CN117615782A - 包含结合至共价肽偶联物的抗体的组合物和方法 - Google Patents
包含结合至共价肽偶联物的抗体的组合物和方法 Download PDFInfo
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Abstract
提供了组合物和方法，其包括结合伴侣，所述结合伴侣能特异性结合至包含共价附接分子的蛋白质或肽上的靶位点。结合伴侣以抗体和抗体衍生物的形式提供，其能特异性结合至已通过分子(如药物)附接进行共价修饰的蛋白质和肽。结合伴侣可以特异性地与存在于主要组织相容性复合物(MHC)中的共价修饰的肽结合。还提供了组合物和方法用于病症预防或治疗的用途。
Description
相关申请的交叉引用
本申请要求于2021年2月26日提交的美国临时申请号63/154,627和于2021年10月7日提交的美国临时申请序列号63/253,499的优先权，其全部公开内容通过引用纳入本文。
关于联邦资助研究的声明
本发明是在政府支持下由国家卫生研究院(National Institutes of Health)授予的基金号CA194864、CA267362和CA049152资助完成。政府对本发明享有一定权利。
序列表
本申请包含以ASCII格式电子提交的序列表并通过引用其全部内容纳入本文。所述ASCII副本创建于2022年2月24日，命名为58636_00482_SL.txt，大小为212,998字节。
背景技术
对能够与靶标(包括与蛋白质或肽共价结合的药物)结合的药剂的需求一直存在且尚未得到满足。具体地，需要改良靶向治疗的疗效，并且还需要增加肿瘤免疫原性和针对细胞内癌基因驱动的癌症的免疫疗法的疗效。本公开与这些需求相关。
发明内容
本公开提供了包含结合伴侣的组合物和方法，所述结合伴侣能特异性结合至包含共价附接分子的蛋白质或肽上的靶位点。据信，这是具有这种结合功能的结合伴侣的首次公开。本公开阐述了利用能特异性结合至已通过附接分子进行共价修饰的蛋白质和肽的多种抗体和抗体衍生物形式的结合伴侣的这种途径，其中所述分子通过多种药物来说明。此外，本公开证明了，能特异性结合已通过附接小分子药物共价修饰的肽的结合伴侣对于在人类白细胞抗原(HLA)情形下(HLA是主要组织相容性复合物(MHC)的代表性实例)呈递时的所述共价修饰的多肽具有特异性。因此，证明了对HLA复合物中的肽-药物偶联物具有特异性的结合伴侣。本公开包括编码所述结合伴侣的多核苷酸以及经修饰以表达结合伴侣的细胞。本公开包括使用结合伴侣的诊断、预防和治疗途径。
附图简要说明
图1.该图描绘了噬菌体展示抗体克隆的噬菌体酶联免疫吸附试验(ELISA)结果。确定了与KRASG12C-GDP和KRASG12C-GDP-ARS-1620偶联物的结合。对于各克隆，图中的条形图从左到右分别是缓冲液、G12C-GDP-ARS和G12C-GDP。
图2.图表显示使用珠结合试验表征的，12C-ARS Fab59对有或没有ARS-1620的、GTPγS-或GDP结合核苷酸状态下的KRASG12C的结合。
图3.该图显示12C-ARS-Fab59特异性结合与ARS-1620偶联的KRASG12C-GDP。
图4.(A)中显示的是使用12C-ARS-Fab59，通过对由细胞系制备的裂解物进行下拉试验来测量ARS-1620/KRASG12C加合物的所得数据。(B)中显示的是在有或没有ARS-1620的情况下处理的、经重构以具有所示KRAS突变体的无RAS MEF(4A)和KCP(KrasG12C；Tp53R172H；Pdx-Cre)小鼠胰腺癌细胞(4B)的全细胞裂解液和12C-ARS Fab-下拉物(PD)的免疫印迹。(C)中显示的是来自经所示处理的H358和MIAPaCa-2细胞的全细胞裂解物和12C-ARS Fab下拉物(PD)。(D)中显示的是来自C的样品中ARS加合物的形成，通过LC/MS-MS试验进行定量。在所有分图中，ARS-1620和SHP099浓度为10μM。
图5.数据显示，12C-ARS-Fab59可用于通过动物组织所制裂解液的下拉试验来测量ARS-1620与突变KRAS的接合。A、B，显示了口饲单独ARS-1620(200mg/kg/d)或其与SHP2抑制剂SHP099(75mg/kg/d)3天后，来自LSL-KRASG12C-Tp53R270H(A)和LSL-KRASG12C(B)肿瘤的裂解物和12C-ARS Fab下拉物(PD)的抗泛RAS和抗ERK2(上样对照)的免疫印迹。
图6.抗体克隆与偶联有KRAS(G12C)肽和多聚Ser肽的AMG510的结合。对于各抗体克隆，条形图从左到右依次为无靶标、KRAS(G12C)、KRAS(G12C)-AMG和无关肽-AMG。两个阴性对照(无靶标和不含偶联药物的KRAS(G12C)肽)的信号太低，在图中不可见。抗体克隆展示在酵母细胞表面，并使用流式细胞术检测与荧光标记的链霉亲和素偶联的靶标的结合。
图7.人IgG1形式的P2AMR-1克隆与偶联有AMG510的KRAS(G12C)肽(圆形)和没有药物偶联的相同肽(方形)的结合。将肽固定在链霉亲和素被覆的珠上，并用荧光标记的二抗检测与珠结合的抗体。显示表观KD值。此处显示的数据来自三重复测量。误差线在符号的大小范围内。
图8.识别呈递于I类MHC分子上的AMG510。将AMG510-RAS(G12C)偶联物(圆形)和未偶联的肽(方形)装载到HLA-A*03:01上，并固定在链霉亲和素被覆的珠上。使用与图2相同的方法检测抗体结合。显示表观KD值。此处显示的数据来自三重复测量。误差线在符号的大小范围内。
图9.所公开构思(称为HapImmune)的卡通展示。
图10.表示能结合MHC/肽-药物偶联复合物的抗体开发的数据。(A)展示不同抗体克隆的噬菌体的多重珠结合试验(MBBA)。(B)对展示不同抗体克隆的噬菌体进行MBBA试验，这些抗体克隆针对：HLA-A*01:01复合偶联有依鲁替尼(Ibrutinib)的BTK肽。(C)对展示不同抗体克隆的噬菌体进行MBBA试验，这些抗体克隆针对：HLA-A*02:01复合偶联有奥西替尼(Osimertinib)的EGFR肽。
图11.使用靶向KRAS(G12C)-AMG510偶联物的纯化抗体的多重珠结合试验(MBBA)的结合滴定图。克隆名称显示在各图表上。抗原命名如图10所示。
图12.图表显示抗体与AMG510-肽偶联物复合HLA的结合不受游离药物AMG510存在的影响。
图13.使用靶向BTK-依鲁替尼偶联物的纯化抗体的多重珠结合试验(MBBA)的结合滴定图。克隆名称显示在各图表上。抗原命名如图10所示。
图14.纯化抗体与细胞表面内源性HLA分子呈递的KRAS(G12C)-AMG510偶联物的结合滴定图。首先将Raji细胞与KRAS(G12C)-AMG510偶联物或KRAS(野生型)肽一起孵育，并洗去多余的偶联物和肽。使用荧光标记的二抗检测到的抗体水平显示为用于染色的IgG浓度的函数。使用1:1结合函数的非线性最小二乘拟合确定表观解离常数(KD)值。此处显示的数据来自三重复测量。
图15.抗体与用AMG510预处理的表达KRAS(G12C)的细胞系的结合。(A)流式细胞术直方图。(B)用或不用AMG510处理的H358细胞的中值荧光强度的定量。(C)对用或不用AMG510处理并用AMRA3-7抗体染色的H358细胞和HEK293T细胞(阴性对照)的中值荧光强度进行定量。
图16.该图显示P2AMR-1IgG与用KRAS(G12C)肽-AMG510偶联物、KRAS(野生型)肽或无肽预孵育的细胞的结合。
图17.该图显示了使用多重珠结合试验(MBBA)测量的IgG形式的纯化抗体与指定药物-肽/HLA复合物的结合。(A)用偶联AMG510的KRAS(G12C)肽复合HLA-A*03:01(作为抗原)确认抗体克隆。(B)用偶联AMG510的KRAS(G12C)肽复合HLA-*11:01(作为抗原)确认抗体克隆。
图18.图表显示单链双抗体(scDb)对于采用外源肽-药物偶联物进行脉冲的细胞的细胞毒性作用。(A)首先用偶联有AMG510的对应于KRAS(G12C)的片段的肽或与KRAS(野生型)对应的对照肽对Raji细胞进行脉冲。在指定浓度的单链双抗体(scDb)存在下，将经脉冲细胞与人T细胞(效靶比＝3:1)共培养。孵育后，对死细胞进行染色并通过流式细胞术检测。此处显示的数据来自三重复测量。误差线表示s.d.。如果误差线不可见，则误差小于符号。(B)使用T2细胞和与偶联有EGFR肽的奥西替尼进行的等效实验。使用偶联有β-巯基乙醇的肽作为阴性对照。
图19.图表显示AMRA3-7_UCHT1 scDb对药物处理的肺癌细胞系的特异性细胞毒性作用。(A)将肺癌细胞系用100nM AMG510处理24小时，然后在AMRA3-7_UCHT1 scDb存在的情况下与人T细胞(E:T＝5:1)共培养。孵育后，测量细胞活力。scDb抗体仅对具有同源KRAS突变(G12C)和HLA(HLA-A3)的AMG510处理的细胞表现出剂量依赖性细胞毒性作用。(B)0.1nM浓度的scDb的细胞毒性作用。此处显示的数据来自四重复测量。
图20.AMR-A3-7和AMR-A3-7D在酵母细胞表面上展示的结合滴定曲线。显示了与HLA-A*03:01的结合，其呈递分别与9聚体和10聚体RAS(G12C)肽(VVGACGVGK和VVVGACGVGK)中的Cys残基偶联的AMG510。
图21.该图显示了AMRA3-7D scDb的细胞杀伤作用。(A)用Raji细胞测试AMRA3-7DscDb的剂量依赖性细胞杀伤作用，该细胞首先用偶联有AMG510的对应于KRAS(G12C)的片段的肽或对应于KRAS(野生型)的对照肽进行脉冲。(B)测试针对仅用AMG510或DMSO处理的H2122非小细胞肺癌细胞系(阴性对照)的AMRA3-7D scDb的细胞杀伤作用。
图22.AMRA3-7D CrossMab的细胞结合和杀伤作用。(A)AMRA3-7D与表达CD3的Jurkat细胞和不表达CD3的Raji细胞的结合。(B)用Raji细胞测试AMRA3-7D CrossMab的剂量依赖性细胞杀伤作用，该细胞首先用偶联有AMG510的对应于KRAS(G12C)的片段的肽或对应于KRAS(野生型)的对照肽进行脉冲。(C)使用仅用AMG510或DMSO处理的H2122非小细胞肺癌细胞系(阴性对照)测试AMRA3-7D CrossMab的细胞杀伤作用。
图23.AMR-A3-7D的深度突变扫描。(a)展示AMRA3-7D及其深度突变扫描文库群体的酵母细胞的代表性流式细胞术概况。(b)深度突变扫描库的分选子集中各位置的突变发生率以热图格式显示。图23公开了“GGWYPA”(SEQ ID NO:155)和“ISYVKKLI”(SEQ ID NO:153)。
图24.OEA2-5的深度突变扫描。(a)展示单链Fv形式的OEA2-5及其深度突变扫描文库群体的酵母细胞的代表性流式细胞术概况。(b)深度突变扫描库的分选子集中各位置的突变发生率以热图格式显示。图24公开了“EYVTMAL”(SEQ ID NO:159)和“YSYWPI”(SEQ IDNO:157)。
具体实施方式
除非另有说明，本文所用的所有科技术语与本发明所属领域普通技术人员所理解的通常含义相同。
本说明书中给出的每个数值范围包括其上限和下限值，以及落入其内的每个较窄的数值范围，就如同所述较窄的数字范围都明确写在本文中。
在本说明书和所附权利要求书中所用的单数形式“一个”、“一种”和“该”包括多个指示物，除非上下文中有明显的表示。本文中，范围可以表示为从“约”一个特定值和/或至“约”另一个特定值。当表述这样的范围时，另一个实施方式包括从所述一个具体值和/或至所述另一具体值。类似地，当通过使用前置词“约”将数值表达为近似值时，可以理解为该特定值构成了另一个实施方式。与数值相关的术语“约”是可任选的，并且表示，例如，±10％。
本公开内容包括本文描述的每个氨基酸序列和编码该氨基酸序列的所有核苷酸序列。包括每个抗体序列及其抗原结合片段。与本文提供的序列具有80-99％相似性(包括端值)以及其间的所有数量和数量范围的多核苷酸和氨基酸序列均包括在本发明中。本文所述的所有氨基酸序列可包括氨基酸取代(如保守取代)，其不会不利地影响包含氨基酸序列的蛋白质的功能。在这方面，本公开提供了如下所述的结合伴侣中某些位置的替代性残基。在某些实例中，通过深度突变扫描确认了替代性残基，这证明了含有所述氨基酸变化的各结合伴侣的结合功能。本公开包括各结合伴侣，其中各替代性残基单独取代原始残基并且与所述替代性残基以任何组合取代。因此，本文所述的任何结合伴侣可以具有任何单一所述残基改变或所述改变的组合。表A、表B、表C和表D中描述了特定抗体的代表性变化。所述变化可在CDR1、CDR2、CDR3及其组合中。所述变化还可以包括氨基酸插入。本公开包括参考特定序列标识符和上述表中描述的那些由替代氨基酸的描述所涵盖的各氨基酸序列。
如上所述，本公开提供了抗体及其抗原结合片段(统称为“结合伴侣”并且各自单独为“结合伴侣”)。术语“抗体”包括本文中的各结合伴侣形式。结合伴侣能特异性结合蛋白质或其片段，或以肽形式提供的肽，其包含共价附接分子。共价附接分子形成肽偶联物。如本文所用，“肽偶联物”意指已被修饰以便其与另一分子共价偶联的任何蛋白质或肽。肽偶联物被认为是一种新型抗原，即新抗原(neoantigen)。共价偶联至蛋白质或肽以形成肽偶联物的其他分子不受具体限制，前提是所述其他分子不是添加至所述肽偶联物的附加氨基酸。在实施方式中，共价偶联至蛋白质或肽的分子具有生物活性或在偶联之前已具有生物活性，或者其在偶联之前可以是生物学惰性的。在实施方式中，所述分子是药物，包括但不限于小分子药物。下文描述了共价连接至肽或蛋白质以形成肽偶联物的药物的代表性和非限制性实例。肽偶联物包括但不限于共价修饰的全长蛋白质及其片段。肽偶联物包括全长蛋白质的片段，其包含共价修饰并且通过例如胞内加工产生。在某些实施方式中，全长蛋白质可在细胞内共价修饰并随后被加工，从而产生全长蛋白质片段形式的肽偶联物。如下文进一步描述的，产生的肽偶联物可被展示在细胞表面上。肽偶联物的细胞表面展示可以是任何形式的细胞表面展示，包括但不限于通过具有胞外区段的任何受体的方式，或者它可以通过任何类型的主要组织相容性复合物(MHC)或人类白细胞抗原(HLA)来展示。下文进一步描述了展示肽偶联物的HLA类型的非限制性实例，并且所述结合伴侣与其特异性结合。
在实施方式中，相对于未与药物结合的相同蛋白质或肽，结合伴侣优先结合至与肽偶联物共价结合时的蛋白质或肽或包含该蛋白质或肽的复合物。因此，在不存在共价附接分子的情况下，本文所述的结合伴侣无法以可检测水平结合至相同的蛋白质或其片段或只能以较低亲和力结合至相同的蛋白质或其片段。在实施方式中，结合伴侣对包含共价附接药物的蛋白质或肽结合的亲和力10-10,000倍(包括10-10,000的所有数字和数字范围)高于对不包含共价结合分子的蛋白质或多肽的亲和力。在这方面，不受任何特定理论的束缚，共价结合分子的存在被认为有助于结合伴侣特异性结合表位的存在。
在实施方式中，经共价结合以形成肽偶联物的分子是药物，并且可以是任何靶向共价抑制剂(TCI)，但抑制性质不是必要的。在实施方式中，该分子能与靶蛋白内的特定残基反应。在实施方式中，该分子能至少部分与包含亲核残基或亲电子残基的蛋白质或肽区段反应。在实施方式中，与该分子反应的蛋白质或肽的区段包含Cys、Lys、Tyr和His中的任一种。在实施方式中，该分子能至少部分地与包含野生型Cys或突变为Cys的残基的蛋白质或肽区段反应，并且因此可以通过所谓的硫系链(sulfur tether)共价附接。在实施方式中，药物是描述于以下文献的任何药物：Ghosh AK,Samanta I,Mondal A,Liu WR,药物发现中的共价抑制(Covalent Inhibition in Drug Discovery).ChemMedChem.2019；14(9):889-906.doi:10.1002/cmdc.201900107或De Cesco等，European Journal of MedicinalChemistry 138(2017)96e114，或Bauer,RA，Drug Discovery Today，第20卷，第9期，2015年9月，其中共价修饰蛋白质靶标的化合物的公开内容通过引用纳入本文。
在非限制性实施方式中，所述Cys、Lys、Tyr和His氨基酸中的任何一种存在于该分子结合的蛋白质或肽中，因为野生型蛋白质已突变为包括所述残基中的一种或其组合。在非限制性实施方式中，该分子能结合至病症(如癌症)相关的蛋白质或肽。在实施方式中，靶标(例如，分子共价结合的蛋白质或肽)是受体，包括但不必限于具有催化活性区段的任何受体。在实施方式中，药物能结合酶(不必是受体)，包括但不限于任何激酶。在实施方式中，蛋白质靶标包含具有一个或多个活化型突变的受体，其促进配体依赖性酶活性。
在实施方式中，该分子靶向并由此共价结合至存在于任何以下蛋白质和/或其变体中的氨基酸序列，所述蛋白质和/或其变体可以包含或不包含突变(如与特定病症相关的突变，所述病症包括但不限于任何类型的癌症)。在实施方式中，蛋白质是描述于以下文献的任何蛋白质：Visscher M等，癌症中获得性半胱氨酸的共价靶向(Covalent Targetingof acquired Cysteines in cancer).Curr Opin Chem Biol.2016；30：61-67.doi:10.1016/j.cbpa.2015.11.004，该描述通过引用纳入本文。Visscher等还教导了识别与疾病相关的突变基因的方法，所述突变基因引入了适合共价修饰的Cys残基。在实施方式中，蛋白质是KRAS、布鲁顿氏酪氨酸激酶(BTK)、表皮生长因子受体(EGFR)家族(也称为ERBB家族)的任何成员，包括但不限于EGFR(ERBB1)、HER2/NEU(ERBB2)、HER3(ERBB3)和HER4(ERBB4)；成纤维细胞生长因子受体(FGFR)；本领域已知的受体激酶，如MET、BRAF、细胞周期蛋白依赖性激酶(CDK)；乙酰胆碱酯酶(ACHE)；TP53、IDH1、GNAS、FBXW7、CTNNB1、DNMT3A、任何组织蛋白酶，包括组织蛋白酶B、C、F、H、K、L、O、S、V、W和X；任何半胱天冬酶；任何与肥胖有关的蛋白质，如胰脂肪酶和METAP2，或任何癌症睾丸抗原。在实施方式中，药物靶向并因此共价结合至任何病毒蛋白，包括但不限于聚合酶，包括任何病毒DNA聚合酶、RNA聚合酶、逆转录酶或RNA依赖性RNA聚合酶，或(例如病毒细胞进入)所需的病毒蛋白，或由任何转座元件编码的蛋白质。在实施方式中，药物靶向EGFR并且可以选自PD168393、PF00299804(达克替尼)、EKB569(佩利替尼)、阿法替尼、WZ4002、奥西替尼(以前称为AZD9291)、PF-06459988、纳扎替尼(nazartinib)、纳古替尼(naquotinib)、奥穆替尼(olmutinib)、阿维替尼(avitinib)和罗西替尼(rociletinib)、来拉替尼(neratinib)、吡咯替尼(pyrotinib)、波齐替尼(pyrotinib)及其衍生物。在实施方式中，药物靶向布鲁顿氏酪氨酸激酶(BTK)，并且可以选自依鲁替尼、阿卡替尼(acalabrutinib)、泽布替尼(zanubrutinib)、CHMFL-BTK-11、ONO/GS-405、PRN1008和CC-292。在实施方式中，药物靶向任何p90核糖体S6激酶(RSK)，并且可以选自氟甲基酮(FMK)和富马酸二甲酯。在实施方式中，药物靶向任何FGFR，并且可以选自FIIN-1、FIIN-2、FIIN-3、BGJ398、AZD4547、PRN1371、FGF401。
在非限制性实施方式中，结合伴侣特异性结合新抗原所包含的位点，所述新抗原包括共价连接的小分子药物或其他共价连接的分子作为特定MHC环境中抗原的组分。
在实施方式中，共价结合以形成肽偶联物的分子靶向任何RAS癌基因蛋白质产物，包括但不必需限于HRAS、NRAS、KRAS4A和KRAS4B。RAS蛋白的氨基酸序列是本领域已知的，本公开中讨论的所有RAS异型的相关部分的残基编号是相同的，其氨基酸序列可从例如UniProt P01116获得，截至本申请或专利的有效申请日，氨基酸序列已纳入本申请或专利。无论G12是否是本公开所述表达RAS肽序列中的第十二个氨基酸，G12位置根据已知的氨基酸序列编号。
在一个实施方式中，该分子共价结合至包含突变的KRAS蛋白或肽。在实施方式中，所述突变是KRAS残基12、13或61中的至少一个。本文提及的任何药物包括其名称的大写和非大写形式。
在实施方式中，药物靶向包含KRAS G12C突变的KRAS蛋白。在非限制性实施方式中，靶向KRAS蛋白的药物选自2E07、6H05、SML-8-73-1、MRTX849、JNJ74699157、LY3499446、ARS-853、ARS-1620、MRTX1275、AMG510或其衍生物。在一个实施方式中，药物包含共价药物的蛋白水解靶向嵌合体(PROTAC)衍生物，其非限制性描述可在doi:10.1021/acscentsci.0c00411中获得，其中PROTAC的描述通过引用纳入本文。在实施方式中，PROTAC是LC-1或LC-2。在实施方式中，本公开涉及自噬介导的降解剂，称为AUTAC，如doi.org/10.1080/15548627.2020.1718362中所述，其中AUTAC的描述通过引用纳入本文。
能结合KRAS(G12C)-AMG510的结合伴侣的非限制性实例在本文中称为AMRA3-7D。本公开内容包括本文描述的AMRA3-7D的所有衍生物，其包括下文通过深度突变分析描述的替代性残基，以及scDb和CrossMab形式，提供了其代表性氨基酸序列。AMRA3-7D的轻链(VL)和重链(VH)的氨基酸序列为：
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPK LLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQISYVKKLI TFGQGTKVEIKRTV(SEQ ID NO:3)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGL EWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY CARGGWYPAMDYWGQGTLVTVSS(SEQ ID NO:4)
能结合表皮生长因子受体(EGFR)-奥西替尼偶联物的结合伴侣的非限制性实例在本文中称为OEA2-5。本公开内容包括本文描述的OEA2-5的所有衍生物，其包括下文通过深度突变分析描述的替代性残基，以及scDb形式，提供了其代表性氨基酸序列。
OEA2-5的轻链(VL)和重链(VH)的氨基酸序列为：
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYSYWPITFGQGTKVEIKRTV(SEQ ID NO:5)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTISSSYIHWVRQAPGKGLEWVAYISPSYGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCAREYVTMALDYWGQGTLVTVSS(SEQ ID NO:6)
在实施方式中，结合伴侣能结合至天然形式(药物或其他分子与其共价附接除外)的蛋白质。“天然形式”是指在药物或其他分子共价附接之前保留其生物学功能的完整蛋白质。在实施方式中，天然形式或蛋白质是其在如通过胞内加工被片段化之前的形式。在实施方式中，结合蛋白因此结合至共价附接至药物或其他分子的全长多肽，并且其中共价结合的药物或其他分子至少部分地允许结合伴侣的优先结合。一般而言，本文中与术语“蛋白质”互换使用的多肽包含多于50个连续氨基酸。在实施方式中，结合伴侣能特异性结合至与药物或其他分子共价附接的完整蛋白质。在其他实施方式中，结合伴侣能特异性结合包含共价结合分子的肽。在实施方式中，结合伴侣能特异性结合具有特定氨基酸序列并共价偶联至另一分子(如药物)的肽。在实施方式中，结合伴侣能优先结合共价结合至分子(如药物)的肽，而肽的序列与此无关。这种优先结合是相对于与未与药物偶联的相同肽的结合而言的。在实施方式中，结合伴侣优先结合至包含KRAS(G12)突变的肽或其变体，其中该变体与含有KRAS(G12)的肽至少50％相似。这种优先结合是相对于分别与未与药物或其他分子共价偶联的含KRAS(G12)的肽或其变体的结合而言的。
在实施方式中，所描述的结合伴侣特异性地结合至肽偶联物，所述肽偶联物具有合适的长度以在主要组织相容性复合物(MHC)(在人类中被称为人白细胞抗原(HLA))呈递，或与非人类动物(包括但不限于非人类哺乳动物)中的MHC或其等效复合物结合。
一般而言，肽偶联物包含少于50个连续氨基酸。在实施方式中，包含所描述表位的肽偶联物因此可以是2-49个氨基酸的长度。在具体的实施方案中，药物或其他分子(所附接的药物可含表位)共价附接的肽可包含4-12个连续的氨基酸，其可能或可能不来自蛋白质加工过程中的较长蛋白质，如由MHC分子加工用于呈递的抗原。在实施方式中，药物偶联至包含7-30个氨基酸或由7-30个氨基酸组成的肽。在实施方式中，药物或其他分子偶联至包含7、8、9、10、11、12、13、14或15个氨基酸或由7、8、9、10、11、12、13、14或15个氨基酸组成的肽，并且其可以在MHC I类情形中呈递。在实施方式中，药物或其他分子偶联至有9-30个氨基酸(包括端值和其间的所有数量和数量范围)的肽，其可以在MHC II类情形中呈递。在实施方式中，药物或其他分子偶联至包含至少7个氨基酸的肽。
在实施方式中，结合伴侣能特异性结合至与药物或其他分子共价偶联的肽偶联物，而与MHC呈递无关。在实施方式中，仅当肽偶联物由MHC分子呈递时，结合伴侣能与肽偶联物特异性结合，其非限制性实例在下文实施例3中描述。在实施方式中，结合伴侣可以在MHC非依赖性和MHC呈递情形中特异性结合至肽偶联物。在实施方式中，MHC-肽偶联复合物包含能与所述结合伴侣特异性结合的抗原。
在实施方式中，结合伴侣相应地能通过可呈递肽偶联物的任何MHC结合至细胞。在实施方式中，HLA由限于I类、II类或III类MHC呈递的细胞表达。在实施方式中，结合伴侣可以结合至表达呈递肽偶联物的I类MHC的细胞。本领域技术人员将认识到，I类MHC包括多态性α链和β2微球蛋白等组分，其中肽偶联物结合至多态性链。
在实施方式中，细胞是抗原呈递细胞(APC)。在实施方式中，细胞是所谓的专职(professional)抗原呈递细胞，因此可以包括但不限于展示II类MHC的巨噬细胞和树突细胞。本领域技术人员将认识到，II类MHC包括MHC多态性α和β链等组分，并且展示的肽偶联物结合至所述链。在其他实施方式中，II类MHC伴肽偶联物展示可涉其他细胞类型(如癌症/肿瘤细胞)，因此本公开提供了使用所述结合伴侣对此类细胞的直接识别，而不需要专职APC。
在实施方式中，肽偶联物由非经典MHC复合物展示，其可包括CD1d、MR1、MHC-E、-F、-G和/或本领域技术人员将认识到的其他新兴家族成员。
本公开包括能与仅由特定MHC类型显示的多肽偶联物特异性结合的结合伴侣，从而提供了区分MHC类型的结合伴侣。本文至少通过图17的方式描述了此类结合伴侣的代表性实例。
在实施方式中，本公开的结合伴侣可以特异性结合由多于一种特定MHC类型展示的包含共价偶联药物或其他分子的肽偶联物。在实施方式中，本公开的结合伴侣可以仅与特定MHC情形下的包含共价偶联药物的肽偶联物特异性结合。在实施方式中，肽偶联物由选自HLA-A、-B、-C及其组合的MHC I类类型展示。在某些方面中，肽偶联物在A*02/B*35/C*04的任何MHC I类的情形中展示。在实施方式中，肽偶联物由DR*01/DR*04/DR*07/DP*04的II类MHC中的任一种展示。在实施方式中，HLA包含A*01:01、A*02:01、A*03:01、A*11:01、A*24:02、A*26:01、B*07:02、B*08:01、B*27:05、B*39:01、B*40:01、B*58:01或B*15:01。抗体的具体实例包括结合至以下的抗体：由HLA-A*03:01和HLA-A*11:01呈递的KRAS(G12C)-AMG510偶联物、由HLA-A*01:01呈递的BTK-依鲁替尼偶联物以及由HLA-A*02:01呈递的EGFR-奥西替尼偶联物。在非限制性实施方式中，本公开提供的scDb对共价结合至由特定HLA呈递的所述肽的特定药物或对共价结合至由两种不同HLA呈递的所述肽的相同药物具有特异性。代表性scDb在实施例4中描述。使用scDb获得的数据如图18和19所示。使用CrossMab形式获得的数据在实施例5及其附图中提供。
在实施方式中，肽偶联物由参与细胞介导的免疫应答的细胞展示，或由可作为细胞介导的免疫应答的靶标的细胞展示。在实施方式中，在任何合适的MHC情形中展示的肽偶联物包含白细胞识别的细胞，包括但不必限于T细胞或自然杀伤(NK)细胞。在实施方式中，T细胞是CD4+T细胞、CD8+T细胞、双阳性CD4+/CD8+T细胞、CD4+/CD8+双阴性T细胞或γδT细胞。因此，如下文进一步描述的，本公开提供了经设计以与呈递的肽偶联物和参与细胞介导的免疫应答的细胞两者相互作用的结合伴侣。在实施方式中，某些所述的结合伴侣能够结合至1)特定MHC和2)特定肽偶联物的复合物。在实施方式中，某些所述的结合伴侣能够结合至由至少两种不同的MHC呈递的特定肽偶联物。
在实施方式中，本公开的任何结合伴侣都包含至少一条链，该链包含互补决定区(CDR)，该互补决定区是来自本文所述任何重链或轻链氨基酸序列的CDR1、CDR2或CDR3。在本说明书的某些实例中，CDR以粗体显示。CDR序列的氨基酸序列通过其在所述重链和轻链氨基酸序列中的位置分别涵盖在本公开中。本公开包括包含所述重链CDR1、CDR2和CDR3的结合伴侣。本公开还包括包含所述轻链CDR1、CDR2和CDR3的结合伴侣。本公开还包括包含所述重链CDR1、CDR2和CDR3以及所述轻链CDR1、CDR2和CDR3的结合伴侣。对于本公开的氨基酸序列中包含有纯化或蛋白质生产标签(如HIS标签和/或AVI标签)的氨基酸，本公开包括以下前提：所述标签的序列可以从氨基酸序列中排除。所述标签之间的氨基酸也可排除。
本公开的结合伴侣可以完整的免疫球蛋白或免疫球蛋白片段的形式提供，包括但不必限于抗原结合(Fab)片段、Fab'片段、(Fab')2片段、Fd(重链的N端部分)片段、Fv片段(两个可变结构域)、双抗体(Db)、dAb片段、单结构域片段或单个单体可变抗体结构域、单链双抗体(scDb)、分离的互补决定区(CDR)、单链可变片段(scFv)以及其他保留抗原结合功能的抗体片段。在实施方式中，一个或多个结合伴侣作为以下物质的组分提供：双特异性T细胞结合物(BiTE)、双特异性杀伤细胞接合物(BiKE)、CrossMab(例如，含有四种不同链的结合伴侣；免疫球蛋白交叉(也称为Fab结构域交换或CrossMab形式)技术(参见例如，WO2009/080253；Schaefer等，Proc.Natl.Sci.USA，108:11187-11192(2011))，或嵌合抗原受体(CAR)，例如用于生产嵌合抗原受体T细胞(例如CAR T细胞)和CAR自然杀伤(NK)细胞以及杀伤性巨噬细胞。本公开包括包含所述重链和轻链可变区的结合伴侣。
在实施方式中，结合伴侣是多价的。在实施方式中，提供了三特异性结合伴侣。在实施方式中，细胞表达CAR形式的一种或多种结合伴侣的至少一个区段。在一个实施方式中，本公开的结合伴侣可以作为与多核苷酸(如RNA多核苷酸)的复合物提供，以形成适体。在实施方式中，多价结合伴侣包括提供对于所需细胞类型上的特定靶标(如任何癌细胞标志物)的特异性的一种结合组分(如互补位)。在实施方式中，提供了三特异性白细胞接合物。在实施方式中，结合伴侣可以是仅在肿瘤微环境中存在的蛋白酶或其他酶存在下才被活化的分子的部分，此类实施方式与例如前抗体有关，其实例在本领域中是已知的，例如在doi:10.1126/scitranslmed.3006682，doi:10.1038/s41467-020-16838-w和doi:10.1038/s41587-019-0135-x中，其中对前抗体和蛋白酶活化的描述通过引用纳入本文。在一个实施方式中，本公开提供了可以移接到抑制剂上的通用半抗原。
在实施方式中，本公开的CAR包含scFv，其包含如本文所述的重链和轻链。如本领域已知的先前描述的CAR，scFv存在于进一步包含CD3ζ链和共刺激结构域的连续多肽中。在实施方式中，共刺激结构域包含4-1BB共刺激结构域或CD28共刺激结构域。CAR还可以含有辅助受体铰链序列，如CD8辅助受体铰链序列。
在实施方式中，本公开的结合伴侣可包含恒定区，例如Fc区。可以包括所述恒定区的任何同种型。包含恒定区的结合伴侣可以特别适用于抗体依赖性细胞介导的细胞毒性(ADCC)，并且因此可以发挥作用以通过多种效应细胞中的任一种的细胞介导的应答来杀死靶细胞。类似地，恒定区可以特别适用于增强补体介导的应答。
在实施方式中，本公开的结合伴侣可以被修饰以使其存在于融合蛋白中。在实施方式中，结合伴侣的抗原结合区段可以存在于融合蛋白中，和/或恒定区可以是融合蛋白的组分。在实施方式中，融合蛋白包含来自至少两种不同蛋白质的氨基酸。融合蛋白可以使用多种标准分子生物学途径中的任何一种来产生，包括但不必需限于从任何合适的表达载体表达。在实施方式中，本文描述的结合伴侣可以存在于有可检测蛋白质(如绿色荧光蛋白(GFP)、增强型GFP(eGFP)、mCherry等)的融合蛋白中。在实施方式中，作为表达载体的替代，可以将编码本文所述的任何结合伴侣的mRNA或化学修饰的mRNA递送至细胞，使得结合伴侣被细胞翻译。
在实施方式中，本文描述的结合伴侣用于携带药物或毒素，并且因此结合伴侣可以作为免疫毒素或以抗体-药物偶联物(ADC)的形式提供。
在实施方式中，可用于产生免疫毒素的试剂包括酶活性毒素及其酶活性片段。合适的酶活性毒素包括但不限于白喉A链、白喉毒素的非结合活性片段、外毒素A链(来自绿脓假单胞菌(Pseudomonas aeruginosa))、蓖麻毒蛋白A链、相思豆毒蛋白A链、蒴莲根毒素A链、α-帚曲菌素、油桐(Aleurites fordii)蛋白、石竹素蛋白、美洲商陆(Phytolacaamericana)蛋白(PAPI、PAPII和PAP-S)、苦瓜(Momordica charantia)抑制剂、麻疯树毒蛋白、巴豆毒蛋白、肥皂草(Sapaonaria officinalis)抑制剂、白树毒素、分裂毒素(mitogellin)、局限曲菌素、酚霉素、依诺霉素和单端孢霉烯族毒素(tricothecenes)。这些可以作为融合蛋白的组分提供，或者可以通过任何合适的偶联途径共价附接至结合伴侣。
结合伴侣可以通过使用任何合适的接头连接至化疗剂以形成抗体药物偶联物(ADC)。在实施方式中，所述接头包含二硫化物、肼或硫醚。所述化疗剂可以可逆地或不可逆地附接至结合伴侣。
可裂解接头对于杀死旁邻细胞可能尤其有用。在实施方式中，可以包括蛋白酶识别位点，以通过在蛋白酶识别位点处蛋白酶识别和裂解的操作从结合伴侣中释放化疗剂。因此ADC可以被认为含有前药。
在实施方式中，本公开的结合伴侣可包含连接序列。作为非限制性实例，ScFv可包含将包含互补位的区段彼此连接的接头。合适的氨基酸接头可主要包含相对小的中性氨基酸(如甘氨酸、丝氨酸和丙氨酸)，并且可以包括富含甘氨酸和丝氨酸的序列的多个拷贝。在具体且非限制性的实施方式中，所述接头包含3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19和20个氨基酸。在实例中，所述接头可以是甘氨酸-丝氨酸-丙氨酸接头G4SA3(SEQ IDNO:11)或甘氨酸-丝氨酸接头(G4S)4接头(SEQ ID NO:12)。在实施方式中，结合伴侣可包括细胞定位信号或分泌信号。在具体的实施方式中，结合伴侣可包含跨膜结构域，因此可以被输送到细胞膜并固定在细胞膜上。对于分泌，可以使用任何合适的分泌信号，并且许多信号都是本领域已知的。
在实施方式中，结合伴侣可以是ADC的部分，因此结合伴侣包含药物。所述药物可以包括但不必限于任何合适的化疗剂。在实施方式中，ADC包含结合伴侣和为抗微管剂、烷化剂或DNA小沟结合剂的化疗剂。在实施方式中，化疗剂包含美登木素生物碱、多拉司他汀、阿里他汀药物类似物或念珠藻素。在实施方式中，化疗剂是多卡霉素衍生物或抗生素，如烯二炔抗生素或吡咯苯并二氮杂卓(PBD)，包括其二聚体。在实施方式中，化疗剂是酶抑制剂，如拓扑异构酶或聚合酶抑制剂。在实施方式中，化疗剂包含阿霉素或含金属化合物(例如含铂化合物)，其非限制性实例包括顺铂、卡铂或奥沙利铂。在实施方式中，ADC包含本文描述的结合伴侣，以及Barf和Kaptein，dx.doi.org/10.1021/jm3003203，J.Med.Chem.2012，55，6243-6262，或Wilson等，dx.doi.org/10.1021/jm400224q，J.Med.Chem.2013，56，7463-7476，或Lambert和Morris，Adv Ther(2017)34:1015-1035中描述的任何药物，其中用作ADC组分的药物的描述通过引用纳入本文。在实施方式中，结合伴侣偶联至细胞因子或以其他方式包括细胞因子，所述细胞因子包括但不必需限于白介素，其包括但不限于IL-2和IL-12，或干扰素(IFN)，从而提供细胞因子偶联物。
为了产生结合伴侣，可以使用任何合适的表达系统。一般而言，编码结合伴侣的多核苷酸用于在任何合适的细胞系统中表达结合伴侣，其非限制性实施方式包括NS0鼠骨髓瘤细胞、人细胞系和中国仓鼠卵巢(CHO)细胞。在实施方式中，本公开提供了可以与编码本文所述的任何CDR或CDR组合的多核苷酸选择性杂交的多核苷酸。在实施方式中，多核苷酸与编码任何所述结合伴侣的重链CDR1、CDR2和CDR3的多核苷酸选择性杂交。在实施方式中，多核苷酸与编码任何所述结合伴侣的轻链CDR1、CDR2和CDR3的多核苷酸选择性杂交。在实施方式中，多核苷酸与编码任何所述结合伴侣的重链或轻链CDR1、CDR2和CDR3的多核苷酸选择性杂交。
在实施方式中，本文所述的结合伴侣可以是融合蛋白的组分。在实施方式中，如对于作为融合蛋白产生的结合伴侣，可以使用肽接头。在实施方式中，所述肽接头包含任何自裂解信号。在实施方式中，所述自裂解信号可以存在于与编码结合伴侣的ORF相同的开放阅读框(ORF)中。自裂解氨基酸序列通常长约18-22个氨基酸。可以使用任何合适的序列，其非限制性实例包括：T2A(EGRGSLLTCGDVEENPGP(SEQ ID NO:7))；P2A(ATNFSLKQAGDVENPGP(SEQID NO:8))；E2A(QCTNYALKLAGDVESNPGP(SEQ ID NO:9))和F2A(VKQTLNFDLKLAGDVESNPGP(SEQ ID NO:10))。
在包含本文所述的结合伴侣的蛋白质的任何片段是文库的组分(包括但不必限于噬菌体展示文库或酵母表面展示文库)的情形范围内，本公开包括以下前提：所述结合伴侣可以不含包含噬菌体或酵母氨基酸序列(包括但不限于噬菌体外壳蛋白或酵母宿主蛋白(包括但不限于Aga2))的所述文库的任何区段。因此，在某些实施方式中，结合伴侣可以存在于融合蛋白中，但融合蛋白不包含细菌噬菌体衣壳蛋白。在实施方式中，本文描述的任何结合伴侣可以不含任何pIII噬菌体外壳蛋白，或M1、fd丝状噬菌体、T4、T7或λ噬菌体蛋白的任何部分。
在实施方式中，本公开的结合伴侣包含可用于诊断或治疗目的的可检测标记物。例如，可检测标记物可用于病理学和/或体内成像途径的结合伴侣的定位。在实施方式中，结合伴侣偶联至多种放射性试剂中的任一种，包括但不限于高放射性原子，如In111、At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212，以及Lu的放射性同位素。在具体实施方式中，如为了成像，结合伴侣可以偶联至用于闪烁研究的放射性原子，例如Tc99m(亚稳态锝-99)、1123，或用于核磁共振(NMR)成像(也称为磁共振成像，或MRI)的自旋标记物(例如1123、1131、1124、F19、C13、N15、O17或钆(III)或锰(II))。在实施方式中，放射性剂适用于CAT扫描或PET成像。在实施方式中，铟111、锝99或碘131可用于平面扫描或单光子发射计算机断层扫描(SPECT)。正电子发射标记物(如氟19碘123和碘124)可用于正电子发射断层扫描。顺磁性离子例如钆(III)或锰(II)可用于磁共振成像MRI。在实施方式中，与所述结合伴侣附接的所述放射性同位素也可用于治疗途径。在实施方式中，放射性剂或同位素包括α发射放射性核素。在实施方式中，放射性剂或同位素包括β发射放射性核素。在一些实施方式中，本公开提供了与诊断剂或治疗剂偶联的本技术的抗体。诊断剂可以包括放射性或非放射性标记物、造影剂(如用于磁共振成像、计算机断层扫描或超声)，并且所述放射性标记物可以是γ-、β-、α-、俄歇电子-、或正电子发射同位素。诊断剂是与抗体部分(即抗体或抗体片段或亚片段)偶联给予的分子，并且可用于通过定位含有抗原的细胞来诊断或检测疾病。
本文描述的任何结合伴侣可以是完全或部分人源化的。用于抗体人源化的技术是本领域已知的并且可适用于本公开。在实施方式中，人源化可以通过例如CDR移接来进行。在实施方式中，为了人源化或以其他方式改善结合伴侣的特征，可以改变可变区中的一个或多个氨基酸。在实施方式中，可以改变框架区中的一个或多个氨基酸。
本公开包括在诊断和治疗方法中应用的结合伴侣。对于治疗途径，在某些实施方式中，结合伴侣可以作为编码结合伴侣的mRNA或DNA多核苷酸来递送。认为给予编码本文所述的任何结合伴侣的DNA或RNA也是将此类结合伴侣递送至个体或一个或多个细胞的方法。递送编码蛋白质的DNA和RNA的方法是本领域已知的，并且在受益于本公开的情况下可以适用于递送结合伴侣。在实施方式中，使用包含病毒载体的一种或多种表达载体。因此，在实施方式中，使用病毒表达载体。病毒表达载体可以用作裸多核苷酸，或者可以包含任何病毒颗粒，包括但不限于有缺陷的干扰颗粒或其他复制缺陷的病毒构建体，以及病毒样颗粒。在实施方式中，表达载体包含修饰的病毒多核苷酸，例如来自腺病毒、疱疹病毒或逆转录病毒。在实施方式中，可以使用适应自小鼠莫罗尼白血病病毒(MLV)的逆转录病毒载体或慢病毒载体，如适应自人类免疫缺陷病毒1型(HIV-1)的慢病毒载体。
在一个实施方式中，使用溶瘤病毒载体。溶瘤病毒(OV)，包括牛痘(OVV)，通过直接溶瘤和通过产生损伤相关分子模式(DAMP)和病毒衍生的病原体相关分子模式(PAMP)刺激先天免疫反应来介导抗癌作用，导致I型干扰素产量增加。此外，OVV介导的溶瘤作用可能有助于肿瘤微环境中宿主抗原呈递细胞直接获取肿瘤衍生抗原，从而改善T细胞启动以及抗肿瘤免疫反应效应阶段的协调。在替代性实施方式中，可以使用重组腺相关病毒(AAV)载体。在某些实施方式中，表达载体是自互补的腺相关病毒(scAAV)。
本公开还包括含有结合伴侣的药物制剂，可通过将其与一种或多种药学上可接受的运载体混合来制备。药学上可接受的运载体包括溶剂、分散介质、等渗剂等。运载体可以是液体、半固体(例如糊剂)或固体运载体。运载体的实例包括水、盐溶液或其他缓冲液(例如磷酸盐、柠檬酸盐缓冲液)、油、醇、蛋白质(如血清白蛋白、明胶)、碳水化合物(如单糖、二糖和其他碳水化合物，包括葡萄糖、蔗糖、海藻糖、甘露糖、甘露醇、山梨糖醇或糊精)、凝胶、脂质、脂质体、树脂、多孔基质、粘合剂、填充剂、包衣、稳定剂、防腐剂、脂质体、抗氧化剂、螯合剂(如EDTA)、成盐抗衡离子(如钠)；非离子表面活性剂(如TWEEN、PLURONICS或聚乙二醇(PEG)或其组合)。在实施方式中，提供了包含一种或多种结合伴侣的脂质体制剂。脂质体制剂包括但不限于脂质体纳米颗粒。
在实施方式中，向有需要的个体给予有效量的一种或多种结合伴侣。在实施方式中，有效量是减少疾病的一种或多种体征或症状和/或降低疾病严重性的量。有效量还可以抑制或预防疾病的发作或疾病复发。精确的剂量可以由个体医生根据待治疗的患者来选择。可以调整剂量并给予提供足够水平的结合伴侣以维持所需效果。可以考虑的其它因素包括疾病状态的严重性和类型、患者的年龄、体重和性别、所需治疗持续时间、给予方法、给予时间和频率、药物组合、反应对治疗的敏感性和/或耐受性/反应。
结合伴侣和包含结合伴侣的药物组合物可以使用任何合适的途径给予有其需要的个体，其实例包括静脉内、肌内、腹膜内、脑脊髓内、皮下、关节内、滑膜内、口服、局部或吸入途径，取决于待治疗的具体病症。所述组合物可以胃肠外或肠内给药。组合物可以用单次给予或多次给予的形式引入，或者可以在一段时间内以连续的方式引入。例如，所述给予可以是预定的给予次数或每日、每周或每月给予，其可以是连续的或间歇性的，如治疗上所指示的那样。
在实施方式中，需要本公开组合物的个体已被诊断患有或怀疑患有癌症。在实施方式中，所述癌症是实体瘤或血液恶性病。在实施方式中，所述癌症是肾细胞癌、乳腺癌、前列腺癌、胰腺癌、肺癌、肝癌、卵巢癌、宫颈癌、结肠癌、食道癌、神经胶质瘤、成胶质细胞瘤或另一种脑癌、胃癌、膀胱癌、睾丸癌、头颈癌、黑色素瘤或其他皮肤癌、任何肉瘤(包括但不限于纤维肉瘤、血管肉瘤、骨肉瘤和横纹肌肉瘤)，以及任何血癌(包括所有类型的白血病、淋巴瘤和骨髓瘤)。在实施方式中，所述个体有治疗任何肿瘤前病症，包括骨髓增生异常综合征或骨髓增殖性肿瘤的需要。在实施方式中，所描述的结合伴侣预防性地用于任何所描述类型的癌症。
在实施方式中，向有其需要的个体给予一种或多种结合伴侣(包括但不必需在药物制剂中)，表现出相对于对照改善的活性。在一个实施方式中，对照包含不同的抗体、不同形式的相同抗体/结合伴侣、或在不添加其它试剂的情况下递送的抗体/结合伴侣。在实施方式中，相对于对照，本文描述的结合伴侣提供改善的抗体依赖性细胞毒性(ADCC)或内化(例如对于ADC)。在实施方式中，对照蛋白或肽不包含共价连接的分子。对照肽可包含与实验肽相同的序列，或者如果实验肽包含突变，则对照肽可包含野生型序列。
本公开的组合物(例如药物制剂)，可以仅含有一种或多于一种结合伴侣，因此包括不同结合伴侣的组合。同样，一种或多种结合伴侣可以与任何其他治疗剂组合，其非限制性实例包括常规化疗剂和T细胞共刺激分子的调节剂，通常称为免疫检查点抑制剂。T细胞共刺激分子是本领域已知的(PMID 30115704)，其包括但不限于CTLA4、PD-1、PD-L1、LAG3、TIM3、TIGIT、VISTA、B7-1、B7-2、PD-L2、LSECtin、半乳凝素-9、CEACAM-1、CD155、CD112、CD28、ICOS、ICOSL、OX40、OX40L、GITR、GITRL、4-1BB、4-1BBL、CD40、CD40L、CD27和CD70。因此，本公开包括使用一种或多种描述的结合伴侣和T细胞共刺激分子(包括但不限于CTLA-4抑制剂、PD-1抑制剂和PD-L1抑制剂)的任何调节剂的联合疗法。作为非限制性实例，抗PD-1剂包括派姆单抗(Pembrolizumab)和纳武单抗(Nivolumab)。抗PD-L1的实例包括阿维鲁单抗(Avelumab)和阿特珠单抗(Atezolizumab)。抗CTLA-4的实例是伊匹单抗(Ipilimumab)。所述结合伴侣还可以与过继免疫疗法的任何形式组合。
在实施方式中，本公开包括向有需要的个体给予一种或多种结合伴侣和至少一种其它试剂以提供叠加效应或大于叠加效应(例如协同结果)。在实施方式中，描述的效果包含抑制癌症生长、抑制转移或其他有益效果。效应或协同效应还可以通过使用至少两种所述结合伴侣的组合来实现。
已经开发了多种技术用于产生结合伴侣，并且这些技术也包括在本公开的范围内。在实施方式中，结合伴侣由宿主细胞通过重组表达载体产生。本公开包括编码本文所述的氨基酸序列的所有多核苷酸序列，包含此类多核苷酸序列的表达载体，以及包含此类表达载体的体外细胞培养物。在实施方式中，细胞培养物包括原核细胞或真核细胞。在实施方式中，所述细胞培养物是哺乳动物细胞。在实施方式中，所述细胞是CHO细胞。在实施方式中，细胞是HEK293细胞及其衍生物。本公开提供了包含结合伴侣和/或表达结合伴侣的细胞培养物的试剂盒。一般而言，所述试剂盒包含一个或多个密封容器，其含有结合伴侣或表达它们的细胞。试剂盒中可以包括用于治疗和/或诊断目的的结合伴侣的使用说明。
经修饰以表达任何所述结合伴侣的细胞包括但不必需限于CD4+T细胞、CD8+T细胞、自然杀伤T细胞、γT细胞和作为T细胞祖细胞的细胞(如造血干细胞或其他淋巴祖细胞(如未成熟胸腺细胞(CD4-CD8-双阴性)细胞或双阳性胸腺细胞(CD4+CD8+))。在实施方式中，所述祖细胞包含标志物，如CD34、CD117(c-kit)和CD90(Thy-1)。在实施方式中，经修饰细胞包含巨噬细胞。所述的经修饰细胞可以用于治疗或预防。
在实施方式中，本公开提供了结合伴侣的生成。该途径包括提供多个不同的结合伴侣，将多个有区别的(例如，不同的)结合伴侣暴露于一种或多种肽偶联物，并选择能与含有共价偶联药物或其他分子的肽偶联物特异性结合，但不结合不包含共价偶联药物或其他分子的蛋白质或肽的结合伴侣。如上所述，该途径可以用需要或不需要蛋白质或肽的氨基酸序列作为抗原决定簇的部分的方式进行。所描述的途径可用于选择结合伴侣，其对肽偶联物作为任何MHC复合物的组分的呈递具有特异性。
在实施方式中，本文描述的结合伴侣以及对于本领域技术人员将由此显而易见的其他结合伴侣可用于确定特定药物或其他分子是否与蛋白质或肽形成共价相互作用。因此，本公开提供了将蛋白质或肽底物暴露于候选药物并使用本文描述的或如本文描述鉴定的结合伴侣来确定药物是否与相关底物形成共价相互作用。该确定可以基于结合伴侣是否与已共价附接至药物的蛋白质或肽结合来做出。该途径可以用来代替当前可用的技术，例如质谱法等。
在实施方式中，本公开的结合伴侣可用于任何免疫学诊断测试，包括但不限于上述成像方法。在实施方式中，本文所述的一种或多种结合伴侣可以用作任何形式的组分，例如酶联免疫吸附试验(ELISA)试验，包括但不限于直接ELISA、夹心ELISA、竞争性ELISA和反向ELISA。在实施方式中，本文描述的一种或多种结合伴侣还可纳入免疫诊断装置(例如微流体装置、侧流装置等)。结合伴侣还可以用于例如western印迹和免疫沉淀试验。
以下实施例旨在说明，对本文公开范围不构成限制。在实施方式中，实施例3中描述的抗体相对于实施例1中描述的抗体具有不同的性质。结合伴侣之间的其他差异是从实施例及其附图中显而易见的。不同的性质包括但不必需限于在特定MHC类型环境下显示的药物偶联物的特异性。因此，当肽偶联物处于特定的MHC复合体中时，结合伴侣可能展示出不同的结合伴侣。
实施例1
本实施例描述了特异性结合ARS-1620的结合伴侣的鉴定和表征，ARS-1620与KRASG12C形成共价相互作用。
具体地，图1显示了噬菌体展示的抗体克隆的噬菌体ELISA。
确定了与KRASG12C-GDP和KRASG12C-GDP-ARS-1620偶联物的结合。缓冲液表示了不含KRASG12C的孔的结合信号。从这些候选物中，确认了四种不同的抗体。其中，12C-ARS-Fab59显示出与共价结合至ARS-1620的KRASG12C-GDP的高亲和力结合。结果示于图2，其显示通过珠结合试验(PMID:33358997)表征的，12C-ARS Fab59与有或没有ARS-1620的、GTPγS-或GDP结合核苷酸状态下的KRASG12C的结合。图3也显示了12C-ARS-Fab59特异性结合与ARS-1620偶联的KRASG12C-GDP。具体地，如图所示说明了，12C-ARS-Fab与有或没有ARS-1620偶联的、GTP S-或GDP结合核苷酸状态下的KRASG12C(左)或WT RAS同种型(右)的结合。
图4(A)显示了使用12C-ARS-Fab59，通过对由细胞系制备的裂解物进行下拉试验来测量ARS-1620/KRASG12C加合物。为了产生如图4所示的数据，对来自在有或没有ARS-1620的情况下处理的用所示KRAS突变体重构的无RAS MEF(4A)和KCP(KrasG12C；Tp53R172H；Pdx-Cre)小鼠胰腺癌细胞(4B)的全细胞裂解液和12C-ARS Fab-下拉物(PD)进行免疫印迹。图4C显示了来自经所示处理的H358和MIAPaCa-2细胞的全细胞裂解物和12C-ARS Fab下拉物(PD)，其用抗泛RAS和抗ERK2抗体(后者为上样对照)进行SDS-PAGE和免疫印迹。图4D中显示的是来自4C的样品中ARS加合物的形成，通过LC/MS-MS试验进行定量。在所有分图中，ARS-1620和SHP099浓度为10μM。
图5显示，12C-ARS-Fab59可用于通过使用从动物组织制得的裂解液进行的下拉试验来测量ARS-1620与突变KRAS的接合。具体地，在图5A-B中，显示了口饲单独ARS-1620(200mg/kg/d)或其与SHP2抑制剂SHP099(75mg/kg/d)3天后，来自LSL-KRASG12C-Tp53R270H(A)和LSL-KRASG12C(B)肿瘤的裂解物和12C-ARS Fab下拉物(PD)的抗泛RAS和抗ERK2(上样对照)的免疫印迹。
为了产生上述结果，使用了以下材料和方法。
RAS核苷酸交换和ARS-1620偶联的RAS的生成
在结合实验和噬菌体展示选择中使用的含有6xHIS标签(SEQ ID NO:13)和AVI标签(1)的纯化RAS(1-174)蛋白通过以下方式制备：使用pH 7.5的20mM Tris-Cl缓冲液(含有5mM EDTA、0.1mM DTT和1mM(终浓度)核苷酸(GDP或GTPγS))以25倍稀释蛋白质储液(通常含有20-100μM RAS)。为了生成ARS结合的RAS，在RAS与GDP的核苷酸交换反应期间添加ARS-1620(最终浓度：100μM)。样品在30℃孵育30分钟。然后添加MgCl2至终浓度20mM以淬灭核苷酸交换反应，并在使用前使该溶液在冰上孵育至少5分钟。
噬菌体展示的针对ARS结合的KRASG12c的抗体片段的选择
已描述了开发针对纯化蛋白质靶标的Fab的一般操作(2)。进行四轮噬菌体展示文库选择，第一轮、第二轮、第三轮和第四轮分别使用100nM、100nM、50nM和20nM的生物素化KRAS(G12C)-GDP+ARS-1620。第一轮回收结合至KRASG12C-GDP+ARS-1620的克隆；第二轮回收了结合至KRASG12C-GDP+ARS-1620的克隆，其先前用KRASG12C-GDP进行预清除；第三轮回收了结合至KRASG12C-GDP+ARS-1620的克隆，其先前已用KRASG12C-GTP预清除。最后一轮回收了与KRASG12C-GDP+ARS-1620结合的克隆，其先前用KRASG12C-GDP进行预清除。珠上捕获的噬菌体用100μl 0.1M Gly-HCl(pH 2.1)洗脱，并立即用35μl 1M Tris-Cl(pH 8)中和。如(2)所述，通过噬菌体ELISA和DNA测序分析回收的克隆。
珠结合试验
先前已描述过通用方法(3)。将50微升(50μl)的M280链霉亲和素珠(赛默飞世尔科技公司)与30nM或4nM的100μl生物素化12C-ARS Fab一起孵育。然后通过添加过量的生物素来封闭珠上的无配体链霉亲和素。用补充型TBST(50mM Tris pH7.5，150mM NaCl，20mMMgCl2，0.1mM DTT，0.05％Tween-20)洗涤珠，并将其分配到96孔U形孔板(格瑞纳(Greiner))的孔中。然后将珠以1:1的比例与稀释在补充型TBS(50mM Tris pH7.5，150mMNaCl，20mM MgCl2，0.1mM DTT)中的纯化RAS蛋白以滴定曲线所示浓度的2x在室温孵育30分钟。将含有结合的Fab和RAS的珠转移至96孔过滤板(密理博公司，MSHVN4550)的孔中，并用补充型TBST洗涤两次，然后与Neutravidin-Dylight 650(赛默飞世尔科技公司)在4℃孵育30分钟。将珠用补充型TBST洗涤两次，然后重新悬浮在补充型TBS中，使用iQue筛选器(赛多利斯)进行流式细胞术。将Dylight650通道中第75-95个百分位群体的中值信号强度视为与靶标的结合信号。通过将结合信号拟合到1:1结合模型来计算KD。
重组Fab的表达、纯化和表征
将噬菌体展示载体转化为Fab表达载体，该载体在重链的羧基末端含有生物素连接酶BirA的底物标签。Fab在大肠杆菌菌株55244(ATCC)中表达，并通过蛋白G亲和层析纯化，然后进行阳离子交换层析，如所述(2)。使用纯化的BirA在体外对纯化的Fab进行生物素化。通常从1L细菌培养物中获得约2-5mg纯化的Fab。SDS-PAGE显示Fab纯度>90％。
KRASG12C-加和物试验
如图所示，用ARS-1620和/或SHP099处理在6孔板中培养的细胞。通过在补充有蛋白酶抑制剂和磷酸酶抑制剂的GTP酶裂解缓冲液(25mM Tris-Cl pH7.2、150mM NaCl、5mMMgCl2、1％NP-40和5％甘油)中孵育15分钟以在分析前即刻裂解细胞。以15,000g离心15分钟后，收集上清液并与链霉亲和素(SA)琼脂糖树脂(赛默飞世尔科技公司(Thermo FisherScientific))在4℃孵育1小时，然后短暂离心，以减少与树脂的非特异性结合。将预澄清的裂解物与结合至SA琼脂糖的生物素化12C-ARS-Fab一起在4℃下旋转孵育1.5小时。然后用GTP酶裂解缓冲液洗涤琼脂糖珠两次，在1x SDS-PAGE样品缓冲液中煮沸，并用泛RAS抗体(Millipore)进行免疫印迹。
免疫印迹
全细胞裂解物在改良放射免疫沉淀(RIPA)缓冲液(50mM Tris-HCl pH 8.0、150mMNaCl、2mM EDTA、1％NP-40和0.1％SDS，不含脱氧胆酸钠)中生成，辅以蛋白酶(40μg/mlPMSF、2μg/ml抗痛剂、2μg/ml胃酶抑素A、20μg/ml亮抑酶肽和20μg/ml抑肽酶)和磷酸酶(10mM NaF、1mM Na3VO4、10mMβ-甘油磷酸盐和10mM焦磷酸钠)抑制剂。通过在微量离心机中通过离心澄清碎片后，使用DC蛋白试验试剂盒(Bio-Rad)对样品进行定量。通过标准SDS-PAGE解析总裂解物蛋白，并在1X转移缓冲液和15％甲醇中转移。将膜与各自的一抗和用IRDye(680nm和800nm)标记的二抗一起孵育，然后使用LICOR装置进行可视化。单克隆泛RAS抗体(克隆Ab-3；OP40-100UG；1:1000)购自密理博公司(Millipore)，小鼠单克隆ERK-2(D2:sc-1647；1:1000)购自圣克鲁兹生物技术公司(Santa Cruz Biotechnology)。
ARS结合至KRASG12C的LC/MS-MS试验
细胞(5x105)用如表中所列的时间处理指定化合物，然后用PBS冲洗两次，准备提取蛋白质并进行LC/MS-MS分析，如(4)所述。LC/MS-MS在纽约大学医学院的PCC蛋白质组学共享资源中心进行。
使用类似的方法获得实施例2中描述的结果。
本实施例所述的抗体如下：
结合至KRAS(G12C)-ARS-1620偶联物的示例性抗体克隆：CDR残基(Kabat编号)以粗体显示。
12C-ARS-Fab59
12C-ARS-Fab56
12C-ARS-Fab30
12C-ARS-Fab85
本参考文献列表适用于实施例1。
1.Spencer-Smith R，Koide A，Zhou Y，Eguchi RR，Sha F，Gajwani P，Santana D，Gupta A，Jacobs M，Herrero-Garcia E，Cobbert J，Lavoie H，Smith M，Rajakulendran T，Dowdell E，Okur MN，Dementieva I，Sicheri F，Therrien M，Hancock JF，Ikura M，KoideS，O'Bryan JP.通过靶向变构调节位点抑制RAS功能(Inhibition of RAS functionthrough targeting an allosteric regulatory site).Nat Chem Biol.2017；13(1):62-8.doi:10.1038/nchembio.2231.PubMed PMID:27820802；PMCID:5193369.
2.Fellouse FA，Esaki K，Birtalan S，Raptis D，Cancasci VJ，Koide A，JhuraniP，Vasser M，Wiesmann C，Kossiakoff AA，Koide S，Sidhu SS.从功能强大的简约噬菌体展示库中高通量生成合成抗体(High-throughput generation of synthetic antibodiesfrom highly functional minimalist phage-displayed libraries).J Mol Biol.2007；373(4):924-40.Epub 2007/09/11.doi:10.1016/j.jmb.2007.08.005.PubMed PMID:17825836.
3.Nishikori S，Hattori T，Fuchs SM，Yasui N，Wojcik J，Koide A，Strahl BD，Koide S.通过定量肽免疫沉淀测定揭示抗组蛋白抗体的广泛亲和力和特异性(Broadranges of affinity and specificity of anti-histone antibodies revealed by aquantitative Peptide immunoprecipitation assay).J Mol Biol.2012；424(5):391-9.Epub 2012/10/09.doi:10.1016/j.jmb.2012.09.022.PubMed PMID:23041298；PMCID:3502729.
4.Patricelli MP，Janes MR，Li LS，Hansen R，Peters U，Kessler LV，Chen Y，Kucharski JM，Feng J，Ely T，Chen JH，Firdaus SJ，Babbar A，Ren P，Liu Y.靶向非活性状态的小分子对致癌KRAS输出的选择性抑制(Selective Inhibition of Oncogenic KRASOutput with Small Molecules Targeting the Inactive State).Cancer Discov.2016；6(3):316-29.Epub 2016/01/08.doi:10.1158/2159-8290.Cd-15-1105.PubMed PMID:26739882.
5.doi.org/10.1084/jem.20201414
实施例2
本实施例提供了能与共价连接至肽的AMG510特异性结合的结合伴侣的描述。
为了产生本实施例中描述的结果，采用了实施例1中描述的一些方法。对于本实施例，AMG510(购自赛莱克化学公司(Selleckchem))偶联于对应于KRAS(G12C)残基4-18的肽：
H2N-YKLVVVGACGVGKSA(dPEG4)(K-长链生物素)-酰胺(SEQ ID NO:22)
和含有中心Cys的多聚Ser肽：
H2N-SSSSCSSSSW(K-长链生物素)-酰胺(SEQ ID NO:23)。
使用已建立的方法，使用这些肽作为靶标对人类单链Fv酵母展示文库进行分选(1-3)。经过几轮文库分选后，筛选出个体克隆。我们开发了三种结合至AMG510的抗体，该AMG510与KRAS(G12C)和多聚Ser肽偶联(图6)。因此，这些抗体主要识别AMG510部分，但不识别偶联物的肽部分。此外，我们还开发了其他对与KRAS(G12C)肽偶联的AMG510具有选择性的克隆。
然后产生了人IgG1形式的一个此类克隆P2AMR-1并进一步表征。在珠结合试验中，它以高表观亲和力与偶联有KRAS(G12C)肽的AMG510结合(图7)(4)。在HLA-A*03:01(白乐津(BioLegend)Flex-T)的情形下，抗体克隆也与偶联较短KRAS(G12C)肽(VVGACGVGK(SEQ IDNO:1))的AMG510紧密结合(图8)。
P2AMR-1检测到已添加至Raji细胞中的与KRAS(G12C)肽偶联的AMG510，已知Raji细胞表达HLA-A*03:01。相比之下，P2AMR-1没有检测到以相同方式装载的KRAS(野生型)肽(图16)。此外，P2AMR-1不结合至添加至未鉴定表达HLA-A*03:01的细胞(例如MV4-11和Expi293细胞)的与KRAS(G12C)肽偶联的AMG510(图16)。
这些结果显示本文提供的抗体(其代表本公开的结合伴侣)以未知偶联伴侣的方式识别AMG510部分，并且它们表明我们的抗体及其衍生物可用于确认细胞表面MHC分子上呈递AMG510-KRAS(G12C)多肽偶联物的细胞。
更一般地，这些结果提出了靶向任何具有与小分子配体形成共价加合物的胞内靶标的细胞的方法。
该实施例显示了以下非限制性结合伴侣，限于所描述作用物的AMG510共价修饰。CDR残基(Kabat方案)以粗体显示。
P2AMR-1
P2AMR-12(该克隆只有重链)
P2AMR-13
本参考文献列表适用于实施例2。
1.Chao G，Lau WL，Hackel BJ，Sazinsky SL，Lippow SM，Wittrup KD.使用酵母表面展示分离和工程化的人类抗体(Isolating and engineering human antibodies usingyeast surface display).Nat Protoc.2006；1(2):755-68.Epub2007/04/05.doi:10.1038/nprot.2006.94.PubMed PMID:17406305.
2.Feldhaus MJ，Siegel RW，Opresko LK，Coleman JR，Feldhaus JM，Yeung YA，Cochran JR，Heinzelman P，Colby D，Swers J，Graff C，Wiley HS，WittrupKD.从非免疫酿酒酵母表面展示文库中流式细胞术分离人抗体(Flow-cytometric isolation of humanantibodies from a nonimmune Saccharomyces cerevisiae surface displaylibrary).Nat Biotechnol.2003；21(2):163-70.Epub 2003/01/22.doi:10.1038/nbt785nbt785[pii].PubMed PMID:12536217.
3.Hattori T，Taft JM，Swist KM，Luo H，Witt H，Slattery M，Koide A，Ruthenburg AJ，Krajewski K，Strahl BD，White KP，Farnham PJ，Zhao Y，Koide S.组蛋白翻译后修饰的重组抗体(Recombinant antibodies to histone post-translationalmodifications).Nat Methods.2013；10(10):992-5.doi:10.1038/nmeth.2605.PubMedPMID:23955773；PMCID:3828030.
4.Nishikori S，Hattori T，Fuchs SM，Yasui N，Wojcik J，Koide A，Strahl BD，Koide S.通过定量肽免疫沉淀测定揭示抗组蛋白抗体的广泛亲和力和特异性(Broadranges of affinity and specificity of anti-histone antibodies revealed by aquantitative Peptide immunoprecipitation assay).J Mol Biol.2012；424(5):391-9.Epub 2012/10/09.doi:10.1016/j.jmb.2012.09.022.PubMed PMID:23041298；PMCID:3502729.
实施例3
本实施例描述了与肽-药物偶联物结合的抗体，但仅在所描述的肽-药物偶联物的特定MHC展示的情形下。抗体如下产生。
抗原制备
将KRAS(G12C)肽((H2N-VVGACGVGK-OH(SEQ ID NO:1)和H2N-VVVGACGVGK-OH(SEQID NO:2))与AMG510(赛莱克化学公司)反应并装载到Flex-T HLA-A*上03:01和Flex-THLA-A*11:01(由白乐津公司生产)，或装载到内部生产的HLA-A*03:01和HLA-A*11:01。以相同的方式将KRAS(WT)肽((H2N-VVGAGGVGK-OH(SEQ ID NO:29))装载到HLA分子上。EGFR肽(H2N-QLMPFGCLL-OH(SEQ ID NO：30))与奥西替尼(赛莱克化学公司)反应并装载到内部生产的Flex-T HLA-A*02:01或HLA-A*02:01上。作为对照，相同的肽与β-巯基乙醇反应并装载到HLA分子上。BTK肽(H2N-YMANGCLLNY-OH(SEQ ID NO:31))与依鲁替尼(赛莱克化学公司)反应并装载到内部生产的Flex-THLA-A*01:01或HLA-A*01:01上。作为对照，相同的肽与β-巯基乙醇反应并装载到HLA分子上。使用Flex-T HLA蛋白制备的肽装载的HLA混合物无需进一步纯化即可使用。使用内部制备的HLA样品制备的肽装载的HLA混合物使用SuperdexS200柱进行尺寸排阻色谱进一步纯化。
抗体噬菌体展示库分选
抗体噬菌体展示文库的分选如前所述进行(1)。简而言之，噬菌体展示文库首先在第一轮中以100nM的浓度对所有四种抗原进行分选，然后在第二轮、第三轮和第四轮中分别以100、50和20nM的单一抗原进行分选。为了富集具有所需特异性的克隆，在第二轮、第三轮和第四轮中使用KRAS(WT)肽装载的MHC分子或β-巯基乙醇处理的肽装载的MHC分子进行反选择。
使用多重珠结合试验测试个体噬菌体克隆的结合(2)。
抗体酵母展示文库分选和克隆表征
抗体克隆以单链Fv(scFv)的形式展示在酵母表面，使用荧光活化的细胞分选进行文库分选，并且个体克隆的表征基本上如前所述进行(Hattori等PMID 23955773；Cao等PMID 17406305)。
深度突变扫描
深度突变扫描按照先前发布的一般程序进行(PMID 32841599)。scFv形式的酵母展示文库包含单一位置与NNK密码子多样化的变体。使用感兴趣的抗原对酵母展示文库进行FACS，以富集结合抗原的克隆库和不结合抗原的克隆库。确定了富集池的DNA序列，并推导出氨基酸取代。
抗体生产
将编码选定抗体克隆的基因从噬菌体展示载体转移至IgG表达载体(pFUSEss-CHIg-hG1和pFUSE2ss-CLIg-hK，英韦沃基公司(InvivoGen)，并使用ExpiCHO细胞系(赛默飞世尔)生产IgG蛋白并使用含有蛋白A的蛋白质捕获装置(GORE)进行纯化。
本实施例中提供的数据涉及图9-15、17，它们提供了以下信息：
图9提供了本公开构思(称为HapImmune)的卡通展示。数字1-7表示相关步骤。1.给予共价抑制剂，它进入拥有靶蛋白的细胞。2.抑制剂结合靶标并与靶标形成共价键。3和4.作为天然蛋白质更新(或在PROTAC的情况下诱导蛋白质降解)的部分，靶标药物偶联物被蛋白酶体系统降解。结果产生了具有偶联药物的肽。5.将肽偶联物纳入相容的MHC分子中。6.MHC/肽-药物偶联物复合物易位至细胞表面。HapImmune抗体识别该复合物。7.表面结合的抗体招募免疫效应细胞(例如NK细胞)，进而起始细胞杀伤活性。设想了多种方式来影响细胞杀伤活性，包括ADCC、ADCP、CDC、BiTE、CAR-T、CAR-NK、ADC和放射性同位素偶联物，但此处未明确描述。
图10显示了能结合MHC/肽-药物偶联复合物的抗体开发的数据。(A)展示不同抗体克隆的噬菌体的多重珠结合试验(MBBA)(1)。对于各噬菌体克隆，测试了与珠上呈现的总共五种抗原的结合：HLA-A*03:01与偶联有AMG510的KRAS(G12C)肽形成复合物(图中表示为HLA-A*03:01_RAS-AMG510)；HLA-A*03:01与KRAS(野生型)肽复合(表示为HLA-A*03:01_WTRAS)；HLA-A*11:01与偶联有AMG510的KRAS(G12C)肽形成复合物(表示为HLA-A*11:01_RAS-AMG510)；HLA-A*11:01与KRAS(野生型)肽复合(表示为HLA-A*11:01_WTRAS)；不呈现抗原的珠子(表示为“无靶标”)。(B)对展示不同抗体克隆的噬菌体进行MBBA试验，这些抗体克隆针对：HLA-A*01:01复合偶联有依鲁替尼的BTK肽(图中表示为HLA-A*01:01_BTK-依鲁替尼)；HLA-A*01:01复合偶联有β-巯基乙醇的BTK肽(表示为HLA-A*01:01_BTK-βme)；不呈现抗原的珠子(表示为“无靶标”)。(C)对展示不同抗体克隆的噬菌体进行MBBA试验，这些抗体克隆针对：HLA-A*02:01复合偶联有奥西替尼的EGFR肽(图中表示为HLA-A*02:01_BTK-奥西替尼)；HLA-A*02:01复合偶联有β-巯基乙醇的EGFR肽(表示为HLA-A*02:01_EGFR-βme)；不呈现抗原的珠子(表示为“无靶标”)。
图11显示了对于靶向KRAS(G12C)-AMG510偶联物的纯化抗体使用多重串珠结合试验(MBBA)进行结合滴定的结果。克隆名称显示在各图表上。抗原命名如图10所示。左列显示与HLA-A*03:01复合物的结合数据，而右列显示与HLA-A*11:01复合物的结合数据。使用1:1结合函数的非线性最小二乘拟合确定表观解离常数(KD)值。野生型RA肽复合物和无靶标肽复合物的数据均接近基线且重叠，因此未确定其表观KD值。此处显示的数据来自三重复测量。误差线在符号的大小范围内。
图12表明抗体与MHC复合物中的药物-肽偶联物的结合不受游离药物存在的影响。图中显示了选择的“AMR”系列抗体与HLA-A*03:01在10μM游离AMG510不存在(白色柱状)和存在(灰色柱状)时的MBBA结合信号，其中所述HLA-A*03:01与偶联有AMG510的KRAS(G12C)肽形成复合物。调整抗体浓度以给出亚饱和信号并显示在括号中。此处显示的数据来自三重复测量。
图13显示使用靶向BTK-依鲁替尼偶联物的纯化抗体的多重珠结合试验(MBBA)的结合滴定的结果。克隆名称显示在各图表上。抗原命名如图10所示。使用1:1结合函数的非线性最小二乘拟合确定表观解离常数(KD)值。与HLA-A*01:01复合的β-巯基乙醇偶联肽和无靶标肽复合物的数据均接近基线且重叠，因此未确定其表观KD值。此处显示的数据来自三重复测量。误差线在符号的大小范围内。
图14显示纯化抗体与细胞表面内源性MHC分子呈现的KRAS(G12C)-AMG510偶联物的结合滴定的结果。首先将Raji细胞与KRAS(G12C)-AMG510偶联物或KRAS(野生型)肽一起孵育，并洗去多余的偶联物和肽。使用荧光标记的二抗检测到的表面结合抗体水平显示为用于染色的IgG浓度的函数。使用1:1结合函数的非线性最小二乘拟合确定表观解离常数(KD)值。此处显示的数据来自三重复测量。
图15显示了抗体结合至用AMG510预处理的表达KRAS(G12C)的细胞系的结果。将非小细胞肺癌细胞系H358与AMG510孵育2天，然后用靶向KRAS(G12C)肽-AMG510偶联物或同种型对照的抗体进行染色，然后用二抗进行检测。(A)流式细胞术直方图。(B)用或不用AMG510处理的H358细胞的中值荧光强度的定量。所用抗体沿横轴标出。(C)对用或不用AMG510处理并用AMRA3-7抗体染色的H358细胞和HEK293T细胞(阴性对照)的中值荧光强度进行定量。
图16与实施例相关并且显示了P2AMR-1IgG与用KRAS(G12C)肽-AMG510偶联物、KRAS(野生型)肽或无肽预孵育的细胞的结合。该抗体与染料标记的二抗预复合，以增强有效结合(亲合力)。当细胞与偶联物孵育时，抗体结合至表达HLA-A*03:01的Raji细胞。
图17显示了使用多重珠结合试验(MBBA)测量的IgG形式的纯化抗体与指定药物-肽/HLA复合物结合的结果。
图18和19在实施例4中进行讨论。
图20显示了AMR-A3-7和AMR-A3-7D在酵母表面上展示的结合滴定曲线的结果。显示了与HLA-A*03:01的结合，其呈递分别与9聚体和10聚体RAS(G12C)肽(VVGACGVGK(SEQ IDNO:1)和VVVGACGVGK)(SEQ ID NO:2)中的Cys残基偶联的AMG510。
图23和24分别显示了AMR-A3-7D和OEA2-5的CDR-L3和CDR-H3的深度突变扫描的结果。
以MHC-药物偶联物特异性方式结合的抗体序列的具体和非限制性实例如下：
与HLA-A*03:01和HLA-A*11:01上呈递的KRAS(G12C)-AMG510偶联物结合的示例性抗体克隆。CDR残基(Kabat方案)以粗体显示。
·AMRA3-2
·AMRA3-7
·AMRA3-7KK
·AMRA3-7D
·AMRA3-8
·AMRA3-11
·AMRA3-15
/>
·AMRA3-17
·AMRA3-18
·AMRA3-21
·AMRA3-22
·AMRA3-23
/>
·AMRA11-1
·AMRA11-2
·AMRA11-15
·AMRA11-16
·AMRA311-2
·AMRA311-10
·AMRA311-14
·AMRA311-16
·AMRA311-17
/>
·AMRA311-18
·AMRA311-19
·AMRA311-20
相对于HLA-A*11:01上呈递的相同偶联物，优先结合HLA-A*03:01上呈递的KRAS(G12C)-AMG510偶联物的抗体克隆。
CDR残基(Kabat方案)以粗体显示。
·AMRA3-5
/>
·AMRA3-6
·AMRA3-9
·AMRA3-10
·AMRA3-13
·AMRA3-19
·AMRA3-24
相对于HLA-A*03:01上呈递的KRAS(G12C)-AMG510偶联物，优先结合HLA-A*11:01上呈递的KRAS(G12C)-AMG510偶联物的抗体克隆。
·AMRA11-3
·AMRA11-4
·AMRA11-7
/>
·AMRA11-8
·AMRA11-9
·AMRA11-10
·AMRA11-11
·AMRA11-12
·AMRA11-13
·AMRA11-14
·AMRA11-18
·AMRA11-20
/>
·AMRA11-22
·AMRA11-24
与HLA-A*01:01上呈递的BTK-依鲁替尼偶联物结合的示例性抗体克隆。CDR残基(Kabat方案)以粗体显示。
·IBA1-4
·IBA1-7
·IBA1-8
·IBA1-12
·IBA1-13
·IBA1-19
·IBA1-21
/>
与HLA-A*02:01上呈递的EGFR-奥西替尼偶联物结合的示例性抗体克隆。CDR残基(Kabat方案)以粗体显示。
·OEA2-1
·OEA2-5
·OEA2-12
·OEA2-16
·OEA2-21
/>
·OEA2-24
与实施例3相关的参考文献：
1.Miller KR，Koide A，Leung B，Fitzsimmons J，Yoder B，Yuan H，Jay M，SidhuSS，Koide S，Collins EJ.合成抗体片段对体内肿瘤的T细胞受体样识别(Tcell receptor-like recognition of tumor in vivo by synthetic antibody fragment).PloSone.2012；7(8):e43746.Epub 2012/08/24.doi:10.1371/journal.pone.0043746.PubMedPMID:22916301；PMCID:3423377.
2.Hattori T，Koide A，Panchenko T，Romero LA，Teng KW，Corrado AD，Koide S.使用现成组件和普通流式细胞仪进行多重珠结合试验(Multiplex bead binding assaysusing off-the-shelf components and common flow cytometers).JImmunolMethods.2020:112952.Epub 2020/12/29.doi:10.1016/j.jim.2020.112952.PubMedPMID:33358997.
实施例4
该实施例显示了Hapimune抗体的单链双抗体(scDb)形式及其在细胞杀伤中的有效性。来自非限制性实施方式的数据呈现在图18和19中。结果如图18和19的简要描述所示。
为了获得图18的结果，将Raji细胞和T2细胞(ATCC)在补充有10％胎牛血清(FBS)和青霉素/链霉素的RPMI中培养。scDb的细胞毒性作用是按照之前发布的方案测量的(参考：PMID 26813960)。简而言之，Raji细胞或T2细胞用羧基荧光素琥珀酰亚胺酯(CSFE，赛默飞世尔，65-0850-84)染色，然后在10μg/mL人β-2微球蛋白存在的情况下与终浓度为10μMKRAS(G12C)-AMG510偶联物或1μMEGFR-奥西替尼一起孵育4小时。使用离心收获细胞并在培养基中洗涤以除去未结合的偶联物和肽。在单链双抗体(scDb)存在下，将肽-药物脉冲细胞与人T细胞(E:T＝3:1)共培养19-21小时。孵育后，收获细胞并用PBS洗涤，然后用固定活力染料eFluor660(赛默飞世尔，65-0864-14)染色。洗涤细胞后，在iQue筛选器(赛多利斯(Sartorius))上分析细胞。
为了获得图19的结果，将肺癌细胞系在补充有10％胎牛血清(FBS)和青霉素/链霉素的RPMI中培养。对于细胞毒性试验，将1x104个细胞/孔接种到96孔平底板中，并在37℃、5％CO2下孵育24小时。将培养基更换为补充有100nM AMG510或DMSO的新鲜培养基，然后将细胞在37℃下孵育24小时。孵育后，细胞与人T细胞(E:T＝5:1)和AMRA3-7_UCHT1 scDb在100IU/mL IL-2存在下于37℃共培养24小时。使用PrestoBlueTM细胞活力试剂(赛默飞世尔，A13261)评估细胞活力。细胞毒性的计算方法是获取给定孔的荧光信号，扣减仅含有T细胞孔的荧光信号，并针对不含scDb的孔的荧光信号进行标准化。
靶向HLA-A*03:01_RAS-AMG510和HLA-A*11:01_RAS-AMG510的示例性单链双抗体克隆
斜体序列分别代表AviTag和HisTag。
·AMRA3-7_UCHT1_scDb
·AMRA311-16_UCHT1_scDb
靶向HLA-A*02:01_EGFR-奥西替尼的示例性单链双抗体克隆
斜体序列分别代表AviTag和HisTag。
·OEA2-5_UCHT1_scDb
·OEA2-21_UCHT1_scDb
实施例5
本实施例显示了用AMRA3-7克隆构建的scDb和2+1CrossMab抗体及其杀伤细胞的有效性。来自非限制性实施方式的数据呈现在图21-22中。
为了获得图21(A)和图22(B)的结果，将Raji细胞(ATCC)在补充有10％胎牛血清(FBS)和青霉素/链霉素的RPMI中培养。scDb和CrossMab的细胞毒性作用是按照先前发布的方案测量的(参考：PMID 26813960)。简而言之，Raji细胞用羧基荧光素琥珀酰亚胺酯(CSFE，赛默飞世尔，65-0850-84)染色，然后在10μg/mL人β-2微球蛋白存在的情况下与10μMKRAS(G12C)-AMG510偶联物或10μM KRAS(WT)肽(终浓度)一起孵育4小时。通过离心收获细胞并在培养基中洗涤以除去未结合的偶联物和肽。在scDb或CrossMab存在下，将肽-药物脉冲细胞与人T细胞(E:T＝3:1)共培养。孵育后，收获细胞并用PBS洗涤，然后用固定活力染料eFluor660(赛默飞世尔，65-0864-14)染色。再次洗涤细胞后，在iQue筛选器(赛多利斯(Sartorius))上分析细胞。
为了获得图21(B)和图22(C)的结果，将H2122细胞(ATCC)在补充有10％胎牛血清(FBS)和青霉素/链霉素的RPMI中培养。对于细胞毒性试验，在1mM AMG510或DMSO和5μg/mL人β-2微球蛋白存在下，将5x103个细胞/孔接种到96孔平底板中，然后在37℃，5％CO2孵育48小时。孵育后，细胞与人T细胞(E:T＝10:1)和AMRA3-7D scDb或CrossMab在10ng/mL IL7和IL15存在下于37℃共培养24小时。使用CytoTox-Glo细胞毒性试验(普洛麦格公司(Promega)，G9290)测量死细胞。通过扣减含有H2122和不含scDb或CrossMab构建体的T细胞孔的信号来计算给定孔的发光信号。
为了获得图22(A)的结果，将Jurkat和Raji细胞(ATCC)在补充有10％胎牛血清(FBS)和青霉素/链霉素的RPMI中培养。用PBS洗涤细胞两次，然后用AMRA3-7D CrossMab在4℃孵育30分钟。用含有1％BSA的PBS(PBS/BSA)洗涤3次后，用Alexa647山羊抗人IgG Fc(杰克逊免疫研究公司(JacksonImmunoResearch)，109-605-098)对细胞进行染色。孵育后，用PBS/BSA洗涤细胞3次并在iQue筛选器(赛多利斯)上进行分析。
·AMRA3-7D_UCHT1_scDb
·AMRA3-7D_CrossMab
>链A.QMY30735.1
EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGLEWVSRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSSASVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY
ACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:149)
>链B.
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWYPAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDGGGGSGGGGSQAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQEKPGQAFRGLIGGTNKRAPGTPARFSGSLLGGKAALTLSGAQPEDEAEYYCALWYSNLWVFGGGTKLTVLSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP(SEQID NO:150)
>链C.
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWYPAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP(SEQ ID NO:151)
>链D.
DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQISYVKKLITFGQGTKVEIKRTVAAPSVFIFPPSDRKLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN
RGEC(SEQ ID NO:152)
图21显示单链双抗体(scDb)形式的AMRA3-7D的细胞毒性作用。(A)首先用偶联有AMG510的与KRAS(G12C)的片段对应的肽或与KRAS(野生型)对应的对照肽对Raji细胞进行脉冲。在指定浓度scDb存在下，将经脉冲细胞与人T细胞(效靶比＝3:1)共培养。孵育17小时后，对死细胞进行染色并通过流式细胞术检测。(B)首先将H2122细胞与AMG510或DMSO孵育。在指定浓度scDb存在下，接着将经脉冲细胞与人T细胞(效靶比＝10:1)共培养。孵育后，通过检测膜受损细胞释放的独特细胞内蛋白酶活性来测量死细胞。此处显示的数据来自三重复测量。误差线表示s.d.。如果误差线不可见，则误差小于符号。抗HLA-A3是阳性对照。
图22显示了CrossMab形式中AMRA3-7D的CD3结合性质和细胞毒性作用。(A)AMRA3-7 CrossMab与Jurkat(CD3阳性)和Raji(CD3阴性)细胞的结合滴定曲线。显示表观KD值。注意，细胞没有用任何肽脉冲。(B、C)AMRA3-7D CrossMab对用外源肽-药物偶联物脉冲的Raji细胞(B)和用药物处理的H2122细胞(C)的细胞毒性作用。所述方法与图22相同。此处显示的数据来自三重复测量。误差线表示s.d.。如果误差线不可见，则误差小于符号。抗HLA-A3作为阳性对照。
实施例6
本实施例显示了AMR-A3-7D和OEA2-5抗体的深度突变分析。来自非限制性实施方式的数据呈现在图23和24中。
为了确定AMR-A3-7D和OEA2-5 CDR中保持抗原结合的突变，我们对残基CDR-L3和CDR-H3进行了深度突变扫描。在酵母展示形式中，使用NNK密码子(N＝A、T、G和C；K＝G和T)将各CDR-L3和CDR-H3残基突变为所有遗传编码的氨基酸，每次突变一个残基。合并所得突变体池，并使用相关抗原(即与AMR-A3-7D的HLA-A*03:01复合的AMG510-KRAS(G12C)肽和与HLA-A*02:01复合的奥西替尼-EGF)对文库进行FACS。我们使用不同的抗原浓度来调整文库分选的严格性。通过在Illumina MiSeq仪器上进行深度测序来分析从能够结合和不能结合的池中回收的载体。通过DNA测序分析推导出不同池中存在的突变。
根据该分析，本公开提供了各CDR位置处的以下允许的突变，如下表所示。作为参考，显示了亲本克隆的VL和VH序列，其中分析的CDR残基以粗体和斜体显示。在实施方式中，本公开包括单独的各突变，以及突变的所有组合。因此，如从表中明显看出的，本公开包括具有1、2、3、4、5、6、7或8个突变的描述的CDR，如表中所示。本公开包括其它的氨基酸机会，如在CDR1、CDR2和框架序列中。
·AMRA3-7D
VL:DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPSRFSGSRSGTD FTLTISSLQP EDFATYYCQQ ISYVKKLITF GQGTKVEIKR TV(SEQ ID NO:3)
VH:EVQLVESGGG LVQPGGSLRL SCAASGFTFSDYSIHWVRQA PGKGLEWVAS ISSSSGSTSYADSVKGRFTI SADTSKNTAY LQMNSLRAED TAVYYCARGG WYPAMDYWGQ GTLVTVSS(SEQ ID NO:4)
/>
OEA2-5的深度突变扫描OEA2-5
/>
从上表中明显可以看出，在一个实施方式中，结合伴侣包含轻链和重链，所述轻链包含互补决定区3(CDR3)，所述互补决定区3包含序列SEQ ID NO:154，并且所述重链包含CDR3，所述CDR3包含SEQ ID NO:156的序列。在另一个实施方式中，结合伴侣包含轻链和重链，所述轻链包含CDR3，所述CDR3包含SEQ ID NO:158的序列，并且所述重链包含CDR3，所述CDR3包含SEQ ID NO:160的序列。
图23描述了AMR-A3-7D的CDR-L3和H3残基的深度突变扫描分析。(a)展示AMRA3-7D或其深度突变扫描文库群体的酵母细胞的代表性流式细胞术概况。测量了与5nM HLA-A*03:01的结合，其呈递与肽VVGACGVGK(SEQ ID NO:1)中的Cys残基偶联的AMG510。亲本抗体AMRA3-7D的概况显示在左侧，深度突变扫描库的分选子集的概况显示在右侧。文库使用1、3和10nM靶标进行分选，分别称为条件1、2和3，非结合剂池使用50nM靶标进行分选。(b)深度突变扫描库的分选子集中各位置的突变流行率以热图形式显示。深度测序读数的数量被标准化为各分选池的总读数并乘以1000。交叉表示野生型氨基酸。
图24描述了OEA2-5的CDR-L3和H3残基的深度突变扫描分析的结果。(a)展示单链Fv形式的OEA2-5及其深度突变扫描文库群体的酵母细胞的代表性流式细胞术概况。测量了与1.5nM链霉亲和素四聚体饱和的生物素化HLA-A*02:01的结合，所述生物素化HLA-A*02:01呈递与肽QLMPFGCLL(SEQ ID NO:30)中Cys残基偶联的奥西替尼。亲本抗体OEA2-5的概况显示在左侧，深度突变扫描库的排序子集的概况显示在右侧。文库使用12.5、2.5和0.5nM靶标进行分选，分别称为条件1、2和3，非结合剂池使用12.5nM靶标进行分选。(b)深度突变扫描库的分选子集中各位置的突变流行率以热图形式显示。深度测序读数的数量被标准化为各分选池的总读数并乘以1000。交叉表示野生型氨基酸。
本领域的技术人员通过考虑说明书和实施本文公开的公开内容，将会明显看出本公开的其他实施方式。本说明书和实例应仅视为示例性的，本公开真正的范围和精神由所附权利要求书来说明。
序列表
<110> 纽约大学(NEW YORK UNIVERSITY)
<120> 包含结合至共价肽偶联物的抗体的组合物和方法
<130> 058636.00402
<140>
<141>
<150> 63/253,499
<151> 2021-10-07
<150> 63/154,627
<151> 2021-02-26
<160> 165
<170> PatentIn版本3.5
<210> 1
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<400> 1
Val Val Gly Ala Cys Gly Val Gly Lys
1 5
<210> 2
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<400> 2
Val Val Val Gly Ala Cys Gly Val Gly Lys
1 5 10
<210> 3
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 3
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ile Ser Tyr Val Lys Lys
85 90 95
Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 4
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 4
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Trp Tyr Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 5
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 5
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Tyr Trp Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 6
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 6
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Ser Ser
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Pro Ser Tyr Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Tyr Val Thr Met Ala Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 7
<211> 18
<212> PRT
<213> 明脉扁刺蛾病毒(Thosea asigna virus)
<400> 7
Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro
1 5 10 15
Gly Pro
<210> 8
<211> 17
<212> PRT
<213> A型捷申病毒(Teschovirus A)
<400> 8
Ala Thr Asn Phe Ser Leu Lys Gln Ala Gly Asp Val Glu Asn Pro Gly
1 5 10 15
Pro
<210> 9
<211> 19
<212> PRT
<213> A型马鼻炎病毒(Teschovirus A)
<400> 9
Gln Cys Thr Asn Tyr Ala Leu Lys Leu Ala Gly Asp Val Glu Ser Asn
1 5 10 15
Pro Gly Pro
<210> 10
<211> 21
<212> PRT
<213>口蹄疫病毒
<400> 10
Val Lys Gln Thr Leu Asn Phe Asp Leu Lys Leu Ala Gly Asp Val Glu
1 5 10 15
Ser Asn Pro Gly Pro
20
<210> 11
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<400> 11
Gly Gly Gly Gly Ser Ala Ala Ala
1 5
<210> 12
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<400> 12
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 13
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
6xHis标签
<400> 13
His His His His His His
1 5
<210> 14
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 14
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Trp Tyr Phe Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 15
<211> 128
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Pro Ser Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Gly Gly Arg Ser Tyr Trp Gln Lys Gln Asp Ser Tyr Phe
100 105 110
Tyr Gln His Gly Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Ser Ser
115 120 125
<210> 16
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 16
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 17
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 17
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Tyr Ser Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Tyr Ser Tyr Ser Glu Phe Arg Tyr Tyr Tyr Ser Gly Gln
100 105 110
Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Ser Ser
115 120 125
<210> 18
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 18
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 19
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 19
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asn Tyr Gly Trp Arg Trp His Leu Val Gly Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 20
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 20
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 21
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 21
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Pro Tyr Val Tyr Tyr Trp Tyr Met Val Gly Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 22
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<400> 22
Tyr Lys Leu Val Val Val Gly Ala Cys Gly Val Gly Lys Ser Ala
1 5 10 15
<210> 23
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<400> 23
Ser Ser Ser Ser Cys Ser Ser Ser Ser Trp
1 5 10
<210> 24
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 24
Gln Ser Val Leu Ile Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Tyr Ala Asp Thr
85 90 95
Asp Thr Ile Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 25
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 25
Gln Val Gln Leu Val Gln Ser Glu Pro Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Thr Asp
20 25 30
Ala Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Tyr Met
35 40 45
Gly Gly Ile Ile Pro Leu Leu Asp Ser Val Asp Tyr Ala Gln Arg Phe
50 55 60
Gln Gly Arg Val Thr Val Ser Ala Asp Lys Ser Thr Gly Thr Ala Tyr
65 70 75 80
Met Glu Val Arg Ser Leu Gly Ser Glu Asp Thr Ala Lys Tyr Tyr Cys
85 90 95
Ala Lys Trp Ser Ser Val Asp Thr Gly Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 26
<211> 126
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 26
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Ile Asn Asp
20 25 30
Pro His Tyr Trp Gly Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Ser Thr Ser His Ser Gly His Thr Tyr Phe Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Ser Met Ser Ile Asp Val Ala Lys Asn Gln Phe
65 70 75 80
Ser Leu Asn Val Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Met Arg Tyr Tyr Tyr Ser Gly Thr Tyr Pro Val Tyr Tyr
100 105 110
Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 27
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 27
Ser Tyr Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Phe Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Ser Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Asp Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu
85 90 95
Asn Gly Pro Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu
100 105 110
<210> 28
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 28
Gln Val Gln Leu Val Gln Ser Glu Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr
20 25 30
Gly Val Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Asn Ser Ala Tyr Ser Asp Ala Phe Asn Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 29
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
<400> 29
Val Val Gly Ala Gly Gly Val Gly Lys
1 5
<210> 30
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<400> 30
Gln Leu Met Pro Phe Gly Cys Leu Leu
1 5
<210> 31
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<400> 31
Tyr Met Ala Asn Gly Cys Leu Leu Asn Tyr
1 5 10
<210> 32
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 32
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Gly Trp Ser Tyr Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 33
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 33
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Tyr Ser Ser
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Pro Tyr Tyr Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Tyr Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 34
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 34
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ile Ser Tyr Val Tyr Ser
85 90 95
Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 35
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 35
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Ser Ser Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Trp Tyr Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 36
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 36
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ile Ser Tyr Val Lys Lys
85 90 95
Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 37
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 37
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Ser Ser Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Trp Tyr Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 38
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 38
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Gln Tyr Gly Tyr Asn
85 90 95
Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 39
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 39
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Ser Tyr Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Ser Tyr Gly Trp Val Gly Pro Gly Trp Arg Ala Ile Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 40
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 40
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Val Tyr Lys
85 90 95
Leu Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 41
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 41
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Tyr Ser Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Pro Gly Trp Tyr Arg Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 42
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 42
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 43
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 43
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Phe Tyr Tyr Gly Trp Trp Ala Met Ala Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 44
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 44
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Gln Trp Tyr Glu Pro
85 90 95
Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 45
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 45
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Tyr Ser Ser
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Tyr Ser Tyr Met Ser Gln Trp Gly Trp Tyr Gln Tyr Ser
100 105 110
Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 46
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 46
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Ser Tyr Thr Tyr Arg
85 90 95
Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 47
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 47
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Ala Trp Trp Ala His Gly Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 48
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 48
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Ser Tyr Trp Tyr Asn
85 90 95
Leu Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 49
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 49
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Ser Tyr
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Ser Ser Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Tyr Ser Met His Phe Pro Trp Gly Tyr Gly Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 50
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 50
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asp Met Pro Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 51
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 51
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Tyr Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Tyr Ser Ser Ser Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Pro Val Asn Tyr Tyr Tyr Gln Gly Ala Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 52
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 52
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Val Phe Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 53
<211> 130
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 53
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Pro Ser Ser Gly Tyr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr His Tyr Met Phe Glu Tyr Asp Lys Gly Glu Ser Lys Trp
100 105 110
Gly Tyr Tyr Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
115 120 125
Ser Ser
130
<210> 54
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 54
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Gln Tyr Phe Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 55
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 55
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Ser Tyr Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Ser Trp Ser Trp Tyr Ser Gly Val Gly Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 56
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 56
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 57
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 57
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Tyr Ser Ser Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Pro Tyr Gly Trp Gly Trp Gly Gly Ser Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 58
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 58
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asp Phe Gln Tyr Leu
85 90 95
Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 59
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 59
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Ser Tyr Tyr Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Lys Trp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 60
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 60
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Tyr Tyr Gln Pro
85 90 95
Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 61
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 61
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Pro Tyr Asn Tyr Asn Trp Tyr Gly Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 62
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 62
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Leu Trp Trp Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 63
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 63
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Ser Tyr Ser Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Gly Ser Tyr Gly Ser Trp Trp Ala Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 64
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 64
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Phe Tyr Phe Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 65
<211> 128
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 65
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Tyr Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Tyr Tyr Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Ser Tyr Tyr Ser Gly Tyr Gly Ser Ser Tyr Pro Tyr Tyr
100 105 110
Met Gly Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 66
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 66
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Ser Tyr Arg Asn Pro
85 90 95
Leu Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 67
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 67
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Met Asn Trp Ser His Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 68
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 68
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 69
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 69
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Tyr Ser Gly Tyr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Trp Tyr Gly His Tyr His Ser Tyr Phe Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 70
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 70
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 71
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 71
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Tyr Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Pro Tyr Gly Ser His Val Tyr Thr Gly Leu Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 72
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 72
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Asn Trp Ala Asp Tyr
85 90 95
Leu Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 73
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 73
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Tyr Ser Ser Arg Tyr Trp Gly Trp Gly Val Ala Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 74
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 74
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Trp Tyr Ser Leu
85 90 95
Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 75
<211> 128
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 75
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Tyr Ser Ser Ser Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ser Phe Pro Gln Trp Tyr Asn Gly Ser Tyr Thr Pro Trp
100 105 110
Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 76
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 76
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Trp Trp Pro Val
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 77
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 77
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Ser Tyr Ser Ser Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Pro Phe Tyr Trp Gly Glu Arg Tyr Ala Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 78
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 78
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Val
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 79
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 79
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Tyr Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Ser Ser Tyr Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Tyr Gly Trp Ser Tyr Gln Gly Trp Ala Gly Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 80
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 80
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 81
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 81
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Pro Tyr Tyr Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Asp Tyr Tyr Trp Gly Trp Tyr Trp Val Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 82
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<220>
<221> MOD_RES
<222> (76)..(76)
<223> 任何氨基酸
<400> 82
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Xaa Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Lys Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 83
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 83
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Tyr Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Met Tyr Tyr Tyr Thr Tyr Pro Gly Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 84
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 84
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Lys Gly Ser Ser Tyr Leu Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 85
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 85
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Tyr Ser Tyr
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Pro Ser Ser Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr His Tyr Gly Gly Trp Ser His Tyr Met Ser Gly Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 86
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 86
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Tyr Tyr Tyr His Lys
85 90 95
Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 87
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 87
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Arg Tyr Gly Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 88
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 88
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Ser Tyr Val Tyr Lys
85 90 95
Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 89
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 89
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Tyr Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Trp Tyr Lys Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 90
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 90
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 91
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 91
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Tyr Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Met Tyr Tyr Tyr Tyr Tyr Pro Gly Ile Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 92
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 92
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Tyr Phe Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 93
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 93
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Pro Tyr Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Pro Tyr Tyr Trp Tyr Gln Tyr Phe Tyr Gly Trp Gly Leu
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 94
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 94
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 95
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 95
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Pro Tyr Trp Trp Asn Tyr Met Ser Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 96
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 96
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Trp Trp Trp Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 97
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 97
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Tyr
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Pro Tyr Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Gln Tyr Tyr Ser Gly His Ser Ser Trp Gly Leu
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 98
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 98
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Trp Tyr Phe Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 99
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 99
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Ser Tyr Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Tyr Asn Glu Tyr Tyr His Asp Tyr Tyr Trp Asp Ala Met
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 100
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 100
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 101
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 101
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Tyr Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Met Tyr Trp Trp Ser Phe Ala Leu Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 102
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 102
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Leu Trp Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 103
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 103
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Ser Tyr Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Gln Tyr His Tyr Asn Tyr Trp Tyr Gly Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 104
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 104
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Pro Met Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 105
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 105
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Pro Tyr Ser Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Asp Tyr Tyr Ala Gly Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 106
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 106
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Tyr Phe Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 107
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 107
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Pro Tyr Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Glu Ser Glu Tyr Ser Gly Thr Tyr Glu Asp Tyr Trp Ala
100 105 110
Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 108
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 108
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Met Trp Trp Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 109
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 109
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Tyr Ser Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Tyr Trp Gln Gly Tyr Leu Ala Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 110
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 110
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 111
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 111
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Tyr Tyr Tyr Tyr Trp Asn Ser Thr Pro Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 112
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 112
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Gly Tyr Pro Val
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 113
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 113
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Tyr Asn Ser Ser Trp Tyr Tyr Ser Asn Trp Trp Tyr Lys
100 105 110
Gly Phe Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
115 120 125
Ser
<210> 114
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 114
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Ser Leu Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 115
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 115
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Tyr Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Ser Tyr Thr Tyr Pro Val Tyr Thr Tyr Tyr Gly Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 116
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 116
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Trp Tyr Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 117
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 117
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Tyr Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Arg Tyr Ser Ser Trp Asn Arg Gly Ala Ile Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 118
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 118
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Trp Trp Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 119
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 119
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Ser Tyr Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Lys Ser Pro Trp Tyr Tyr Gln Gly Ile Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 120
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 120
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr His Tyr Trp Ala Ser
85 90 95
Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 121
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 121
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Ser Tyr Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Tyr Ser Ser Ser Tyr Tyr Val Trp Pro Gly Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 122
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 122
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Trp Trp Lys Ser
85 90 95
Leu Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 123
<211> 126
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 123
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Tyr Tyr Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Met His Tyr Ser Trp Gln Glu Tyr Tyr Ser Tyr Asp Trp Gly
100 105 110
Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 124
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 124
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Pro Tyr Tyr Pro Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 125
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 125
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Pro Ser Tyr Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Gln Gly Tyr Tyr Gln Pro Ala Leu Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 126
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 126
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Lys Tyr Tyr Tyr
85 90 95
Pro Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 127
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 127
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Pro Tyr Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Gly Tyr Gly Trp Tyr Trp Tyr Gly Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 128
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 128
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly His Asp Met Asn Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 129
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 129
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Ser Ser Tyr Gly Tyr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Tyr Tyr Trp Tyr Gly Gly Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 130
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 130
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Trp Met Ser Asp Ser
85 90 95
Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 131
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 131
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Pro Ser Ser Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Trp Trp Tyr Trp Met Ala Trp Asp Tyr Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 132
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 132
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Met Gln Tyr Ser Gly Trp
85 90 95
Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 133
<211> 130
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 133
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Tyr Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Ser Tyr Ser Ser Gly Tyr Gly Tyr Tyr Asp Tyr Phe
100 105 110
Asp Trp Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
115 120 125
Ser Ser
130
<210> 134
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 134
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 135
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 135
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Gly Tyr Val Trp Gly Gly Tyr Trp Gly Trp Trp Tyr
100 105 110
Ser Lys Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
115 120 125
Ser
<210> 136
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 136
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Trp Asn Tyr Tyr
85 90 95
Leu Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 137
<211> 126
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 137
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Tyr Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Tyr Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Gln Tyr Tyr Gly Ser Leu Tyr Tyr Ser Gln Gln Trp Ala
100 105 110
Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 138
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 138
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 139
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 139
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Pro Ser Ser Pro Tyr Phe Met Ser Trp Gly Trp Tyr Trp
100 105 110
Gln Tyr Gly Ile Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
115 120 125
Ser
<210> 140
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 140
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Trp Gly Gly Leu
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 141
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 141
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Pro Ser Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Met Tyr Glu Trp Trp His Trp Ala Ile Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 142
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 142
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ser Leu Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
<210> 143
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 143
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Gly His Tyr Leu Tyr Tyr Trp Gly Trp Gly Trp Tyr Trp
100 105 110
Ser Ala Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
115 120 125
Ser
<210> 144
<211> 514
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 144
Asp Ile Val Arg Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ile
85 90 95
Ser Tyr Val Tyr Ser Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu
100 105 110
Ile Lys Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro
115 120 125
Glu Leu Val Lys Pro Gly Ala Ser Met Lys Ile Ser Cys Lys Ala Ser
130 135 140
Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His
145 150 155 160
Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val
165 170 175
Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp
180 185 190
Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu
195 200 205
Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser
210 215 220
Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
225 230 235 240
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
260 265 270
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr
275 280 285
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
290 295 300
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly
305 310 315 320
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
325 330 335
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp
340 345 350
Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
355 360 365
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
370 375 380
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
385 390 395 400
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
405 410 415
Ala Ser Ile Tyr Ser Ser Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
420 425 430
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
435 440 445
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
450 455 460
Ala Arg Gly Gly Trp Tyr Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr
465 470 475 480
Leu Val Thr Val Ser Ser Leu Glu Gly Gly Gly Gly Leu Asn Asp Ile
485 490 495
Phe Glu Ala Gln Lys Ile Glu Trp His Glu Ser Arg His His His His
500 505 510
His His
<210> 145
<211> 517
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 145
Asp Ile Val Arg Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser
85 90 95
Ser Ser Ser Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu
115 120 125
Val Lys Pro Gly Ala Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr
130 135 140
Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys
145 150 155 160
Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr
165 170 175
Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser
180 185 190
Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser
195 200 205
Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp
210 215 220
Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
245 250 255
Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg
260 265 270
Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn
275 280 285
Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr
290 295 300
Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly
305 310 315 320
Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp
325 330 335
Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe
340 345 350
Ala Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Glu Val
355 360 365
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
370 375 380
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Ser Ser Ser Ile
385 390 395 400
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Tyr
405 410 415
Ile Ser Ser Tyr Ser Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly
420 425 430
Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln
435 440 445
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
450 455 460
Tyr Trp Tyr Gly His Tyr His Ser Tyr Phe Gly Leu Asp Tyr Trp Gly
465 470 475 480
Gln Gly Thr Leu Val Thr Val Ser Ser Leu Glu Gly Gly Gly Gly Leu
485 490 495
Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His Glu Ser Arg His
500 505 510
His His His His His
515
<210> 146
<211> 512
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 146
Asp Ile Val Arg Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr
85 90 95
Ser Tyr Trp Pro Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu
115 120 125
Val Lys Pro Gly Ala Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr
130 135 140
Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys
145 150 155 160
Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr
165 170 175
Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser
180 185 190
Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser
195 200 205
Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp
210 215 220
Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
245 250 255
Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg
260 265 270
Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn
275 280 285
Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr
290 295 300
Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly
305 310 315 320
Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp
325 330 335
Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe
340 345 350
Ala Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Glu Val
355 360 365
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
370 375 380
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Ser Ser Tyr Ile
385 390 395 400
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Tyr
405 410 415
Ile Ser Pro Ser Tyr Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys Gly
420 425 430
Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln
435 440 445
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
450 455 460
Glu Tyr Val Thr Met Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val
465 470 475 480
Thr Val Ser Ser Leu Glu Gly Gly Gly Gly Leu Asn Asp Ile Phe Glu
485 490 495
Ala Gln Lys Ile Glu Trp His Glu Ser Arg His His His His His His
500 505 510
<210> 147
<211> 516
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 147
Asp Ile Val Arg Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser
85 90 95
Ser Trp Gly Gly Leu Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu
115 120 125
Leu Val Lys Pro Gly Ala Ser Met Lys Ile Ser Cys Lys Ala Ser Gly
130 135 140
Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly
145 150 155 160
Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser
165 170 175
Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys
180 185 190
Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp
195 200 205
Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp
210 215 220
Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
245 250 255
Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp
260 265 270
Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu
275 280 285
Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr
290 295 300
Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser
305 310 315 320
Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu
325 330 335
Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr
340 345 350
Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Glu
355 360 365
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
370 375 380
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser Tyr
385 390 395 400
Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala
405 410 415
Ser Ile Ser Pro Ser Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val Lys
420 425 430
Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu
435 440 445
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
450 455 460
Arg Asp Met Tyr Glu Trp Trp His Trp Ala Ile Asp Tyr Trp Gly Gln
465 470 475 480
Gly Thr Leu Val Thr Val Ser Ser Leu Glu Gly Gly Gly Gly Leu Asn
485 490 495
Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His Glu Ser Arg His His
500 505 510
His His His His
515
<210> 148
<211> 514
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 148
Asp Ile Val Arg Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ile
85 90 95
Ser Tyr Val Lys Lys Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu
100 105 110
Ile Lys Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro
115 120 125
Glu Leu Val Lys Pro Gly Ala Ser Met Lys Ile Ser Cys Lys Ala Ser
130 135 140
Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His
145 150 155 160
Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val
165 170 175
Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp
180 185 190
Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu
195 200 205
Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser
210 215 220
Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
225 230 235 240
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
260 265 270
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr
275 280 285
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
290 295 300
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly
305 310 315 320
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
325 330 335
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp
340 345 350
Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
355 360 365
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
370 375 380
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
385 390 395 400
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
405 410 415
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
420 425 430
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
435 440 445
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
450 455 460
Ala Arg Gly Gly Trp Tyr Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr
465 470 475 480
Leu Val Thr Val Ser Ser Leu Glu Gly Gly Gly Gly Leu Asn Asp Ile
485 490 495
Phe Glu Ala Gln Lys Ile Glu Trp His Glu Ser Arg His His His His
500 505 510
His His
<210> 149
<211> 232
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 149
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Val
115 120 125
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
130 135 140
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
145 150 155 160
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
165 170 175
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
180 185 190
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
195 200 205
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
210 215 220
Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 150
<211> 671
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 150
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Trp Tyr Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Gly Gly
210 215 220
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln Glu Pro
225 230 235 240
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
245 250 255
Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gln Glu
260 265 270
Lys Pro Gly Gln Ala Phe Arg Gly Leu Ile Gly Gly Thr Asn Lys Arg
275 280 285
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
290 295 300
Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala Glu Tyr
305 310 315 320
Tyr Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly Gly Thr
325 330 335
Lys Leu Thr Val Leu Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
340 345 350
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
355 360 365
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
370 375 380
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
385 390 395 400
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
405 410 415
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
420 425 430
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
435 440 445
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
450 455 460
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
465 470 475 480
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
485 490 495
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
500 505 510
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
515 520 525
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
530 535 540
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
545 550 555 560
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
565 570 575
Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp
580 585 590
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
595 600 605
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
610 615 620
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
625 630 635 640
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
645 650 655
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
660 665 670
<210> 151
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 151
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Trp Tyr Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys
355 360 365
Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
<210> 152
<211> 216
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 152
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ile Ser Tyr Val Lys Lys
85 90 95
Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Arg Lys Leu Lys
115 120 125
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
130 135 140
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
145 150 155 160
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
165 170 175
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
180 185 190
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
195 200 205
Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 153
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<400> 153
Ile Ser Tyr Val Lys Lys Leu Ile
1 5
<210> 154
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> A, I, L, P, S, T, 或V
<220>
<221> MOD_RES
<222> (2)..(2)
<223> K, R, S, 或T
<220>
<221> MOD_RES
<222> (3)..(3)
<223> F 或Y
<220>
<221> MOD_RES
<222> (4)..(4)
<223> I, R, T, 或V
<220>
<221> MOD_RES
<222> (5)..(5)
<223> A, E, H, K, L, M, N, Q, R, S, T, 或Y
<220>
<221> MOD_RES
<222> (6)..(6)
<223> K 或R
<220>
<221> MOD_RES
<222> (7)..(7)
<223> A, C, D, E, G, H, K, L, M, N, P, Q, R, S, T, V, 或W
<220>
<221> MOD_RES
<222> (8)..(8)
<223> I, L, 或V
<400> 154
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 155
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<400> 155
Gly Gly Trp Tyr Pro Ala
1 5
<210> 156
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<220>
<221> MOD_RES
<222> (2)..(2)
<223> A, C, E, G, H, K, L, M, N, P, Q, R, S, T, W, 或Y
<220>
<221> MOD_RES
<222> (3)..(3)
<223> G, P, R, T, 或W
<220>
<221> MOD_RES
<222> (4)..(4)
<223> A, D, E, F, G, H, I, K, M, N, Q, R, S, T, W, 或Y
<220>
<221> MOD_RES
<222> (5)..(5)
<223> A, P, 或V
<220>
<221> MOD_RES
<222> (6)..(6)
<223> A, C, G, K, L, M, Q, R, S, T, 或Y
<400> 156
Gly Xaa Xaa Xaa Xaa Xaa
1 5
<210> 157
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<400> 157
Tyr Ser Tyr Trp Pro Ile
1 5
<210> 158
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<220>
<221> MOD_RES
<222> (2)..(2)
<223> A 或S
<220>
<221> MOD_RES
<222> (3)..(3)
<223> A, C, D, E, F, G, H, I, K, L, M, N, Q, R, S, T, V, W, 或Y
<220>
<221> MOD_RES
<222> (6)..(6)
<223> E, I, 或P
<400> 158
Tyr Xaa Xaa Trp Pro Xaa
1 5
<210> 159
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<400> 159
Glu Tyr Val Thr Met Ala Leu
1 5
<210> 160
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> D 或E
<220>
<221> MOD_RES
<222> (2)..(2)
<223> E, F, L, Q, S, W, 或Y
<220>
<221> MOD_RES
<222> (3)..(3)
<223> I, T, 或V
<220>
<221> MOD_RES
<222> (4)..(4)
<223> A, E, N, S, 或T
<220>
<221> MOD_RES
<222> (5)..(5)
<223> F, M, 或Y
<220>
<221> MOD_RES
<222> (6)..(6)
<223> A, C, G, S, 或T
<220>
<221> MOD_RES
<222> (7)..(7)
<223> A, C, E, F, H, I, K, L, M, N, P, Q, S, T, 或V
<400> 160
Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 161
<211> 488
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 161
Asp Ile Val Arg Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ile
85 90 95
Ser Tyr Val Tyr Ser Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu
100 105 110
Ile Lys Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro
115 120 125
Glu Leu Val Lys Pro Gly Ala Ser Met Lys Ile Ser Cys Lys Ala Ser
130 135 140
Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His
145 150 155 160
Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val
165 170 175
Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp
180 185 190
Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu
195 200 205
Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser
210 215 220
Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
225 230 235 240
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
260 265 270
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr
275 280 285
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
290 295 300
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly
305 310 315 320
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
325 330 335
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp
340 345 350
Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
355 360 365
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
370 375 380
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
385 390 395 400
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
405 410 415
Ala Ser Ile Tyr Ser Ser Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val
420 425 430
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
435 440 445
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
450 455 460
Ala Arg Gly Gly Trp Tyr Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr
465 470 475 480
Leu Val Thr Val Ser Ser Leu Glu
485
<210> 162
<211> 491
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 162
Asp Ile Val Arg Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser
85 90 95
Ser Ser Ser Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu
115 120 125
Val Lys Pro Gly Ala Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr
130 135 140
Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys
145 150 155 160
Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr
165 170 175
Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser
180 185 190
Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser
195 200 205
Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp
210 215 220
Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
245 250 255
Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg
260 265 270
Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn
275 280 285
Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr
290 295 300
Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly
305 310 315 320
Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp
325 330 335
Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe
340 345 350
Ala Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Glu Val
355 360 365
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
370 375 380
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Ser Ser Ser Ile
385 390 395 400
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Tyr
405 410 415
Ile Ser Ser Tyr Ser Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly
420 425 430
Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln
435 440 445
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
450 455 460
Tyr Trp Tyr Gly His Tyr His Ser Tyr Phe Gly Leu Asp Tyr Trp Gly
465 470 475 480
Gln Gly Thr Leu Val Thr Val Ser Ser Leu Glu
485 490
<210> 163
<211> 486
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 163
Asp Ile Val Arg Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr
85 90 95
Ser Tyr Trp Pro Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu
115 120 125
Val Lys Pro Gly Ala Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr
130 135 140
Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys
145 150 155 160
Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr
165 170 175
Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser
180 185 190
Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser
195 200 205
Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp
210 215 220
Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
245 250 255
Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg
260 265 270
Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn
275 280 285
Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr
290 295 300
Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly
305 310 315 320
Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp
325 330 335
Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe
340 345 350
Ala Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Glu Val
355 360 365
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
370 375 380
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Ser Ser Tyr Ile
385 390 395 400
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Tyr
405 410 415
Ile Ser Pro Ser Tyr Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys Gly
420 425 430
Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln
435 440 445
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
450 455 460
Glu Tyr Val Thr Met Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val
465 470 475 480
Thr Val Ser Ser Leu Glu
485
<210> 164
<211> 490
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 164
Asp Ile Val Arg Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser
85 90 95
Ser Trp Gly Gly Leu Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu
115 120 125
Leu Val Lys Pro Gly Ala Ser Met Lys Ile Ser Cys Lys Ala Ser Gly
130 135 140
Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly
145 150 155 160
Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser
165 170 175
Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys
180 185 190
Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp
195 200 205
Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp
210 215 220
Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
245 250 255
Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp
260 265 270
Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu
275 280 285
Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr
290 295 300
Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser
305 310 315 320
Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu
325 330 335
Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr
340 345 350
Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Glu
355 360 365
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
370 375 380
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser Tyr
385 390 395 400
Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala
405 410 415
Ser Ile Ser Pro Ser Tyr Gly Tyr Thr Ser Tyr Ala Asp Ser Val Lys
420 425 430
Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu
435 440 445
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
450 455 460
Arg Asp Met Tyr Glu Trp Trp His Trp Ala Ile Asp Tyr Trp Gly Gln
465 470 475 480
Gly Thr Leu Val Thr Val Ser Ser Leu Glu
485 490
<210> 165
<211> 488
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成
的多聚肽
<400> 165
Asp Ile Val Arg Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ile
85 90 95
Ser Tyr Val Lys Lys Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu
100 105 110
Ile Lys Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro
115 120 125
Glu Leu Val Lys Pro Gly Ala Ser Met Lys Ile Ser Cys Lys Ala Ser
130 135 140
Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His
145 150 155 160
Gly Lys Asn Leu Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val
165 170 175
Ser Thr Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp
180 185 190
Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu
195 200 205
Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser
210 215 220
Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Thr Leu Thr Val Ser
225 230 235 240
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
260 265 270
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr
275 280 285
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
290 295 300
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly
305 310 315 320
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
325 330 335
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp
340 345 350
Thr Phe Ala Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
355 360 365
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
370 375 380
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
385 390 395 400
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
405 410 415
Ala Ser Ile Ser Ser Ser Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val
420 425 430
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
435 440 445
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
450 455 460
Ala Arg Gly Gly Trp Tyr Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr
465 470 475 480
Leu Val Thr Val Ser Ser Leu Glu
485
Claims (39)
1.一种结合伴侣，其能与包含共价连接分子的蛋白质或肽(肽偶联物)上的位点特异性结合。
2.根据权利要求1所述的结合伴侣，其中所述结合伴侣不结合，或只能以较低亲和力结合不包含所述共价连接分子的对照蛋白质或对照肽。
3.根据权利要求1所述的结合伴侣，其中所述结合伴侣能特异性结合至所述肽偶联物，所述肽偶联物与主要组织相容性复合物(MHC)形成复合物。
4.根据权利要求3所述的结合伴侣，其中所述MHC是人白细胞抗原(HLA)。
5.根据权利要求1所述的结合伴侣，其中所述肽偶联物上的位点包含亲核或亲电残基，所述残基任选地是Cys、Lys、Tyr或His中的一种。
6.根据权利要求5所述的结合伴侣，其中所述位点包含该Cys。
7.根据权利要求6所述的结合伴侣，其中所述分子共价连接至该Cys。
8.根据权利要求1所述的结合伴侣，其中所述位点作为完整蛋白质中的肽偶联物存在，其中任选地所述完整蛋白质处于其天然构象。
9.根据权利要求1-8中任一项所述的结合伴侣，其中所述结合伴侣包含完整抗体、抗原结合(Fab)片段、Fab'片段、(Fab')2片段、Fd、Fv、dAb、单域片段或单个单体可变抗体结构域、单链双抗体(scDb)、单链可变片段(scFv)、双特异性T细胞接合物(BiTE)、双特异性杀伤细胞接合物(BiKE)、CrossMab、三特异性结合伴侣，或嵌合抗原受体(CAR)。
10.根据权利要求9所述的结合伴侣，其中所述结合伴侣偶联至可检测标记物、或化疗剂、放射性同位素或毒素。
11.根据权利要求9所述的结合伴侣，其中所述结合伴侣是融合蛋白的组分。
12.根据权利要求9所述的结合伴侣，其中所述肽偶联物包含与癌症相关的蛋白质区段。
13.根据权利要求9所述的结合伴侣，其中所述肽偶联物包含具有酶活性的蛋白质，并且其中共价连接分子是所述具有酶活性的蛋白质的抑制剂。
14.根据权利要求13所述的结合伴侣，其中所述具有酶活性的蛋白质是激酶或GTP酶。
15.根据权利要求9所述的结合伴侣，其中所述肽偶联物包含突变，并且其中所述肽偶联物的肽组分是以下或衍生自：布鲁顿酪氨酸激酶(BTK)、选自EGFR(ERBB1)、HER2/NEU(ERBB2)、HER3(ERBB3)和HER4(ERBB4)的任何表皮生长因子受体(EGFR)家族成员；MET(HGFR)；任何成纤维细胞生长因子受体(FGFR)；任何细胞周期蛋白依赖性激酶(CDK)；乙酰胆碱酯酶(ACHE)；p90核糖体S6激酶(RSK)；TP53、IDH1、GNAS、FBXW7、CTNNB1、DNMT3A、选自组织蛋白酶B、C、F、H、K、L、O、S、V、W和X的组织蛋白酶；任何半胱天冬酶；和与肥胖有关的蛋白质，任选地是胰脂肪酶或METAP2。
16.根据权利要求9所述的结合伴侣，其中所述多肽偶联物包含KRASG12C突变。
17.根据权利要求9所述的结合伴侣，其中所述肽偶联物包含KRASG12C突变，并且药物包含G12C抑制剂。
18.根据权利要求9所述的结合伴侣，其中所述肽偶联物包含EGFR的片段并且药物包含EGFR家族激酶的抑制剂。
19.根据权利要求9所述的结合伴侣，其中所述分子是以下中的一种：AMG510、奥西替尼、ARS-1620、MRTX849、JNJ74699157、LY3499446、MRTX-1275或G12C降解剂。
20.根据权利要求9所述的结合伴侣，其中所述结合伴侣能特异性结合至KRAS(G12C)-AMG510肽偶联物或HLA-A*03:01和/或HLA-A*11:01上呈递的所述肽偶联物。
21.根据权利要求9所述的结合伴侣，其中所述结合剂能特异性结合至肽偶联物，所述肽偶联物是任选地在HLA-A*01:01上呈递的BTK-依鲁替尼。
22.根据权利要求9所述的结合伴侣，其中所述结合剂能特异性结合至肽偶联物，所述肽偶联物是任选地在HLA-A*02:01上呈递的表皮生长因子受体(EGFR)-奥西替尼偶联物。
23.根据权利要求9所述的结合伴侣，其中所述结合伴侣包含至少一条重链(VH)，或至少一对轻链(VL)和重链，其各自与包含以下序列的重链和轻链对具有至少90％同一性：
AMRA3-7D:
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQISYVKKLITFGQGTKVEIKRTV(SEQ ID NO:3)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWYPAMDYWGQGTLVTVSS(SEQ ID NO:4)；
OEA2-5:
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYSYWPITFGQGTKVEIKRTV(SEQ ID NO:5)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTISSSYIHWVRQAPGKGLEWVAYISPSYGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCAREYVTMALDYWGQGTLVTVSS(SEQ ID NO:6)
P2AMR-1
VL:QSVLIQPRSVSGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSKRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCGSYADTDTIVFGTGTKLTVL(SEQ ID NO:24)
VH:QVQLVQSEPEVKKPGSSVKLSCKASGGTFSTDAITWVRQAPGQGLEYMGGIIPLLDSVDYAQRFQGRVTVSADKSTGTAYMEVRSLGSEDTAKYYCAKWSSVDTGLDYWGQGTLVTVSS(SEQ ID NO:25)
P2AMR-12
VH:QVQLQESGPGLVKPSETLSLTCTVSGDSIINDPHYWGWIRQSPGKGLEWIGSTSHSGHTYFNPSLKSRVSMSIDVAKNQFSLNVRSVTAADTAVYYCARMRYYYSGTYPVYYFDYWGQGTLVTVSS(SEQ ID NO:26)
P2AMR-13
VL:SYVLTQPPSASGTPGQRVTISCSGSSSNIGSNFVSWYQQLPGTAPKLLISSNNQRPSGVPDRFSGSKSDTSASLAISGLQSEDEADYYCAAWDDSLNGPVFGGGTQLTVL(SEQ ID NO:27)
VH:QVQLVQSEAEVKKPGSSVKVSCKASGGTFSRYGVSWVRQAPGQGLEWMGGIIPMFGTANYAQKFQGRVTITADESTSTAYMELRSLRSEDTAVYYCARGDNSAYSDAFNIWGQGTMVTVSS(SEQ ID NO:28)
AMRA3-2
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSGWSYPITFGQGTKVEIKRTV(SEQ ID NO:32)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFYSSYIHWVRQAPGKGLEWVASISPYYGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARSSYYALDYWGQGTLVTVSS(SEQ ID NO:33)
AMRA3-7
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQISYVYSLITFGQGTKVEIKRTV(SEQ ID NO:34)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSIHWVRQAPGKGLEWVASIYSSYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWYPAMDYWGQGTLVTVSS(SEQ ID NO:35)
AMRA3-7KK
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQISYVKKLITFGQGTKVEIKRTV(SEQ ID NO:36)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSIHWVRQAPGKGLEWVASIYSSYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWYPAMDYWGQGTLVTVSS(SEQ ID NO:37)
AMRA3-8
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDLATYYCQQYQYGYNLITFGQGTKVEIKRTV(SEQ ID NO:38)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTISYSSIHWVRQAPGKGLEWVASIYSYSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYSYGWVGPGWRAIDYWGQGTLVTVSS(SEQ ID NO:39)
AMRA3-11
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSSSVYKLLTFGQGTKVEIKRTV(SEQ ID NO:40)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTVYYSSIHWVRQAPGKGLEWVASISSSYSYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTALYYCARGGPGWYRAMDYWGQGTLVTVSS(SEQ ID NO:41)
AMRA3-15
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSSSSLITFGQGTKVEIKRTV(SEQ ID NO:42)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSSSSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGYFYYGWWAMAFDYWGQGTLVTVSS(SEQ ID NO:43)
AMRA3-17
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSQWYEPLITFGQGTKVEIKRTV(SEQ ID NO:44)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTIYSSYIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARSYSYMSQWGWYQYSGMDYWGQGTLVTVSS(SEQ ID NO:45)
AMRA3-18
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGSYTYRLITFGQGTKVEIKRTV(SEQ ID NO:46)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTVSYSSIHWVRQAPGKGLEWVASISSSSGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYAWWAHGLDYWGQGTLVTVSS(SEQ ID NO:47)
AMRA3-21
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYWYNLFTFGQGTKVEIKRTV(SEQ ID NO:48)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASIYSSYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARQYSMHFPWGYGMDYWGQGTLVTVSS(SEQ ID NO:49)
AMRA3-22
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSDMPPITFGQGTKVEIKRTV(SEQ ID NO:50)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFYSSSIHWVRQAPGKGLEWVAYIYSSSGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARPVNYYYQGALDYWGQGTLVTVSS(SEQ ID NO:51)
AMRA3-23
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYYVFPITFGQGTKVEIKRTV(SEQ ID NO:52)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTVYSSSIHWVRQAPGKGLEWVASISPSSGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYHYMFEYDKGESKWGYYGFDYWGQGTLVTVSS(SEQ ID NO:53)
AMRA11-1
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSQYFPITFGQGTKVEIKRTV(SEQ ID NO:54)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTISYSSIHWVRQAPGKGLEWVASIYSYYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARNSWSWYSGVGMDYWGQGTLVTVSS(SEQ ID NO:55)
AMRA11-2
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSSSSLITFGQGTKVEIKRTV(SEQ ID NO:56)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTISSSSIHWVRQAPGKGLEWVASISSYSSSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYPYGWGWGGSGLDYWGQGTLVTVSS(SEQ ID NO:57)
AMRA11-15
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQFDFQYLITFGQGTKVEIKRTV(SEQ ID NO:58)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTVYYSSIHWVRQAPGKGLEWVASIYSYYGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGEKWALDYWGQGTLVTVSS(SEQ ID NO:59)
AMRA11-16
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYMYYQPLITFGQGTKVEIKRTV(SEQ ID NO:60)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTVYYSSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCAREPYNYNWYGMDYWGQGTLVTVSS(SEQ ID NO:61)
AMRA311-2
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSLWWPITFGQGTKVEIKRTV(SEQ ID NO:62)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTVSSSSIHWVRQAPGKGLEWVASIYSYSGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARHGSYGSWWALDYWGQGTLVTVSS(SEQ ID NO:63)
AMRA311-10
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYFYFPITFGQGTKVEIKRTV(SEQ ID NO:64)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFYSSSIHWVRQAPGKGLEWVASISSYYGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARASYYSGYGSSYPYYMGLDYWGQGTLVTVSS(SEQ ID NO:65)
AMRA311-14
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGSYRNPLLTFGQGTKVEIKRTV(SEQ ID NO:66)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSIHWVRQAPGKGLEWVASISSSSGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARMNWSHYAMDYWGQGTLVTVSS(SEQ ID NO:67)
AMRA311-16
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSSSSLITFGQGTKVEIKRTV(SEQ ID NO:68)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTISSSSIHWVRQAPGKGLEWVAYISSYSGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYWYGHYHSYFGLDYWGQGTLVTVSS(SEQ ID NO:69)
AMRA311-17
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSSSSLITFGQGTKVEIKRTV(SEQ ID NO:70)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTISSSSIHWVRQAPGKGLEWVASISSYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYPYGSHVYTGLDYWGQGTLVTVSS(SEQ ID NO:71)
AMRA311-18
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQWNWADYLVTFGQGTKVEIKRTV(SEQ ID NO:72)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTISSSSIHWVRQAPGKGLEWVASIYSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARVYSSRYWGWGVAFDYWGQGTLVTVSS(SEQ ID NO:73)
AMRA311-19
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYYWYSLITFGQGTKVEIKRTV(SEQ ID NO:74)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTVYSSSIHWVRQAPGKGLEWVAYIYSSSGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRSFPQWYNGSYTPWPAMDYWGQGTLVTVSS(SEQ ID NO:75)
AMRA311-20
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYMWWPVTFGQGTKVEIKRTV(SEQ ID NO:76)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTVSSSSIHWVRQAPGKGLEWVASIYSYSSYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARPFYWGERYALDYWGQGTLVTVSS(SEQ ID NO:77)
AMRA3-5
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSYSTLVTFGQGTKVEIKRTV(SEQ ID NO:78)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFYSSSIHWVRQAPGKGLEWVASIYSSYGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARIYGWSYQGWAGMDYWGQGTLVTVSS(SEQ ID NO:79)
AMRA3-6
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSSSSLITFGQGTKVEIKRTV(SEQ ID NO:80)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTISYSSIHWVRQAPGKGLEWVASIYPYYGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGDYYWGWYWVAMDYWGQGTLVTVSS(SEQ ID NO:81)
AMRA3-9
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTIXSLQPEDFATYYCQKSSSSLITFGQGTKVEIKRTV(SEQ ID NO:82)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSSSYIHWVRQAPGKGLEWVASISSSYGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARMYYYTYPGMDYWGQGTLVTVSS(SEQ ID NO:83)
AMRA3-10
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQKGSSYLLTFGQGTKVEIKRTV(SEQ ID NO:84)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTIYSYSIHWVRQAPGKGLEWVASISPSSGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYHYGGWSHYMSGMDYWGQGTLVTVSS(SEQ ID NO:85)
AMRA3-13
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQNYYYHKLITFGQGTKVEIKRTV(SEQ ID NO:86)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSYSSIHWVRQAPGKGLEWVASISSSYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGRYGGMDYWGQGTLVTVSS(SEQ ID NO:87)
AMRA3-19
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQLSYVYKLITFGQGTKVEIKRTV(SEQ ID NO:88)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFYSSSIHWVRQAPGKGLEWVASISSSYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGWYKAMDYWGQGTLVTVSS(SEQ ID NO:89)
AMRA3-24
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSSSSLITFGQGTKVEIKRTV(SEQ ID NO:90)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSYSSIHWVRQAPGKGLEWVASISSSYGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARMYYYYYPGIDYWGQGTLVTVSS(SEQ ID NO:91)
AMRA11-3
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDLATYYCQQYYYFPITFGQGTKVEIKRTV(SEQ ID NO:92)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSSSSIHWVRQAPGKGLEWVASISPYYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARSPYYWYQYFYGWGLDYWGQGTLVTVSS(SEQ ID NO:93)
AMRA11-4
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSSSSLITFGQGTKVEIKRTV(SEQ ID NO:94)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSYSSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARSPYWWNYMSAMDYWGQGTLVTVSS(SEQ ID NO:95)
AMRA11-7
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGWWWPFTFGQGTKVEIKRTV(SEQ ID NO:96)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTVSSYSIHWVRQAPGKGLEWVASISPYYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWSWQYYSGHSSWGLDYWGQGTLVTVSS(SEQ ID NO:97)
AMRA11-8
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSWYFPLTFGQGTKVEIKRTV(SEQ ID NO:98)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTVSSSSIHWVRQAPGKGLEWVASIYSYYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWYNEYYHDYYWDAMDYWGQGTLVTVSS(SEQ ID NO:99)
AMRA11-9
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSSSSLITFGQGTKVEIKRTV(SEQ ID NO:100)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTLYYSSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWMYWWSFALDYWGQGTLVTVSS(SEQ ID NO:101)
AMRA11-10
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSYLWPITFGQGTKVEIKRTV(SEQ ID NO:102)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTVSSSSIHWVRQAPGKGLEWVASIYSYYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWQYHYNYWYGMDYWGQGTLVTVSS(SEQ ID NO:103)
AMRA11-11
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYPMSLITFGQGTKVEIKRTV(SEQ ID NO:104)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTVSYSSIHWVRQAPGKGLEWVASISPYSGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGYDYYAGLDYWGQGTLVTVSS(SEQ ID NO:105)
AMRA11-12
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYYYFPITFGQGTKVEIKRTV(SEQ ID NO:106)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSYYSIHWVRQAPGKGLEWVASISPYYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWESEYSGTYEDYWAGMDYWGQGTLVTVSS(SEQ ID NO:107)
AMRA11-13
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYMWWPITFGQGTKVEIKRTV(SEQ ID NO:108)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTISYSSIHWVRQAPGKGLEWVASISSSYSYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARTGYWQGYLALDYWGQGTLVTVSS(SEQ ID NO:109)
AMRA11-14
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSSSSLITFGQGTKVEIKRTV(SEQ ID NO:110)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTISYSSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARTYYYYWNSTPAMDYWGQGTLVTVSS(SEQ ID NO:111)
AMRA11-18
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSYGYPVTFGQGTKVEIKRTV(SEQ ID NO:112)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSSSSIHWVRQAPGKGLEWVASISSSYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWYNSSWYYSNWWYKGFGMDYWGQGTLVTVSS(SEQ ID NO:113)
AMRA11-20
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYYSSLFTFGQGTKVEIKRTV(SEQ ID NO:114)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFYSSSIHWVRQAPGKGLEWVASISSSYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARTSYTYPVYTYYGFDYWGQGTLVTVSS(SEQ ID NO:115)
AMRA11-22
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSWYYPLTFGQGTKVEIKRTV(SEQ ID NO:116)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTLYSSSIHWVRQAPGKGLEWVASISSSYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYRYSSWNRGAIDYWGQGTLVTVSS(SEQ ID NO:117)
AMRA11-24
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSYWWPLTFGQGTKVEIKRTV(SEQ ID NO:118)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTVSSSSIHWVRQAPGKGLEWVASIYSYYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWSKSPWYYQGIDYWGQGTLVTVSS(SEQ ID NO:119)
IBA1-4
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYHYWASLITFGQGTKVEIKRTV(SEQ ID NO:120)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTVSSSSIHWVRQAPGKGLEWVASIYSYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARQYSSSYYVWPGMDYWGQGTLVTVSS(SEQ ID NO:121)
IBA1-7
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSYWWKSLVTFGQGTKVEIKRTV(SEQ ID NO:122)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTLSSSSIHWVRQAPGKGLEWVASISSYYGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARMHYSWQEYYSYDWGMDYWGQGTLVTVSS(SEQ ID NO:123)
IBA1-8
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQPYYPLITFGQGTKVEIKRTV(SEQ ID NO:124)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTISYSSIHWVRQAPGKGLEWVASIYPSYGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWQGYYQPALDYWGQGTLVTVSS(SEQ ID NO:125)
IBA1-12
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSSKYYYPITFGQGTKVEIKRTV(SEQ ID NO:126)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTISSSSIHWVRQAPGKGLEWVASISPYYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWGYGWYWYGLDYWGQGTLVTVSS(SEQ ID NO:127)
IBA1-13
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGHDMNPVTFGQGTKVEIKRTV(SEQ ID NO:128)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTLSSSSIHWVRQAPGKGLEWVASIYSSYGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYYYWYGGMDYWGQGTLVTVSS(SEQ ID NO:129)
IBA1-19
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSWMSDSLITFGQGTKVEIKRTV(SEQ ID NO:130)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSYSSIHWVRQAPGKGLEWVASIYPSSGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGWWYWMAWDYAMDYWGQGTLVTVSS(SEQ ID NO:131)
IBA1-21
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQMQYSGWLITFGQGTKVEIKRTV(SEQ ID NO:132)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTISSSSIHWVRQAPGKGLEWVASISSYYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYSYSSGYGYYDYFDWGAMDYWGQGTLVTVSS(SEQ ID NO:133)
OEA2-1
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSSSSLITFGQGTKVEIKRTV(SEQ ID NO:134)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSSSSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYGYVWGGYWGWWYSKALDYWGQGTLVTVSS(SEQ ID NO:135)
OEA2-12
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYDWNYYLVTFGQGTKVEIKRTV(SEQ ID NO:136)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTIYSSSIHWVRQAPGKGLEWVASISSYYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYQYYGSLYYSQQWAMDYWGQGTLVTVSS(SEQ ID NO:137)
OEA2-16
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSSSSLITFGQGTKVEIKRTV(SEQ ID NO:138)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSSSSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARSPSSPYFMSWGWYWQYGIDYWGQGTLVTVSS(SEQ ID NO:139)
OEA2-21
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSSWGGLVTFGQGTKVEIKRTV(SEQ ID NO:140)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSSSYIHWVRQAPGKGLEWVASISPSYGYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARDMYEWWHWAIDYWGQGTLVTVSS(SEQ ID NO:141)
OEA2-24
VL:DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSSSSLITFGQGTKVEI KRTV(SEQ ID NO:142)
VH:EVQLVESGGGLVQPGGSLRLSCAASGFTFSSSSIHWVRQAPGKGLEWV ASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYGHY LYYWGWGWYWSAALDYWGQGTLVTVSS(SEQ ID NO:143)。
24.根据权利要求9所述的结合伴侣，其中所述结合伴侣包含轻链和重链，所述轻链包含含有SEQ ID NO:154序列的互补决定区3(CDR3)，所述重链包含含有SEQ ID NO:156序列的CDR3，或其中所述结合伴侣包含轻链和重链，所述轻链包含含有SEQ ID NO:158序列的CDR3，所述重链包含含有SEQ ID NO:160序列的CDR3。
25.根据权利要求9所述的结合伴侣，其中所述结合伴侣是单链双抗体(scDb)且包含与SEQ ID NO:165、SEQ ID NO:161、SEQ ID NO:162、SEQ ID NO:163或SEQ ID NO:164有至少95％同一性的序列。
26.根据权利要求9所述的结合伴侣，其中所述结合伴侣是CrossMab形式并且包含SEQID NO:149的序列。
27.根据权利要求24所述的结合伴侣，其中所述结合伴侣包含嵌合抗原受体。
28.根据权利要求27所述的结合伴侣，其中所述结合伴侣由T细胞或自然杀伤细胞表达。
29.一种包含肽偶联物和如权利要求9所述结合剂的复合物。
30.根据权利要求9所述的结合伴侣，其中所述结合伴侣包含Fc区段。
31.能编码根据权利要求9所述的结合伴侣的多核苷酸，其中所述多核苷酸包含DNA或mRNA，其中如果所述多核苷酸包含DNA，则所述DNA任选地是表达载体的组分。
32.一种真核细胞，其包含能编码根据权利要求9所述的结合伴侣的多核苷酸，其中所述细胞任选地是全能、专能或多能干细胞，其中任选地所述干细胞具有诱导干细胞表型，或其中所述细胞任选地是白细胞，并且其中所述白细胞任选地是T细胞或自然杀伤细胞。
33.一种方法，其包括向有需要的个体给予包含如权利要求9所述的结合伴侣或编码所述结合伴侣的多核苷酸的组合物。
34.根据权利要求33所述的方法，其中所述结合伴侣与化疗剂、放射性同位素或毒素偶联。
35.一种方法，其包括向有需要的个体给予根据权利要求32所述的细胞。
36.一种包括检测肽偶联物的方法，所述方法包括形成包含如权利要求9所述的肽偶联物和结合伴侣的复合物，其中所述结合伴侣以可检测方式标记，并且检测所述以可检测方式标记的结合伴侣的存在以确定所述肽偶联物的存在。
37.根据权利要求36所述的方法，其中检测所述结合伴侣包括诊断指示，并且其中所述结合伴侣任选地包含放射性偶联物。
38.根据权利要求36所述的方法，其中所述结合伴侣结合肽偶联物，并且其中所述肽偶联物存在于癌细胞表面，其中任选地所述癌细胞存在于肿瘤中。
39.根据权利要求36所述的方法，其包括使用根据权利要求9所述的结合伴侣筛选结合至包含共价附接分子的蛋白质或肽的多个分子。
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|---|---|---|---|
| US63/154,627 | 2021-02-26 | ||
| US202163253499P | 2021-10-07 | 2021-10-07 | |
| US63/253,499 | 2021-10-07 | ||
| PCT/US2022/018171 WO2022183112A2 (en) | 2021-02-26 | 2022-02-28 | Compositions and methods comprising antibodies that bind to covalent peptide conjugates |
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