leu Gly Thr Leu Arg Gly Cys Tyr Asn
210 215 220
Gln Ser Glu Asp Gly Ser His Thr Ile Gln Ile Met Tyr Gly Cys Asp
225 230 235 240
Val Gly Pro Asp Gly Arg Phe Leu Arg Gly Tyr Arg Gln Asp Ala Tyr
245 250 255
Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr
260 265 270
Ala Ala Asp Met Ala Ala Gln Ile Thr Lys Arg Lys Trp Glu Ala Ala
275 280 285
His Ala Ala Glu Gln Gln Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu
290 295 300
Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Thr
305 310 315 320
Asp Pro Pro Lys Thr His Met Thr His His Pro Ile Ser Asp His Glu
325 330 335
Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr
340 345 350
Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu
355 360 365
Val Glu Thr Arg Pro Cys Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala
370 375 380
Val Val Val Pro Ser Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln
385 390 395 400
His Glu Gly Leu Pro Lys Pro Leu Thr Leu Arg Trp Glu Ala Ala Ala
405 410 415
Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
420 425 430
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
435 440 445
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
450 455 460
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
465 470 475 480
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
485 490 495
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
500 505 510
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
515 520 525
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
530 535 540
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
545 550 555 560
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
565 570 575
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
580 585 590
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
595 600 605
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
610 615 620
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
625 630 635 640
Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
645 650 655
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
660 665 670
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
675 680 685
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
690 695 700
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
705 710 715 720
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
725 730 735
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
740 745 750
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
755 760 765
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
770 775 780
Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly
785 790 795 800
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser
805 810 815
Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp
820 825 830
Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu
835 840 845
Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu
850 855 860
Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu
865 870 875 880
Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp
885 890 895
Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu
900 905 910
Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu
915 920 925
Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu
930 935 940
Thr
945
<210>539
<211>945
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>539
Val Met Ala Pro Arg Thr Leu Ile Leu Gly Cys Gly Gly Ser Gly Gly
1 5 1015
Gly Gly Ser Gly Gly Gly Gly Ser Ile Gln Arg Thr Pro Lys Ile Gln
202530
Val Tyr Ser Cys His Pro Ala Glu Asn Gly Lys Ser Asn Phe Leu Asn
354045
Cys Tyr Val Ser Gly Phe His Pro Ser Asp Ile Glu Val Asp Leu Leu
505560
Lys Asn Gly Glu Arg Ile Glu Lys Val Glu His Ser Asp Leu Ser Phe
65707580
Ser Lys Asp Trp Ser Phe Tyr Leu Leu Tyr Tyr Thr Glu Phe Thr Pro
859095
Thr Glu Lys Asp Glu Tyr Ala Cys Arg Val Asn His Val Thr Leu Ser
100 105 110
Gln Pro Lys Ile Val Lys Trp Asp Arg Asp Met Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser His Ser Leu Lys
130 135 140
Tyr Phe His Thr Ser Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe
145 150 155 160
Ile Ser Val Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Asn
165 170 175
Asp Ala Ala Ser Pro Arg Met Val Pro Arg Ala Pro Trp Met Glu Gln
180 185 190
Glu Gly Ser Glu Tyr Trp Asp Arg Glu Thr Arg Ser Ala Arg Asp Thr
195 200 205
Ala Gln Ile Phe Arg Val Asn Leu Arg Thr Leu Arg Gly Cys Tyr Asn
210 215 220
Gln Ser Glu Ala Gly Ser His Thr Leu Gln Trp Met His Gly Cys Glu
225 230 235 240
Leu Gly Pro Asp Arg Arg Phe Leu Arg Gly Tyr Glu Gln Phe Ala Tyr
245 250 255
Asp Gly Lys Asp Tyr Leu Thr Leu Asn Glu Asp Leu Arg Ser Trp Thr
260 265 270
Ala Val Asp Thr Ala Ala Gln Ile Ser Glu Gln Lys Ser Asn Asp Ala
275 280 285
Ser Glu Ala Glu His Gln Arg Ala Tyr Leu Glu Asp Thr Cys Val Glu
290 295 300
Trp Leu His Lys Tyr Leu Glu Lys Gly Lys Glu Thr Leu Leu His Leu
305 310 315 320
Glu Pro Pro Lys Thr His Val Thr His His Pro Ile Ser Asp His Glu
325 330 335
Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr
340 345 350
Leu Thr Trp Gln Gln Asp Gly Glu Gly His Thr Gln Asp Thr Glu Leu
355 360 365
Val Glu Thr Arg Pro Cys Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala
370 375 380
Val Val Val Pro Ser Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln
385 390 395 400
His Glu Gly Leu Pro Glu Pro Val Thr Leu Arg Trp Lys Ala Ala Ala
405 410 415
Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
420 425 430
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
435 440 445
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
450 455 460
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
465 470 475 480
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
485 490 495
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
500 505 510
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
515 520 525
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
530 535 540
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
545 550 555 560
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
565 570 575
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
580 585 590
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
595 600 605
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
610 615 620
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
625 630 635 640
Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
645 650 655
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
660 665 670
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
675 680 685
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
690 695 700
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
705 710 715 720
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
725 730 735
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
740 745 750
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
755 760 765
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
770 775 780
Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly
785 790 795 800
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser
805 810 815
Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp
820 825 830
Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu
835 840 845
Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu
850 855 860
Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu
865 870 875 880
Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp
885 890 895
Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu
900 905 910
Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu
915 920 925
Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu
930 935 940
Thr
945
<210>540
<211>945
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>540
Ile Val Thr Asp Phe Ser Val Ile Lys Gly Cys Gly Gly Ser Gly Gly
1 5 1015
Gly Gly Ser Gly Gly Gly Gly Ser Ile Gln Arg Thr Pro Lys Ile Gln
202530
Val Tyr Ser Cys His Pro Ala Glu Asn Gly Lys Ser Asn Phe Leu Asn
354045
Cys Tyr Val Ser Gly Phe His Pro Ser Asp Ile Glu Val Asp Leu Leu
505560
Lys Asn Gly Glu Arg Ile Glu Lys Val Glu His Ser Asp Leu Ser Phe
65707580
Ser Lys Asp Trp Ser Phe Tyr Leu Leu Tyr Tyr Thr Glu Phe Thr Pro
859095
Thr Glu Lys Asp Glu Tyr Ala Cys Arg Val Asn His Val Thr Leu Ser
100 105 110
Gln Pro Lys Ile Val Lys Trp Asp Arg Asp Met Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser His Ser Met Arg
130 135 140
Tyr Phe Tyr Thr Ser Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe
145 150 155 160
Ile Ala Val Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser
165 170 175
Asp Ala Ala Ser Gln Arg Met Glu Pro Arg Ala Pro Trp Ile Glu Gln
180 185 190
Glu Gly Pro Glu Tyr Trp Asp Gln Glu Thr Arg Asn Val Lys Ala Gln
195 200 205
Ser Gln Thr Asp Arg Val Asp Leu Gly Thr Leu Arg Gly Cys Tyr Asn
210 215 220
Gln Ser Glu Asp Gly Ser His Thr Ile Gln Ile Met Tyr Gly Cys Asp
225 230 235 240
Val Gly Pro Asp Gly Arg Phe Leu Arg Gly Tyr Arg Gln Asp Ala Tyr
245 250 255
Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr
260 265 270
Ala Ala Asp Met Ala Ala Gln Ile Thr Lys Arg Lys Trp Glu Ala Ala
275 280 285
His Ala Ala Glu Gln Gln Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu
290 295 300
Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Thr
305 310 315 320
Asp Pro Pro Lys Thr His Met Thr His His Pro Ile Ser Asp His Glu
325 330 335
Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr
340 345 350
Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu
355 360 365
Val Glu Thr Arg Pro Cys Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala
370 375 380
Val Val Val Pro Ser Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln
385 390 395 400
His Glu Gly Leu Pro Lys Pro Leu Thr Leu Arg Trp Glu Ala Ala Ala
405 410 415
Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
420 425 430
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
435 440 445
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
450 455 460
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
465 470 475 480
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
485 490 495
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
500 505 510
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
515 520 525
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
530 535 540
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
545 550 555 560
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
565 570 575
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
580 585 590
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
595 600 605
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
610 615 620
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
625 630 635 640
Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
645 650 655
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
660 665 670
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
675 680 685
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
690 695 700
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
705 710 715 720
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
725 730 735
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
740 745 750
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
755 760 765
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
770 775 780
Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly
785 790 795 800
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser
805 810 815
Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp
820 825 830
Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu
835 840 845
Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu
850 855 860
Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu
865 870 875 880
Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp
885 890 895
Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu
900 905 910
Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu
915 920 925
Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu
930 935 940
Thr
945
<210>541
<211>945
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>541
Gly Ile Leu Gly Phe Val Phe Thr Leu Gly Cys Gly Gly Ser Gly Gly
1 5 1015
Gly Gly Ser Gly Gly Gly Gly Ser Ile Gln Arg Thr Pro Lys Ile Gln
202530
Val Tyr Ser Cys His Pro Ala Glu Asn Gly Lys Ser Asn Phe Leu Asn
354045
Cys Tyr Val Ser Gly Phe His Pro Ser Asp Ile Glu Val Asp Leu Leu
505560
Lys Asn Gly Glu Arg Ile Glu Lys Val Glu His Ser Asp Leu Ser Phe
65707580
Ser Lys Asp Trp Ser Phe Tyr Leu Leu Tyr Tyr Thr Glu Phe Thr Pro
859095
Thr Glu Lys Asp Glu Tyr Ala Cys Arg Val Asn His Val Thr Leu Ser
100 105 110
Gln Pro Lys Ile Val Lys Trp Asp Arg Asp Met Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser His Ser Met Arg
130 135 140
Tyr Phe Phe Thr Ser Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe
145 150 155 160
Ile Ala Val Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser
165 170 175
Asp Ala Ala Ser Gln Arg Met Glu Pro Arg Ala Pro Trp Ile Glu Gln
180 185 190
Glu Gly Pro Glu Tyr Trp Asp Gly Glu Thr Arg Lys Val Lys Ala His
195 200 205
Ser Gln Thr His Arg Val Asp Leu Gly Thr Leu Arg Gly Cys Tyr Asn
210 215 220
Gln Ser Glu Ala Gly Ser His Thr Val Gln Arg Met Tyr Gly Cys Asp
225 230 235 240
Val Gly Ser Asp Trp Arg Phe Leu Arg Gly Tyr His Gln Tyr Ala Tyr
245 250 255
Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu Asp Leu Arg Ser Trp Thr
260 265 270
Ala Ala Asp Met Ala Ala Gln Thr Thr Lys His Lys Trp Glu Ala Ala
275 280 285
His Val Ala Glu Gln Leu Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu
290 295 300
Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Thr
305 310 315 320
Asp Ala Pro Lys Thr His Met Thr His His Ala Val Ser Asp His Glu
325 330 335
Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe Tyr Pro Ala Glu Ile Thr
340 345 350
Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu
355 360 365
Val Glu Thr Arg Pro Cys Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala
370 375 380
Val Val Val Pro Ser Gly Gln Glu Gln Arg Tyr Thr Cys His Val Gln
385 390 395 400
His Glu Gly Leu Pro Lys Pro Leu Thr Leu Arg Trp Glu Ala Ala Ala
405 410 415
Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
420 425 430
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
435 440 445
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
450 455 460
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
465 470 475 480
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
485 490 495
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
500 505 510
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
515 520 525
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
530 535 540
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
545 550 555 560
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
565 570 575
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
580 585 590
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
595 600 605
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
610 615 620
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
625 630 635 640
Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
645 650 655
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
660 665 670
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
675 680 685
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
690 695 700
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
705 710 715 720
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
725 730 735
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
740 745 750
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
755 760 765
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
770 775 780
Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly
785 790 795 800
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser
805 810 815
Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp
820 825 830
Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu
835 840 845
Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu
850 855 860
Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu
865 870 875 880
Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp
885 890 895
Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu
900 905 910
Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu
915 920 925
Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu
930 935 940
Thr
945
<210>542
<211>945
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>542
Val Met Ala Pro Arg Thr Leu Phe Leu Gly Cys Gly Gly Ser Gly Gly
1 5 1015
Gly Gly Ser Gly Gly Gly Gly Ser Ile Gln Arg Thr Pro Lys Ile Gln
202530
Val Tyr Ser Cys His Pro Ala Glu Asn Gly Lys Ser Asn Phe Leu Asn
354045
Cys Tyr Val Ser Gly Phe His Pro Ser Asp Ile Glu Val Asp Leu Leu
505560
Lys Asn Gly Glu Arg Ile Glu Lys Val Glu His Ser Asp Leu Ser Phe
65707580
Ser Lys Asp Trp Ser Phe Tyr Leu Leu Tyr Tyr Thr Glu Phe Thr Pro
859095
Thr Glu Lys Asp Glu Tyr Ala Cys Arg Val Asn His Val Thr Leu Ser
100 105 110
Gln Pro Lys Ile Val Lys Trp Asp Arg Asp Met Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser His Ser Leu Lys
130 135 140
Tyr Phe His Thr Ser Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe
145 150 155 160
Ile Ser Val Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Asn
165 170 175
Asp Ala Ala Ser Pro Arg Met Val Pro Arg Ala Pro Trp Met Glu Gln
180 185 190
Glu Gly Ser Glu Tyr Trp Asp Arg Glu Thr Arg Ser Ala Arg Asp Thr
195 200 205
Ala Gln Ile Phe Arg Val Asn Leu Arg Thr Leu Arg Gly Cys Tyr Asn
210 215 220
Gln Ser Glu Ala Gly Ser His Thr Leu Gln Trp Met His Gly Cys Glu
225 230 235 240
Leu Gly Pro Asp Arg Arg Phe Leu Arg Gly Tyr Glu Gln Phe Ala Tyr
245 250 255
Asp Gly Lys Asp Tyr Leu Thr Leu Asn Glu Asp Leu Arg Ser Trp Thr
260 265 270
Ala Val Asp Thr Ala Ala Gln Ile Ser Glu Gln Lys Ser Asn Asp Ala
275 280 285
Ser Glu Ala Glu His Gln Arg Ala Tyr Leu Glu Asp Thr Cys Val Glu
290 295 300
Trp Leu His Lys Tyr Leu Glu Lys Gly Lys Glu Thr Leu Leu His Leu
305 310 315 320
Glu Pro Pro Lys Thr His Val Thr His His Pro Ile Ser Asp His Glu
325 330 335
Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr
340 345 350
Leu Thr Trp Gln Gln Asp Gly Glu Gly His Thr Gln Asp Thr Glu Leu
355 360 365
Val Glu Thr Arg Pro Cys Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala
370 375 380
Val Val Val Pro Ser Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln
385 390 395 400
His Glu Gly Leu Pro Glu Pro Val Thr Leu Arg Trp Lys Ala Ala Ala
405 410 415
Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
420 425 430
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
435 440 445
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
450 455 460
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
465 470 475 480
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
485 490 495
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
500 505 510
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
515 520 525
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
530 535 540
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
545 550 555 560
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
565 570 575
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
580 585 590
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
595 600 605
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
610 615 620
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
625 630 635 640
Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
645 650 655
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
660 665 670
Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
675 680 685
Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr
690 695 700
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
705 710 715 720
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
725 730 735
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
740 745 750
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
755 760 765
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
770 775 780
Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly
785 790 795 800
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser
805 810 815
Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp
820 825 830
Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu
835 840 845
Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu
850 855 860
Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu
865 870 875 880
Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp
885 890 895
Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu
900 905 910
Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu
915 920 925
Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu
930 935 940
Thr
945
<210>543
<211>946
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>543
Glu Leu Ala Gly Ile Gly Ile Leu Thr Val Gly Cys Gly Gly Ser Gly
1 5 1015
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile Gln Arg Thr Pro Lys Ile
202530
Gln Val Tyr Ser Cys His Pro Ala Glu Asn Gly Lys Ser Asn Phe Leu
354045
Asn Cys Tyr Val Ser Gly Phe His Pro Ser Asp Ile Glu Val Asp Leu
505560
Leu Lys Asn Gly Glu Arg Ile Glu Lys Val Glu His Ser Asp Leu Ser
65707580
Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu Tyr Tyr Thr Glu Phe Thr
859095
Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg Val Asn His Val Thr Leu
100 105 110
Ser Gln Pro Lys Ile Val Lys Trp Asp Arg Asp Met Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser His Ser Met
130 135 140
Arg Tyr Phe Phe Thr Ser Val Ser Arg Pro Gly Arg Gly Glu Pro Arg
145 150 155 160
Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp
165 170 175
Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg Ala Pro Trp Ile Glu
180 185 190
Gln Glu Gly Pro Glu Tyr Trp Asp Gly Glu Thr Arg Lys Val Lys Ala
195 200 205
His Ser Gln Thr His Arg Val Asp Leu Gly Thr Leu Arg Gly Cys Tyr
210 215 220
Asn Gln Ser Glu Ala Gly Ser His Thr Val Gln Arg Met Tyr Gly Cys
225 230 235 240
Asp Val Gly Ser Asp Trp Arg Phe Leu Arg Gly Tyr His Gln Tyr Ala
245 250 255
Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu Asp Leu Arg Ser Trp
260 265 270
Thr Ala Ala Asp Met Ala Ala Gln Thr Thr Lys His Lys Trp Glu Ala
275 280 285
Ala His Val Ala Glu Gln Leu Arg Ala Tyr Leu Glu Gly Thr Cys Val
290 295 300
Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg
305 310 315 320
Thr Asp Ala Pro Lys Thr His Met Thr His His Ala Val Ser Asp His
325 330 335
Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe Tyr Pro Ala Glu Ile
340 345 350
Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu
355 360 365
Leu Val Glu Thr Arg Pro Cys Gly Asp Gly Thr Phe Gln Lys Trp Ala
370 375 380
Ala Val Val Val Pro Ser Gly Gln Glu Gln Arg Tyr Thr Cys His Val
385 390 395 400
Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu Arg Trp Glu Ala Ala
405 410 415
Ala Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
420 425 430
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
435 440 445
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
450 455 460
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
465 470 475 480
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
485 490 495
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
500 505 510
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
515 520 525
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
530 535 540
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
545 550 555 560
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
565 570 575
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
580 585 590
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
595 600 605
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
610 615 620
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
625 630 635 640
Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
645 650 655
Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu
660 665 670
Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile
675 680 685
Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe
690 695 700
Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu
705 710 715 720
Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys
725 730 735
Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile
740 745 750
Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala
755 760 765
Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe
770 775 780
Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly
785 790 795 800
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr
805 810 815
Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu
820 825 830
Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys
835 840 845
Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr
850 855 860
Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu
865 870 875 880
Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg
885 890 895
Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser
900 905 910
Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val
915 920 925
Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr
930 935 940
Leu Thr
945
<210>544
<211>923
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<220>
<221>变体
<222>(636)..(637)
<223>Xaa可为任何天然存在的氨基酸
<400>544
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Phe Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gly Glu
180 185 190
Thr Arg Lys Val Lys Ala His Ser Gln Thr His Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Val
210 215 220
Gln Arg Met Tyr Gly Cys Asp Val Gly Ser Asp Trp Arg Phe Leu Arg
225 230 235 240
Gly Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Cys Ala Gln Thr Thr
260 265 270
Lys His Lys Trp Glu Ala Ala His Val Ala Glu Gln Leu Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Ala Pro Lys Thr His Met Thr His
305 310 315 320
His Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Gln Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Xaa Xaa Ala Pro Thr
625 630 635 640
Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu
645 650 655
Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys
660 665 670
Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr
675 680 685
Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu
690 695 700
Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg
705 710 715 720
Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser
725 730 735
Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val
740 745 750
Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr
755 760 765
Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
770 775 780
Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
785 790 795 800
Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
805 810 815
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala
820 825 830
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
835 840 845
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
850 855 860
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
865 870 875 880
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
885 890 895
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
900 905 910
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
915 920
<210>545
<211>923
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<220>
<221>变体
<222>(636)..(637)
<223>Xaa可为任何天然存在的氨基酸
<400>545
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Phe Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gly Glu
180 185 190
Thr Arg Lys Val Lys Ala His Ser Gln Thr His Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Val
210 215 220
Gln Arg Met Tyr Gly Cys Asp Val Gly Ser Asp Trp Arg Phe Leu Arg
225 230 235 240
Gly Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Thr Thr
260 265 270
Lys His Lys Trp Glu Ala Ala His Val Ala Glu Gln Leu Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Ala Pro Lys Thr His Met Thr His
305 310 315 320
His Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Gln Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Xaa Xaa Ala Pro Thr
625 630 635 640
Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu
645 650 655
Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys
660 665 670
Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr
675 680 685
Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu
690 695 700
Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg
705 710 715 720
Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser
725 730 735
Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val
740 745 750
Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr
755 760 765
Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
770 775 780
Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
785 790 795 800
Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
805 810 815
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala
820 825 830
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
835 840 845
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
850 855 860
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
865 870 875 880
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
885 890 895
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
900 905 910
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
915 920
<210>546
<211>923
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<220>
<221>变体
<222>(636)..(637)
<223>Xaa可为任何天然存在的氨基酸
<400>546
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
130 135 140
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
145 150 155 160
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
165 170 175
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
180 185 190
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
195 200 205
Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
210 215 220
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
225 230 235 240
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
245 250 255
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
260 265 270
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
275 280 285
Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
290 295 300
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
305 310 315 320
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
325 330 335
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
340 345 350
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Cys Gly Asp Gly
355 360 365
Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln
370 375 380
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
385 390 395 400
Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr His Thr Cys Pro
405 410 415
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
420 425 430
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
435 440 445
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
450 455 460
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
465 470 475 480
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
485 490 495
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
500 505 510
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
515 520 525
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
530 535 540
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
545 550 555 560
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
565 570 575
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
580 585 590
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
595 600 605
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
610 615 620
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Xaa Xaa Ala Pro Thr
625 630 635 640
Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu
645 650 655
Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys
660 665 670
Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr
675 680 685
Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu
690 695 700
Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg
705 710 715 720
Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser
725 730 735
Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val
740 745 750
Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr
755 760 765
Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
770 775 780
Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
785 790 795 800
Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
805 810 815
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala
820 825 830
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
835 840 845
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
850 855 860
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
865 870 875 880
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
885 890 895
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
900 905 910
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
915 920
<210>547
<211>943
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>位点
<222>(1)..(1)
<223>在位置1的氨基酸连接至表位。
<220>
<221>变体
<222>(656)..(657)
<223>Xaa可为任何天然存在的氨基酸
<400>547
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 1015
Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Cys His Pro Ala Glu Asn
202530
Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser
354045
Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val
505560
Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu
65707580
Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg
859095
Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg
100 105 110
Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser
145 150 155 160
Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr
165 170 175
Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln
180 185 190
Arg Met Glu Pro Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr
195 200 205
Trp Asp Gln Glu Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg
210 215 220
Val Asp Leu Gly Thr Leu Arg Gly Cys Tyr Asn Gln Ser Glu Asp Gly
225 230 235 240
Ser His Thr Ile Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly
245 250 255
Arg Phe Leu Arg Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr
260 265 270
Ile Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala
275 280 285
Ala Gln Ile Thr Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln
290 295 300
Gln Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr
305 310 315 320
Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr
325 330 335
His Met Thr His His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys
340 345 350
Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg
355 360 365
Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro
370 375 380
Cys Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser
385 390 395 400
Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro
405 410 415
Lys Pro Leu Thr Leu Arg Trp Glu Ala Ala Ala Gly Gly Asp Lys Thr
420 425 430
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
435 440 445
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
450 455 460
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
465 470 475 480
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
485 490 495
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
500 505 510
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
515 520 525
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
530 535 540
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
545 550 555 560
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
565 570 575
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
580 585 590
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
595 600 605
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
610 615 620
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
625 630 635 640
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Xaa
645 650 655
Xaa Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu
660 665 670
Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr
675 680 685
Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro
690 695 700
Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu
705 710 715 720
Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His
725 730 735
Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu
740 745 750
Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr
755 760 765
Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser
770 775 780
Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
785 790 795 800
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser
805 810 815
Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln
820 825 830
Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg
835 840 845
Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys
850 855 860
His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu
865 870 875 880
Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile
885 890 895
Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr
900 905 910
Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu
915 920 925
Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
930 935 940
<210>548
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>548
Gly Ser His Ser Leu Lys Tyr Phe His Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Asn Asp Ala Ala Ser Pro Arg Met Val Pro Arg
354045
Ala Pro Trp Met Glu Gln Glu Gly Ser Glu Tyr Trp Asp Arg Glu Thr
505560
Arg Ser Ala Arg Asp Thr Ala Gln Ile Phe Arg Val Asn Leu Arg Thr
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Trp Met His Gly Cys Glu Leu Gly Pro Asp Arg Arg Phe Leu Arg Gly
100 105 110
Tyr Glu Gln Phe Ala Tyr Asp Gly Lys Asp Tyr Leu Thr Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Val Asp Thr Ala Ala Gln Ile Ser Glu
130 135 140
Gln Lys Ser Asn Asp Ala Ser Glu Ala Glu His Gln Arg Ala Tyr Leu
145 150 155 160
Glu Asp Thr Cys Val Glu Trp Leu His Lys Tyr Leu Glu Lys Gly Lys
165 170 175
Glu Thr Leu Leu His Leu Glu Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Gln Asp Gly Glu Gly His
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Val Thr Leu
260 265 270
Arg Trp Lys
275
<210>549
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>549
Gly Ser His Ser Leu Lys Tyr Phe His Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Asn Asp Ala Ala Ser Pro Arg Met Val Pro Arg
354045
Ala Pro Trp Met Glu Gln Glu Gly Ser Glu Tyr Trp Asp Arg Glu Thr
505560
Arg Ser Ala Arg Asp Thr Ala Gln Ile Phe Arg Val Asn Leu Arg Thr
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Trp Met His Gly Cys Glu Leu Gly Pro Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Glu Gln Phe Ala Tyr Asp Gly Lys Asp Tyr Leu Thr Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Val Asp Thr Ala Ala Gln Ile Ser Glu
130 135 140
Gln Lys Ser Asn Asp Ala Ser Glu Ala Glu His Gln Arg Ala Tyr Leu
145 150 155 160
Glu Asp Thr Cys Val Glu Trp Leu His Lys Tyr Leu Glu Lys Gly Lys
165 170 175
Glu Thr Leu Leu His Leu Glu Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Gln Asp Gly Glu Gly His
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Val Thr Leu
260 265 270
Arg Trp Lys
275
<210>550
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>550
Gly Ser His Ser Met Arg Tyr Phe Ser Ala Ala Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Met Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ser Ala Cys Pro Arg Met Glu Pro Arg
354045
Ala Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Glu Glu Glu Thr
505560
Arg Asn Thr Lys Ala His Ala Gln Thr Asp Arg Met Asn Leu Gln Thr
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Ser Ser His Thr Leu Gln
859095
Trp Met Ile Gly Cys Asp Leu Gly Ser Asp Gly Arg Leu Leu Arg Gly
100 105 110
Tyr Glu Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Leu Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Ser Lys
130 135 140
Arg Lys Cys Glu Ala Ala Asn Val Ala Glu Gln Arg Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu His Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Met Leu Gln Arg Ala Asp Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Val Phe Asp Tyr Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Ile Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Val Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Leu Met Leu
260 265 270
Arg Trp Lys
275
<210>551
<211>275
<212>PRT
<213>智人(Homo sapiens)
<400>551
Gly Ser His Ser Met Arg Tyr Phe Ser Ala Ala Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Met Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ser Ala Cys Pro Arg Met Glu Pro Arg
354045
Ala Pro Trp Val Glu Gln Glu Gly Pro Glu Tyr Trp Glu Glu Glu Thr
505560
Arg Asn Thr Lys Ala His Ala Gln Thr Asp Arg Met Asn Leu Gln Thr
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Ser Ser His Thr Leu Gln
859095
Trp Met Ile Gly Cys Asp Leu Gly Ser Asp Gly Arg Leu Ile Arg Gly
100 105 110
Tyr Glu Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Leu Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Ala Ala Gln Ile Ser Lys
130 135 140
Arg Lys Cys Glu Ala Ala Asn Val Ala Glu Gln Arg Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu His Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Met Leu Gln Arg Ala Asp Pro Pro Lys Thr His Val Thr His His
180 185 190
Pro Val Phe Asp Tyr Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Ile Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Val Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro Leu Met Leu
260 265 270
Arg Trp Lys
275
<210>552
<211>1255
<212>PRT
<213>智人(Homo sapiens)
<400>552
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 1015
Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr Pro Gly
202530
Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro Ser Ser
354045
Thr Glu Lys Asn Ala Val Ser Met Thr Ser Ser Val Leu Ser Ser His
505560
Ser Pro Gly Ser Gly Ser Ser Thr Thr Gln Gly Gln Asp Val Thr Leu
65707580
Ala Pro Ala Thr Glu Pro Ala Ser Gly Ser Ala Ala Thr Trp Gly Gln
859095
Asp Val Thr Ser Val Pro Val Thr Arg Pro Ala Leu Gly Ser Thr Thr
100 105 110
Pro Pro Ala His Asp Val Thr Ser Ala Pro Asp Asn Lys Pro Ala Pro
115 120 125
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
130 135 140
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
145 150 155 160
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
165 170 175
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
180 185 190
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
195 200 205
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
210 215 220
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
225 230 235 240
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
245 250 255
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
260 265 270
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
275 280 285
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
290 295 300
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
305 310 315 320
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
325 330 335
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
340 345 350
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
355 360 365
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
370 375 380
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
385 390 395 400
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
405 410 415
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
420 425 430
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
435 440 445
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
450 455 460
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
465 470 475 480
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
485 490 495
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
500 505 510
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
515 520 525
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
530 535 540
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
545 550 555 560
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
565 570 575
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
580 585 590
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
595 600 605
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
610 615 620
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
625 630 635 640
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
645 650 655
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
660 665 670
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
675 680 685
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
690 695 700
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
705 710 715 720
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
725 730 735
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
740 745 750
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
755 760 765
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
770 775 780
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
785 790 795 800
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
805 810 815
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
820 825 830
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
835 840 845
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
850 855 860
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
865 870 875 880
Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His
885 890 895
Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala
900 905 910
Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro
915 920 925
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Asn
930 935 940
Arg Pro Ala Leu Gly Ser Thr Ala Pro Pro Val His Asn Val Thr Ser
945 950 955 960
Ala Ser Gly Ser Ala Ser Gly Ser Ala Ser Thr Leu Val His Asn Gly
965 970 975
Thr Ser Ala Arg Ala Thr Thr Thr Pro Ala Ser Lys Ser Thr Pro Phe
980 985 990
Ser Ile Pro Ser His His Ser AspThr Pro Thr Thr LeuAla Ser His
995 1000 1005
Ser ThrLys Thr Asp Ala SerSer Thr His His SerSer Val Pro
1010 1015 1020
Pro LeuThr Ser Ser Asn HisSer Thr Ser Pro GlnLeu Ser Thr
1025 1030 1035
Gly ValSer Phe Phe Phe LeuSer Phe His Ile SerAsn Leu Gln
1040 1045 1050
Phe AsnSer Ser Leu Glu AspPro Ser Thr Asp TyrTyr Gln Glu
1055 1060 1065
Leu GlnArg Asp Ile Ser GluMet Phe Leu Gln IleTyr Lys Gln
1070 1075 1080
Gly GlyPhe Leu Gly Leu SerAsn Ile Lys Phe ArgPro Gly Ser
1085 1090 1095
Val ValVal Gln Leu Thr LeuAla Phe Arg Glu GlyThr Ile Asn
1100 1105 1110
Val HisAsp Val Glu Thr GlnPhe Asn Gln Tyr LysThr Glu Ala
1115 1120 1125
Ala SerArg Tyr Asn Leu ThrIle Ser Asp Val SerVal Ser Asp
1130 1135 1140
Val ProPhe Pro Phe Ser AlaGln Ser Gly Ala GlyVal Pro Gly
1145 1150 1155
Trp GlyIle Ala Leu Leu ValLeu Val Cys Val LeuVal Ala Leu
1160 1165 1170
Ala IleVal Tyr Leu Ile AlaLeu Ala Val Cys GlnCys Arg Arg
1175 1180 1185
Lys AsnTyr Gly Gln Leu AspIle Phe Pro Ala ArgAsp Thr Tyr
1190 1195 1200
His ProMet Ser Glu Tyr ProThr Tyr His Thr HisGly Arg Tyr
1205 1210 1215
Val ProPro Ser Ser Thr AspArg Ser Pro Tyr GluLys Val Ser
1220 1225 1230
Ala GlyAsn Gly Gly Ser SerLeu Ser Tyr Thr AsnPro Ala Val
1235 1240 1245
Ala AlaThr Ser Ala Asn Leu
1250 1255
<210>553
<211>264
<212>PRT
<213>智人(Homo sapiens)
<400>553
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 1015
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
202530
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
354045
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Phe Asn
505560
Ser Ser Leu Glu Asp Pro Ser Thr Asp Tyr Tyr Gln Glu Leu Gln Arg
65707580
Asp Ile Ser Glu Met Phe Leu Gln Ile Tyr Lys Gln Gly Gly Phe Leu
859095
Gly Leu Ser Asn Ile Lys Phe Arg Pro Gly Ser Val Val Val Gln Leu
100 105 110
Thr Leu Ala Phe Arg Glu Gly Thr Ile Asn Val His Asp Val Glu Thr
115 120 125
Gln Phe Asn Gln Tyr Lys Thr Glu Ala Ala Ser Arg Tyr Asn Leu Thr
130 135 140
Ile Ser Asp Val Ser Val Ser Asp Val Pro Phe Pro Phe Ser Ala Gln
145 150 155 160
Ser Gly Ala Gly Val Pro Gly Trp Gly Ile Ala Leu Leu Val Leu Val
165 170 175
Cys Val Leu Val Ala Leu Ala Ile Val Tyr Leu Ile Ala Leu Ala Val
180 185 190
Cys Gln Cys Arg Arg Lys Asn Tyr Gly Gln Leu Asp Ile Phe Pro Ala
195 200 205
Arg Asp Thr Tyr His Pro Met Ser Glu Tyr Pro Thr Tyr His Thr His
210 215 220
Gly Arg Tyr Val Pro Pro Ser Ser Thr Asp Arg Ser Pro Tyr Glu Lys
225 230 235 240
Val Ser Ala Gly Asn Gly Gly Ser Ser Leu Ser Tyr Thr Asn Pro Ala
245 250 255
Val Ala Ala Thr Ser Ala Asn Leu
260
<210>554
<211>255
<212>PRT
<213>智人(Homo sapiens)
<400>554
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 1015
Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr Pro Gly
202530
Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro Ser Ser
354045
Thr Glu Lys Asn Ala Phe Asn Ser Ser Leu Glu Asp Pro Ser Thr Asp
505560
Tyr Tyr Gln Glu Leu Gln Arg Asp Ile Ser Glu Met Phe Leu Gln Ile
65707580
Tyr Lys Gln Gly Gly Phe Leu Gly Leu Ser Asn Ile Lys Phe Arg Pro
859095
Gly Ser Val Val Val Gln Leu Thr Leu Ala Phe Arg Glu Gly Thr Ile
100 105 110
Asn Val His Asp Val Glu Thr Gln Phe Asn Gln Tyr Lys Thr Glu Ala
115 120 125
Ala Ser Arg Tyr Asn Leu Thr Ile Ser Asp Val Ser Val Ser Asp Val
130 135 140
Pro Phe Pro Phe Ser Ala Gln Ser Gly Ala Gly Val Pro Gly Trp Gly
145 150 155 160
Ile Ala Leu Leu Val Leu Val Cys Val Leu Val Ala Leu Ala Ile Val
165 170 175
Tyr Leu Ile Ala Leu Ala Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly
180 185 190
Gln Leu Asp Ile Phe Pro Ala Arg Asp Thr Tyr His Pro Met Ser Glu
195 200 205
Tyr Pro Thr Tyr His Thr His Gly Arg Tyr Val Pro Pro Ser Ser Thr
210 215 220
Asp Arg Ser Pro Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly Ser Ser
225 230 235 240
Leu Ser Tyr Thr Asn Pro Ala Val Ala Ala Thr Ser Ala Asn Leu
245 250 255
<210>555
<211>203
<212>PRT
<213>智人(Homo sapiens)
<400>555
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 1015
Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr Pro Gly
202530
Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro Ser Ser
354045
Thr Glu Lys Asn Ala Ile Pro Ala Pro Thr Thr Thr Lys Ser Cys Arg
505560
Glu Thr Phe Leu Lys Cys Phe Cys Arg Phe Ile Asn Lys Gly Val Phe
65707580
Trp Ala Ser Pro Ile Leu Ser Ser Val Ser Asp Val Pro Phe Pro Phe
859095
Ser Ala Gln Ser Gly Ala Gly Val Pro Gly Trp Gly Ile Ala Leu Leu
100 105 110
Val Leu Val Cys Val Leu Val Ala Leu Ala Ile Val Tyr Leu Ile Ala
115 120 125
Leu Ala Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly Gln Leu Asp Ile
130 135 140
Phe Pro Ala Arg Asp Thr Tyr His Pro Met Ser Glu Tyr Pro Thr Tyr
145 150 155 160
His Thr His Gly Arg Tyr Val Pro Pro Ser Ser Thr Asp Arg Ser Pro
165 170 175
Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly Ser Ser Leu Ser Tyr Thr
180 185 190
Asn Pro Ala Val Ala Ala Thr Ser Ala Asn Leu
195 200
<210>556
<211>150
<212>PRT
<213>智人(Homo sapiens)
<400>556
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 1015
Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr Pro Gly
202530
Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro Ser Ser
354045
Thr Glu Lys Asn Ala Phe Asn Ser Ser Leu Glu Asp Pro Ser Thr Asp
505560
Tyr Tyr Gln Glu Leu Gln Arg Asp Ile Ser Glu Met Ala Val Cys Gln
65707580
Cys Arg Arg Lys Asn Tyr Gly Gln Leu Asp Ile Phe Pro Ala Arg Asp
859095
Thr Tyr His Pro Met Ser Glu Tyr Pro Thr Tyr His Thr His Gly Arg
100 105 110
Tyr Val Pro Pro Ser Ser Thr Asp Arg Ser Pro Tyr Glu Lys Val Ser
115 120 125
Ala Gly Asn Gly Gly Ser Ser Leu Ser Tyr Thr Asn Pro Ala Val Ala
130 135 140
Ala Thr Ser Ala Asn Leu
145 150
<210>557
<211>159
<212>PRT
<213>智人(Homo sapiens)
<400>557
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 1015
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
202530
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
354045
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Phe Asn
505560
Ser Ser Leu Glu Asp Pro Ser Thr Asp Tyr Tyr Gln Glu Leu Gln Arg
65707580
Asp Ile Ser Glu Met Ala Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly
859095
Gln Leu Asp Ile Phe Pro Ala Arg Asp Thr Tyr His Pro Met Ser Glu
100 105 110
Tyr Pro Thr Tyr His Thr His Gly Arg Tyr Val Pro Pro Ser Ser Thr
115 120 125
Asp Arg Ser Pro Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly Ser Ser
130 135 140
Leu Ser Tyr Thr Asn Pro Ala Val Ala Ala Thr Ser Ala Asn Leu
145 150 155
<210>558
<211>158
<212>PRT
<213>智人(Homo sapiens)
<400>558
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 1015
Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr Pro Gly
202530
Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro Ser Ser
354045
Thr Glu Lys Asn Ala Ile Pro Ala Pro Thr Thr Thr Lys Ser Cys Arg
505560
Glu Thr Phe Leu Lys Cys Phe Cys Arg Phe Ile Asn Lys Gly Val Phe
65707580
Trp Ala Ser Pro Ile Leu Ser Ser Val Trp Gly Trp Gly Ala Arg Leu
859095
Gly His Arg Ala Ala Gly Ala Gly Leu Cys Ser Gly Cys Ala Gly His
100 105 110
Cys Leu Ser His Cys Leu Gly Cys Leu Ser Val Pro Pro Lys Glu Leu
115 120 125
Arg Ala Ala Gly His Leu Ser Ser Pro Gly Tyr Leu Pro Ser Tyr Glu
130 135 140
Arg Val Pro His Leu Pro His Pro Trp Ala Leu Cys Ala Pro
145 150 155
<210>559
<211>475
<212>PRT
<213>智人(Homo sapiens)
<400>559
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 1015
Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr Pro Gly
202530
Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro Ser Ser
354045
Thr Glu Lys Asn Ala Val Ser Met Thr Ser Ser Val Leu Ser Ser His
505560
Ser Pro Gly Ser Gly Ser Ser Thr Thr Gln Gly Gln Asp Val Thr Leu
65707580
Ala Pro Ala Thr Glu Pro Ala Ser Gly Ser Ala Ala Thr Trp Gly Gln
859095
Asp Val Thr Ser Val Pro Val Thr Arg Pro Ala Leu Gly Ser Thr Thr
100 105 110
Pro Pro Ala His Asp Val Thr Ser Ala Pro Asp Asn Lys Pro Ala Pro
115 120 125
Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr
130 135 140
Arg Pro Ala Pro Gly Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser
145 150 155 160
Ala Pro Asp Asn Arg Pro Ala Leu Gly Ser Thr Ala Pro Pro Val His
165 170 175
Asn Val Thr Ser Ala Ser Gly Ser Ala Ser Gly Ser Ala Ser Thr Leu
180 185 190
Val His Asn Gly Thr Ser Ala Arg Ala Thr Thr Thr Pro Ala Ser Lys
195 200 205
Ser Thr Pro Phe Ser Ile Pro Ser His His Ser Asp Thr Pro Thr Thr
210 215 220
Leu Ala Ser His Ser Thr Lys Thr Asp Ala Ser Ser Thr His His Ser
225 230 235 240
Thr Val Pro Pro Leu Thr Ser Ser Asn His Ser Thr Ser Pro Gln Leu
245 250 255
Ser Thr Gly Val Ser Phe Phe Phe Leu Ser Phe His Ile Ser Asn Leu
260 265 270
Gln Phe Asn Ser Ser Leu Glu Asp Pro Ser Thr Asp Tyr Tyr Gln Glu
275 280 285
Leu Gln Arg Asp Ile Ser Glu Met Phe Leu Gln Ile Tyr Lys Gln Gly
290 295 300
Gly Phe Leu Gly Leu Ser Asn Ile Lys Phe Arg Pro Gly Ser Val Val
305 310 315 320
Val Gln Leu Thr Leu Ala Phe Arg Glu Gly Thr Ile Asn Val His Asp
325 330 335
Val Glu Thr Gln Phe Asn Gln Tyr Lys Thr Glu Ala Ala Ser Arg Tyr
340 345 350
Asn Leu Thr Ile Ser Asp Val Ser Val Ser Asp Val Pro Phe Pro Phe
355 360 365
Ser Ala Gln Ser Gly Ala Gly Val Pro Gly Trp Gly Ile Ala Leu Leu
370 375 380
Val Leu Val Cys Val Leu Val Ala Leu Ala Ile Val Tyr Leu Ile Ala
385 390 395 400
Leu Ala Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly Gln Leu Asp Ile
405 410 415
Phe Pro Ala Arg Asp Thr Tyr His Pro Met Ser Glu Tyr Pro Thr Tyr
420 425 430
His Thr His Gly Arg Tyr Val Pro Pro Ser Ser Thr Asp Arg Ser Pro
435 440 445
Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly Ser Ser Leu Ser Tyr Thr
450 455 460
Asn Pro Ala Val Ala Ala Thr Ser Ala Asn Leu
465 470 475
<210>560
<211>282
<212>PRT
<213>智人(Homo sapiens)
<400>560
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 1015
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
202530
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
354045
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Leu Ser
505560
Thr Gly Val Ser Phe Phe Phe Leu Ser Phe His Ile Ser Asn Leu Gln
65707580
Phe Asn Ser Ser Leu Glu Asp Pro Ser Thr Asp Tyr Tyr Gln Glu Leu
859095
Gln Arg Asp Ile Ser Glu Met Phe Leu Gln Ile Tyr Lys Gln Gly Gly
100 105 110
Phe Leu Gly Leu Ser Asn Ile Lys Phe Arg Pro Gly Ser Val Val Val
115 120 125
Gln Leu Thr Leu Ala Phe Arg Glu Gly Thr Ile Asn Val His Asp Val
130 135 140
Glu Thr Gln Phe Asn Gln Tyr Lys Thr Glu Ala Ala Ser Arg Tyr Asn
145 150 155 160
Leu Thr Ile Ser Asp Val Ser Val Ser Asp Val Pro Phe Pro Phe Ser
165 170 175
Ala Gln Ser Gly Ala Gly Val Pro Gly Trp Gly Ile Ala Leu Leu Val
180 185 190
Leu Val Cys Val Leu Val Ala Leu Ala Ile Val Tyr Leu Ile Ala Leu
195 200 205
Ala Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly Gln Leu Asp Ile Phe
210 215 220
Pro Ala Arg Asp Thr Tyr His Pro Met Ser Glu Tyr Pro Thr Tyr His
225 230 235 240
Thr His Gly Arg Tyr Val Pro Pro Ser Ser Thr Asp Arg Ser Pro Tyr
245 250 255
Glu Lys Val Ser Ala Gly Asn Gly Gly Ser Ser Leu Ser Tyr Thr Asn
260 265 270
Pro Ala Val Ala Ala Thr Ser Ala Asn Leu
275 280
<210>561
<211>219
<212>PRT
<213>智人(Homo sapiens)
<400>561
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 1015
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
202530
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
354045
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Phe Asn
505560
Ser Ser Leu Glu Asp Pro Ser Thr Asp Tyr Tyr Gln Glu Leu Gln Arg
65707580
Asp Ile Ser Glu Met Phe Leu Gln Ile Tyr Lys Gln Gly Gly Phe Leu
859095
Gly Leu Ser Asn Ile Lys Phe Arg Pro Gly Ser Val Val Val Gln Leu
100 105 110
Thr Leu Ala Phe Arg Glu Gly Thr Ile Asn Val His Asp Val Glu Thr
115 120 125
Gln Phe Asn Gln Tyr Lys Thr Glu Ala Ala Ser Arg Tyr Asn Leu Thr
130 135 140
Ile Ser Asp Val Ser Val Trp Gly Trp Gly Ala Arg Leu Gly His Arg
145 150 155 160
Ala Ala Gly Ala Gly Leu Cys Ser Gly Cys Ala Gly His Cys Leu Ser
165 170 175
His Cys Leu Gly Cys Leu Ser Val Pro Pro Lys Glu Leu Arg Ala Ala
180 185 190
Gly His Leu Ser Ser Pro Gly Tyr Leu Pro Ser Tyr Glu Arg Val Pro
195 200 205
His Leu Pro His Pro Trp Ala Leu Cys Ala Pro
210 215
<210>562
<211>238
<212>PRT
<213>智人(Homo sapiens)
<400>562
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 1015
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
202530
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
354045
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Ile Tyr
505560
Lys Gln Gly Gly Phe Leu Gly Leu Ser Asn Ile Lys Phe Arg Pro Gly
65707580
Ser Val Val Val Gln Leu Thr Leu Ala Phe Arg Glu Gly Thr Ile Asn
859095
Val His Asp Val Glu Thr Gln Phe Asn Gln Tyr Lys Thr Glu Ala Ala
100 105 110
Ser Arg Tyr Asn Leu Thr Ile Ser Asp Val Ser Val Ser Asp Val Pro
115 120 125
Phe Pro Phe Ser Ala Gln Ser Gly Ala Gly Val Pro Gly Trp Gly Ile
130 135 140
Ala Leu Leu Val Leu Val Cys Val Leu Val Ala Leu Ala Ile Val Tyr
145 150 155 160
Leu Ile Ala Leu Ala Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly Gln
165 170 175
Leu Asp Ile Phe Pro Ala Arg Asp Thr Tyr His Pro Met Ser Glu Tyr
180 185 190
Pro Thr Tyr His Thr His Gly Arg Tyr Val Pro Pro Ser Ser Thr Asp
195 200 205
Arg Ser Pro Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly Ser Ser Leu
210 215 220
Ser Tyr Thr Asn Pro Ala Val Ala Ala Thr Ser Ala Asn Leu
225 230 235
<210>563
<211>217
<212>PRT
<213>智人(Homo sapiens)
<400>563
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 1015
Val Leu Thr Gly Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser
202530
Val Pro Ser Ser Thr Glu Lys Asn Ala Ile Tyr Lys Gln Gly Gly Phe
354045
Leu Gly Leu Ser Asn Ile Lys Phe Arg Pro Gly Ser Val Val Val Gln
505560
Leu Thr Leu Ala Phe Arg Glu Gly Thr Ile Asn Val His Asp Val Glu
65707580
Thr Gln Phe Asn Gln Tyr Lys Thr Glu Ala Ala Ser Arg Tyr Asn Leu
859095
Thr Ile Ser Asp Val Ser Val Ser Asp Val Pro Phe Pro Phe Ser Ala
100 105 110
Gln Ser Gly Ala Gly Val Pro Gly Trp Gly Ile Ala Leu Leu Val Leu
115 120 125
Val Cys Val Leu Val Ala Leu Ala Ile Val Tyr Leu Ile Ala Leu Ala
130 135 140
Val Cys Gln Cys Arg Arg Lys Asn Tyr Gly Gln Leu Asp Ile Phe Pro
145 150 155 160
Ala Arg Asp Thr Tyr His Pro Met Ser Glu Tyr Pro Thr Tyr His Thr
165 170 175
His Gly Arg Tyr Val Pro Pro Ser Ser Thr Asp Arg Ser Pro Tyr Glu
180 185 190
Lys Val Ser Ala Gly Asn Gly Gly Ser Ser Leu Ser Tyr Thr Asn Pro
195 200 205
Ala Val Ala Ala Thr Ser Ala Asn Leu
210 215
<210>564
<211>241
<212>PRT
<213>智人(Homo sapiens)
<400>564
Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr
1 5 1015
Val Leu Thr Ala Thr Thr Ala Pro Lys Pro Ala Thr Val Val Thr Gly
202530
Ser Gly His Ala Ser Ser Thr Pro Gly Gly Glu Lys Glu Thr Ser Ala
354045
Thr Gln Arg Ser Ser Val Pro Ser Ser Thr Glu Lys Asn Ala Phe Leu
505560
Gln Ile Tyr Lys Gln Gly Gly Phe Leu Gly Leu Ser Asn Ile Lys Phe
65707580
Arg Pro Gly Ser Val Val Val Gln Leu Thr Leu Ala Phe Arg Glu Gly
859095
Thr Ile Asn Val His Asp Val Glu Thr Gln Phe Asn Gln Tyr Lys Thr
100 105 110
Glu Ala Ala Ser Arg Tyr Asn Leu Thr Ile Ser Asp Val Ser Val Ser
115 120 125
Asp Val Pro Phe Pro Phe Ser Ala Gln Ser Gly Ala Gly Val Pro Gly
130 135 140
Trp Gly Ile Ala Leu Leu Val Leu Val Cys Val Leu Val Ala Leu Ala
145 150 155 160
Ile Val Tyr Leu Ile Ala Leu Ala Val Cys Gln Cys Arg Arg Lys Asn
165 170 175
Tyr Gly Gln Leu Asp Ile Phe Pro Ala Arg Asp Thr Tyr His Pro Met
180 185 190
Ser Glu Tyr Pro Thr Tyr His Thr His Gly Arg Tyr Val Pro Pro Ser
195 200 205
Ser Thr Asp Arg Ser Pro Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly
210 215 220
Ser Ser Leu Ser Tyr Thr Asn Pro Ala Val Ala Ala Thr Ser Ala Asn
225 230 235 240
Leu
<210>565
<211>142
<212>PRT
<213>智人(Homo sapiens)
<400>565
Met Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys Asp
1 5 1015
His Arg Ile Ser Thr Phe Lys Asn Trp Pro Phe Leu Glu Gly Cys Ala
202530
Cys Thr Pro Glu Arg Met Ala Glu Ala Gly Phe Ile His Cys Pro Thr
354045
Glu Asn Glu Pro Asp Leu Ala Gln Cys Phe Phe Cys Phe Lys Glu Leu
505560
Glu Gly Trp Glu Pro Asp Asp Asp Pro Ile Glu Glu His Lys Lys His
65707580
Ser Ser Gly Cys Ala Phe Leu Ser Val Lys Lys Gln Phe Glu Glu Leu
859095
Thr Leu Gly Glu Phe Leu Lys Leu Asp Arg Glu Arg Ala Lys Asn Lys
100 105 110
Ile Ala Lys Glu Thr Asn Asn Lys Lys Lys Glu Phe Glu Glu Thr Ala
115 120 125
Glu Lys Val Arg Arg Ala Ile Glu Gln Leu Ala Ala Met Asp
130 135 140
<210>566
<211>137
<212>PRT
<213>智人(Homo sapiens)
<400>566
Met Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys Asp
1 5 1015
His Arg Ile Ser Thr Phe Lys Asn Trp Pro Phe Leu Glu Gly Cys Ala
202530
Cys Thr Pro Glu Arg Met Ala Glu Ala Gly Phe Ile His Cys Pro Thr
354045
Glu Asn Glu Pro Asp Leu Ala Gln Cys Phe Phe Cys Phe Lys Glu Leu
505560
Glu Gly Trp Glu Pro Asp Asp Asp Pro Met Gln Arg Lys Pro Thr Ile
65707580
Arg Arg Lys Asn Leu Arg Lys Leu Arg Arg Lys Cys Ala Val Pro Ser
859095
Ser Ser Trp Leu Pro Trp Ile Glu Ala Ser Gly Arg Ser Cys Leu Val
100 105 110
Pro Glu Trp Leu His His Phe Gln Gly Leu Phe Pro Gly Ala Thr Ser
115 120 125
Leu Pro Val Gly Pro Leu Ala Met Ser
130 135
<210>567
<211>165
<212>PRT
<213>智人(Homo sapiens)
<400>567
Met Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys Asp
1 5 1015
His Arg Ile Ser Thr Phe Lys Asn Trp Pro Phe Leu Glu Gly Cys Ala
202530
Cys Thr Pro Glu Arg Met Ala Glu Ala Gly Phe Ile His Cys Pro Thr
354045
Glu Asn Glu Pro Asp Leu Ala Gln Cys Phe Phe Cys Phe Lys Glu Leu
505560
Glu Gly Trp Glu Pro Asp Asp Asp Pro Ile Gly Pro Gly Thr Val Ala
65707580
Tyr Ala Cys Asn Thr Ser Thr Leu Gly Gly Arg Gly Gly Arg Ile Thr
859095
Arg Glu Glu His Lys Lys His Ser Ser Gly Cys Ala Phe Leu Ser Val
100 105 110
Lys Lys Gln Phe Glu Glu Leu Thr Leu Gly Glu Phe Leu Lys Leu Asp
115 120 125
Arg Glu Arg Ala Lys Asn Lys Ile Ala Lys Glu Thr Asn Asn Lys Lys
130 135 140
Lys Glu Phe Glu Glu Thr Ala Glu Lys Val Arg Arg Ala Ile Glu Gln
145 150 155 160
Leu Ala Ala Met Asp
165
<210>568
<211>561
<212>PRT
<213>智人(Homo sapiens)
<400>568
Met Glu Ser Arg Gly Arg Arg Cys Pro Glu Met Ile Ser Val Leu Gly
1 5 1015
Pro Ile Ser Gly His Val Leu Lys Ala Val Phe Ser Arg Gly Asp Thr
202530
Pro Val Leu Pro His Glu Thr Arg Leu Leu Gln Thr Gly Ile His Val
354045
Arg Val Ser Gln Pro Ser Leu Ile Leu Val Ser Gln Tyr Thr Pro Asp
505560
Ser Thr Pro Cys His Arg Gly Asp Asn Gln Leu Gln Val Gln His Thr
65707580
Tyr Phe Thr Gly Ser Glu Val Glu Asn Val Ser Val Asn Val His Asn
859095
Pro Thr Gly Arg Ser Ile Cys Pro Ser Gln Glu Pro Met Ser Ile Tyr
100 105 110
Val Tyr Ala Leu Pro Leu Lys Met Leu Asn Ile Pro Ser Ile Asn Val
115 120 125
His His Tyr Pro Ser Ala Ala Glu Arg Lys His Arg His Leu Pro Val
130 135 140
Ala Asp Ala Val Ile His Ala Ser Gly Lys Gln Met Trp Gln Ala Arg
145 150 155 160
Leu Thr Val Ser Gly Leu Ala Trp Thr Arg Gln Gln Asn Gln Trp Lys
165 170 175
Glu Pro Asp Val Tyr Tyr Thr Ser Ala Phe Val Phe Pro Thr Lys Asp
180 185 190
Val Ala Leu Arg His Val Val Cys Ala His Glu Leu Val Cys Ser Met
195 200 205
Glu Asn Thr Arg Ala Thr Lys Met Gln Val Ile Gly Asp Gln Tyr Val
210 215 220
Lys Val Tyr Leu Glu Ser Phe Cys Glu Asp Val Pro Ser Gly Lys Leu
225 230 235 240
Phe Met His Val Thr Leu Gly Ser Asp Val Glu Glu Asp Leu Thr Met
245 250 255
Thr Arg Asn Pro Gln Pro Phe Met Arg Pro His Glu Arg Asn Gly Phe
260 265 270
Thr Val Leu Cys Pro Lys Asn Met Ile Ile Lys Pro Gly Lys Ile Ser
275 280 285
His Ile Met Leu Asp Val Ala Phe Thr Ser His Glu His Phe Gly Leu
290 295 300
Leu Cys Pro Lys Ser Ile Pro Gly Leu Ser Ile Ser Gly Asn Leu Leu
305 310 315 320
Met Asn Gly Gln Gln Ile Phe Leu Glu Val Gln Ala Ile Arg Glu Thr
325 330 335
Val Glu Leu Arg Gln Tyr Asp Pro Val Ala Ala Leu Phe Phe Phe Asp
340 345 350
Ile Asp Leu Leu Leu Gln Arg Gly Pro Gln Tyr Ser Glu His Pro Thr
355 360 365
Phe Thr Ser Gln Tyr Arg Ile Gln Gly Lys Leu Glu Tyr Arg His Thr
370 375 380
Trp Asp Arg His Asp Glu Gly Ala Ala Gln Gly Asp Asp Asp Val Trp
385 390 395 400
Thr Ser Gly Ser Asp Ser Asp Glu Glu Leu Val Thr Thr Glu Arg Lys
405 410 415
Thr Pro Arg Val Thr Gly Gly Gly Ala Met Ala Gly Ala Ser Thr Ser
420 425 430
Ala Gly Arg Lys Arg Lys Ser Ala Ser Ser Ala Thr Ala Cys Thr Ser
435 440 445
Gly Val Met Thr Arg Gly Arg Leu Lys Ala Glu Ser Thr Val Ala Pro
450 455 460
Glu Glu Asp Thr Asp Glu Asp Ser Asp Asn Glu Ile His Asn Pro Ala
465 470 475 480
Val Phe Thr Trp Pro Pro Trp Gln Ala Gly Ile Leu Ala Arg Asn Leu
485 490 495
Val Pro Met Val Ala Thr Val Gln Gly Gln Asn Leu Lys Tyr Gln Glu
500 505 510
Phe Phe Trp Asp Ala Asn Asp Ile Tyr Arg Ile Phe Ala Glu Leu Glu
515 520 525
Gly Val Trp Gln Pro Ala Ala Gln Pro Lys Arg Arg Arg His Arg Gln
530 535 540
Asp Ala Leu Pro Gly Pro Cys Ile Ala Ser Thr Pro Lys Lys His Arg
545 550 555 560
Gly
<210>569
<211>906
<212>PRT
<213>智人(Homo sapiens)
<400>569
Met Glu Ser Arg Ile Trp Cys Leu Val Val Cys Val Asn Leu Cys Ile
1 5 1015
Val Cys Leu Gly Ala Ala Val Ser Ser Ser Ser Thr Ser His Ala Thr
202530
Ser Ser Thr His Asn Gly Ser His Thr Ser Arg Thr Thr Ser Ala Gln
354045
Thr Arg Ser Val Tyr Ser Gln His Val Thr Ser Ser Glu Ala Val Ser
505560
His Arg Ala Asn Glu Thr Ile Tyr Asn Thr Thr Leu Lys Tyr Gly Asp
65707580
Val Val Gly Val Asn Thr Thr Lys Tyr Pro Tyr Arg Val Cys Ser Met
859095
Ala Gln Gly Thr Asp Leu Ile Arg Phe Glu Arg Asn Ile Ile Cys Thr
100 105 110
Ser Met Lys Pro Ile Asn Glu Asp Leu Asp Glu Gly Ile Met Val Val
115 120 125
Tyr Lys Arg Asn Ile Val Ala His Thr Phe Lys Val Arg Val Tyr Gln
130 135 140
Lys Val Leu Thr Phe Arg Arg Ser Tyr Ala Tyr Ile Tyr Thr Thr Tyr
145 150 155 160
Leu Leu Gly Ser Asn Thr Glu Tyr Val Ala Pro Pro Met Trp Glu Ile
165 170 175
His His Ile Asn Lys Phe Ala Gln Cys Tyr Ser Ser Tyr Ser Arg Val
180 185 190
Ile Gly Gly Thr Val Phe Val Ala Tyr His Arg Asp Ser Tyr Glu Asn
195 200 205
Lys Thr Met Gln Leu Ile Pro Asp Asp Tyr Ser Asn Thr His Ser Thr
210 215 220
Arg Tyr Val Thr Val Lys Asp Gln Trp His Ser Arg Gly Ser Thr Trp
225 230 235 240
Leu Tyr Arg Glu Thr Cys Asn Leu Asn Cys Met Leu Thr Ile Thr Thr
245 250 255
Ala Arg Ser Lys Tyr Pro Tyr His Phe Phe Ala Thr Ser Thr Gly Asp
260 265 270
Val Val Tyr Ile Ser Pro Phe Tyr Asn Gly Thr Asn Arg Asn Ala Ser
275 280 285
Tyr Phe Gly Glu Asn Ala Asp Lys Phe Phe Ile Phe Pro Asn Tyr Thr
290 295 300
Ile Val Ser Asp Phe Gly Arg Pro Asn Ala Ala Pro Glu Thr His Arg
305 310 315 320
Leu Val Ala Phe Leu Glu Arg Ala Asp Ser Val Ile Ser Trp Asp Ile
325 330 335
Gln Asp Glu Lys Asn Val Thr Cys Gln Leu Thr Phe Trp Glu Ala Ser
340 345 350
Glu Arg Thr Ile Arg Ser Glu Ala Glu Asp Ser Tyr His Phe Ser Ser
355 360 365
Ala Lys Met Thr Ala Thr Phe Leu Ser Lys Lys Gln Glu Val Asn Met
370 375 380
Ser Asp Ser Ala Leu Asp Cys Val Arg Asp Glu Ala Ile Asn Lys Leu
385 390 395 400
Gln Gln Ile Phe Asn Thr Ser Tyr Asn Gln Thr Tyr Glu Lys Tyr Gly
405 410 415
Asn Val Ser Val Phe Glu Thr Ser Gly Gly Leu Val Val Phe Trp Gln
420 425 430
Gly Ile Lys Gln Lys Ser Leu Val Glu Leu Glu Arg Leu Ala Asn Arg
435 440 445
Ser Ser Leu Asn Ile Thr His Arg Thr Arg Arg Ser Thr Ser Asp Asn
450 455 460
Asn Thr Thr His Leu Ser Ser Met Glu Ser Val His Asn Leu Val Tyr
465 470 475 480
Ala Gln Leu Gln Phe Thr Tyr Asp Thr Leu Arg Gly Tyr Ile Asn Arg
485 490 495
Ala Leu Ala Gln Ile Ala Glu Ala Trp Cys Val Asp Gln Arg Arg Thr
500 505 510
Leu Glu Val Phe Lys Glu Leu Ser Lys Ile Asn Pro Ser Ala Ile Leu
515 520 525
Ser Ala Ile Tyr Asn Lys Pro Ile Ala Ala Arg Phe Met Gly Asp Val
530 535 540
Leu Gly Leu Ala Ser Cys Val Thr Ile Asn Gln Thr Ser Val Lys Val
545 550 555 560
Leu Arg Asp Met Asn Val Lys Glu Ser Pro Gly Arg Cys Tyr Ser Arg
565 570 575
Pro Val Val Ile Phe Asn Phe Ala Asn Ser Ser Tyr Val Gln Tyr Gly
580 585 590
Gln Leu Gly Glu Asp Asn Glu Ile Leu Leu Gly Asn His Arg Thr Glu
595 600 605
Glu Cys Gln Leu Pro Ser Leu Lys Ile Phe Ile Ala Gly Asn Ser Ala
610 615 620
Tyr Glu Tyr Val Asp Tyr Leu Phe Lys Arg Met Ile Asp Leu Ser Ser
625 630 635 640
Ile Ser Thr Val Asp Ser Met Ile Ala Leu Asp Ile Asp Pro Leu Glu
645 650 655
Asn Thr Asp Phe Arg Val Leu Glu Leu Tyr Ser Gln Lys Glu Leu Arg
660 665 670
Ser Ser Asn Val Phe Asp Leu Glu Glu Ile Met Arg Glu Phe Asn Ser
675 680 685
Tyr Lys Gln Arg Val Lys Tyr Val Glu Asp Lys Val Val Asp Pro Leu
690 695 700
Pro Pro Tyr Leu Lys Gly Leu Asp Asp Leu Met Ser Gly Leu Gly Ala
705 710 715 720
Ala Gly Lys Ala Val Gly Val Ala Ile Gly Ala Val Gly Gly Ala Val
725 730 735
Ala Ser Val Val Glu Gly Val Ala Thr Phe Leu Lys Asn Pro Phe Gly
740 745 750
Ala Phe Thr Ile Ile Leu Val Ala Ile Ala Val Val Ile Ile Thr Tyr
755 760 765
Leu Ile Tyr Thr Arg Gln Arg Arg Leu Cys Thr Gln Pro Leu Gln Asn
770 775 780
Leu Phe Pro Tyr Leu Val Ser Ala Asp Gly Thr Thr Val Thr Ser Gly
785 790 795 800
Ser Thr Lys Asp Thr Ser Leu Gln Ala Pro Pro Ser Tyr Glu Glu Ser
805 810 815
Val Tyr Asn Ser Gly Arg Lys Gly Pro Gly Pro Pro Ser Ser Asp Ala
820 825 830
Ser Thr Ala Ala Pro Pro Tyr Thr Asn Glu Gln Ala Tyr Gln Met Leu
835 840 845
Leu Ala Leu Ala Arg Leu Asp Ala Glu Gln Arg Ala Gln Gln Asn Gly
850 855 860
Thr Asp Ser Leu Asp Gly Gln Thr Gly Thr Gln Asp Lys Gly Gln Lys
865 870 875 880
Pro Asn Leu Leu Asp Arg Leu Arg His Arg Lys Asn Gly Tyr Arg His
885 890 895
Leu Lys Asp Ser Asp Glu Glu Glu Asn Val
900 905
<210>570
<211>4
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>570
Ala Pro Ala Pro
1
<210>571
<211>10
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>571
Gly Gly Gly Gly Pro Gly Gly Gly Gly Pro
1 5 10
<210>572
<211>50
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(50)
<223>在位置1至50的Gly Gly Gly Gly Ser的各拷贝存在或不存在,使得Gly GlyGl Gly Ser的拷贝数在1至10范围内。
<400>572
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 1015
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
202530
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
354045
Gly Ser
50
<210>573
<211>100
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(100)
<223>在位置1至100的Glu Ala Ala Ala Lys的各拷贝存在或不存在,使得Glu AlaAla Ala Lys的拷贝数在1至20范围内。
<400>573
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu
1 5 1015
Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala
202530
Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala
354045
Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala
505560
Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
65707580
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu
859095
Ala Ala Ala Lys
100
<210>574
<211>101
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(2)..(101)
<223>在位置2至101的Glu Ala Ala Ala Lys的各拷贝存在或不存在,使得Glu AlaAla Ala Lys的拷贝数在1至20范围内。
<400>574
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 1015
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu
202530
Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala
354045
Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala
505560
Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala
65707580
Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
859095
Glu Ala Ala Ala Lys
100
<210>575
<211>102
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(2)..(101)
<223>在位置2至101的Glu Ala Ala Ala Lys的各拷贝存在或不存在,使得Glu AlaAla Ala Lys的拷贝数在1至20范围内。
<400>575
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 1015
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu
202530
Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala
354045
Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala
505560
Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala
65707580
Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
859095
Glu Ala Ala Ala Lys Ala
100
<210>576
<211>206
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(2)..(101)
<223>在位置2至101的Glu Ala Ala Ala Lys的各拷贝存在或不存在,使得Glu AlaAla Ala Lys的拷贝数在1至20范围内。
<220>
<221>变体
<222>(106)..(205)
<223>在位置106至205的Glu Ala Ala Ala Lys的各拷贝存在或不存在,使得GluAla Ala Ala Lys的拷贝数在1至20范围内。
<400>576
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 1015
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu
202530
Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala
354045
Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala
505560
Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala
65707580
Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
859095
Glu Ala Ala Ala Lys Ala Leu Glu Ala Glu Ala Ala Ala Lys Glu Ala
100 105 110
Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala
115 120 125
Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala
130 135 140
Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
145 150 155 160
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu
165 170 175
Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala
180 185 190
Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala
195 200 205
<210>577
<211>40
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(40)
<223>在位置1至40的Lys Pro的各拷贝存在或不存在,使得Lys Pro的拷贝数在1至20范围内。
<400>577
Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro
1 5 1015
Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro
202530
Lys Pro Lys Pro Lys Pro Lys Pro
3540
<210>578
<211>40
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(40)
<223>在位置1至40的Glu Pro的各拷贝存在或不存在,使得Glu Pro的拷贝数在1至20范围内。
<400>578
Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro
1 5 1015
Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro
202530
Glu Pro Glu Pro Glu Pro Glu Pro
3540
<210>579
<211>60
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(60)
<223>在位置1至60的Thr Pro Arg的各拷贝存在或不存在,使得Thr Pro Arg的拷贝数在1至20范围内。
<400>579
Thr Pro Arg Thr Pro Arg Thr Pro Arg Thr Pro Arg Thr Pro Arg Thr
1 5 1015
Pro Arg Thr Pro Arg Thr Pro Arg Thr Pro Arg Thr Pro Arg Thr Pro
202530
Arg Thr Pro Arg Thr Pro Arg Thr Pro Arg Thr Pro Arg Thr Pro Arg
354045
Thr Pro Arg Thr Pro Arg Thr Pro Arg Thr Pro Arg
505560
<210>580
<211>40
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(40)
<223>在位置1至40的Ala Pro的各拷贝存在或不存在,使得Ala Pro的拷贝数在1至20范围内。
<400>580
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 1015
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
202530
Ala Pro Ala Pro Ala Pro Ala Pro
3540
<210>581
<400>581
000
<210>582
<211>51
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(2)..(51)
<223>在位置2至51的Glu Ala Ala Ala Lys的各拷贝存在或不存在,使得Glu AlaAla Ala Lys的拷贝数在1至10范围内。
<400>582
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 1015
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu
202530
Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala
354045
Ala Ala Lys
50
<210>583
<211>52
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(2)..(51)
<223>在位置2至51的Glu Ala Ala Ala Lys的各拷贝存在或不存在,使得Glu AlaAla Ala Lys的拷贝数在1至10范围内。
<400>583
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 1015
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu
202530
Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala
354045
Ala Ala Lys Ala
50
<210>584
<211>20
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(20)
<223>在位置1至20的Ala Pro的各拷贝存在或不存在,使得Ala Pro的拷贝数在1至10范围内。
<400>584
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 1015
Ala Pro Ala Pro
20
<210>585
<211>20
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(20)
<223>在位置1至20的Glu Pro的各拷贝存在或不存在,使得Glu Pro的拷贝数在1至10范围内。
<400>585
Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro
1 5 1015
Glu Pro Glu Pro
20
<210>586
<211>20
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(20)
<223>在位置1至20的Lys Pro的各拷贝存在或不存在,使得Lys Pro的拷贝数在1至10范围内。
<400>586
Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro
1 5 1015
Lys Pro Lys Pro
20
<210>587
<211>20
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(6)..(20)
<223>在位置6至20的Gly Gly Gly Gly Ser的各拷贝存在或不存在,使得Gly GlyGly Gly Ser的拷贝数在1至3范围内。
<400>587
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 1015
Gly Gly Gly Ser
20
<210>588
<211>25
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(6)..(25)
<223>在位置6至25的Gly Gly Gly Gly Ser的各拷贝存在或不存在,使得Gly GlyGly Gly Ser的拷贝数在2至4范围内。
<400>588
Cys Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 1015
Gly Gly Gly Ser Gly Gly Gly Gly Ser
2025
<210>589
<211>25
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(6)..(25)
<223>在位置6至25的Gly Gly Gly Gly Ser的各拷贝存在或不存在,使得Gly GlyGly Gly Ser的拷贝数在2至4范围内。
<400>589
Gly Cys Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 1015
Gly Gly Gly Ser Gly Gly Gly Gly Ser
2025
<210>590
<211>25
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(20)
<223>在位置1至20的Gly Gly Gly Gly Ser的各拷贝存在或不存在,使得Gly GlyGly Gly Ser的拷贝数在2至4范围内。
<400>590
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 1015
Gly Gly Gly Ser Gly Cys Gly Gly Ser
2025
<210>591
<211>35
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(35)
<223>在位置1至35的Gly Gly Gly Gly Ser的各拷贝存在或不存在,使得Gly GlyGly Gly Ser的拷贝数为2、3、4或7。
<400>591
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 1015
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
202530
Gly Gly Ser
35
<210>592
<211>20
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(20)
<223>在位置1至20的Ala Pro的各拷贝存在或不存在,使得Ala Pro的拷贝数在2至10范围内。
<400>592
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 1015
Ala Pro Ala Pro
20
<210>593
<211>20
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(20)
<223>在位置1至20的Glu Pro的各拷贝存在或不存在,使得Glu Pro的拷贝数在2至10范围内。
<400>593
Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro
1 5 1015
Glu Pro Glu Pro
20
<210>594
<211>20
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(20)
<223>在位置1至20的Lys Pro的各拷贝存在或不存在,使得Lys Pro的拷贝数在2至10范围内。
<400>594
Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro
1 5 1015
Lys Pro Lys Pro
20
<210>595
<211>12
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(12)
<223>在位置1至12的Ala Pro的各拷贝存在或不存在,使得Ala Pro的拷贝数在2至6范围内。
<400>595
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 10
<210>596
<211>12
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(12)
<223>在位置1至12的Glu Pro的各拷贝存在或不存在,使得Glu Pro的拷贝数在2至6范围内。
<400>596
Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro
1 5 10
<210>597
<211>12
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(1)..(12)
<223>在位置1至12的Lys Pro的各拷贝存在或不存在,使得Lys Pro的拷贝数在2至6范围内。
<400>597
Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro Lys Pro
1 5 10
<210>598
<211>12
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<220>
<221>变体
<222>(2)..(11)
<223>在位置2至11的Glu Ala Ala Ala Lys的各拷贝存在或不存在,使得Glu AlaAla Ala Lys的拷贝数在1至2范围内。
<400>598
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala
1 5 10
<210>599
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>599
Gly Ser His Ser Met Arg Tyr Phe Phe Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gly Glu Thr
505560
Arg Lys Val Lys Ala His Ser Gln Thr His Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Val Gln
859095
Arg Met Tyr Gly Cys Asp Val Gly Ser Asp Trp Arg Phe Leu Arg Gly
100 105 110
Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Thr Thr Lys
130 135 140
His Lys Trp Glu Ala Ala His Val Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Ala Pro Lys Thr His Met Thr His His
180 185 190
Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Gln Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>600
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>600
Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu Thr
505560
Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile Gln
859095
Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Lys
130 135 140
Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr Leu
145 150 155 160
Glu Gly Arg Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Leu
275
<210>601
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>601
Gly Ser His Ser Met Arg Tyr Phe Ser Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Glu Glu Thr
505560
Gly Lys Val Lys Ala His Ser Gln Thr Asp Arg Glu Asn Leu Arg Ile
65707580
Ala Leu Arg Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln
859095
Met Met Phe Gly Cys Asp Val Gly Ser Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr His Gln Tyr Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Lys
130 135 140
Arg Lys Trp Glu Ala Ala His Val Ala Glu Gln Gln Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Asp Gly Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
<210>602
<211>276
<212>PRT
<213>人工序列(Artificial sequence)
<220>
<223>合成序列
<400>602
Gly Ser His Ser Met Arg Tyr Phe Thr Thr Ser Val Ser Arg Pro Gly
1 5 1015
Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln
202530
Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg
354045
Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Arg Asn Thr
505560
Arg Asn Val Lys Ala His Ser Gln Ile Asp Arg Val Asp Leu Gly Thr
65707580
Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His Thr Ile Gln
859095
Met Met Tyr Gly Cys Asp Val Gly Ser Asp Gly Arg Phe Leu Arg Gly
100 105 110
Tyr Gln Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu
115 120 125
Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Gln
130 135 140
Arg Lys Trp Glu Ala Ala Arg Val Ala Glu Gln Leu Arg Ala Tyr Leu
145 150 155 160
Glu Gly Thr Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys
165 170 175
Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His
180 185 190
Ala Val Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe
195 200 205
Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln
210 215 220
Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr
225 230 235 240
Phe Gln Lys Trp Ala Ser Val Val Val Pro Ser Gly Gln Glu Gln Arg
245 250 255
Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu
260 265 270
Arg Trp Glu Pro
275
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