CN114269389A - 靶向紧密连接蛋白18.2的抗体药物偶联物 - Google Patents
靶向紧密连接蛋白18.2的抗体药物偶联物 Download PDFInfo
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- CN114269389A CN114269389A CN202080053845.0A CN202080053845A CN114269389A CN 114269389 A CN114269389 A CN 114269389A CN 202080053845 A CN202080053845 A CN 202080053845A CN 114269389 A CN114269389 A CN 114269389A
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Abstract
提供了抗体药物偶联物,其包括连接至抗体或其片段的药物部分,所述抗体或其片段对野生型人紧密连接蛋白18.2(CLDN18.2)蛋白具有结合特异性。所述抗体或其片段与CLDN18.2的β3‑β4环(SEQ ID NO:30的第45‑63位残基,NYQGLWRSCVRESSGFTEC)和β5链(SEQ ID NO:30的第169‑172位残基,YTFG)结合。
Description
背景技术
紧密连接蛋白,如紧密连接蛋白18.2(claudin 18.2),被认为是癌症免疫疗法的有希望的靶点。紧密连接蛋白形成紧密细胞连接的重要组成部分的蛋白质家族。它们建立了一个细胞旁屏障,控制细胞之间的分子流动。这些蛋白质在细胞质中具有N末端和C末端。不同的紧密连接蛋白在不同的组织中表达,其功能的改变与相应组织的癌症形成有关。紧密连接蛋白-1在结肠癌中表达,紧密连接蛋白-18在胃癌中表达,紧密连接蛋白-10在肝细胞癌中表达。
紧密连接蛋白-18有两种亚型,亚型1和亚型2。亚型2(紧密连接蛋白18.2或CLDN18.2)是一种高度选择性的细胞谱系标志物。紧密连接蛋白18.2在正常组织中的表达严格局限于胃粘膜的分化上皮细胞,但在胃干细胞区不存在。紧密连接蛋白18.2在恶性转化时保留,并在相当一部分原发性胃癌及其转移灶中表达。在胰腺、食管、卵巢和肺肿瘤中也经常发现紧密连接蛋白18.2的异位激活。这些数据表明,CLDN18.2在正常组织中具有高度受限的表达模式,在多种人类癌症中频繁异位激活。
发明内容
本文发现抗紧密连接蛋白18.2抗体选择性地与野生型紧密连接蛋白18.2和常见突变体M149L结合,并且不与其他紧密连接蛋白18亚型结合,如紧密连接蛋白18.1。在一个令人惊讶和意外的发现中,本公开证明,这些抗体在诱导受体介导的抗体内化方面非常有效,特别是与正在进行临床开发的先导抗紧密连接蛋白18.2抗体IMAB362(克劳昔单抗(claudiximab))相比。因此,当与药物部分结合时,这些抗体能够有效地将药物递送到靶细胞中,如过表达紧密连接蛋白18.2蛋白的癌细胞。
本公开的抗体诱导受体介导的抗体内化的能力大大增强可能归因于这些抗体与紧密连接蛋白18.2蛋白结合的方式。如实施例14所证明的以及图20所说明的,紧密连接蛋白18.2蛋白上对与抗体结合重要的氨基酸残基包括那些对稳定细胞外环的构象重要的氨基酸残基(例如W30、L49、W50、C53、C63和R80)。更重要的是,考虑参与与抗体结合的残基包括N45、Y46、G48、V54、R55、E56、S58、F60和E62(位于第一细胞外环的β3链和β4链之间),以及Y169和G172(位于第二细胞外环的β5)。相比之下,据信已知的抗紧密连接蛋白18.2抗体仅结合所述细胞外环之一。
根据本公开的一个实施方案,提供了一种抗体药物偶联物,包括共价连接至抗体或其片段的药物部分,所述抗体或其片段对野生型人紧密连接蛋白18.2(CLDN18.2)蛋白具有结合特异性,其中所述抗体或其片段与CLDN18.2的β3-β4环和β5链结合。所述β3-β4环由SEQ ID NO:30的第45-63位残基(NYQGLWRSCVRESSGFTEC)组成,所述β5链由SEQ ID NO:30的第169-172位残基(YTFG)组成。
在一些实施方案中,药物部分的数量与抗体或片段的数量的比例为1:1至20:1。在一些实施方案中,所述比例为2:1至10:1。在一些实施方案中,所述比例为2:1至6:1。在一些实施方案中,所述比例为约2:1、2.5:1、3:1、3.5:1、4:1、4.5:1或5:1。
在一些实施方案中,所述抗体或其片段不与β1和β2结合,或以比与β3-β4环或β5链低至少10倍的亲和力与β1或β2结合。在一些实施方案中,所述抗体或其片段不与CLDN18.1蛋白结合,或以比与CLDN18.2低至少10倍的亲和力与CLDN18.1结合。
在一些实施方案中,所述抗体或其片段以至少是对野生型CLDN18.2蛋白的亲和力的1%的亲和力结合CLDN18.2 M149L突变体。
在一些实施方案中,所述抗体或其片段与选自由N45、Y46、G48、V54、R55、E56、S58、F60和E62组成的组中的至少一个氨基酸残基、以及选自由SEQ ID NO:30的Y169和G172组成的组中的至少一个氨基酸残基结合。
所述药物部分可以是细胞毒剂或细胞抑制剂、免疫抑制剂、放射性同位素、毒素等。所述药物部分一旦在癌细胞中释放,可以抑制癌细胞的增殖,或导致癌细胞的凋亡。药物部分的实例选自由DM1(美登素,N2'-脱乙酰基-N2'-(3-巯基-1-氧代丙基)-或N2'-脱乙酰基-N2'-(3-巯基-1-氧代丙基)-美登素)、mc-MMAD(6-马来酰亚胺己酰基-单甲基澳瑞他汀-D或N-甲基-L-缬氨酰-N-[(1S,2R)-2-甲氧基-4-[(2S)-2-[(1R,2R)-1-甲氧基-2-甲基-3-氧代-3-[[(1S)-2-苯基-1-(2-噻唑基)乙基]氨基]丙基]-1-吡咯烷基]-1-[(1S)-1-甲基丙基]-4-氧代丁基]-N-甲基-(9Cl)-L-缬氨酰胺)、mc-MMAF(马来酰亚胺己酰基-单甲基澳瑞他汀F或N-[6-(2,5-二氢-2,5-二氧代-1H-吡咯-1-基)-1-氧代己基]-N-甲基-L-缬氨酰-L-缬氨酰-(3R,4S,5S)-3-甲氧基-5-甲基-4-(甲氨基)庚酰-(αR,βR,2S)-β-甲氧基-α-甲基-2-吡咯烷丙酰基-L-苯丙氨酸)和mc-Val-Cit-PABA-MMAE(6-马来酰亚胺己酰基-ValcCit-(对氨基苄氧基羰基)-单甲基澳瑞他汀E或N-[[[4-[[N-[6-(2,5-二氢-2,5-二氧-1H-吡咯-1-基)-1-氧代己基]-L-缬氨酰-N5-(氨基羰基)-L-鸟氨酰]氨基]苯基]甲氧基]羰基]-N-甲基-L-缬氨酰-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-羟基-1-甲基-2-苯乙基]氨基]-1-甲氧基-2-甲基-3-氧代丙基]-1-吡咯烷基]-2-甲氧基-1-[(1S)-1-甲基丙基]-4-氧代丁基]-N-甲基-L-缬氨酰胺)组成的组。DM1是微管蛋白抑制剂美登素的衍生物,而MMAD、MMAE和MMAF是澳瑞他汀衍生物。
还提供了治疗疾病和病症的方法和用途。在一个实施方案中,提供了一种在有需要的患者中治疗癌症的方法,包括向所述患者施用本公开的抗体药物偶联物。
附图说明
图1通过流式细胞术显示所有小鼠在DNA免疫后的小鼠血清与转染CLD 18A2的HEK293细胞发生高滴度反应,CLD 18A1作为阴性对照。
图2通过细胞ELISA或流式细胞术显示杂交瘤上清液可以与转染人CLD18A2的HEK293细胞结合。
图3通过流式细胞术显示,与阳性参考抗体相比,纯化的鼠抗体可以以高EC50与转染人CLD18A2的MKN45细胞结合。
图4通过流式细胞术显示纯化的鼠抗体可以以高EC50与内源性表达带有M149L突变的人CLD18A2的SU620细胞结合,而参考抗体则不能。
图5通过流式细胞术显示纯化的鼠抗体可以以高EC50与转染小鼠CLD18A2的HEK293细胞结合。
图6通过流式细胞术显示纯化的鼠抗体可以以高EC50与转染猕猴CLD18A2的HEK293细胞结合。
图7通过流式细胞术显示纯化的鼠抗体可以以高EC50与转染人CLD18A2的HEK293细胞结合。
图8通过流式细胞术显示,与阳性参考抗体相比,嵌合抗体可以以高EC50与转染人CLD18A2的MKN45细胞结合。
图9通过流式细胞术显示嵌合抗体可以与转染人CLD18A1的MKN45细胞结合。
图10通过流式细胞术显示,与阳性参考抗体相比,人源化抗体可以以高EC50与转染人CLD18A2的MKN45细胞结合。
图11通过流式细胞术显示人源化抗体不能与转染人CLD18A1的MKN45细胞结合。
图12通过流式细胞术显示,与阳性参考抗体相比,具有CDR突变的人源化抗体可以以高EC50与转染人CLD18A2的MKN45细胞结合。
图13通过流式细胞术显示具有CDR突变的人源化抗体不能与转染人CLD18A1的MKN45细胞结合。
图14显示了去风险化的变体与细胞表面CLD18A2具有有效结合力。
图15显示了CLD18A2的某些突变对指定抗体与转染这些突变体的HEK293细胞的结合具有显著影响,表明这些氨基酸残基构成了表位的至少一部分。
图16显示,与175D10相比,抗体4F11E2、72C1B6A3和120B7B2在高表达紧密连接蛋白18.2和低表达紧密连接蛋白18.2的CHO-K1细胞中均具有优越的结合力。
图17显示了使用175D10抗体作为参考物的4F11E2、72C1B6A3和120B7B2的有效ADCC试验结果。
图18显示了4F11E2、72C1B6A3和120B7B2的S239D/I332E版本在ADCC试验中优于175D10对应物。
图19显示了4F11E2、72C1B6A3和120B7B2也比175D10具有更好的ADCP效应。
图20说明了紧密连接蛋白的3D结构和基序结构。
图21显示了测试嵌合抗体与参考抗体IMAB362相比在表达紧密连接蛋白18.2的CHO细胞上的内化结果。
图22显示了测试人源化抗体与参考抗体IMAB362相比在表达紧密连接蛋白18.2的CHO细胞上的内化结果。
图23显示了测试人源化抗体与参考抗体IMAB362相比在表达紧密连接蛋白18.2的MKN45细胞上的内化结果。
图24显示了抗体和其药物偶联物的结合亲和力。
图25A-C显示了测试抗体-MMAE偶联物在DAN-G、NUGC或SCG-7901转染子中内化后的细胞毒性。
图26显示了测试抗体-MMAE偶联物在内源性表达人紧密连接蛋白18.2的SNU620中内化后的细胞毒性。
图27比较了抗体药物偶联物与单独的抗体在受试动物中对肿瘤生长的减少。
图28显示了抗体药物偶联物的平均或单个肿瘤减少效果。
具体实施方式
定义
需要注意的是,术语“一个(a)”或“一种(an)”实体是指该实体中的一个或多个;例如,“抗体”被理解为代表一个或多个抗体。因此,术语“一个(a)”(或“一种(an))、“一个或多个”和“至少一个”在本文中可以互换使用。
如本文所用,术语“多肽”旨在涵盖单数“多肽”以及复数“多肽”,并指由单体(氨基酸)通过酰胺键(也称为肽键)线性连接组成的分子。术语“多肽”是指两个或更多个氨基酸的任意一条或多条链,而不是指产物的具体长度。因此,肽、二肽、三肽、寡肽、“蛋白质”、“氨基酸链”或任意其他用于指两个或更多个氨基酸的一条或多条链的术语,都包含在“多肽”的定义中,而且术语“多肽”可以用于代替这些术语中的任意一个,或与之互换使用。术语“多肽”也意指多肽表达后修饰的产物,包括但不限于糖基化、乙酰化、磷酸化、酰胺化、通过已知的保护/封闭基团衍生化、蛋白水解切割或通过非天然存在的氨基酸修饰。多肽可以来自天然生物来源或通过重组技术产生,但不一定由指定的核酸序列翻译而来。其可以以任何方式产生,包括通过化学合成。
如本文所用的关于细胞、核酸(如DNA或RNA)的术语“分离的”,是指分别从存在于大分子的天然来源中的其他DNA或RNA中分离的分子。如本文所用,术语“分离的”还指通过重组DNA技术产生时基本不含细胞材料、病毒材料或培养基的核酸或肽,或在化学合成时基本不含化学前体或其他化学品的核酸或肽。此外,“分离的核酸”意在包括不是作为片段天然存在并且不会在天然状态下被发现的核酸片段。术语“分离的”在本文也用于指从其他细胞蛋白或组织中分离的细胞或多肽。分离的多肽意在包括纯化的多肽和重组的多肽。
如本文所用,与多肽或多核苷酸有关的术语“重组”意指天然不存在的多肽或多核苷酸形式,其中一个非限制性实例可通过将通常不会一起出现的多核苷酸或多肽结合而生成。
“同源性”或“同一性”或“相似性”是指两个肽或两个核酸分子之间的序列相似性。同源性可以通过比较每个序列中的位置来确定,这些序列可以为了比较的目的而被比对。当比较序列中的某个位置被相同的碱基或氨基酸占据时,那么这些分子在该位置上是同源的。序列之间的同源性程度是序列共享的匹配或同源位置数量的函数。“不相关”或“非同源”的序列与本公开的序列之一具有低于40%的同一性,但优选低于25%的同一性。
多核苷酸或多核苷酸区域(或多肽或多肽区域)与另一个序列具有一定百分比(例如60%、65%、70%、75%、80%、85%、90%、95%、98%或99%)的“序列同一性”是指,在比对时,该百分比的碱基(或氨基酸)在两个序列的比较中是相同的。这种比对和百分比同源性或序列同一性可以使用本领域已知的软件程序来确定,例如Ausubel等编辑的CurrentProtocols in MolecularBiology(2007)中描述的那些。优选地,使用默认参数进行比对。一种使用默认参数的比对程序是BLAST。特别是程序为BLASTN和BLASTP,使用以下默认参数:遗传代码(genetic code)=标准;过滤器(filter)=无;链(strand)=两个(both);截止点(cutoff)=60;期望值(expect)=10;矩阵(Matrix)=BLOSUM62;说明(Descriptions)=50个序列;排序方式(sort by)=高分;数据库(Databases)=非冗余,GenBank+EMBL+DDBJ+PDB+GenBank CDS翻译+SwissProtein+SPupdate+PIR。生物学上等效的多核苷酸是具有上述特定百分比同源性并且编码具有相同或相似生物学活性的多肽的那些。
术语“等效核酸或多核苷酸”是指具有与核酸或其互补物的核苷酸序列具有一定程度同源性或序列同一性的核苷酸序列的核酸。双链核酸的同源物旨在包括具有与核苷酸序列或其互补物具有一定程度同源性的核苷酸序列的核酸。一方面,核酸的同源物能够与核酸或其互补物杂交。同样,“等效多肽”是指与参考多肽的氨基酸序列具有一定程度同源性,或序列同一性的多肽。在一些方面,所述序列同一性至少约为70%、75%、80%、85%、90%、95%、98%或99%。在一些方面,与参考多肽或多核苷酸相比,等效多肽或多核苷酸具有一个、两个、三个、四个或五个添加、缺失、取代及其组合。在一些方面,所述等效序列保留了参考序列的活性(例如表位结合)或结构(例如盐桥)。
杂交反应可以在不同“严格”条件下进行。通常,低严格杂交反应是在约40℃下、约10×SSC或同等离子强度/温度的溶液中进行。中等严格杂交通常在约50℃下、约6×SSC中进行,高严格杂交反应通常在约60℃下、约1×SSC中进行。杂交反应也可以在本领域技术人员公知的“生理条件”下进行。生理条件的一个非限制性实例是在细胞中通常发现的温度、离子强度、pH和Mg2+浓度。
多核苷酸由特定顺序的四种核苷酸碱基组成:腺嘌呤(A);胞嘧啶(C);鸟嘌呤(G);胸腺嘧啶(T);当多核苷酸为RNA时,尿嘧啶(U)表示胸腺嘧啶。因此,术语“多核苷酸序列”是多核苷酸分子的字母表示。这种字母表示可以输入到具有中央处理单元的计算机中的数据库中,并用于生物信息学应用,如功能基因组学和同源性检索。术语“多态性”是指基因或其部分的多于一种形式的共存。基因的一部分中至少有两种不同形式,即两种不同的核苷酸序列,被称为“基因的多态区”。多态区可以是单个核苷酸,其特性在不同等位基因中不同。
术语“多核苷酸”和“寡核苷酸”可互换使用,是指任意长度的核苷酸的聚合形式,可以是脱氧核糖核苷酸或核糖核苷酸或其类似物。多核苷酸可以具有任意三维结构并且可以执行任何已知或未知的功能。以下是多核苷酸的非限制性实例:基因或基因片段(例如探针、引物、EST或SAGE标签)、外显子、内含子、信使RNA(mRNA)、转运RNA、核糖体RNA、核酶、cDNA、dsRNA、siRNA、miRNA、重组多核苷酸、支链多核苷酸、质粒、载体、任何序列的分离DNA、任何序列的分离RNA、核酸探针和引物。多核苷酸可以包含修饰的核苷酸,如甲基化的核苷酸和核苷酸类似物。如果存在,可以在多核苷酸组装之前或之后赋予对核苷酸结构的修饰。核苷酸的序列可以被非核苷酸组分中断。多核苷酸可以在聚合后进一步修饰,如通过与标记组分的偶联。该术语还指双链分子和单链分子。除非另有说明或要求,本公开的任何实施方案中的多核苷酸都包括双链形式和已知或预测构成双链形式的两种互补单链形式中的每一种。
应用于多核苷酸的术语“编码”是指一种多核苷酸,如果在其天然状态下或当通过本领域技术人员公知的方法操作时,可以被转录和/或翻译以产生多肽和/或其片段的mRNA,则该多核苷酸被称为“编码”多肽。反义链是这种核酸的互补物,编码序列可以从中推导出来。
如本文所用,“抗体”或“抗原结合多肽”是指特异性识别和结合抗原的多肽或多肽复合物。抗体可以是完整的抗体和任何抗原结合片段或其单链。因此,术语“抗体”包括任何含有蛋白质或肽的分子,所述分子包括具有与抗原结合的生物活性的免疫球蛋白分子的至少一部分。这样的实例包括但不限于重链或轻链或其配体结合部分的互补性决定区(CDR)、重链或轻链可变区、重链或轻链恒定区、框架(FR)区或其任意部分,或结合蛋白的至少一部分。
如本文所用,术语“抗体片段”或“抗原结合片段”是抗体的一部分,如F(ab')2、F(ab)2、Fab'、Fab、Fv、scFv等等。无论结构如何,抗体片段与完整抗体识别的相同抗原结合。术语“抗体片段”包括适配体(aptamer)、镜像异构体(spiegelmer)和双抗体(diabody)。术语“抗体片段”还包括任何合成的或基因工程蛋白质,通过与特定的抗原结合形成复合物发挥类似于抗体的作用。
“单链可变片段”或“scFv”是指免疫球蛋白的重链可变区(VH)和轻链可变区(VL)的融合蛋白。在一些方面,这些区域以10至约25个氨基酸的短接头肽连接。所述接头可以富含甘氨酸以提高灵活性,以及富含丝氨酸或苏氨酸以提高溶解度,并且可以连接VH的N末端和VL的C末端,反之亦然。尽管去掉了恒定区并引入了所述接头,该蛋白仍保留了原始免疫球蛋白的特异性。ScFv分子在本领域是已知的,例如在美国专利5,892,019中有所描述。
术语抗体包括可以在生物化学上区分的各种广泛类别的多肽。本领域技术人员将理解重链分类为gamma、mu、alpha、delta或epsilon(γ、μ、α、δ、ε)以及其中的一些亚类(例如γ1-γ4)。正是这条链的性质决定了抗体的“类别”分别为IgG、IgM、IgA、IgG或IgE。免疫球蛋白的亚类(同种型),例如IgG1、IgG2、IgG3、IgG4、IgG5等已充分表征,并且已知会赋予功能的特殊性。鉴于本公开,这些类别和同种型中的每一个的修饰版本对于本领域技术人员而言是容易辨别的,并且因此属于本公开的范围。所有的免疫球蛋白类别显然都在本公开的范围内,下面的讨论将通常针对免疫球蛋白分子的IgG类别。关于IgG,标准的免疫球蛋白分子包括两条相同的分子量约为23,000道尔顿的轻链多肽,以及两条相同的分子量为53,000-70,000的重链多肽。这四条链通常通过二硫键连接成“Y”构型,其中轻链从“Y”的口开始将重链括起来并持续贯穿可变区。
本公开的抗体、抗原结合多肽、变体或其衍生物包括但不限于多克隆、单克隆、多特异性、人源、人源化、灵长类化或嵌合抗体、单链抗体、表位结合片段例如Fab、Fab'和F(ab')2、Fd、Fv、单链Fv(scFv)、单链抗体、二硫键连接的Fv(sdFv)、包含VK或VH结构域的片段、由Fab表达库产生的片段,以及抗独特型(抗Id)抗体(包括例如本文所公开的LIGHT抗体的抗Id抗体)。本公开的免疫球蛋白或抗体分子可以是免疫球蛋白分子的任何类型(例如IgG、IgE、IgM、IgD、IgA和IgY)、类别(例如IgGl、IgG2、IgG3、IgG4、IgAl和IgA2)或亚类。
轻链分为kappa或lambda(κ、λ)。每类重链可以与kappa或lambda轻链结合。一般来说,轻链与重链相互共价结合,并且当免疫球蛋白由杂交瘤、B细胞或基因工程宿主细胞产生时,两条重链的“尾”部通过二硫键共价连接或非共价连接而相互结合。在重链中,氨基酸序列从Y构型的分叉端的N末端延伸到每条链底部的C末端。
轻链和重链都分为结构和功能同源的区域。术语“恒定”和“可变”是在功能上使用的。在这方面,应理解轻链部分的可变结构域(VK)和重链部分的可变结构域(VH)决定了抗原识别和特异性。相反,轻链的恒定结构域(CK)和重链的恒定结构域(CH1、CH2或CH3)赋予重要的生物学特性,如分泌、跨胎盘迁移、Fc受体结合、补体结合等。按照惯例,恒定区结构域的编号随着它们远离抗原结合位点或抗体的氨基末端而增加。N末端部分是可变区并且在C末端部分是恒定区;CH3和CK结构域实际上分别包含重链和轻链的羧基末端。
如上所述,可变区允许抗体选择性识别并特异性结合抗原上的表位。也就是说,抗体的VK结构域和VH结构域或互补决定区(CDR)的子集组合形成可变区,所述可变区定义了三维抗原结合位点。这种四元抗体结构形成存在于Y的每个臂末端的抗原结合位点。更具体地说,抗原结合位点是由VH和VK链中每条链上的三个CDR(即CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3)定义。在一些情况下,例如,源自骆驼物种或基于骆驼免疫球蛋白工程化的某些免疫球蛋白分子,完整的免疫球蛋白分子可以只由重链组成,没有轻链。参见例如Hamers-Casterman等,Nature 363:446-448(1993)。
在天然存在的抗体中,每个抗原结合域中存在的六个“互补决定区”或“CDR”是氨基酸的短的、非连续的序列,由于抗体在水性环境中呈现其三维构型,这些氨基酸被特异性定位以形成抗原结合域。抗原结合域中的其余氨基酸,称为“框架”区,显示出较少的分子间差异性。框架区主要采用β片层构象,CDR形成环状连接所述β片层结构,并且在某些情况下形成β片层结构的一部分。因此,框架区起到形成支架的作用,通过链间、非共价相互作用将CDR定位在正确的方向。由定位的CDR形成的抗原结合域定义了与免疫活性抗原上的表位互补的表面。该互补的表面促进抗体与其同源表位的非共价结合。对于任何给定的重链或轻链可变区,本领域普通技术人员可以容易地鉴定分别包含CDR和框架区的氨基酸,因为它们已经被精确定义(参见“Sequences of Proteins of Immunological Interest”,Kabat,E.等,美国卫生与公众服务部,(1983);以及Chothia和Lesk,J.MoI.Biol.,196:901-917(1987))。
如果本领域内使用和/或接受的术语有两个或更多个定义,本文所用术语的定义旨在包括所有这些含义,除非明确指出相反。一个具体的例子是使用术语“互补决定区”(“CDR”)来描述在重链和轻链多肽的可变区中发现的非连续抗原结合位点。该特定区域描述于Kabat等,美国卫生与公众服务部,“Sequences of Proteins of ImmunologicalInterest”(1983)以及Chothia等,J.MoI.Biol.,196:901-917(1987),其全部内容通过引用并入本文。根据Kabat和Chothia的CDR定义包括在相互比较时氨基酸残基的重叠或子集。然而,应用任何一个定义来指代抗体或其变体的CDR旨在落入本文定义和使用的术语的范围内。包含由以上引用的每个文献所定义的CDR的合适的氨基酸残基在下表中列出作为比较。包含特定CDR的确切残基数将根据CDR的序列和大小而变化。给定抗体的可变区氨基酸序列,本领域技术人员可以常规地确定哪些残基包含特定的CDR。
Kabat | Chothia | |
CDR-H1 | 31-35 | 26-32 |
CDR-H2 | 50-65 | 52-58 |
CDR-H3 | 95-102 | 95-102 |
CDR-L1 | 24-34 | 26-32 |
CDR-L2 | 50-56 | 50-52 |
CDR-L3 | 89-97 | 91-96 |
Kabat等还定义了适用于任何抗体的可变结构域序列的编号系统。本领域普通技术人员可以明确地将这种“Kabat编号”系统分配给任何可变结构域序列,而无需依赖序列本身以外的任何实验数据。如本文所用,“Kabat编号”是指由Kabat等,美国卫生与公众服务部,“Sequences of Proteins of Immunological Interest”(1983)中提出的编号系统。
除上表外,Kabat编号系统对CDR区的描述如下:CDR-H1起始于约第31个氨基酸(即第一个半胱氨酸残基后约9个残基),包括约5-7个氨基酸,并终止于下一个色氨酸残基处。CDR-H2起始于CDR-H1末端后的第15个残基,包括约16-19个氨基酸,并终止于下一个精氨酸或赖氨酸残基处。CDR-H3起始于CDR-H2末端后约第33个氨基酸残基,包括3-25个氨基酸,并终止于序列W-G-X-G,其中X是任意氨基酸。CDR-L1起始于约第24个残基(即在半胱氨酸残基之后),包括约10-17个残基,并终止于下一个色氨酸残基处。CDR-L2起始于CDR-L1末端后约第16个残基,包括约7个残基。CDR-L3起始于CDR-L2末端后约第33个残基(即在半胱氨酸残基之后),包括约7-11个残基并终止于序列F或W-G-X-G,其中X是任意氨基酸。
本文公开的抗体可以来自任何动物来源,包括鸟类和哺乳动物。优选地,所述抗体是人、鼠、驴、兔、山羊、豚鼠、骆驼、美洲驼、马或鸡的抗体。在另一实施方案中,所述可变区可以是软骨鱼纲(condricthoid)来源(例如来自鲨鱼)。
如本文所用,术语“重链恒定区”包含源自免疫球蛋白重链的氨基酸序列。包含重链恒定区的多肽包含以下至少一种:CH1结构域、铰链结构域(例如上、中和/或下铰链区)、CH2结构域、CH3结构域,或其变体或片段。例如,用于本公开的抗原结合多肽可以包括含有CH1结构域的多肽链;含有CH1结构域、至少一部分铰链结构域和CH2结构域的多肽链;含有CH1结构域和CH3结构域的多肽链;含有CH1结构域、至少一部分铰链结构域和CH3结构域的多肽链,或含有CH1结构域、至少一部分铰链结构域、CH2结构域和CH3结构域的多肽链。在另一实施方案中,本公开的多肽包括含有CH3结构域的多肽链。此外,用于本公开的抗体可以缺少至少一部分CH2结构域(例如,全部或部分的CH2结构域)。如上所述,本领域普通技术人员将理解,重链恒定区可以被修饰,从而使它们在氨基酸序列上与天然存在的免疫球蛋白分子不同。
本文公开的抗体的重链恒定区可以源自不同的免疫球蛋白分子。例如,多肽的重链恒定区可以包含源自IgG1分子的CH1结构域以及源自IgG3分子的铰链区。在另一个实例中,重链恒定区可以包含部分源自IgG1分子且部分源自IgG3分子的铰链区。在另一个实例中,重链部分可以包含部分源自IgG1分子且部分源自IgG4分子的嵌合铰链。
如本文所用,术语“轻链恒定区”包含源自抗体轻链的氨基酸序列。优选地,所述轻链恒定区包含kappa恒定结构域或lambda恒定结构域的至少一种。
“轻链-重链对”是指轻链和重链的集合,可以通过轻链的CL结构域和重链的CH1结构域之间的二硫键形成二聚体。
如前所述,各种免疫球蛋白类别的恒定区的亚单位结构和三维构型是公知的。如本文所用,术语“VH结构域”包括免疫球蛋白重链的氨基末端可变结构域,并且术语“CH1结构域”包括免疫球蛋白重链的第一个(最氨基末端)恒定区结构域。所述CH1结构域与VH结构域相邻并且位于免疫球蛋白重链分子铰链区的氨基末端。
如本文所用的术语“CH2结构域”包括重链分子的部分,例如使用传统的编号方案,从抗体的约第244个残基延伸至第360个残基(第244个残基至第360个残基,Kabat编号系统;以及第231个残基至第340个残基,EU编号系统;参见Kabat等,美国卫生与公众服务部,“Sequences of Proteins of Immunological Interest”(1983)。CH2结构域的独特之处在于它没有与另一个结构域紧密配对。相反,在完整的天然IgG分子的两个CH2结构域之间插有两条N-连接的支化碳水化合物链。也有资料显示,CH3结构域从CH2结构域延伸到IgG分子的C末端并且包含大约108个残基。
如本文所用,术语“铰链区”包括将CH1结构域连接到CH2结构域的重链分子的部分。所述铰链区包含约25个残基并且是灵活的,因此允许两个N末端抗原结合区独立移动。铰链区可以细分为三个不同的结构域:上、中和下铰链结构域(Roux等,J.Immunol 161:4083(1998))。
如本文所用的术语“二硫键”包括两个硫原子之间形成的共价键。氨基酸半胱氨酸包含一个硫醇基团,可以与第二个硫醇基团形成二硫键或桥。在大多数天然存在的IgG分子中,CH1和CK区通过一个二硫键连接,并且两条重链通过在使用Kabat编号系统对应于第239位和第242位(第226位或第229位,EU编号系统)的两个二硫键连接。
如本文所用,术语“嵌合抗体”将被认为是指任意抗体,其中免疫活性区或位点从第一物种获得或衍生,并且恒定区(根据本公开,可以是完整的、部分的或修饰的)从第二物种获得。在某些实施方案中,目标结合区或位点将来自非人类来源(例如小鼠或灵长类),并且恒定区是人的。
如本文所用,“人源化百分比”是通过确定人源化结构域和种系结构域之间的框架氨基酸差异(即非CDR差异)的数量,从氨基酸总数中减去该数量,然后除以氨基酸总数并乘以100计算的。
“特异性结合”或“对……具有特异性”通常是指抗体通过其抗原结合结构域与表位结合,并且结合需要抗原结合结构域和表位之间的某种互补性。根据该定义,当抗体通过其抗原结合结构域与表位结合比抗体与随机的、不相关的表位结合更容易时,该抗体被称为“特异性结合”该表位。术语“特异性”在本文中用于限定某一抗体与某表位结合的相对亲和力。例如,可以认为对于一个给定的表位,抗体“A”比抗体“B”具有更高的特异性,或者说抗体“A”与表位“C”的结合比与相关表位“D”的结合有更高的特异性。
如本文所用,术语“治疗(treat)”或“治疗(treatment)”是指治疗性治疗和预防性或预防措施,其中目的是预防或减缓(减轻)不希望的生理变化或紊乱,如癌症的进展。有益的或期望的临床结果包括但不限于症状的缓解、疾病程度的减轻、疾病的稳定(即,不恶化)状态、疾病进展的延迟或减缓、疾病状态的改善或缓和,以及缓解(无论是部分还是全部),无论是可检测的还是不可检测的。“治疗(Treatment)”还可以指与未接受治疗的预期生存期相比延长生存期。需要治疗的那些包括已经患有该病症或紊乱的那些,以及易于患有该病症或紊乱的那些或要预防该病症或紊乱的那些。
“受试者”或“个体”或“动物”或“患者”或“哺乳动物”是指需要诊断、预后或治疗的任何受试者,特别是哺乳动物受试者。哺乳动物受试者包括人类、家畜、农场动物和动物园、运动或宠物动物如狗、猫、豚鼠、兔、大鼠、小鼠、马、牛、奶牛等。
如本文所用,诸如“对需要治疗的患者”或“需要治疗的受试者”的短语包括将从例如用于检测、诊断程序和/或治疗的本公开的抗体或组合物的施用中受益的受试者,如哺乳动物受试者。
抗紧密连接蛋白18.2抗体和片段
本公开提供了对野生型紧密连接蛋白18.2和常见突变体M149L(SU620细胞内源性表达该突变)都具有高亲和力的抗紧密连接蛋白18.2抗体。据发明人所知,目前所有已知的抗紧密连接蛋白18.2蛋白都不与该突变体结合。因此,本公开的抗体具有能够靶向野生型和M149L突变体紧密连接蛋白18.2蛋白的独特优势。这一优势很重要,因为相当一部分癌症患者携带这种常见的突变。还值得注意的是,本公开的抗体不与其他紧密连接蛋白18亚型即紧密连接蛋白18.1结合(或以低得多的亲和力结合紧密连接蛋白18.1)。
本公开的抗体和片段即使在使用临床候选药物作为参考物时也表现出优越的特性。175D10(IMAB362;克劳昔单抗)目前正在进行治疗胃和胃食管交界处腺癌的III期临床试验。与175D10相比,本发明的抗体和片段不仅表现出更强的结合活性,而且在各种不同条件下也表现出更高的ADCC和ADCP活性。
同样重要的是,本公开证明了这些抗体在诱导受体介导的抗体内化方面非常有效,即使与IMAB362相比也是如此。本公开的抗体诱导受体介导的抗体内化的能力大大增加,考虑可以归因于这些抗体如何与紧密连接蛋白18.2蛋白结合。如实施例14所证明的以及图20所说明的,紧密连接蛋白18.2蛋白上对与抗体结合重要的氨基酸残基包括那些对稳定细胞外环的构象重要的氨基酸残基(例如W30、L49、W50、C53、C63和R80)。W30、L49和W50是W-LW-C-C共有基序的一部分,有助于稳定环1的构象。C53和C63形成β-链间二硫键。R80可能对维持细胞表面平行的紧密连接蛋白18.2分子之间的相互作用、或对稳定环1的构象重要。
对抗体结合同样重要的还有残基N45、Y46、G48、V54、R55、E56、S58、F60、E62、Y169和G172。其中,N45、Y46、G48、V54、R55、E56、S58、F60和E62位于β3链内,或穿过β4链中的C63。该区域由SEQ ID NO:30的第45-63位残基(NYQGLWRSCVRESSGFTEC)组成,在此称为“β3至β4环”,它是紧密连接蛋白18.2的第一细胞外环(环1)的一部分。相比之下,Y169和G172是第二细胞外环(环2)的β5链(SEQ ID NO:30的第169-172位残基;YTFG)的一部分。
本公开的抗体诱导受体介导的抗体内化的活性大大增加,考虑是由于它们与β3至β4环和β5链的残基结合的能力。在这种情况下,据信已知的抗紧密连接蛋白18.2抗体只与这些环之一结合。
实验数据还表明,与已知抗体相比,本公开的抗体具有更高的结合特异性和改善的ADCC和ADCP。
人紧密连接蛋白18.2序列
根据本公开的一个实施方案,提供了一种对野生型人紧密连接蛋白18.2(CLDN18.2)蛋白具有结合特异性的抗体或其片段,其中所述抗体或其片段同时与CLDN18.2的所述第一细胞外环和所述第二细胞外环结合。在一些实施方案中,所述抗体或其片段同时与CLDN18.2的所述β3-β4环和所述β5链结合。
根据本公开的另一个实施方案,提供了一种对野生型人紧密连接蛋白18.2(CLDN18.2)蛋白具有结合特异性的抗体或其片段,其中所述抗体或其片段进一步与所述CLDN18.2蛋白的M149L突变体结合。在一些实施方案中,所述抗体或其片段不与人野生型紧密连接蛋白18.1(CLDN18.1)蛋白结合,或不以大于与所述野生型CLDN18.2蛋白的亲和力约1%的亲和力结合CLDN18.1。
抗体或片段与蛋白质的结合亲和力可以用本领域已知的许多方法测量。例如,可以用独立的CLDN18.1蛋白或CLDN18.2蛋白进行无细胞测定。然而,优选地,用模拟实际结合环境的细胞表面上的CLDN18.1蛋白或CLDN18.2蛋白进行测量。在实验例中充分例证了这样的结合测定。
在一些实施方案中,所述抗体或其片段对M149L突变体具有的结合亲和力是对所述野生型CLDN18.2蛋白的亲和力的至少1%,或者至少0.001%、0.01%、0.1%、0.5%、2%、3%、5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、60%、70%、80%、90%、95%、98%或99%。
在一些实施方案中,所述抗体或其片段不与人CLDN18.1结合。在一些实施方案中,与结合CLDN18.2相比,所述抗体或其片段与人CLDN18.1的结合弱得多,例如但不限于,不高于10%、5%、2%、1%、0.5%、0.1%、0.05%、0.01%、0.005%或0.001%。
如上所述,本公开的所述抗体及其片段在不同于已知抗体的表位处与紧密连接蛋白18.2结合(参见图4;至少参考抗体与M149相互作用,而本公开的抗体则没有)。因此,在一个实施方案中,提供了一种与野生型人紧密连接蛋白18.2(CLDN18.2)蛋白具有结合特异性的抗体或其片段,其中所述抗体或其片段与所述野生型CLDN18.2蛋白之间的结合涉及的氨基酸残基包括所述野生型CLDN18.2蛋白的选自由N45、Y46、G48、V54、R55、E56、S58、F60和E62组成的组中的至少一个氨基酸残基;以及选自由Y169和G172组成的组中的至少一个氨基酸残基。
在一些实施方案中,所述抗体或其片段与CLDN18.2的N45结合。在一些实施方案中,所述抗体或其片段与CLDN18.2的Y46结合。在一些实施方案中,所述抗体或其片段与CLDN18.2的G48结合。在一些实施方案中,所述抗体或其片段与CLDN18.2的L49结合。在一些实施方案中,所述抗体或其片段与CLDN18.2的W50结合。在一些实施方案中,所述抗体或其片段与CLDN18.2的C53结合。在一些实施方案中,所述抗体或其片段与CLDN18.2的V54结合。在一些实施方案中,所述抗体或其片段与CLDN18.2的R55结合。在一些实施方案中,所述抗体或其片段与CLDN18.2的E56结合。在一些实施方案中,所述抗体或其片段与CLDN18.2的E58结合。在一些实施方案中,所述抗体或其片段与CLDN18.2的F60结合。在一些实施方案中,所述抗体或其片段与CLDN18.2的E62结合。在一些实施方案中,所述抗体或其片段与CLDN18.2的C63结合。
在一些实施方案中,所述抗体或其片段与选自N45、Y46、G48、V54、R55、E56、S58、F60和E62中的至少两个氨基酸残基结合。在一些实施方案中,所述抗体或其片段与选自N45、Y46、G48、V54、R55、E56、S58、F60和E62中的至少三个氨基酸残基结合。在一些实施方案中,所述抗体或其片段与选自N45、Y46、G48、V54、R55、E56、S58、F60和E62中的至少四个氨基酸残基结合。在一些实施方案中,所述抗体或其片段与选自N45、Y46、G48、V54、R55、E56、S58、F60和E62中的至少五个氨基酸残基结合。
在一些实施方案中,所述抗体或其片段至少与CLDN18.2的Y169结合。在一些实施方案中,所述抗体或其片段至少与CLDN18.2的G172结合。在一些实施方案中,所述抗体或其片段与选自CLDN18.2的Y169和G172中的至少两个氨基酸残基结合。
在一些实施方案中,所述结合涉及的氨基酸残基包含所述野生型CLDN18.2蛋白的W30;选自由N45、Y46、G48、V54、R55、E56、S58、F60和E62组成的组中的两个、三个、四个、五个或更多个氨基酸残基;以及选自由Y169和G172组成的组中的至少一个氨基酸残基。在一些实施方案中,所述结合涉及的氨基酸残基包含所述野生型CLDN18.2蛋白的W30、N45、Y46、G48、V54、R55、E56、S58、F60、E62和Y169。
与其他氨基酸(如G48、L49、W50、C53、V54、R55、E56)相比,CLDN18.2上与这些氨基酸的结合较弱。在一些实施方案中,比较的是与175D10相同氨基酸处的结合。例如,本公开的所述抗体或片段与175D10(IMGT/2D结构-DB卡号:10473)相比与D28、Q33、N38、V43、G59和V79中的至少一个、两个、三个、四个、五个或全部的结合较弱。
在一些实施方案中,所述抗体或其片段不与所述CLDN18.2蛋白的M149L结合。在一些实施方案中,所述抗体或其片段与所述CLDN18.2蛋白的M149L突变体结合。
根据本公开的一个实施方案,提供了一种抗体或其片段,包含重链和轻链可变结构域,其CDR区如表A的CDR组合所示。
表A.测试抗体的CDR组合(Kabat编号)
表B.120B7B2的CDR(Kabat编号)
表C.72C1B6A3的CDR(Kabat编号)
表D.4F11E2的CDR(Kabat编号)
含有这些CDR区的抗体,无论是小鼠、人源化的还是嵌合的,都具有有效的紧密连接蛋白18.2结合和抑制活性。如实施例11和12所示,可以修饰CDR内的某些残基以保留或改善该特性或减少其具有翻译后修饰(PTM)的可能性。这种修饰的CDR可称为亲和力成熟的CDR或去风险化的CDR。
表B-D的第三列提供了去风险化的CDR的非限制性实例。亲和力成熟的CDR可以包括具有一个、两个或三个氨基酸的添加、缺失和/或取代的那些。在一些实施方案中,所述取代可以是保守的取代。
“保守的氨基酸取代”是指其中的氨基酸残基被具有类似侧链的氨基酸残基取代。本领域中已定义了具有类似侧链的氨基酸残基家族,包括碱性侧链(例如赖氨酸、精氨酸、组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷的极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸)、非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸)、β-分支侧链(例如苏氨酸、缬氨酸、异亮氨酸)和芳香侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。因此,免疫球蛋白多肽中的非必需氨基酸残基优选被来自相同侧链家族的另一个氨基酸残基取代。在另一实施方案中,氨基酸串可以用结构相似的串取代,该串在侧链家族成员的顺序和/或组成上不同。
下表提供了保守的氨基酸取代的非限制性实例,其中0或更高的相似度得分表示两个氨基酸之间的保守取代。
表E.氨基酸相似度矩阵
C | G | P | S | A | T | D | E | N | Q | H | K | R | V | M | I | L | F | Y | W | |
W | -8 | -7 | -6 | -2 | -6 | -5 | -7 | -7 | -4 | -5 | -3 | -3 | 2 | -6 | -4 | -5 | -2 | 0 | 0 | 17 |
Y | 0 | -5 | -5 | -3 | -3 | -3 | -4 | -4 | -2 | -4 | 0 | -4 | -5 | -2 | -2 | -1 | -1 | 7 | 10 | |
F | -4 | -5 | -5 | -3 | -4 | -3 | -6 | -5 | -4 | -5 | -2 | -5 | -4 | -1 | 0 | 1 | 2 | 9 | ||
L | -6 | -4 | -3 | -3 | -2 | -2 | -4 | -3 | -3 | -2 | -2 | -3 | -3 | 2 | 4 | 2 | 6 | |||
I | -2 | -3 | -2 | -1 | -1 | 0 | -2 | -2 | -2 | -2 | -2 | -2 | -2 | 4 | 2 | 5 | ||||
M | -5 | -3 | -2 | -2 | -1 | -1 | -3 | -2 | 0 | -1 | -2 | 0 | 0 | 2 | 6 | |||||
V | -2 | -1 | -1 | -1 | 0 | 0 | -2 | -2 | -2 | -2 | -2 | -2 | -2 | 4 | ||||||
R | -4 | -3 | 0 | 0 | -2 | -1 | -1 | -1 | 0 | 1 | 2 | 3 | 6 | |||||||
K | -5 | -2 | -1 | 0 | -1 | 0 | 0 | 0 | 1 | 1 | 0 | 5 | ||||||||
H | -3 | -2 | 0 | -1 | -1 | -1 | 1 | 1 | 2 | 3 | 6 | |||||||||
Q | -5 | -1 | 0 | -1 | 0 | -1 | 2 | 2 | 1 | 4 | ||||||||||
N | -4 | 0 | -1 | 1 | 0 | 0 | 2 | 1 | 2 | |||||||||||
E | -5 | 0 | -1 | 0 | 0 | 0 | 3 | 4 | ||||||||||||
D | -5 | 1 | -1 | 0 | 0 | 0 | 4 | |||||||||||||
T | -2 | 0 | 0 | 1 | 1 | 3 | ||||||||||||||
A | -2 | 1 | 1 | 1 | 2 | |||||||||||||||
S | 0 | 1 | 1 | 1 | ||||||||||||||||
P | -3 | -1 | 6 | |||||||||||||||||
G | -3 | 5 | ||||||||||||||||||
C | 12 |
表F.保守的氨基酸取代
因此,在一个实施方案中,提供了一种与野生型人紧密连接蛋白18.2(CLDN18.2)蛋白具有结合特异性的抗体或其片段,其中所述抗体或其片段包含轻链可变区和重链可变区,所述轻链可变区包含轻链互补决定区CDRL1、CDRL2和CDRL3,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,并且其中所述CDRL1、CDRL2、CDRL3、CDRH1、CDRH2和CDRH3选自表A的组合1-33或组合1-33中的每一个,其中CDRL1、CDRL2、CDRL3、CDRH1、CDRH2和CDRH3中的一个或多个分别包含一个、两个或三个氨基酸的添加、缺失、保守的氨基酸取代或其组合。
在一些实施方案中,提供的抗CLDN18.2抗体或片段包含CDRL1、CDRL2、CDRL3、CDRH1、CDRH2和CDRH3,其中每一个均选自表A或表B-D。例如,提供了与野生型人紧密连接蛋白18.2(CLDN18.2)蛋白具有结合特异性的抗体或其片段,其中所述抗体或其片段包含轻链可变区和重链可变区,所述轻链可变区包含轻链互补决定区CDRL1、CDRL2和CDRL3,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,并且其中:所述CDRL1包含选自SEQ IDNO:208-226的组的氨基酸序列,或包含由SEQ ID NO:208-226中的任何一个通过一个、两个或三个氨基酸的添加、缺失、氨基酸取代而衍生的氨基酸序列;所述CDRL2包含选自SEQ IDNO:227-233的组的氨基酸序列,或包含由SEQ ID NO:227-233中的任何一个通过氨基酸的添加、缺失、氨基酸取代而衍生的氨基酸序列;所述CDRL3包含选自SEQ ID NO:3、8、13、19和42-58的组的氨基酸序列,或包含由SEQ ID NO:3、8、13、19和42-58中的任何一个通过一个、两个或三个氨基酸的添加、缺失、氨基酸取代而衍生的氨基酸序列;所述CDRH1包含选自SEQID NO:234-254的组的氨基酸序列,或包含由SEQ ID NO:234-254中的任何一个通过一个、两个或三个氨基酸的添加、缺失、氨基酸取代而衍生的氨基酸序列;所述CDRH2包含选自SEQID NO:255-280的组的氨基酸序列,或包含由SEQ ID NO:255-280中的任何一个通过一个、两个或三个氨基酸的添加、缺失、氨基酸取代而衍生的氨基酸序列;并且所述CDRH3包含选自SEQ ID NO:281-303的组的氨基酸序列,或包含由SEQ ID NO:281-303中的任何一个通过一个、两个或三个氨基酸的添加、缺失、氨基酸取代而衍生的氨基酸序列。
在一些实施方案中,所述CDRL1包含选自SEQ ID NO:208-226、304-305和308-309的组的氨基酸序列;所述CDRL2包含选自SEQ ID NO:227-233的组的氨基酸序列;所述CDRL3包含选自SEQ ID NO:3、8、13、19、20和42-58的组的氨基酸序列;所述CDRH1包含选自SEQ IDNO:234-254的组的氨基酸序列;所述CDRH2包含选自SEQ ID NO:255-280、306、310和311的组的氨基酸序列;并且所述CDRH3包含选自SEQ ID NO:281-303、307和312-314的组的氨基酸序列。
抗体120B7B2已被证明是紧密连接蛋白18.2的有效抑制剂。表B提供了其CDR序列以及一些去风险化的版本。在一个实施方案中,本公开提供了一种与野生型人紧密连接蛋白18.2(CLDN18.2)蛋白具有结合特异性的抗体或其片段,其中所述抗体或其片段包含轻链可变区和重链可变区,所述轻链可变区包含轻链互补决定区CDRL1、CDRL2和CDRL3,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,并且其中:所述CDRL1包含QSLLNSGNQKNY(SEQ ID NO:1)、QSLLNAGNQKNY(SEQ ID NO:17)或QSLLESGNQKNY(SEQ ID NO:18)的氨基酸序列,或来自SEQ ID NO:1、17或18的具有一个、两个或三个氨基酸取代的氨基酸序列,所述CDRL2包含WAS(SEQ ID NO:2)的氨基酸序列,或来自SEQ ID NO:2的具有一个或两个氨基酸取代的氨基酸序列,所述CDRL3包含CQNGYYFPFT(SEQ ID NO:3)、QNAYYFPFT(SEQ ID NO:19)或QEGYYFPFT(SEQ ID NO:20)的氨基酸序列,或来自SEQ ID NO:3、19或20的具有一个、两个或三个氨基酸取代的氨基酸序列,所述CDRH1包含GYTFTGYI(SEQ ID NO:4)的氨基酸序列,或来自SEQ ID NO:4的具有一个、两个或三个氨基酸取代的氨基酸序列,所述CDRH2包含INPYNDGT(SEQ ID NO:5)或INPYNDDT(SEQ ID NO:21)的氨基酸序列,或来自SEQ ID NO:5或21的具有一个、两个或三个氨基酸取代的氨基酸序列,并且所述CDRH3包含ARAYFGNSFAY(SEQ ID NO:6)或ARAYFGNAFAY(SEQ ID NO:22)的氨基酸序列,或来自SEQ IDNO:6或22的具有一个、两个或三个氨基酸取代的氨基酸序列。
有趣的是注意到来自不同抗体的CDR具有很高的同源性(参见表A)。然后预期每个相应的CDR可以互换而不会很大地影响所述抗体或片段的结合亲和力或活性。或者,CDR中每个特定的氨基酸可以用来自不同抗体的相应CDR中存在的另一个氨基酸取代。
在一些实施方案中,提供了一种与野生型人紧密连接蛋白18.2(CLDN18.2)蛋白具有结合特异性的抗体或其片段。在一些实施方案中,所述抗体或其片段包含轻链可变区和重链可变区,所述轻链可变区包含轻链互补决定区CDRL1、CDRL2和CDRL3,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,并且其中:所述CDRL1包含SEQ ID NO:210、304或305的氨基酸序列,或来自SEQ ID NO:210、304或305的具有一个、两个或三个氨基酸取代的氨基酸序列,所述CDRL2包含SEQ ID NO:227的氨基酸序列,或来自SEQ ID NO:227的具有一个或两个氨基酸取代的氨基酸序列;所述CDRL3包含SEQ ID NO:3、19或20的氨基酸序列,或来自SEQ ID NO:3、19或20的具有一个、两个或三个氨基酸取代的氨基酸序列;所述CDRH1包含SEQ ID NO:253的氨基酸序列,或来自SEQ ID NO:253的具有一个、两个或三个氨基酸取代的氨基酸序列;所述CDRH2包含SEQ ID NO:278或306的氨基酸序列,或来自SEQ ID NO:278或306的具有一个、两个或三个氨基酸取代的氨基酸序列;并且所述CDRH3包含SEQ IDNO:303或307的氨基酸序列,或来自SEQ ID NO:303或307的具有一个、两个或三个氨基酸取代的氨基酸序列。
在一些实施方案中,所述CDRL1包含SEQ ID NO:210、304或305的氨基酸序列,所述CDRL2包含SEQ ID NO:227的氨基酸序列,所述CDRL3包含SEQ ID NO:3、19或20的氨基酸序列,所述CDRH1包含SEQ ID NO:253的氨基酸序列,所述CDRH2包含SEQ ID NO:278或306的氨基酸序列,所述CDRH3包含SEQ ID NO:303或307的氨基酸序列。
轻链可变区的非限制性实例包含选自由SEQ ID NO:141、192-195和206-207组成的组的氨基酸序列,或生物等效物,如与选自由SEQ ID NO:141、192-195和206-207组成的组的氨基酸序列具有至少90%序列同一性的肽。
重链可变区的非限制性实例包含选自由SEQ ID NO:171、188-191和205组成的组的氨基酸序列,或生物等效物,如与选自由SEQ ID NO:171、188-191和205组成的组的氨基酸序列具有至少90%序列同一性的肽。
在一些实施方案中,所述CDRL1包含SEQ ID NO:304的氨基酸序列,所述CDRL2包含SEQ ID NO:227的氨基酸序列,所述CDRL3包含SEQ ID NO:19的氨基酸序列,所述CDRH1包含SEQ ID NO:253的氨基酸序列,所述CDRH2包含SEQ ID NO:306的氨基酸序列,并且所述CDRH3包含SEQ ID NO:307的氨基酸序列。所述抗体或片段的一个非限制性实例包括包含SEQ ID NO:206的氨基酸序列的轻链可变区以及包含SEQ ID NO:205的氨基酸序列的重链可变区。
同样,72C1B6A3已被证明是一种好的抗体。因此,在另一实施方案中,提供了一种与野生型人紧密连接蛋白18.2(CLDN18.2)蛋白具有结合特异性的抗体或其片段,其中所述抗体或其片段包含轻链可变区和重链可变区,所述轻链可变区包含轻链互补决定区CDRL1、CDRL2和CDRL3,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,并且其中:所述CDRL1包含SEQ ID NO:210、304或305的氨基酸序列,或来自SEQ ID NO:210、304或305的具有一个、两个或三个氨基酸取代的氨基酸序列,所述CDRL2包含SEQ ID NO:229的氨基酸序列,或来自SEQ ID NO:229的具有一个或两个氨基酸取代的氨基酸序列,所述CDRL3包含SEQID NO:8的氨基酸序列,或来自SEQ ID NO:8的具有一个、两个或三个氨基酸取代的氨基酸序列,所述CDRH1包含SEQ ID NO:242的氨基酸序列,或来自SEQ ID NO:242的具有一个、两个或三个氨基酸取代的氨基酸序列,所述CDRH2包含SEQ ID NO:263的氨基酸序列,或来自SEQ ID NO:263的具有一个、两个或三个氨基酸取代的氨基酸序列,并且所述CDRH3包含SEQID NO:289的氨基酸序列,或来自SEQ ID NO:289的具有一个、两个或三个氨基酸取代的氨基酸序列。
在一些实施方案中,所述CDRL1包含SEQ ID NO:210、304或305的氨基酸序列,所述CDRL2包含SEQ ID NO:229的氨基酸序列,所述CDRL3包含SEQ ID NO:8的氨基酸序列,所述CDRH1包含SEQ ID NO:242的氨基酸序列,所述CDRH2包含SEQ ID NO:263的氨基酸序列,并且所述CDRH3包含SEQ ID NO:289的氨基酸序列。
轻链可变区的非限制性实例包含选自由SEQ ID NO:124、185-187和203-204组成的组的氨基酸序列,或生物等效物,如与选自由SEQ ID NO:124、185-187和203-204组成的组的氨基酸序列具有至少90%序列同一性的肽。
重链可变区的非限制性实例包含选自由SEQ ID NO:153和181-184组成的组的氨基酸序列,或生物等效物,如与选自由SEQ ID NO:153和181-184组成的组的氨基酸序列具有至少90%序列同一性的肽。
在一些实施方案中,所述CDRL1包含SEQ ID NO:304的氨基酸序列,所述CDRL2包含SEQ ID NO:229的氨基酸序列,所述CDRL3包含SEQ ID NO:8的氨基酸序列,所述CDRH1包含SEQ ID NO:242的氨基酸序列,所述CDRH2包含SEQ ID NO:263的氨基酸序列,并且所述CDRH3包含SEQ ID NO:289的氨基酸序列。抗体或其片段的一个非限制性实例包括包含SEQID NO:203的氨基酸序列的轻链可变区以及包含SEQ ID NO:181的氨基酸序列的重链可变区。
此外,4F11E2已被证明是一种好的抗体。因此,在另一实施方案中,提供了一种与野生型人紧密连接蛋白18.2(CLDN18.2)蛋白具有结合特异性的抗体或其片段,其中所述抗体或其片段包含轻链可变区和重链可变区,所述轻链可变区包含轻链互补决定区CDRL1、CDRL2和CDRL3,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,并且其中:所述CDRL1包含SEQ ID NO:216、308或309的氨基酸序列,或来自SEQ ID NO:216、308或309的具有一个、两个或三个氨基酸取代的氨基酸序列,所述CDRL2包含SEQ ID NO:227的氨基酸序列,或来自SEQ ID NO:227的具有一个或两个氨基酸取代的氨基酸序列,所述CDRL3包含SEQID NO:13的氨基酸序列,或来自SEQ ID NO:13的具有一个、两个或三个氨基酸取代的氨基酸序列,所述CDRH1包含SEQ ID NO:246的氨基酸序列,或来自SEQ ID NO:246的具有一个、两个或三个氨基酸取代的氨基酸序列,所述CDRH2包含SEQ ID NO:268、310或311的氨基酸序列,或来自SEQ ID NO:268、310或311的具有一个、两个或三个氨基酸取代的氨基酸序列,并且所述CDRH3包含SEQ ID NO:294、312、313或314的氨基酸序列,或来自SEQ ID NO:294、312、313或314的具有一个、两个或三个氨基酸取代的氨基酸序列。
在一些实施方案中,所述CDRL1包含SEQ ID NO:216、308或309的氨基酸序列,所述CDRL2包含SEQ ID NO:227的氨基酸序列,所述CDRL3包含SEQ ID NO:13的氨基酸序列,所述CDRH1包含SEQ ID NO:246的氨基酸序列,所述CDRH2包含SEQ ID NO:268、310或311的氨基酸序列,并且所述CDRH3包含SEQ ID NO:294、312、313或314的氨基酸序列。
轻链可变区的非限制性实例包含选自由SEQ ID NO:129、178-180和201-202组成的组的氨基酸序列,或生物等效物,如与选自由SEQ ID NO:129、178-180和201-202组成的组的氨基酸序列具有至少90%序列同一性的肽。
重链可变区的非限制性实例包含选自由SEQ ID NO:159、175-177和196-200组成的组的氨基酸序列,或生物等效物,如与选自由SEQ ID NO:159、175-177和196-200组成的组的氨基酸序列具有至少90%序列同一性的肽。
在一些实施方案中,所述CDRL1包含SEQ ID NO:309的氨基酸序列,所述CDRL2包含SEQ ID NO:227的氨基酸序列,所述CDRL3包含SEQ ID NO:13的氨基酸序列,所述CDRH1包含SEQ ID NO:246的氨基酸序列,所述CDRH2包含SEQ ID NO:311的氨基酸序列,并且所述CDRH3包含SEQ ID NO:294的氨基酸序列。所述抗体或片段的一个非限制性实例包括包含SEQ ID NO:202的氨基酸序列的轻链可变区以及包含SEQ ID NO:197的氨基酸序列的重链可变区。
在一些实施方案中,所述抗体是人源化抗体。如实施例9所示,人源化抗体可以包含小鼠对应物的一个或多个回复突变。此类回复突变的实例示于表3中。在一些实施方案中,所述抗体或片段可以包括一个、两个、三个、四个、五个或更多个所述回复突变。
在一些实施方案中,本公开的所述抗紧密连接蛋白18.2抗体包含SEQ ID NO:117-144、178-180、185-187、192-195、201-202、203-204或206-207中任何一个的VL,以及SEQ IDNO:145-174、175-177、181-184、188-191、196-200或205中任何一个的VH,或它们各自的生物等效物。VH或VL的生物等效物是包括指定氨基酸且具有总体80%、85%、90%、95%、98%或99%序列同一性的序列。因此,SEQ ID NO:145的生物等效物可以是与SEQ ID NO:145具有总体80%、85%、90%、95%、98%或99%的序列同一性,但保留了CDR,并任选地保留一个或多个或所有的回复突变的VH。
本领域普通技术人员还将理解,本文公开的抗体可以被修饰,使得其氨基酸序列与其所源自的天然存在的结合多肽不同。例如,源自指定蛋白质的多肽或氨基酸序列可以与起始序列相似,例如具有一定百分比的同一性,例如,其可以与起始序列的60%、70%、75%、80%、85%、90%、95%、98%或99%相同。
在某些实施方案中,所述抗体包含氨基酸序列或者一个或多个通常与抗体无关的部分。下面将更详细地描述示例性的修饰。例如,本公开的抗体可以包含柔性接头序列,或可被修饰以添加功能性部分(例如PEG、药物、毒素或标记)。
本公开的抗体、变体或其衍生物包括修饰的衍生物,即通过任何类型的分子与抗体的共价连接,使得共价连接不会妨碍抗体与表位结合。例如,但不作为限制,所述抗体可以被修饰,例如通过糖基化、乙酰化、聚乙二醇化、磷酸化、磷酸化、酰胺化、通过已知保护/封闭基团衍生化、蛋白水解切割、与细胞配体或其他蛋白质连接,等等。诸多化学修饰中的任一种都可以通过已知的技术进行,包括但不限于特异性的化学裂解、乙酰化、甲酰化、代谢合成衣霉素等。此外,所述抗体可以包含一个或多个非典型氨基酸。
抗体药物偶联物
在一些实施方案中,所述抗体或片段可以与治疗剂、前药、肽、蛋白质、酶、病毒、脂质、生物反应调节剂、药物制剂或PEG偶联。
在一个实施方案中,本公开的抗体或片段共价连接至药物部分。所述药物部分可以是,或被修饰以包括与所述抗体上的偶联位点反应的基团。例如,药物部分可以通过烷基化(例如,在抗体的ε-氨基赖氨酸或N末端)、氧化碳水化合物的还原胺化、羟基和羧基之间的酯交换、氨基或羧基的酰胺化以及与硫醇的偶联来连接。
在一些实施方案中,每个抗体分子偶联的药物部分的数量p介于1至8;1至7、1至6、1至5、1至4、1至3或1至2的平均值。在一些实施方案中,p介于2至8、2至7、2至6、2至5、2至4或2至3的平均值。在其他实施方案中,p为1、2、3、4、5、6、7或8的平均值。在一些实施方案中,p介于约1至约20、约1至约10、约2至约10、约2至约9、约1至约8、约1至约7、约1至约6、约1至约5、约1至约4、约1至约3或约1至约2的平均值。在一些实施方案中,p介于约2至约8、约2至约7、约2至约6、约2至约5、约2至约4或约2至约3。
例如,当蛋白质的化学活化导致形成游离硫醇基团时,所述蛋白质可以与巯基反应剂偶联。一方面,该试剂是一种对游离硫醇基团基本上特异的试剂。例如,此类试剂包括马来酰亚胺、卤代乙酰胺(例如碘代、溴代或氯代)、卤代酯(例如碘代、溴代或氯代)、卤代甲基酮(例如碘代、溴代或氯代)、苄基卤化物(例如碘化物、溴化物或氯化物)、乙烯基砜和吡啶基硫。
所述药物可以通过接头与所述抗体或片段连接。合适的接头包括例如可切割的和不可切割的接头。可切割的接头通常在细胞内条件下易于切割。合适的可切割接头包括例如可被胞内蛋白酶(如溶酶体蛋白酶或胞内体蛋白酶)切割的肽接头。在示例性实施方案中,接头可以是二肽接头,如缬氨酸-瓜氨酸(val-cit)、苯丙氨酸-赖氨酸(phe-lys)接头,或马来酰亚胺基己酸-缬氨酸-瓜氨酸-对氨基苯甲氧基羰基(mc-Val-Cit-PABA)接头。另一种接头是磺基琥珀酰亚胺基-4-[N-马来酰亚胺基甲基]环己烷-1-羧酸酯(smcc)。磺基-smcc偶联经由马来酰亚胺基与巯基(硫醇基,-SH)反应而发生,同时其磺基-NHS酯对伯胺有反应性(如在赖氨酸及蛋白质或肽的N末端中可见)。再一种接头是马来酰亚胺己酰基(mc)。其他合适的接头包括在特定pH或pH范围内水解的接头,如腙接头。其他合适的可切割接头包括二硫化物接头。该接头可以与所述抗体共价连接直至使所述抗体必须在细胞内降解以便药物被释放的程度,例如mc接头等。
接头可以包含用于与所述抗体连接的基团。例如,接头可以包含氨基、羟基、羧基或巯基反应性基团(例如,马来酰亚胺、卤代乙酰胺(例如碘代、溴代或氯代)、卤代酯(例如碘代、溴代或氯代)、卤代甲基酮(例如碘代、溴代或氯代)、苄基卤化物(例如碘化物、溴化物或氯化物)、乙烯基砜和吡啶基硫)。
在一些实施方案中,所述药物部分是细胞毒剂或细胞抑制剂、免疫抑制剂、放射性同位素、毒素等。偶联物可用于抑制肿瘤细胞或癌细胞的增殖,引起肿瘤或癌细胞的凋亡,或用于治疗患者的癌症。所述偶联物可以相应地用于治疗动物癌症的各种场合。所述偶联物可以用于将药物递送至肿瘤细胞或癌细胞。不受理论束缚,在一些实施方案中,所述偶联物与表达紧密连接蛋白18.2的癌细胞结合或缔合,并且所述偶联物和/或药物可以通过受体介导的内吞作用被摄取到肿瘤细胞或癌细胞内。
一旦进入细胞,偶联物中(例如,在接头中)的一个或多个特定肽序列被一种或多种肿瘤细胞或癌细胞相关的蛋白酶水解切割,引起药物释放。然后释放的药物在细胞内自由迁移并诱导细胞毒性或细胞抑制或其他活性。在一些实施方案中,所述药物从肿瘤细胞或癌细胞外的抗体切割,并且所述药物随后穿透细胞,或在细胞表面发挥作用。
药物部分或有效载荷的实例选自由DM1(美登素,N2'-脱乙酰基-N2'-(3-巯基-1-氧代丙基)-或N2'-脱乙酰基-N2'-(3-巯基-1-氧代丙基)-美登素)、mc-MMAD(6-马来酰亚胺己酰基-单甲基澳瑞他汀-D或N-甲基-L-缬氨酰-N-[(1S,2R)-2-甲氧基-4-[(2S)-2-[(1R,2R)-1-甲氧基-2-甲基-3-氧代-3-[[(1S)-2-苯基-1-(2-噻唑基)乙基]氨基]丙基]-1-吡咯烷基]-1-[(1S)-1-甲基丙基]-4-氧代丁基]-N-甲基-(9Cl)-L-缬氨酰胺)、mc-MMAF(马来酰亚胺己酰基-单甲基澳瑞他汀F或N-[6-(2,5-二氢-2,5-二氧代-1H-吡咯-1-基)-1-氧代己基]-N-甲基-L-缬氨酰-L-缬氨酰-(3R,4S,5S)-3-甲氧基-5-甲基-4-(甲氨基)庚酰-(αR,βR,2S)-β-甲氧基-α-甲基-2-吡咯烷丙酰基-L-苯丙氨酸)和mc-Val-Cit-PABA-MMAE(6-马来酰亚胺己酰基-ValcCit-(对氨基苄氧基羰基)-单甲基澳瑞他汀E或N-[[[4-[[N-[6-(2,5-二氢-2,5-二氧-1H-吡咯-1-基)-1-氧代己基]-L-缬氨酰-N5-(氨基羰基)-L-鸟氨酰]氨基]苯基]甲氧基]羰基]-N-甲基-L-缬氨酰-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-羟基-1-甲基-2-苯乙基]氨基]-1-甲氧基-2-甲基-3-氧代丙基]-1-吡咯烷基]-2-甲氧基-1-[(1S)-1-甲基丙基]-4-氧代丁基]-N-甲基-L-缬氨酰胺)组成的组。DM1是微管蛋白抑制剂美登素的衍生物,而MMAD、MMAE和MMAF是澳瑞他汀衍生物。在一些实施方案中,所述药物部分选自由mc-MMAF和mc-Val-Cit-PABA-MMAE组成的组。在一些实施方案中,所述药物部分是美登木素或澳瑞他汀。
所述抗体或片段可以与治疗剂缀合或融合,治疗剂可以包括可检测标记(如放射性标记)、免疫调节剂、激素、酶、寡核苷酸、光活性治疗剂或诊断剂、细胞毒剂(可以是药物或毒素)、超声增强剂、非放射性标记、其组合以及本领域已知的其他此类试剂。
所述抗体可以通过与化学发光化合物偶联被可检测地标记。然后通过检测化学反应过程中产生的发光的存在来确定化学发光标签的抗原结合多肽的存在。特别有用的化学发光标记化合物的实例是鲁米诺、异鲁米诺、热敏吖啶酯、咪唑、吖啶盐和草酸酯。
所述抗体也可以使用发射荧光的金属如152Eu或镧系元素的其他金属进行可检测地标记。这些金属可以使用诸如二乙基三胺五乙酸(DTPA)或乙二胺四乙酸(EDTA)等金属螯合基团连接到抗体上。将各种部分缀合到抗体的技术是公知的,参见例如Arnon等,“Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”,在Monoclonal Antibodies And Cancer Therapy中,Reisfeld等(编辑),第243-56页(AlanR.Liss公司(1985);Hellstrom等,“Antibodies For Drug Delivery”,在ControlledDrugDelivery(第2版)中,Robinson等(编辑),Marcel Dekker公司,第623-53页(1987);Thorpe,“Antibody Carriers Of Cytotoxic Agents in Cancer Therapy:A Review”,在Monoclonal Antibodies'84:BiologicalAnd ClinicalApplications中,Pinchera等(编辑),第475-506页(1985);“Analysis,Results,And Future Prospective Of TheTherapeutic Use Of Radiolabeled Antibody In Cancer Therapy”,在MonoclonalAntibodies For Cancer Detection and Therapy中,Baldwin等(编辑),美国学术出版社,第303-16页(1985),以及Thorpe等,“The Preparation and Cytotoxic Properties OfAntibody-Toxin Conjugates”,Immunol.Rev.(52:119-58(1982))。
编码抗体的多核苷酸与制备抗体的方法
本公开还提供了编码本公开的抗体、变体或其衍生物的分离的多核苷酸或核酸分子。本公开的多核苷酸可以在同一个多核苷酸分子上或在单独的多核苷酸分子上编码抗原结合多肽、变体或其衍生物的整个重链和轻链可变区。此外,本公开的多核苷酸可以在同一个多核苷酸分子上或在单独的多核苷酸分子上编码抗原结合多肽、变体或其衍生物的部分重链和轻链可变区。
制备抗体的方法是本领域公知的并且在本文中有描述。在某些实施方案中,本公开的抗原结合多肽的可变区和恒定区都是全人源的。可以使用本领域中描述的和如本文描述的技术来制备全人源抗体。例如,针对特定抗原的全人源抗体可以通过向转基因动物施用所述抗原来制备,该转基因动物已被改造成在应对抗原激发时产生这种抗体,但其内源性基因座已失效。可以用于制备这种抗体的示例性技术描述于美国专利6,150,584、6,458,592、6,420,140中,其全部内容以引用方式并入。
治疗方法
如本文所述,本公开的抗体、变体或衍生物可以用于某些治疗和诊断方法。
本公开进一步涉及基于抗体的疗法,其涉及将本公开的抗体、片段或抗体药物偶联物施用于患者(例如动物、哺乳动物和人类)以治疗本文所述的一种或多种紊乱或病症。本公开的治疗性化合物包括但不限于本公开的抗体(包括如本文所述的变体及其衍生物)和编码本公开的抗体(包括如本文所述的变体及其衍生物)的核酸或多核苷酸。
本公开的所述抗体也可以用于治疗或抑制癌症。如前文所提供的,紧密连接蛋白18.2可以过表达于肿瘤细胞中,特别是胃、胰腺、食管、卵巢和肺部肿瘤。已证明抑制紧密连接蛋白18.2对治疗肿瘤有用。
因此,在一些实施方案中,提供了在有需要的患者中治疗癌症的方法。在一个实施方案中,所述方法需要向患者施用有效量的本公开的抗体、片段或抗体药物偶联物。在一些实施方案中,患者体内至少有一种癌细胞(例如基质细胞)过表达紧密连接蛋白18.2。
本公开还提供了细胞疗法,如嵌合抗原受体(CAR)T细胞疗法。可以使用合适的细胞,其与本公开的抗紧密连接蛋白18.2抗体接触(或者替代性地被改造以表达本公开的抗紧密连接蛋白18.2抗体)。通过这种接触或改造,然后可以将所述细胞引入需要治疗的癌症患者。所述癌症患者可以患有本文所公开的任意类型的癌症。所述细胞(例如T细胞)可以是例如肿瘤浸润T淋巴细胞、CD4+T细胞、CD8+T细胞或其组合,但不限于此。
在一些实施方案中,所述细胞是从所述癌症患者自身分离的。在一些实施方案中,所述细胞由供体提供或来自细胞库。当所述细胞从所述癌症患者分离出来时,不希望发生的免疫反应可以被最小化。
癌症的非限制性实例包括膀胱癌、乳腺癌、结肠直肠癌、子宫内膜癌、食道癌、头颈癌、肾癌、白血病、肝癌、肺癌、淋巴瘤、黑色素瘤、胰腺癌、前列腺癌和甲状腺癌。在一些实施方案中,所述癌症是胃癌、胰腺癌、食道癌、卵巢癌和肺癌中的一种或多种。
可以用本公开的抗体或变体或其衍生物治疗、预防、诊断和/或预后的与细胞存活增加有关的其他疾病或病症,包括但不限于恶性肿瘤和相关疾病的进展和/或转移,如白血病(包括急性白血病(例如急性淋巴细胞白血病、急性髓系白血病(包括成髓细胞、早幼粒细胞、髓单核细胞、单核细胞和红细胞白血病))和慢性白血病(例如慢性髓系(粒细胞)白血病和慢性淋巴细胞白血病))、真性红细胞增多症、淋巴瘤(例如霍奇金病和非霍奇金病)、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症、重链病以及实体瘤,所述实体瘤包括但不限于肉瘤和癌,如纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤文氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、肾母细胞瘤、宫颈癌、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突神经胶质瘤、脑膜瘤(menangioma)、黑色素瘤、神经母细胞瘤和视网膜母细胞瘤。
任何特定患者的特定剂量和治疗方案将取决于多种因素,包括所用的特定抗体、其变体或衍生物、患者的年龄、体重、一般健康状况、性别和饮食,以及给药时间、排泄率、药物组合以及所治疗的特定疾病的严重程度。医疗护理人员对这些因素的判断属于本领域普通技术。用量还将取决于要治疗的个体患者、给药途径、制剂类型、所用化合物的特性、疾病的严重程度和所需效果。用量可以通过本领域公知的药理学和药代动力学原理确定。
所述抗体、片段或抗体药物偶联物的给药方法包括但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内、硬膜外和口服途径。所述抗原结合多肽或组合物可以通过任何方便的途径给药,例如通过输注或团注,通过上皮或粘膜皮肤内层吸收(例如口腔粘膜、直肠和肠道粘膜等),并且可以与其他生物活性剂一起给药。因此,含有本公开的抗原结合多肽的药物组合物可以口服、直肠、肠胃外、脑池内、阴道内、腹腔内、局部(如通过粉剂、软膏、滴剂或透皮贴剂)、鼻腔或作为口服或鼻腔喷雾给药。
如本文所用术语“肠胃外”是指包括静脉内、肌内、腹膜内、胸腔内、皮下和关节内注射和输注的给药方式,。
给药可以是全身性的或局部的。此外,可能需要通过任何合适的途径将本公开的抗体引入中枢神经系统,包括脑室内和鞘内注射;脑室内注射可以通过脑室内导管来促进,例如,连接到储液器,如Ommaya储液器。也可以采用肺部给药,例如,通过使用吸入器或雾化器,以及用雾化剂配制。
可能需要将本公开的抗原结合多肽或组合物局部施用于需要治疗的区域;这可以通过例如但不限于手术期间的局部输注、局部应用,例如,在手术后与伤口敷料结合、通过注射、通过导管、通过栓剂或通过植入物来实现,所述植入物为多孔、无孔或凝胶状材料,包括膜,如硅胶(sialastic)膜或者纤维。优选地,在施用本公开的蛋白质(包括抗体)时,必须注意使用不吸收蛋白质的材料。
可以通过标准临床技术确定可有效治疗、抑制和预防炎性、免疫或恶性疾病、紊乱或病症的本公开的抗体、片段或抗体药物偶联物的用量。此外,可以任选地采用体外测定来帮助确定最佳剂量范围。制剂中使用的精确剂量还取决于给药途径以及疾病、紊乱或病症的严重性,并且应根据从业者的判断和每个患者的情况来决定。有效剂量可以从体外或动物模型试验系统得出的剂量反应曲线中推算出来。
作为一般建议,本公开的抗体、片段或抗体药物偶联物施用于患者的剂量通常为患者体重的0.1mg/kg至100mg/kg,介于患者体重的0.1mg/kg至20mg/kg之间,或患者体重的1mg/kg至10mg/kg。通常,由于对外源多肽的免疫反应,人抗体在人体内的半衰期比来自其他物种的抗体更长。因此,较低剂量的人抗体和较不频繁的给药通常是可能的。此外,可以通过修饰(例如脂化)来增强抗体的吸收和组织渗透(例如,进入脑中)来减少本公开的抗体的给药剂量和频率。
在另一实施方案中,本公开的组合物与细胞因子联合施用。可以与本公开的组合物一起施用的细胞因子包括但不限于IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-10、IL-12、IL-13、IL-15、抗CD40、CD40L和TNF-α。
在另外的实施方案中,本公开的所述组合物与其他治疗或预防方案例如放射疗法联合施用。
组合物
本公开还提供了药物组合物。该药物组合物包含有效量的抗体、片段或抗体药物偶联物,以及可接受的载体。在一些实施方案中,所述组合物进一步包括第二抗癌剂(例如免疫检查点抑制剂)。
在一个具体的实施方案中,术语“药学上可接受的”是指经联邦或州政府的监管机构批准,或在美国药典或其他普遍认可的药典中列出用于动物,尤其是用于人类。此外,“药学上可接受的载体”将通常是任何类型的无毒固体、半固体或液体填料、稀释剂、封装材料或制剂助剂。
术语“载体”是指与治疗剂一起施用的稀释剂、佐剂、赋形剂或溶媒。该药物载体可以是无菌液体,如水和油,包括石油、动物、植物或合成来源的那些,如花生油、大豆油、矿物油、芝麻油等。当静脉内施用所述药物组合物时,水是优选的载体。盐水溶液和葡萄糖及甘油水溶液也可用作液体载体,特别是用于注射液。合适的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石粉、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。如果需要,所述组合物还可以包含少量的润湿剂或乳化剂,或pH缓冲剂,如醋酸盐、柠檬酸盐或磷酸盐。抗菌剂,如苯甲醇或对羟基苯甲酸甲酯;抗氧化剂,如抗坏血酸或亚硫酸氢钠;螯合剂,如乙二胺四乙酸;还设想了用于调整张度的试剂,如氯化钠或葡萄糖。这些组合物可以采用溶液、悬浮液、乳液、片剂、丸剂、胶囊、粉剂、缓释制剂等形式。所述组合物可以与传统的粘合剂和载体如甘油三酯配制成栓剂。口服制剂可以包括标准载体,如药用级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。E.W.Martin的《雷明顿制药科学(Remington's Pharmaceutical Sciences)》中描述了合适的药物载体的实例,通过引用并入本文。该组合物将包含治疗有效量的抗原结合多肽,优选以纯化的形式,连同适量的载体,以提供用于适当施用于患者的形式。所述制剂应适合给药方式。母制剂可以封装在安瓿、一次性注射器或者玻璃或塑料制成的多剂量小瓶中。
在一个实施方案中,所述组合物按照常规程序配制为适合于静脉内施用给人类的药物组合物。通常,用于静脉内给药的组合物是无菌等渗水性缓冲液中的溶液。必要时,所述组合物还可包括增溶剂和局部麻醉剂如利多卡因,以减轻注射部位的疼痛。通常,成分以单位剂型形式单独或混合在一起提供,例如,作为干燥的冻干粉或无水浓缩物在标有活性剂的量的密封容器(如安瓿或小袋)中。当所述组合物通过输注给药时,可以用含有无菌药用级水或生理盐水的输液瓶配药。如果所述组合物通过注射给药,可以提供无菌注射用水或生理盐水的安瓿,以便在给药前混合所述成分。
本公开的化合物可以配制成中性或盐形式。药学上可接受的盐包括与阴离子形成的盐,如衍生自盐酸、磷酸、乙酸、草酸、酒石酸等的那些,以及与阳离子形成的盐,如衍生自钠、钾、铵、钙、氢氧化铁、异丙胺、三乙胺、2-乙氨基乙醇、组氨酸、普鲁卡因等的那些。
实施例1:产生针对人紧密连接蛋白18亚型2(CLD 18A2)的鼠单克隆抗体
a.免疫
用编码人紧密连接蛋白18.2(CLD 18A2)片段的真核表达载体免疫Balb/c和C57/BL6小鼠。在第1天和第10天将50μg的质粒DNA注射到股四头肌(肌内注射,i.m.)。在第20天使用瞬时转染编码人CLD 18A2的核酸的HEK293细胞通过流式细胞术监测小鼠血清中针对人CLD 18A2的抗体的存在。通过腹腔注射5x 107个瞬时转染编码人CLD 18A2核酸的HEK293细胞,在融合前三天和前两天对具有可检测免疫反应的小鼠(图1)进行增强免疫。
b.生成CLD18A2的人单克隆抗体的杂交瘤的产生
根据标准方案分离小鼠脾细胞,并与PEG融合到小鼠骨髓瘤细胞系。然后用转染编码人CLD18的核酸的HEK293细胞,通过细胞ELISA筛选产生的杂交瘤以生成具有CLD18A2特异性的免疫球蛋白。
使用50%的PEG(罗氏诊断公司,CRL738641),将来自免疫小鼠脾脏淋巴细胞的单细胞悬液与P3X63Ag8U.1非分泌性小鼠骨髓瘤细胞(ATCC,CRL 1597)以2:1的比例融合。将细胞以大约3x104个/孔接种在平底微量滴定板中,然后在含有10%胎牛血清、2%杂交瘤融合和克隆补充剂(HFCS,罗氏诊断公司,CRL 1363735)外加10mM HEPES、0.055mM 2-巯基乙醇、50μg/ml庆大霉素和1x HAT(Sigma,CRLH0262)的选择性培养基中孵育大约两周。10至14天后,通过细胞ELISA筛选各个孔的抗CLD 18A2单克隆抗体(图2)。重新接种分泌抗体的杂交瘤,通过FACS再次用表达CLD18A2或CLD18A1的HEK293进行筛选,如果仍为CLD18A2阳性且CLD18A1阴性,则通过限制性稀释进行亚克隆。然后在体外培养稳定的亚克隆以在组织培养基中产生少量抗体用于表征。从每个杂交瘤中选择至少一个克隆,其保留了母细胞的反应性(通过FACS)。每个克隆产生三小瓶细胞库并储存在液氮中。
c.与CLD 18A2结合且不与CLD18A1结合的单克隆抗体的选择
为了确定抗体的同种型,进行了同种型ELISA。小鼠monoAB ID试剂盒(Zymed,CRL90-6550)用于确定已鉴定的CLD18A2反应性单克隆抗体的Ig亚类。产生了三十二个杂交瘤细胞系:64G11B4、65G8B8、56E8F10F4、54A2C4、44F6B11、15C2B7、20F1E10、72C1B6A3、58G2C2、101C4F12、103A10B2、40C10E3、78E8G9G6、4F11E2、10G7G11、12F1F4、78C10B6G4、119G11D9、113G12E5E6、116A8B7、105F7G12、84E9E12、103F4D4、110C12B6、85H12E8、103H2B4、103F6D3、113E12F7、120B7B2、111B12D11、111E7E2和100F4G12,进一步细节如下所示:
64G11B4,小鼠单克隆IgG1、κ抗体
65G8B8,小鼠单克隆IgG1、κ抗体
56E8F10F4,小鼠单克隆IgG1、κ抗体
54A2C4,小鼠单克隆IgG1、κ抗体
44F6B11,小鼠单克隆IgG1、κ抗体
15C2B7,小鼠单克隆IgG1、κ抗体
20F1E10,小鼠单克隆IgG1、κ抗体
72C1B6A3,小鼠单克隆IgG1、κ抗体
58G2C2,小鼠单克隆IgG2a、κ抗体
101C4F12,小鼠单克隆IgG2b、κ抗体
103A10B2,小鼠单克隆IgG2b、κ抗体
40C10E3,小鼠单克隆IgG1、λ抗体
78E8G9G6,小鼠单克隆IgG1、κ抗体
4F11E2,小鼠单克隆IgG1、κ抗体
10G7G11,小鼠单克隆IgG1、κ抗体
12F1F4,小鼠单克隆IgG1、κ抗体
78C10B6G4,小鼠单克隆IgG1、κ抗体
119G11D9,小鼠单克隆IgG1、κ抗体
113G12E5E6,小鼠单克隆IgG1、κ抗体
116A8B7,小鼠单克隆IgG1、κ抗体
105F7G12,小鼠单克隆IgG1、κ抗体
84E9E12,小鼠单克隆IgG1、κ抗体
103F4D4,小鼠单克隆IgG1、κ抗体
110C12B6,小鼠单克隆IgG1、κ抗体
85H12E8,小鼠单克隆IgG1、κ抗体
103H2B4,小鼠单克隆IgG1、κ抗体
103F6D3,小鼠单克隆IgG1、κ抗体
113E12F7,小鼠单克隆IgG2a、κ抗体
120B7B2,小鼠单克隆IgG2a、κ抗体
111B12D11,小鼠单克隆IgG2a、κ抗体
111E7E2,小鼠单克隆IgG2a、κ抗体
100F4G12,小鼠单克隆IgG3、κ抗体。
实施例2.杂交瘤测序
收获杂交瘤细胞(1×107)并使用上述用于脾脏组织的Tri试剂提取总RNA。根据上述制造商的说明,使用SuperScript III试剂盒制备cDNA。所得cDNA产物用作PCR模板,引物为VhRevU和VhForU,所得300bp PCR产物用PCR净化试剂盒净化,并用相同引物测序。还使用轻链V区特异性引物VkRev7和VkFor(仅用于可变区)或KappaFor引物(用于整个κ轻链)进行PCR反应。对净化过的PCR产物进行测序反应以获得以下抗体的DNA序列:64G11B4、65G8B8、56E8F10F4、54A2C4、44F6B11,、15C2B7、20F1E10、72C1B6A3、58G2C2、101C4F12、103A10B2、40C10E3、78E8G9G6、4F11E2、10G7G11、12F1F4、78C10B6G4、119G11D9、113G12E5E6、116A8B7、105F7G12、84E9E12、103F4D4、110C12B6、85H12E8、103H2B4、103F6D3、113E12F7、120B7B2、111B12D11、111E7E2和100F4G12。其可变序列(VH和VL)如下表1所示。
表1.抗体可变区的序列
实施例3.与CLD18A2反应的单克隆抗体的生产和纯化
为了产生毫克量的抗体以进行功能表征,将杂交瘤细胞以2x106个细胞/ml接种在基于透析的生物反应器(CELLine CL1000,Integra,库尔,瑞士)。每周收获一次含有抗体的上清液。使用Melon Gel(Pierce,罗克福德,美国)纯化每种小鼠单克隆抗体,并通过硫酸铵沉淀进行浓缩。通过十二烷基硫酸钠凝胶电泳和考马斯染色估计抗体浓度和纯度。
实施例4.与CLD18A2反应的鼠单克隆抗体的结合
从烧瓶中收获过表达CLD18A2的MKN45细胞。将100μl、1×106细胞/ml的细胞与图3所示的从100nM到0.003nM的3倍连续稀释的一抗在冰上孵育30分钟。用200μl的FACS缓冲液洗涤两次后,将细胞与二抗在冰上孵育30分钟。用200μl的FACS缓冲液洗涤细胞两次,然后转移到BD Falcon 5ml管中并通过FACS进行分析。通过流式细胞术的研究结果显示,与阳性参考抗体相比,纯化的鼠抗体可以以高EC50与转染人CLD18A2的MKN45细胞结合。
实施例5.与CLD18A2突变体反应的鼠单克隆抗体的结合
从烧瓶中收获内源性表达带有M149L突变的CLD18A2的SU620细胞。将100μl、1×106个细胞/ml的细胞与图4所示的从100nM到0.003nM的3倍连续稀释的一抗在冰上孵育30分钟。用200μl的FACS缓冲液洗涤两次后,将细胞与二抗在冰上孵育30分钟。用200μl的FACS缓冲液洗涤细胞两次,然后转移到BD Falcon 5ml管中并通过FACS进行分析。通过流式细胞术的研究结果显示,纯化的鼠抗体可以以高EC50与内源性表达带有M149L突变的人CLD18A2的SU620细胞结合,而参考抗体则不能(图4)。
实施例6.与小鼠和猕猴CLD18A2反应的鼠单克隆抗体的结合
为了评估这些抗体与小鼠和猕猴CLD18A2的交叉反应性,从烧瓶中收获过表达小鼠、猕猴或人CLD18A2的HEK293细胞。将100μl、1×106个细胞/ml的细胞与图3所示的从100nM到0.003nM的3倍连续稀释的一抗在冰上孵育30分钟。用200μl的FACS缓冲液洗涤两次后,将细胞与二抗在冰上孵育30分钟。用200μl的FACS缓冲液洗涤细胞两次,然后转移到BDFalcon 5ml管中并通过FACS进行分析。通过流式细胞术的研究结果显示,纯化的鼠抗体可以以高EC50与小鼠和猕猴CLD18A2结合,至少与参考抗体相似(图5、6和7)。
实施例7.与CLD18A2反应的嵌合抗体的结合
合成产生鼠VH和VK基因,然后分别克隆到含有人γ1和人κ恒定结构域的载体中。纯化的嵌合抗体由转染的CHO细胞产生。
从烧瓶中收获稳定表达人CLD18A2或CLD18A1的MKN45细胞。将100μl、1×106个细胞/ml的细胞与图4所示的从100nM到0.003nM的3倍连续稀释的初级嵌合抗体在冰上孵育30分钟。用200μl的FACS缓冲液洗涤两次后,将细胞与二抗在冰上孵育30分钟。用200μl的FACS缓冲液洗涤细胞两次,然后转移到BD Falcon 5ml管中并通过FACS进行分析。研究结果显示,嵌合抗体可以以高EC50与人CLD18A2结合,但不与CLD18A1结合(图8和9)。
实施例8.嵌合抗体的抗体依赖性细胞毒性(ADCC)
ADCC报告基因生物测定在ADCC MOA通路激活的早期使用另一种读数:通过效应细胞中的NFAT(活化T细胞的核因子)通路激活基因转录。此外,ADCC报告基因生物测定使用稳定表达FcγRIIIa受体(V158(高亲和力)变体)和驱动萤火虫荧光素酶表达的NFAT反应元件的工程化Jurkat细胞作为效应细胞。ADCC MOA中的抗体生物活性通过NFAT通路激活后产生的荧光素酶进行定量;效应细胞中的荧光素酶活性通过发光读数进行定量(图1)。信号高,且测定背景低。
在有或没有ADCC生物测定靶细胞(表达紧密连接蛋白18.2)的情况下,将连续稀释的紧密连接蛋白18.2嵌合单克隆抗体或参考抗体与工程化的Jurkat效应细胞(ADCC生物测定效应细胞)在37℃下孵育6小时。使用Bio-GloTM试剂对荧光素酶活性进行定量(表2)。结果显示这些嵌合抗体具有非常强的ADCC活性。
表2.测试抗体的EC50
抗体 | EC50(pM) |
4F11E2 | 22.18 |
12F1F4 | 36.77 |
64G11B4 | 125.7 |
72C186A3 | 46.32 |
78E8G9G6 | 15.86 |
103F6D3 | 79.53 |
120B7B2 | 5.806 |
参考抗体 | 458.5 |
实施例9.4F11E2、72C1B6A3和120B7B2小鼠单抗的人源化
采用单抗4F11E2、72C1B6A3和120B7B2可变区基因来创建人源化的单抗。在该过程的第一步中,将单抗的VH和VL的氨基酸序列与现有的人Ig基因序列数据库进行比较,以找到整体最佳匹配的人类种系Ig基因序列。
所述人源化抗体的氨基酸序列列于下表3中。
表3.人源化序列
人源化的VH和VL基因是合成产生的,然后分别克隆到含有人γ1和人κ恒定结构域的载体中。人VH和人VL的配对产生所述人源化抗体(参见表4)。
表4.带有VH和VL区的人源化抗体
4F11E2
72C1B6A3
120B7B2
实施例10.与CLD18A2反应的人源化抗体的结合
从烧瓶中收获稳定表达人CLD18A2或CLD18A1的MKN45细胞。将100μl、1×106个细胞/ml的细胞与图4所示的从100nM到0.003nM的3倍连续稀释的初级人源化抗体在冰上孵育30分钟。用200μl的FACS缓冲液洗涤两次后,将细胞与二抗在冰上孵育30分钟。用200μl的FACS缓冲液洗涤细胞两次,然后转移到BD Falcon 5ml管中并通过FACS进行分析。研究结果显示,所示的人源化抗体可以以高EC50与人CLD18A2结合,但不与CLD18A1结合(图10和11)。
实施例11.与CLD18A2反应的PTM(转录后翻译)去风险人源化抗体的结合
翻译后修饰(PTM)在治疗性蛋白质的开发过程中会引起问题,如异质性增加、生物活性降低、稳定性降低、免疫原性、片段化和聚集。PTM的潜在影响取决于其位置,在某些情况下还取决于溶剂暴露。针对以下潜在的PTM分析了序列的CDR:天冬酰胺脱酰胺化、天冬氨酸异构化、游离半胱氨酸硫醇基团、N-糖基化、氧化、潜在水解位点的片段化等。
为了降低在4F11E2、72C1B6A3和120B7B2中发生PTM的风险,对VH和VL中的一些相关氨基酸进行突变。然后产生了九种抗体:
*氨基酸位置(例如N55)是根据相应的VH或VL氨基酸序列中的氨基酸残基编号,而非Kabat或Chothia。
从烧瓶中收获稳定表达人CLD18A2或CLD18A1的MKN45细胞。将100μl、1×106个细胞/ml的细胞与图4所示的从100nM到0.003nM的3倍连续稀释的初级突变人源化抗体在冰上孵育30分钟。用200μl的FACS缓冲液洗涤两次后,将细胞与二抗在冰上孵育30分钟。用200μl的FACS缓冲液洗涤细胞两次,然后转移到BD Falcon 5ml管中并通过FACS进行分析。研究结果显示,所示的抗体可以以高EC50与人CLD18A2结合,但不与CLD18A1结合(图12和13)。
为了评估4F11E2d(HC N55E/LC S32A)和4F11E2d(H N55E N104Q/LC S32A)的去风险化的变体的抗原结合效力,在基于细胞的结合测定中测试了变体。将从100nM开始连续稀释的抗CLDN18.2抗体与105个细胞在冰上孵育30分钟。用FACS缓冲液洗涤后,将细胞与APC标记的二抗在冰上再孵育30分钟。通过FACS分析与抗体结合的细胞。变体显示出与细胞表面紧密连接蛋白18.2的有效结合(图14)。
实施例12.PTM去风险化的人源化抗体的抗体依赖性细胞毒性(ADCC)
在有或没有ADCC生物测定靶细胞(表达紧密连接蛋白18.2)的情况下,将连续稀释的紧密连接蛋白18.2PTM去风险化的人源化抗体或参考抗体与工程化的Jurkat效应细胞(ADCC生物测定效应细胞)在37℃下诱导孵育6小时。使用Bio-GloTM试剂对荧光素酶活性进行定量(表5)。结果显示这些人源化抗体具有非常强的ADCC活性。
表5.ADCC
No. | 测试抗体 | EC50(pM) |
1 | 4F11E2-HC N55Q-LC N31E | 238.1 |
2 | 4F11E2-HC N55Q-LC S32A | 413.9 |
3 | 4F11E2-HC N55E-LCS32A | 148.1 |
4 | 72C1B6A3-HC WT-LC N31E | 1651 |
5 | 72C1B6A3-HC WT-LCS32A | 190.5 |
6 | 120B7B2-HC G57D&104A-LC-N96E&N31E | 492.6 |
7 | 120B7B2-HC G57D&10 4A-LC-S32A&G97A | 113.9 |
参考抗体 | 参考抗体 | 158.3 |
实施例13.表位作图
将紧密连接蛋白18.2的胞外结构域的所有氨基酸分别突变为A。将每个突变的或野生型紧密连接蛋白18.2转染到Hek293细胞。通过指定的抗体来评估紧密连接蛋白18.2的表达。结果示于图15中(仅显示突变后减少结合的氨基酸残基)。
如图15所示,氨基酸W30、N45、Y46、G48、L49、W50、C53、V54、R55、E56、S58、F60、E62、C63、R80、Y169和G172参与了三种测试抗体4F11E2(H4F)、72C186A3(H72C1)和120B7B2(120)或者参考抗体175D10(IMAB362)的结合。W30似乎在紧密连接蛋白18.2的第一胞外结构域的前半部分形成了一个残基团。N45、Y46、G48、L49、W50、C53、V54、R55、E56、S58、F60、E62和C63似乎是同一胞外结构域内的第二个残基团。另一方面,Y169和G172位于或接近第二胞外结构域。
各种紧密连接蛋白的晶体结构已被解析。如图20所示(改编自Suzuki等,Ann.N.Y.Acad.Sci.,1397:25-34),紧密连接蛋白包含四个跨膜段,短的胞内N末端、包含一个共有的W-LW-C-C基序的大的第一细胞外环(环1,或ECS1)、较短的第二细胞外环(环2,或ECS2),以及细胞内C末端尾部。环1包含四条β链β1、β2、β3和β4,并且环包含一条β链,β5。
W30、L49和W50突变为丙氨酸可能破坏了环1构象的稳定。C53或C63的突变可能破坏了β3和β4之间的二硫键。R80可能对维持细胞表面平行的紧密连接蛋白18.2分子之间的相互作用,或对稳定环1的构象重要。其余的残基,包括N45、Y46、G48、V54、R55、E56、S58、F60和E62(在β3至β4环中),以及Y169和G172(在β5中),可能为此处测试的抗体的结合提供了界面。
实施例14.人源化4F11E2、72C1B6A3和120B7B2抗体与基准175D10紧密连接蛋白18.2抗体的比较
基于细胞的结合
为了比较人源化抗紧密连接蛋白18.2抗体:4F11E2(HC N55E/LC S32A)、72C1B6A3(HC WT/LC S32A)和120B7B2(HC G57D S104A/LC S32A G97A)与基准抗体175D10(IMAB362),本实施例确定了人紧密连接蛋白18.2的表达细胞中基于细胞的结合。根据人CLDN18.2的表达水平,将稳定表达人CLD18A2的CHO-K1细胞分为高表达者和低表达者。将从100nM开始连续稀释的抗CLDN18.2抗体与105个细胞在冰上孵育30分钟。用FACS缓冲液洗涤后,将细胞与APC标记的二抗在冰上再孵育30分钟。通过FACS分析与抗体结合的细胞。
如图16所示,4F11E2、72C1B6A3和120B7B2在高表达紧密连接蛋白18.2和低表达紧密连接蛋白18.2的CHO-K1细胞中都显示了优于175D10的结合力。
ADCC试验
为了进一步比较人源化抗紧密连接蛋白18.2抗体:4F11E2(HC N55E/LC S32A)、72C1B6A3(HC WT/LC S32A)和120B7B2(HC G57D S104A/LC S32A G97A)与基准抗体175D10(IMAB362)的ADCC效应,本实施例进行了基于细胞的ADCC试验。简而言之,在不同剂量抗紧密连接蛋白18.2抗体的存在下,NK92细胞与过表达紧密连接蛋白18.2的293细胞共培养。如图17所示,4F11E2、72C1B6A3和120B7B2显示出优于175D10抗体的ADCC效力。
对于某些治疗性抗体,增强的ADCC可以增加基于抗体的靶向治疗的治疗窗口。增强的ADCC可以通过工程化Fc区(如带有S239D/I332E突变)来实现。在基于NK92细胞的ADCC试验中,与带有相同S239D/I332E突变的对照抗体175D10相比,Fc区带有S239D/I332E突变的抗体4H11E2、72C1B6A3和120B7B2对过表达紧密连接蛋白18.2的293细胞具有更强的NK92介导的细胞杀伤(图18)。
抗体依赖的细胞吞噬作用(ADCP)
在体外试验中评估了抗CLDN 18.2单抗对巨噬细胞吞噬肿瘤细胞的影响,其中,在不同浓度抗CLDN18.2单抗的存在下,CLDN18.2阳性的NUG-C4细胞与人分化的巨噬细胞共同培养。简而言之,CD14+单核细胞从人外周血单核细胞(PBMC)中纯化出来,并在体外分化6天成为成熟的巨噬细胞。收集单核细胞衍生的巨噬细胞(MDM)并作为效应细胞重新接种在24孔培养皿过夜。在不同浓度抗CLDN18.2单抗的存在下,将表达CLDN18.2-eGFP的NUG-C4作为靶细胞,以每个吞噬细胞5个肿瘤细胞的比例添加到MDM。孵育3小时后,用PBS洗去未被吞噬的靶细胞,收集剩余的吞噬细胞并用巨噬细胞标记物CD14染色,然后进行流式细胞术分析。吞噬指数是通过定量GFP+细胞在CD14+细胞中的百分比来计算的,与IgG对照进行标准化。
如图19所示,所有的C18.2单抗以浓度依赖的方式明显增强了NUG-C4细胞的吞噬作用。在野生型IgG1和S239D/I332E突变的IgG1形式中,4H11E2、72C1B6A3和120B7B2抗体表现出比参考抗体175D10更强的ADCP效果。
综上所述,该实施例表明,新开发的4F11E2、72C1B6A3和120B7B2抗体比参考抗体175D10具有更强的基于细胞的结合和ADCC/ADCP效力。预计这些新抗体的改进特性可以归因于这些抗体与参考抗体175D10相比具有更高的结合特异性。例如,图15中,175D10与紧密连接蛋白18.2的相互作用在整个谱中都很强,其中包括与D28、Q33、N38和V43的强结合,然后是与G59和V79的强结合。相比之下,所述新抗体4F11E2、72C1B6A3和120B7B2对第一胞外结构域的前半部分的W30具有较高的特异性,对第一胞外结构域的后半部分的G48至E56具有较高的特异性。新抗体对同样位于后半部分的Y46也具有略强的结合力。它们与D28、Q33、N38、V43、G59和V79的结合相当弱,这可能有助于改善所述新抗体的ADCC和ADCP。
实施例15.pHAb与紧密连接蛋白18.2抗体的偶联
使用基于pHAb反应性染料的内化试验来确定CLDN18.2结合的抗紧密连接蛋白18.2抗体的内化。pHAb染料是pH传感器染料,在pH>7时具有非常低的荧光,并且当溶液的pH变为酸性时,荧光会急剧增加。pHAb染料在532nm处具有最大激发值(Ex),在560nm处具有最大发射值(Em)。pHAb染料偶联抗体可以用于监测受体介导的抗体内化。当抗体-pHAb染料偶联物与其细胞膜上的受体结合时,它表现出最小的荧光。然而,在受体介导的内化中,抗体-pHAb染料偶联物进入pH值为酸性的内体和溶酶体囊泡,导致pHAb染料发出荧光。这种荧光可以使用各种技术进行检测,包括细胞成像、流式细胞术和带有适当过滤器的基于荧光板的阅读器。
实验方案:
A.抗体的生产
通过瞬时转染ExpiCHO细胞产生27种嵌合抗体、3种人源化抗体和1种对照IgG1,并通过蛋白A亲和层析纯化。
B.使用pHAb硫醇反应性染料进行磁珠上抗体的偶联
2.将50μl的磁珠浆液加入1.5ml微量离心管中。将管置于磁力架上10秒钟。
3.移除并丢弃储存缓冲液。
4.加入250μl的PBS(pH7.4)。混合并将管置于磁力架上10秒钟。移除并丢弃缓冲液。
5.将含有100μg抗体的1.0ml样品加入到磁珠中。
6.在室温下混合样品60分钟。通过持续搅拌使磁珠保持悬浮状态。
7.将管置于磁力架上10秒钟。移除上清液。
8.加入250μl的硫醇偶联缓冲液(含有1mM EDTA的10mM磷酸盐缓冲液,pH 7.0)并混合。将管置于磁力架上10秒钟。移除并丢弃缓冲液。重复该步骤,共洗涤两次。
9.加入100μl的硫醇偶联缓冲液。
10.加入DTT至2.5mM的终浓度。
11.在室温下混合样品60分钟。通过持续搅拌使磁珠保持悬浮状态。
12.将管置于磁力架上10秒钟并丢弃缓冲液。
13.加入250μl的硫醇偶联缓冲液并混合。将管置于磁力架上10秒钟。移除并丢弃缓冲液。重复该步骤,共洗涤两次。
14.加入100μl的硫醇偶联缓冲液。
15.快速离心pHAb硫醇反应性染料(G9835)(即,在台式离心机中以14,000×g离心5-10秒),并通过将25μl 1:1的DMSO-水混合物添加到0.25mg的染料中,溶解成10mg/ml。通过涡旋进行混合。染料可能需要1-3分钟才能完全溶解。在使用前制作此溶液。
16.在100μg的抗体中加入1.2μl的pHAb硫醇反应性染料,使染料过量20摩尔。
17.混合60分钟。通过持续搅拌使磁珠保持悬浮状态。
18.将管置于磁力架上10秒钟。移除并丢弃上清液。19.加入250μl的硫醇偶联缓冲液并混合。置于磁力架上10秒。移除并丢弃结合/洗涤缓冲液(PBS.pH7.4)。
20.重复步骤19,共洗涤两次。
21.加入100μl的洗脱缓冲液(0.1M甘氨酸,pH3.0)至磁珠。
22.在室温下混合5分钟。
23.将管置于磁力架上10秒钟。移除洗脱样品并转移至含有5μl中和缓冲液(1MTris-HCl,pH9.0)的新的微量离心管中。
测试抗体的抗体浓度和染料抗体比(DAR)示于表6中。
表6.染料抗体比(DAR)
实施例16.紧密连接蛋白18.2抗体的内化的筛选
以0.05%胰蛋白酶/EDTA(Gibco,25300-054)收获稳定转染的人CLDN18.2 MKN45细胞,并以每孔90μl、20K的密度接种于96孔黑色板(Thermo Scientific#165305)中。在用pHAb标记的抗体处理之前,将板孵育20-24小时。
对于内化,将pHAb偶联的紧密连接蛋白18.2抗体以两种浓度(20nM和100nM)加入到细胞中,在平板混合器上轻轻混合1-2分钟,然后孵育过夜以允许内化(几小时后可以检测到内化)。在Tecan Infinity M1000 Pro荧光板阅读器上以Ex/Em:532nm/560nm读板。为了达到更高的灵敏度,在读板前用PBS代替培养基。
通过DAR标准化的结果示于表7。测试抗体的内化效率高于参考抗体IMAB362。
表7.内化结果
实施例17.嵌合紧密连接蛋白18.2抗体在CHO-紧密连接蛋白18.2细胞上内化的EC50
用0.05%胰蛋白酶/EDTA(Gibco,25300-054)收获稳定转染的人CLDN18.2 CHO细胞,并以每孔90μl、10K的密度接种于96孔黑色板(Thermo Scientific#165305)中。在用pHAb标记的抗体处理前,将板孵育20-24小时。
对于内化,将pHAb偶联的嵌合紧密连接蛋白18.2抗体以不同浓度(100nM、30nM、10nM、3nM、1nM、0.3nM、0.1nM、0.03nM和0.01nM)加入到细胞中,在平板混合器上轻轻混合1-2分钟,然后孵育过夜以允许内化(几小时后可以检测到内化)。在Tecan Infinity M1000Pro荧光板阅读器上以Ex/Em:532nm/560nm读板。为了达到更高的灵敏度,在读板前用PBS代替培养基。
以DAR标准化的结果示于图21。测试抗体的内化效率再次高于参考抗体IMAB362。
实施例18.人源化紧密连接蛋白18.2抗体在CHO-紧密连接蛋白18.2细胞上内化的EC50
用0.05%胰蛋白酶/EDTA(Gibco,25300-054)收获稳定转染的人CLDN18.2 CHO细胞,并以每孔90μl、10K的密度接种于96孔黑色板(Thermo Scientific#165305)中。在用pHAb标记的抗体处理前,将板孵育20-24小时。
对于内化,将pHAb偶联的人源化紧密连接蛋白18.2抗体以不同浓度(100nM、30nM、10nM、3nM、1nM、0.3nM、0.1nM、0.03nM和0.01nM)加入到细胞中,在平板混合器上轻轻混合1-2分钟,然后孵育过夜以允许内化(几小时后可检测到内化)。在Tecan Infinity M1000 Pro荧光板阅读器上以Ex/Em:532nm/560nm读板。为了达到更高的灵敏度,在读板前用PBS代替培养基。
以DAR标准化的结果示于图22,其显示了测试抗体的内化效率高于参考抗体IMAB362。
实施例19.人源化紧密连接蛋白18.2抗体在MKN45-紧密连接蛋白18.2细胞上内化的EC50
用0.05%胰蛋白酶/EDTA(Gibco,25300-054)收获稳定转染的人CLDN18.2 MKN45细胞,并以每孔90μl、10K的密度接种于96孔黑色板(Thermo Scientific#165305)中。在用pHAb标记的抗体处理前,将板孵育20-24小时。
对于内化,将pHAb偶联的人源化紧密连接蛋白18.2抗体以不同浓度(100nM、30nM、10nM、3nM、1nM、0.3nM、0.1nM、0.03nM和0.01nM)加入到细胞中,在平板混合器上轻轻混合1-2分钟,然后孵育过夜以允许内化(几小时后可检测到内化)。在Tecan Infinity M1000 Pro荧光板阅读器上以Ex/Em:532nm/560nm读板。为了达到更高的灵敏度,在读板前用PBS代替培养基。
以DAR标准化的结果示于图23,其显示了测试抗体的内化效率高于参考抗体IMAB362。
实施例20.抗体药物偶联物
每种抗体与大约三倍的TCEP混合,并在37℃下搅拌2小时。反应体系迅速滴在超过八倍的VC-MMAE上并在冰上孵育1小时,在药物接头上加入20倍过量的半胱氨酸以终止反应。最后,通过在PBS中平衡的Sephadex G-25洗脱将ADC产物纯化,并通过离心超滤浓缩。在无菌条件下通过0.2μm过滤器过滤偶联物,并储存在-80℃用于分析和测试。通过紫外分光光度法分析药物抗体比,通过SEC-HPLC分析单体含量,通过RP-HPLC分析游离药物含量。vcMMAE偶联的抗体的(DAR)示于表8。
表8.vcMMAE偶联抗体的DAR
实施例21.抗CLDN18.2裸抗体和抗体药物偶联物的相对结合亲和力和特异性
本实施例使用CLDN18.2阳性和阴性细胞系通过流式细胞术测定抗CLDN18.2裸抗体和抗体药物偶联物的相对结合亲和力和特异性。
用0.05%胰蛋白酶/EDTA(Gibco,25300-054)从指数生长的培养基中收获细胞,并使用Neubauer计数室进行计数。以1,500rpm(468×g)离心细胞5分钟,弃去上清液,将细胞重悬于FACS缓冲液中(含2%FCS的PBS(Gibco,10270-106)用于分析毒素偶联抗体,含2%FCS和2mM EDTA的PBS用于筛选CLDN18.2反应性裸抗体)至2×106个细胞/ml。将每孔100μl的细胞悬液(相当于2×105个细胞/孔)转移到圆底96孔微量滴定板。以1500rpm离心1分钟后,弃去上清液,将细胞重悬在于含有适当浓度的毒素偶联抗体或裸抗体的FACS缓冲液中(最高20μg/ml用于相对亲和力测量或50μg/ml用于表达对照),在4℃下孵育30-45分钟(表8)。以1500rpm离心细胞1分钟并弃去上清液。以FACS缓冲液洗涤三次后,将细胞重悬于含APC偶联抗人IgG(Jackson Immuno Research,109-136-170)或APC偶联山羊-抗小鼠IgG(Jackson Immuno Research,115-136-146)或蛋白质L-FITC(1μg/ml,嵌合mAB294的分析)的FACS缓冲液中,并在4℃孵育30分钟(表3)。孵育后,每份样品加入100μl FACS缓冲液,以1500rpm离心细胞1分钟并弃去上清液。用FACS缓冲液的洗涤步骤重复两次。最后,将细胞重悬于100μl FACS缓冲液中,并使用BD FACS阵列生物分析仪测定结合力。
应该注意的是,毒素偶联抗体和裸抗体以相等的浓度应用。结果示于图24。
实施例22.在DAN-G、NUGC或SCG-7901转染子中,带有MMAE的紧密连接蛋白18.2人源化抗体的细胞毒性比带有MMAE的IMAB362更有效
用0.05%胰蛋白酶/EDTA(Gibco,25300-054)收获过表达人紧密连接蛋白18.2的细胞(DAN-G、NUGC或SCG-7901转染子),重悬于细胞培养液中,并将50μl的细胞悬液在96孔细胞培养板中每孔接种相应数量的细胞。24小时后,加入稀释在50μl培养基中的适当浓度的毒素偶联IMAB362或对照抗体,再培养细胞72小时。使用CellTiter-发光细胞活力测试仪(G7572)测定带有MMAE的紧密连接蛋白18.2人源化抗体对细胞活力的影响。
1.准备培养基中有哺乳动物细胞的不透明壁多孔板,96孔板每孔100μl,或384孔板每孔25μl。多孔板必须与所用的发光光度计兼容。
2.准备含有无细胞培养基的对照孔,以获得背景发光值。
3.在实验孔中加入测试化合物,并按照培养方案孵育。4.在室温下平衡板及其内容物约30分钟。
5.加入与每个孔中存在的细胞培养基体积相等的CellTiter-试剂(例如,对于96孔板,在含有细胞的100μl培养基中加入100μl的试剂,或者对于384孔板,在含有细胞的25μl培养基中加入25μl的试剂)。
6.在轨道式振荡器上混合内容物2分钟以诱导细胞裂解。
7.让板在室温下孵育10分钟以稳定发光信号。注意:标准板内不均匀的发光信号可能由温度梯度、细胞接种不均匀或多孔板的边缘效应引起。
8.记录发光。
测试结果示于图25A-C。BG2001-C和BG2001-D在与MMAE偶联时,与参考IMAB362-NMAE偶联物相比,在所有测试细胞中都具有大大增加的细胞毒性。因此这些结果证明了本公开的抗体在内化偶联药物方面的改进能力。
实施例23.在内源性表达人紧密连接蛋白18.2的SNU620中,带有MMAE的紧密连接蛋白18.2人源化抗体的细胞毒性比带有MMAE的IMAB362更有效
将SNU620细胞重悬于细胞培养基中,并将50μl的细胞悬液在96孔细胞培养板中每孔接种相应数量的细胞。24小时后,加入稀释在50μl培养基中的适当浓度的毒素偶联抗体(包括参考抗体IMAB362),再培养细胞72小时。使用发光细胞活力测试仪(G7572)测定带有MMAE的紧密连接蛋白18.2人源化抗体对细胞活力的影响。如图26所示,与参考抗体IMAB362相比(一种正处于临床开发的先导抗紧密连接蛋白18.2抗体),BG2001-C和BG2001-D在递送偶联的MMAE到SNU620细胞中的效果都更有效。
实施例24.抗体药物偶联物的体内功效
本实施例测试了其中一种抗体药物偶联物(ADC)与单独的抗体(单克隆抗体)相比,在移植有人肿瘤细胞的裸鼠中减少肿瘤生长的功效。
将0.1mL(5×105个细胞)人类患者来源的细胞(与基底胶1:1混合)皮下接种在每只小鼠的右背部。当平均肿瘤体积达到60~80mm3时,选择30只小鼠进行治疗实验。
接种后18天,选择5只具有肿瘤大小在330-520mm3范围内的小鼠进行各项治疗三周(1mg/kg、3mg/mk、10mg/kg或20mg/kgADC,每周一次)。为了进行比较,仅抗体(单克隆抗体)治疗为10mg/kg(每周两次)。
结果示于图27。10mg/kg和20mg/kg的ADC都完全抑制了肿瘤的生长,而没有降低动物的体重。图28显示每只动物的平均肿瘤减少效果和单个肿瘤减少效果。因此,ADC的肿瘤减少效果比单独的抗体大得多。
***
本公开的范围不受所描述的具体实施方案的限制,所述具体实施方案旨在作为本公开的个别方面的单一说明,并且功能上等效的任何组合物或方法均在本公开的范围内。对本领域技术人员显而易见的是,可以在不脱离本公开的精神或范围的情况下对本公开的方法和组合物进行各种修改和变化。因此,本公开旨在涵盖本公开的修改和变化,只要它们落入所附权利要求及其等效物的范围内。
在本说明书中提到的所有出版物和专利申请通过引用并入本文,其程度与每个单独的出版物或专利申请被具体地和单独地指明为通过引用而并入相同。
序列表
<110> 礼新医药科技(上海)有限公司
<120> 靶向紧密连接蛋白18.2的抗体药物偶联物
<130> FSP1V213969JW
<150> PCT/CN2019/115760
<151> 2019-11-05
<160> 314
<170> PatentIn version 3.5
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<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<220>
<221> X
<222> (4)..(4)
<223> 空的
<400> 7
Arg Ala Ser Xaa
1
<210> 8
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 8
Gln Asn Asp Tyr Ile Tyr Pro Tyr Thr
1 5
<210> 9
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 9
Gly Tyr Thr Phe Thr Thr Tyr Pro
1 5
<210> 10
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 10
Phe His Pro Tyr Asn Asp Asp Thr
1 5
<210> 11
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 11
Ala Arg Arg Ala Tyr Gly Tyr Pro Tyr Ala Met Asp Tyr
1 5 10
<210> 12
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 12
Gln Ser Leu Leu Asn Ser Gly Asn Arg Lys Asn Tyr
1 5 10
<210> 13
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 13
Gln Asn Ala Tyr Ser Tyr Pro Phe Thr
1 5
<210> 14
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 14
Gly Phe Thr Phe Ser Thr Phe Gly
1 5
<210> 15
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 15
Ile Thr Ser Gly Asn Ser Pro Ile
1 5
<210> 16
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 16
Ala Arg Ser Ser Tyr Tyr Gly Asn Ser Met Asp Tyr
1 5 10
<210> 17
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 17
Gln Ser Leu Leu Asn Ala Gly Asn Gln Lys Asn Tyr
1 5 10
<210> 18
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 18
Gln Ser Leu Leu Glu Ser Gly Asn Gln Lys Asn Tyr
1 5 10
<210> 19
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 19
Gln Asn Ala Tyr Tyr Phe Pro Phe Thr
1 5
<210> 20
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 20
Gln Glu Gly Tyr Tyr Phe Pro Phe Thr
1 5
<210> 21
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 21
Ile Asn Pro Tyr Asn Asp Asp Thr
1 5
<210> 22
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 22
Ala Arg Ala Tyr Phe Gly Asn Ala Phe Ala Tyr
1 5 10
<210> 23
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 23
Gln Ser Leu Leu Glu Ser Gly Asn Arg Lys Asn Tyr
1 5 10
<210> 24
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 24
Gln Ser Leu Leu Asn Ala Gly Asn Arg Lys Asn Tyr
1 5 10
<210> 25
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 25
Ile Thr Ser Gly Gln Ser Pro Ile
1 5
<210> 26
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 26
Ile Thr Ser Gly Glu Ser Pro Ile
1 5
<210> 27
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 27
Ala Arg Ser Ser Tyr Tyr Gly Gln Ser Met Asp Tyr
1 5 10
<210> 28
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 28
Ala Arg Ser Ser Tyr Tyr Gly Glu Ser Met Asp Tyr
1 5 10
<210> 29
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 29
Ala Arg Ser Ser Tyr Tyr Gly Asn Ala Met Asp Tyr
1 5 10
<210> 30
<211> 261
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 30
Met Ala Val Thr Ala Cys Gln Gly Leu Gly Phe Val Val Ser Leu Ile
1 5 10 15
Gly Ile Ala Gly Ile Ile Ala Ala Thr Cys Met Asp Gln Trp Ser Thr
20 25 30
Gln Asp Leu Tyr Asn Asn Pro Val Thr Ala Val Phe Asn Tyr Gln Gly
35 40 45
Leu Trp Arg Ser Cys Val Arg Glu Ser Ser Gly Phe Thr Glu Cys Arg
50 55 60
Gly Tyr Phe Thr Leu Leu Gly Leu Pro Ala Met Leu Gln Ala Val Arg
65 70 75 80
Ala Leu Met Ile Val Gly Ile Val Leu Gly Ala Ile Gly Leu Leu Val
85 90 95
Ser Ile Phe Ala Leu Lys Cys Ile Arg Ile Gly Ser Met Glu Asp Ser
100 105 110
Ala Lys Ala Asn Met Thr Leu Thr Ser Gly Ile Met Phe Ile Val Ser
115 120 125
Gly Leu Cys Ala Ile Ala Gly Val Ser Val Phe Ala Asn Met Leu Val
130 135 140
Thr Asn Phe Trp Met Ser Thr Ala Asn Met Tyr Thr Gly Met Gly Gly
145 150 155 160
Met Val Gln Thr Val Gln Thr Arg Tyr Thr Phe Gly Ala Ala Leu Phe
165 170 175
Val Gly Trp Val Ala Gly Gly Leu Thr Leu Ile Gly Gly Val Met Met
180 185 190
Cys Ile Ala Cys Arg Gly Leu Ala Pro Glu Glu Thr Asn Tyr Lys Ala
195 200 205
Val Ser Tyr His Ala Ser Gly His Ser Val Ala Tyr Lys Pro Gly Gly
210 215 220
Phe Lys Ala Ser Thr Gly Phe Gly Ser Asn Thr Lys Asn Lys Lys Ile
225 230 235 240
Tyr Asp Gly Gly Ala Arg Thr Glu Asp Glu Val Gln Ser Tyr Pro Ser
245 250 255
Lys His Asp Tyr Val
260
<210> 31
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 31
Gln Ser Leu Leu Asn Ser Gly Asn Gln Arg Asn Tyr
1 5 10
<210> 32
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 32
Gln Ser Leu Leu Asn Ser Gly Asn Leu Lys Asn Tyr
1 5 10
<210> 33
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 33
Gln Ser Leu Leu Asn Gly Gly Asn Gln Lys Asn Tyr
1 5 10
<210> 34
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 34
Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Lys Tyr
1 5 10
<210> 35
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 35
Gln Ser Leu Phe Asn Ser Gly Asn Gln Arg Asn Tyr
1 5 10
<210> 36
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 36
Met Ser Leu Phe Asn Ser Gly Asn Gln Lys Ser Tyr
1 5 10
<210> 37
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 37
Gln Ser Leu Phe Asn Ser Gly Asn Gln Lys Asn Tyr
1 5 10
<210> 38
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 38
Gln Ser Val Phe Asn Ser Gly Asn Gln Lys Asn Tyr
1 5 10
<210> 39
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<220>
<221> X
<222> (4)..(4)
<223> 空的
<400> 39
Gly Ala Ser Xaa
1
<210> 40
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<220>
<221> X
<222> (4)..(4)
<223> 空的
<400> 40
Trp Ala Phe Xaa
1
<210> 41
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<220>
<221> X
<222> (4)..(4)
<223> 空的
<400> 41
Trp Ser Ser Xaa
1
<210> 42
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 42
Gln Asn Asp Tyr Phe Tyr Pro Phe Thr
1 5
<210> 43
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 43
Gln Asn Val Tyr Ile Tyr Pro Phe Thr
1 5
<210> 44
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 44
Gln Asn Asp Tyr Tyr Phe Pro Phe Thr
1 5
<210> 45
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 45
Gln Asn Asp Leu Tyr Tyr Pro Trp Thr
1 5
<210> 46
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 46
Gln Asn Gly Tyr Ser Tyr Pro Phe Thr
1 5
<210> 47
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 47
Gln Asn Asn Tyr Tyr Phe Pro Leu Thr
1 5
<210> 48
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 48
Gln Asn Val Tyr Ser Tyr Pro Leu Thr
1 5
<210> 49
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 49
Gln Asn Ser Tyr Ser Tyr Pro Phe Thr
1 5
<210> 50
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 50
Gln Asn Asn Phe Ile Tyr Pro Leu Thr
1 5
<210> 51
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 51
His Asn Asp Tyr Ile Tyr Pro Leu Thr
1 5
<210> 52
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 52
Gln Asn Asn Tyr Tyr Tyr Pro Phe Thr
1 5
<210> 53
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 53
Gln Asn Ala Tyr Tyr Tyr Pro Leu Thr
1 5
<210> 54
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 54
Gln Asn Ala Tyr Phe Tyr Pro Cys Thr
1 5
<210> 55
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 55
Gln Asn Asp Tyr Tyr Phe Pro Leu Thr
1 5
<210> 56
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 56
Gln Asn Ala Tyr Phe Tyr Pro Phe Thr
1 5
<210> 57
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 57
Gln Asn Asn Tyr Phe Tyr Pro Leu Thr
1 5
<210> 58
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 58
Gln Asn Asn Tyr Ile Tyr Pro Leu Ala
1 5
<210> 59
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 59
Gly Tyr Ala Phe Thr Asn Tyr Leu
1 5
<210> 60
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 60
Gly Phe Ser Leu Thr Ser Tyr Gly
1 5
<210> 61
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 61
Gly Phe Thr Phe Asn Ser Phe Gly
1 5
<210> 62
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 62
Gly Phe Thr Phe Asn Thr Asn Ala
1 5
<210> 63
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 63
Gly Tyr Thr Phe Pro Thr Tyr Ser
1 5
<210> 64
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 64
Gly Phe Thr Phe Ser Asn Tyr Gly
1 5
<210> 65
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 65
Gly Tyr Thr Phe Thr Asn Tyr Gly
1 5
<210> 66
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 66
Gly Tyr Thr Phe Thr Lys Tyr Gly
1 5
<210> 67
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 67
Gly Phe Ser Leu Ser Ser Tyr Gly
1 5
<210> 68
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 68
Gly Leu Ser Leu Thr Ser Phe Gly
1 5
<210> 69
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 69
Gly Phe Ser Leu Ile Ser Tyr Gly
1 5
<210> 70
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 70
Gly Phe Ser Leu Asn Thr Tyr Gly
1 5
<210> 71
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 71
Gly Phe Ser Leu Ile Asn Tyr Gly
1 5
<210> 72
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 72
Gly Tyr Thr Phe Thr Gly Phe Leu
1 5
<210> 73
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 73
Asp Phe Ser Leu Thr Lys Tyr Gly
1 5
<210> 74
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 74
Gly Tyr Ser Ile Thr Ser Gly Tyr Phe
1 5
<210> 75
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 75
Gly Phe Ser Leu Ser Asn Tyr Gly
1 5
<210> 76
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 76
Gly Tyr Ser Phe Thr Asn Phe Leu
1 5
<210> 77
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 77
Ile Asn Pro Gly Asn Gly Gly Ser
1 5
<210> 78
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 78
Ile Trp Gly Asp Gly Asn Thr
1 5
<210> 79
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 79
Ile Ser Gly Gly Ser Asn Thr Ile
1 5
<210> 80
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 80
Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr
1 5 10
<210> 81
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 81
Ile Asn Pro Gly Asn Gly Gly Ser Asn
1 5
<210> 82
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 82
Ile Asn Pro Ser Thr Ile Tyr Thr
1 5
<210> 83
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 83
Phe Ser Tyr Gly Asp Ser His Asn
1 5
<210> 84
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 84
Ile Asn Ala Asn Thr Gly Glu Pro
1 5
<210> 85
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 85
Ile Ser Thr Asn Thr Gly Glu Pro
1 5
<210> 86
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 86
Ile Asn Pro Gly Arg Ser Gly Thr
1 5
<210> 87
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 87
Ile Trp Ala Gly Gly Ser Thr
1 5
<210> 88
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 88
Ile Trp Ala Gly Gly Arg Thr
1 5
<210> 89
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 89
Met Leu Ser Asp Gly Asn Thr
1 5
<210> 90
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 90
Ile Arg Gly Asp Gly Asn Thr
1 5
<210> 91
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 91
Ile Trp Thr Gly Gly Asn Thr
1 5
<210> 92
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 92
Ile Ser Tyr Asp Gly Ser Asn
1 5
<210> 93
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 93
Ile Trp Ala Gly Gly Asn Thr
1 5
<210> 94
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 94
Ile Asn Pro Thr Asn Gly Arg Thr
1 5
<210> 95
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 95
Ile Asn Pro Asn Thr Ile Tyr Thr
1 5
<210> 96
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 96
Ala Arg Ile Tyr Tyr Gly Asn Ser Phe Ala Tyr
1 5 10
<210> 97
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 97
Ala Lys Gln Gly Leu Tyr Gly His Ala Met Asp Tyr
1 5 10
<210> 98
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 98
Thr Arg Leu Ala Leu Gly Asn Ala Met Asp Tyr
1 5 10
<210> 99
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 99
Val Ser Gly Ala Tyr Tyr Gly Asn Ser Lys Ala Phe Asp Tyr
1 5 10
<210> 100
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 100
Ala Arg Glu Gly Tyr Gly Arg Gly Asn Ala Met Asp Tyr
1 5 10
<210> 101
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 101
Ala Arg Phe Gly Arg Gly Asn Thr Met Asp Tyr
1 5 10
<210> 102
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 102
Ala Arg Leu Thr Arg Gly Asn Ser Phe Asp Tyr
1 5 10
<210> 103
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 103
Ala Arg Leu Val Arg Gly Asn Ser Phe Asp Phe
1 5 10
<210> 104
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 104
Ala Arg Thr Arg Tyr Gly Gly Asn Ala Met Asp Tyr
1 5 10
<210> 105
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 105
Ala Arg Ser Leu Tyr Gly Asn Ser Leu Asp Ser
1 5 10
<210> 106
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 106
Ala Arg Ser Leu Tyr Gly Asn Ser Phe Asp Tyr
1 5 10
<210> 107
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 107
Ala Arg Asp Arg Tyr Gly Gly Asn Ser Leu Asp Tyr
1 5 10
<210> 108
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 108
Ala Arg His Lys Ala Tyr Gly Asn Ala Met Asp Tyr
1 5 10
<210> 109
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 109
Ala Lys Val Gly Arg Gly Asn Ala Met Asp His
1 5 10
<210> 110
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 110
Ala Arg Leu Asp Tyr Gly Asn Ala Met Asp Tyr
1 5 10
<210> 111
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 111
Ala Arg Asn Gly Tyr Tyr Gly Asn Ala Met Asp Tyr
1 5 10
<210> 112
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 112
Gly Arg Leu Asp Tyr Gly Asn Ala Met Asp Tyr
1 5 10
<210> 113
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 113
Ala Ser Phe Arg Phe Phe Ala Tyr
1 5
<210> 114
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 114
Ala Arg His Gly Tyr Gly Lys Gly Asn Ala Met Asp Asn
1 5 10
<210> 115
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 115
Ala Arg Ile Tyr Tyr Gly Asn Ser Met Asp Tyr
1 5 10
<210> 116
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 116
Ala Arg Ser Leu Tyr Gly Asn Ser Phe Asp His
1 5 10
<210> 117
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 117
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Arg Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Asp Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Phe Tyr Pro Phe Thr Phe Gly Ala Gly Thr Asn Leu Glu Leu
100 105 110
Lys
<210> 118
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 118
Asp Ile Met Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Thr Gly
1 5 10 15
Glu Lys Val Thr Leu Thr Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Leu Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly His
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Val Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Thr Val Tyr Tyr Cys Gln Asn
85 90 95
Val Tyr Ile Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Met
100 105 110
Arg
<210> 119
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 119
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Tyr Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Ala Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Tyr Phe Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 120
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 120
Asp Thr Val Met Thr Gln Phe Pro Ser Ser Leu Ser Val Ser Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Gly
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Leu Tyr Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Phe
100 105 110
Lys
<210> 121
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 121
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Ile Met Ser Cys Lys Ser Asn Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Lys Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Glu Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Arg Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Gly Tyr Ser Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Met
100 105 110
Lys
<210> 122
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 122
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Gly Lys Val Thr Val Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Thr Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asn Tyr Tyr Phe Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
100 105 110
Lys
<210> 123
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 123
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Phe Asn Ser
20 25 30
Gly Asn Gln Arg Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Ile Leu Thr
65 70 75 80
Ile Thr Lys Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Val Tyr Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
100 105 110
Lys
<210> 124
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 124
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Arg Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Ser Arg Glu Ser Gly Val
50 55 60
Pro Val Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ile Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Met
100 105 110
Asn
<210> 125
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 125
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Thr Leu Leu Ile Phe Trp Ala Phe Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Asn Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ser Tyr Ser Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 126
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 126
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Arg Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Arg Leu Leu Ile Tyr Trp Ser Ser Thr Arg Asp Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asn Phe Ile Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
100 105 110
Lys
<210> 127
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 127
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Pro Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Arg Ser Ser Met Ser Leu Phe Asn Ser
20 25 30
Gly Asn Gln Lys Ser Tyr Leu Ser Trp Tyr His Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Asp Ser Gly Val
50 55 60
Pro Val Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys His Asn
85 90 95
Asp Tyr Ile Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
100 105 110
Lys
<210> 128
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 128
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Asn Cys Arg Ser Ile Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Arg Ser Val Leu Asp Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ser Tyr Ser Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Met
100 105 110
Lys
<210> 129
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 129
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Leu Thr Cys Arg Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Arg Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Ile Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Tyr Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Lys
100 105 110
Lys
<210> 130
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 130
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Lys Ser Ser Gln Ser Leu Phe Asn Ser
20 25 30
Gly Asn Gln Arg Asn Tyr Leu Thr Trp Tyr Gln Arg Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Tyr Phe Thr Leu Thr
65 70 75 80
Val Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Tyr Phe Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Lys
100 105 110
Lys
<210> 131
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 131
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Arg
1 5 10 15
Glu Arg Val Ser Met Thr Cys Lys Ser Ser Gln Ser Leu Phe Asn Ser
20 25 30
Gly Asn Gln Arg Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ser Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Ile Tyr Phe Cys Gln Asn
85 90 95
Asn Tyr Tyr Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 132
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 132
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Arg Val Thr Met Arg Cys Arg Ser Thr Gln Ser Leu Phe Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Gly Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Tyr Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Arg
100 105 110
Lys
<210> 133
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 133
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Arg Val Thr Met Ser Cys Lys Pro Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Leu Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Lys Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Phe Tyr Pro Cys Thr Phe Gly Gly Gly Thr Lys Leu Glu Met
100 105 110
Lys
<210> 134
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 134
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Arg Cys Arg Ser Thr Gln Ser Leu Phe Asn Ser
20 25 30
Gly Asn Gln Arg Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Tyr Tyr Pro Leu Thr Phe Gly Val Gly Thr Lys Leu Glu Arg
100 105 110
Lys
<210> 135
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 135
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Arg Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Leu Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Lys Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Phe Tyr Pro Cys Thr Phe Gly Gly Gly Thr Lys Leu Glu Met
100 105 110
Lys
<210> 136
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 136
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Thr Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val Phe Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Val Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Ala Arg Phe Thr Gly Ser Gly Ser Gly Thr Val Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Tyr Phe Pro Leu Thr Phe Gly Ala Gly Thr Arg Leu Glu Leu
100 105 110
Lys
<210> 137
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 137
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Gln Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Leu Ser Cys Arg Ser Ser Gln Ser Leu Leu Asn Gly
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Tyr Phe Thr Phe Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Phe Tyr Pro Phe Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
100 105 110
Lys
<210> 138
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 138
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Arg Asn Tyr Leu Ser Trp Tyr Gln Gln Glu Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Asn Ile Gln Ala Glu Asp Leu Ala Leu Tyr Phe Cys Gln Asn
85 90 95
Ala Tyr Phe Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 139
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 139
Asp Ile Leu Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asn Tyr Phe Tyr Pro Leu Thr Phe Gly Val Gly Thr Lys Leu Glu Leu
100 105 110
Lys
<210> 140
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 140
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Thr Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Phe Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Tyr Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asn Tyr Ile Tyr Pro Leu Ala Phe Gly Thr Gly Thr Lys Leu Glu Leu
100 105 110
Lys
<210> 141
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 141
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Arg Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Met Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Gly Gln Ala Glu Asp Leu Ala Ile Tyr Phe Cys Gln Asn
85 90 95
Gly Tyr Tyr Phe Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Thr
100 105 110
Lys
<210> 142
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 142
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Arg Cys Arg Ser Ser Gln Ser Leu Phe Asn Ser
20 25 30
Gly Asn Gln Arg Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asn Tyr Ile Tyr Pro Leu Ala Phe Gly Ala Gly Thr Lys Leu Glu Leu
100 105 110
Lys
<210> 143
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 143
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Phe Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asn Tyr Ile Tyr Pro Leu Ala Phe Gly Ala Gly Thr Lys Leu Glu Leu
100 105 110
Lys
<210> 144
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 144
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Arg Cys Lys Ser Thr Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Arg Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Glu Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Tyr Tyr Pro Leu Thr Phe Gly Pro Gly Thr Lys Leu Glu Arg
100 105 110
Lys
<210> 145
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 145
Gln Val Gln Leu His Gln Ser Gly Thr Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr
20 25 30
Leu Leu Glu Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Gly Asn Gly Gly Ser Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Ile Tyr Tyr Gly Asn Ser Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 146
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 146
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Gly Asp Gly Asn Thr Ile Tyr His Ser Ala Leu Lys
50 55 60
Ser Arg Leu Ser Ile Ser Arg Asp Asn Ser Lys Arg Gln Val Phe Leu
65 70 75 80
Lys Val Asn Ser Leu Gln Ile Asp Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Lys Gln Gly Leu Tyr Gly His Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Ile Val Ser Ser
115
<210> 147
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 147
Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asn Ser Phe
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Ser Gly Gly Ser Asn Thr Ile His Tyr Leu Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Thr Arg Leu Ala Leu Gly Asn Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Ile Val Ser Ser
115
<210> 148
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 148
Glu Val Gln His Val Glu Thr Gly Gly Gly Leu Val Gln Pro Lys Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Asn
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Met
65 70 75 80
Leu Tyr Val Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Ser Gly Ala Tyr Tyr Gly Asn Ser Lys Ala Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 149
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 149
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Pro Thr Tyr
20 25 30
Ser Ile His Trp Leu Lys Gln Gly Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Thr Ile Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Tyr Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Ile Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Tyr Gly Arg Gly Asn Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 150
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 150
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Phe Ser Tyr Gly Asp Ser His Asn Tyr Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Ile Ala Lys Asp Ala Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Phe Gly Arg Gly Asn Thr Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Leu
115
<210> 151
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 151
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Arg Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Ala Trp Ile Asn Ala Asn Thr Gly Glu Pro Thr Tyr Ala Glu Glu Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Arg Ser Ala Tyr
65 70 75 80
Leu Gln Ile Asn Ser Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Leu Thr Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 152
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 152
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Lys Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Ser Thr Asn Thr Gly Glu Pro Thr Tyr Ala Glu Glu Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Phe
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Leu Val Arg Gly Asn Ser Phe Asp Phe Trp Gly Gln Gly Ile
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 153
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 153
Gln Val Gln Leu Gln Gln Ser Gly Gly Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Phe Gly Tyr Thr Phe Thr Thr Tyr
20 25 30
Pro Ile Glu Trp Met Lys Gln Asn His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Asn Phe His Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Lys Leu Thr Val Glu Lys Ser Ser Ser Thr Val Tyr
65 70 75 80
Leu Glu Val Ser Arg Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Tyr Gly Tyr Pro Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 154
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 154
Gln Val His Leu Gln Gln Ser Gly Ala Glu Val Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr
20 25 30
Leu Ile Glu Trp Ile Lys Lys Arg Pro Gly Gln Gly Leu Glu Trp Val
35 40 45
Gly Val Ile Asn Pro Gly Arg Ser Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Thr Arg Tyr Gly Gly Asn Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 155
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 155
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Gln Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Ala Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asp Ser Ala Leu Met
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Arg Thr Arg Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ser Leu Tyr Gly Asn Ser Leu Asp Ser Trp Gly Pro Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 156
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 156
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Leu Ser Leu Thr Ser Phe
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Tyr Leu
65 70 75 80
Lys Met His Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Ser Leu Tyr Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr Ala
100 105 110
Leu Thr Val Ser Ser
115
<210> 157
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 157
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr
20 25 30
Gly Val Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ala Ala Ile Arg Ser Asp Gly Ile Ile Thr Tyr Asn Ser Val Leu Lys
50 55 60
Ser Arg Leu Arg Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Phe Tyr Cys Ala
85 90 95
Arg Trp Phe Arg Gly Asn Val Leu Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 158
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 158
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Arg Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Tyr Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Asp Arg Tyr Gly Gly Asn Ser Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 159
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 159
Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Thr Ser Gly Asn Ser Pro Ile Tyr Phe Thr Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Thr Ser Leu Gly Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Tyr Gly Asn Ser Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 160
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 160
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Ile Ser Gly Phe Ser Leu Asn Thr Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Val Val Met Leu Ser Asp Gly Asn Thr Val Tyr Asn Ser Ser Leu Lys
50 55 60
Ser Arg Leu Ser Leu Thr Lys Asp Asn Ser Lys Ser Gln Leu Leu Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg His Lys Ala Tyr Gly Asn Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 161
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 161
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Asn Tyr
20 25 30
Gly Val Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Gly Asp Gly Asn Thr Asn Tyr Gln Ser Ala Leu Arg
50 55 60
Ser Arg Leu Ser Ile Arg Lys Asp Thr Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Leu Asn Ser Val His Thr Asp Gly Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Lys Val Gly Arg Gly Asn Ala Met Asp His Trp Gly Gln Gly Ile Ser
100 105 110
Val Ile Val Ser Ser
115
<210> 162
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 162
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Asn Tyr
20 25 30
Gly Val Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Arg Gly Asp Gly Asn Thr Asn Tyr Gln Ser Ala Leu Arg
50 55 60
Ser Arg Leu Ser Ile Arg Lys Asp Thr Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Leu Asn Ser Val His Thr Asp Gly Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Lys Val Gly Arg Gly Asn Ala Met Asp His Trp Gly Gln Gly Ile Ser
100 105 110
Val Ile Val Ser Ser
115
<210> 163
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 163
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Phe
20 25 30
Leu Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Ser Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Phe
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Asp Tyr Gly Asn Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 164
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 164
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Asp Phe Ser Leu Thr Lys Tyr
20 25 30
Gly Val His Trp Phe Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Thr Gly Gly Asn Thr Asp Tyr Asn Pro Ala Leu Ile
50 55 60
Pro Arg Leu Ser Phe Arg Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Ser Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asn Gly Tyr Tyr Gly Asn Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 165
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 165
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ser Ser Gly Tyr Thr Phe Thr Gly Phe
20 25 30
Leu Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Ser Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Gly Arg Leu Asp Tyr Gly Asn Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 166
<211> 115
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 166
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Ser Cys Ser Val Thr Gly Tyr Ser Ile Thr Ser Gly
20 25 30
Tyr Phe Trp Thr Trp Phe Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Lys Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Ser Phe Arg Phe Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ala
115
<210> 167
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 167
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Tyr
20 25 30
Gly Val Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Asn Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Arg Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Arg Tyr Tyr Cys Ala
85 90 95
Arg His Gly Tyr Gly Lys Gly Asn Ala Met Asp Asn Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 168
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 168
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Pro Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Phe
20 25 30
Leu Thr His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Thr Asn Gly Arg Thr Tyr Tyr Asn Glu Lys Phe
50 55 60
Lys Arg Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Val Tyr
65 70 75 80
Met Gln Leu Ser Asn Leu Thr Pro Glu Asp Ser Ala Val Phe Tyr Cys
85 90 95
Ala Arg Ile Tyr Tyr Gly Asn Ser Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 169
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 169
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Pro Thr Tyr
20 25 30
Ser Ile His Trp Leu Lys Gln Gly Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Asn Thr Ile Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Tyr Lys Thr Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Ile Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Tyr Gly Arg Gly Asn Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 170
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 170
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Thr Gly Phe Ser Leu Ser Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asp Ser Ala Leu Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Arg Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Thr Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Ser Leu Tyr Gly Asn Ser Phe Asp His Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 171
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 171
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Ile Ile Gln Trp Met Lys Gln Lys Pro Gly Leu Gly Leu Glu Trp Ile
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Gln Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Asn Ala Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Tyr Phe Gly Asn Ser Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 172
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 172
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asp Ser Thr Leu Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Arg Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Thr Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Ser Leu Tyr Gly Asn Ser Phe Asp His Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 173
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 173
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Ala His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asp Ser Ala Leu Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Arg Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Thr Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Ser Leu Tyr Gly Asn Ser Phe Asp His Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 174
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 174
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Phe
20 25 30
Leu Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Ser Glu Arg Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Asp Tyr Gly Asn Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 175
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 175
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 Thr Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Thr Ser Gly Asn Ser Pro Ile Tyr Phe Thr Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Tyr Gly Asn Ser Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 176
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 176
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 Thr Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Thr Ser Gly Asn Ser Pro Ile Tyr Phe Thr Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Tyr Gly Asn Ser Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 177
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 177
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 Thr Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Thr Ser Gly Asn Ser Pro Ile Tyr Phe Thr Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Tyr Gly Asn Ser Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 178
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 178
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Arg Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 179
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 179
Asp Thr Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Arg Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 180
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 180
Asp Thr Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Leu Asn Cys Arg Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Arg Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 181
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 181
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr
20 25 30
Pro Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Asn Phe His Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Tyr Gly Tyr Pro Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 182
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 182
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr
20 25 30
Pro Ile Glu Trp Met Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Asn Phe His Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Tyr Gly Tyr Pro Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 183
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 183
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr
20 25 30
Pro Ile Glu Trp Met Lys Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Asn Phe His Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Val Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Tyr Gly Tyr Pro Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 184
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 184
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr
20 25 30
Pro Ile Glu Trp Met Lys Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Asn Phe His Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Val Tyr
65 70 75 80
Leu Glu Val Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Tyr Gly Tyr Pro Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 185
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 185
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Ser Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ile Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 186
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 186
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Ser Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ile Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 187
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 187
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Ser Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ile Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 188
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 188
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Ile Ile Gln Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Gln Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Tyr Phe Gly Asn Ser Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 189
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 189
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Ile Ile Gln Trp Met Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Gln Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser Ala Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Tyr Phe Gly Asn Ser Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 190
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 190
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Ile Ile Gln Trp Met Lys Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Gln Phe
50 55 60
Lys Gly Arg Ala Thr Ile Thr Ser Asp Thr Ser Ala Ser Ala Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Tyr Phe Gly Asn Ser Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 191
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 191
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Ile Ile Gln Trp Met Lys Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Gln Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Ser Asp Thr Ser Ala Ser Ala Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Tyr Phe Gly Asn Ser Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 192
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 192
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Gly Tyr Tyr Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 193
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 193
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Met Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Gly Tyr Tyr Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 194
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 194
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Met Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Gly Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln Asn
85 90 95
Gly Tyr Tyr Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 195
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 195
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Met Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Gly Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln Asn
85 90 95
Gly Tyr Tyr Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 196
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 196
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 Thr Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Thr Ser Gly Gln Ser Pro Ile Tyr Phe Thr Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Tyr Gly Asn Ser Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 197
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 197
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 Thr Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Thr Ser Gly Glu Ser Pro Ile Tyr Phe Thr Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Tyr Gly Asn Ser Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 198
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 198
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 Thr Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Thr Ser Gly Glu Ser Pro Ile Tyr Phe Thr Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Tyr Gly Gln Ser Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 199
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 199
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 Thr Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Thr Ser Gly Glu Ser Pro Ile Tyr Phe Thr Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Tyr Gly Glu Ser Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 200
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 200
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 Thr Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Thr Ser Gly Glu Ser Pro Ile Tyr Phe Thr Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Tyr Gly Asn Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 201
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 201
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Leu Leu Glu Ser
20 25 30
Gly Asn Arg Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 202
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 202
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Leu Leu Asn Ala
20 25 30
Gly Asn Arg Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 203
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 203
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ala
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Ser Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ile Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 204
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 204
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Glu Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Ser Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ile Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 205
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 205
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Ile Ile Gln Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Gln Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Tyr Phe Gly Asn Ala Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 206
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 206
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ala
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Tyr Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 207
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 207
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Glu Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Glu
85 90 95
Gly Tyr Tyr Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 208
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 208
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Arg Asn Tyr Leu
1 5 10 15
Thr
<210> 209
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 209
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Leu Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 210
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 210
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 211
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 211
Lys Ser Ser Gln Ser Leu Leu Asn Gly Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 212
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 212
Lys Ser Asn Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Lys Tyr Leu
1 5 10 15
Thr
<210> 213
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 213
Lys Ser Ser Gln Ser Leu Phe Asn Ser Gly Asn Gln Arg Asn Tyr Leu
1 5 10 15
Thr
<210> 214
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 214
Arg Ser Ser Met Ser Leu Phe Asn Ser Gly Asn Gln Lys Ser Tyr Leu
1 5 10 15
Ser
<210> 215
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 215
Arg Ser Ile Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ser
<210> 216
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 216
Arg Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Arg Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 217
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 217
Arg Ser Thr Gln Ser Leu Phe Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 218
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 218
Lys Pro Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 219
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 219
Arg Ser Thr Gln Ser Leu Phe Asn Ser Gly Asn Gln Arg Asn Tyr Leu
1 5 10 15
Thr
<210> 220
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 220
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 221
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 221
Lys Ser Ser Gln Ser Val Phe Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 222
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 222
Arg Ser Ser Gln Ser Leu Leu Asn Gly Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 223
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 223
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Arg Asn Tyr Leu
1 5 10 15
Ser
<210> 224
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 224
Lys Ser Ser Gln Ser Leu Phe Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 225
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 225
Arg Ser Ser Gln Ser Leu Phe Asn Ser Gly Asn Gln Arg Asn Tyr Leu
1 5 10 15
Thr
<210> 226
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 226
Lys Ser Thr Gln Ser Leu Leu Asn Ser Gly Asn Gln Arg Asn Tyr Leu
1 5 10 15
Thr
<210> 227
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 227
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 228
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 228
Gly Ala Ser Thr Arg Glu Ser
1 5
<210> 229
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 229
Arg Ala Ser Ser Arg Glu Ser
1 5
<210> 230
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 230
Trp Ala Phe Thr Arg Glu Ser
1 5
<210> 231
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 231
Trp Ser Ser Thr Arg Asp Ser
1 5
<210> 232
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 232
Trp Ala Ser Thr Arg Asp Ser
1 5
<210> 233
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 233
Trp Ser Ser Thr Arg Glu Ser
1 5
<210> 234
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 234
Asn Tyr Leu Leu Glu
1 5
<210> 235
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 235
Ser Tyr Gly Val Ser
1 5
<210> 236
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 236
Ser Phe Gly Met Asn
1 5
<210> 237
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 237
Thr Asn Ala Met Asn
1 5
<210> 238
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 238
Thr Tyr Ser Ile His
1 5
<210> 239
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 239
Asn Tyr Gly Met Ser
1 5
<210> 240
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 240
Asn Tyr Gly Met Asn
1 5
<210> 241
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 241
Lys Tyr Gly Met Asn
1 5
<210> 242
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 242
Thr Tyr Pro Ile Glu
1 5
<210> 243
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 243
Asn Tyr Leu Ile Glu
1 5
<210> 244
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 244
Ser Tyr Gly Val His
1 5
<210> 245
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 245
Ser Phe Gly Val His
1 5
<210> 246
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 246
Thr Phe Gly Met His
1 5
<210> 247
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 247
Thr Tyr Gly Val His
1 5
<210> 248
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 248
Asn Tyr Gly Val Ser
1 5
<210> 249
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 249
Gly Phe Leu Met His
1 5
<210> 250
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 250
Lys Tyr Gly Val His
1 5
<210> 251
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 251
Ser Gly Tyr Phe Trp
1 5
<210> 252
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 252
Asn Phe Leu Thr His
1 5
<210> 253
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 253
Gly Tyr Ile Ile Gln
1 5
<210> 254
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 254
Ser Tyr Gly Ala His
1 5
<210> 255
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 255
Glu Ile Asn Pro Gly Asn Gly Gly Ser Asn Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 256
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 256
Val Ile Trp Gly Asp Gly Asn Thr Ile Tyr His Ser Ala Leu Lys Ser
1 5 10 15
<210> 257
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 257
Phe Ile Ser Gly Gly Ser Asn Thr Ile His Tyr Leu Asp Thr Val Lys
1 5 10 15
Gly
<210> 258
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 258
Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys Asp
<210> 259
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 259
Tyr Ile Asn Pro Ser Thr Ile Tyr Thr Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Tyr
<210> 260
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 260
Thr Phe Ser Tyr Gly Asp Ser His Asn Tyr Tyr Ser Asp Ser Val Lys
1 5 10 15
Gly
<210> 261
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 261
Trp Ile Asn Ala Asn Thr Gly Glu Pro Thr Tyr Ala Glu Glu Phe Lys
1 5 10 15
Gly
<210> 262
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 262
Trp Ile Ser Thr Asn Thr Gly Glu Pro Thr Tyr Ala Glu Glu Phe Lys
1 5 10 15
Gly
<210> 263
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 263
Asn Phe His Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 264
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 264
Val Ile Asn Pro Gly Arg Ser Gly Thr Asn Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 265
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 265
Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asp Ser Ala Leu Met Ser
1 5 10 15
<210> 266
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 266
Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met Ser
1 5 10 15
<210> 267
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 267
Val Ile Trp Ala Gly Gly Arg Thr Asn Tyr Asn Ser Ala Leu Met Ser
1 5 10 15
<210> 268
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 268
Tyr Ile Thr Ser Gly Asn Ser Pro Ile Tyr Phe Thr Asp Thr Val Lys
1 5 10 15
Gly
<210> 269
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 269
Val Met Leu Ser Asp Gly Asn Thr Val Tyr Asn Ser Ser Leu Lys Ser
1 5 10 15
<210> 270
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 270
Val Ile Trp Gly Asp Gly Asn Thr Asn Tyr Gln Ser Ala Leu Arg Ser
1 5 10 15
<210> 271
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 271
Val Ile Arg Gly Asp Gly Asn Thr Asn Tyr Gln Ser Ala Leu Arg Ser
1 5 10 15
<210> 272
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 272
Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Ser Glu Lys Phe Lys
1 5 10 15
Gly
<210> 273
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 273
Val Ile Trp Thr Gly Gly Asn Thr Asp Tyr Asn Pro Ala Leu Ile Pro
1 5 10 15
<210> 274
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 274
Tyr Ile Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu Lys Asn
1 5 10 15
<210> 275
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 275
Val Ile Trp Ala Gly Gly Asn Thr Asn Tyr Asn Ser Ala Leu Met Ser
1 5 10 15
<210> 276
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 276
Glu Ile Asn Pro Thr Asn Gly Arg Thr Tyr Tyr Asn Glu Lys Phe Lys
1 5 10 15
Arg
<210> 277
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 277
Tyr Ile Asn Pro Asn Thr Ile Tyr Thr Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Tyr
<210> 278
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 278
Phe Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Gln Phe Lys
1 5 10 15
Gly
<210> 279
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 279
Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asp Ser Thr Leu Met Ser
1 5 10 15
<210> 280
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 280
Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Ser Glu Arg Phe Lys
1 5 10 15
Gly
<210> 281
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 281
Ile Tyr Tyr Gly Asn Ser Phe Ala Tyr
1 5
<210> 282
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 282
Gln Gly Leu Tyr Gly His Ala Met Asp Tyr
1 5 10
<210> 283
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 283
Leu Ala Leu Gly Asn Ala Met Asp Tyr
1 5
<210> 284
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 284
Gly Ala Tyr Tyr Gly Asn Ser Lys Ala Phe Asp Tyr
1 5 10
<210> 285
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 285
Glu Gly Tyr Gly Arg Gly Asn Ala Met Asp Tyr
1 5 10
<210> 286
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 286
Phe Gly Arg Gly Asn Thr Met Asp Tyr
1 5
<210> 287
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 287
Leu Thr Arg Gly Asn Ser Phe Asp Tyr
1 5
<210> 288
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 288
Leu Val Arg Gly Asn Ser Phe Asp Phe
1 5
<210> 289
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 289
Arg Ala Tyr Gly Tyr Pro Tyr Ala Met Asp Tyr
1 5 10
<210> 290
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 290
Thr Arg Tyr Gly Gly Asn Ala Met Asp Tyr
1 5 10
<210> 291
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 291
Ser Leu Tyr Gly Asn Ser Leu Asp Ser
1 5
<210> 292
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 292
Ser Leu Tyr Gly Asn Ser Phe Asp Tyr
1 5
<210> 293
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 293
Asp Arg Tyr Gly Gly Asn Ser Leu Asp Tyr
1 5 10
<210> 294
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 294
Ser Ser Tyr Tyr Gly Asn Ser Met Asp Tyr
1 5 10
<210> 295
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 295
His Lys Ala Tyr Gly Asn Ala Met Asp Tyr
1 5 10
<210> 296
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 296
Val Gly Arg Gly Asn Ala Met Asp His
1 5
<210> 297
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 297
Leu Asp Tyr Gly Asn Ala Met Asp Tyr
1 5
<210> 298
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 298
Asn Gly Tyr Tyr Gly Asn Ala Met Asp Tyr
1 5 10
<210> 299
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 299
Phe Arg Phe Phe Ala Tyr
1 5
<210> 300
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 300
His Gly Tyr Gly Lys Gly Asn Ala Met Asp Asn
1 5 10
<210> 301
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 301
Ile Tyr Tyr Gly Asn Ser Met Asp Tyr
1 5
<210> 302
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 302
Ser Leu Tyr Gly Asn Ser Phe Asp His
1 5
<210> 303
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 303
Ala Tyr Phe Gly Asn Ser Phe Ala Tyr
1 5
<210> 304
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 304
Lys Ser Ser Gln Ser Leu Leu Asn Ala Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 305
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 305
Lys Ser Ser Gln Ser Leu Leu Glu Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 306
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 306
Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Gln Phe Lys
1 5 10 15
Gly
<210> 307
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 307
Ala Tyr Phe Gly Asn Ala Phe Ala Tyr
1 5
<210> 308
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 308
Arg Ser Ser Gln Ser Leu Leu Glu Ser Gly Asn Arg Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 309
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 309
Arg Ser Ser Gln Ser Leu Leu Asn Ala Gly Asn Arg Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 310
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 310
Tyr Ile Thr Ser Gly Gln Ser Pro Ile Tyr Phe Thr Asp Thr Val Lys
1 5 10 15
Gly
<210> 311
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 311
Tyr Ile Thr Ser Gly Glu Ser Pro Ile Tyr Phe Thr Asp Thr Val Lys
1 5 10 15
Gly
<210> 312
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 312
Ser Ser Tyr Tyr Gly Gln Ser Met Asp Tyr
1 5 10
<210> 313
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 313
Ser Ser Tyr Tyr Gly Glu Ser Met Asp Tyr
1 5 10
<210> 314
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 314
Ser Ser Tyr Tyr Gly Asn Ala Met Asp Tyr
1 5 10
Claims (29)
1.一种抗体药物偶联物,包括共价连接至抗体或其片段的药物部分,所述抗体或其片段对野生型人紧密连接蛋白18.2(CLDN18.2)蛋白具有结合特异性,其中所述抗体或其片段与CLDN18.2的β3-β4环和β5链结合,其中所述β3-β4环由SEQ ID NO:30的第45-63位残基(NYQGLWRSCVRESSGFTEC)组成,并且所述β5链由SEQ ID NO:30的第169-172位残基(YTFG)组成。
2.根据权利要求1所述的抗体药物偶联物,其中所述抗体或其片段连接至2至10个所述药物部分。
3.根据权利要求1所述的抗体药物偶联物,其中所述抗体或其片段连接至2至6个所述药物部分。
4.根据前述任一项权利要求所述的抗体药物偶联物,其中所述抗体或其片段不与β1和β2结合,或以比与所述β3-β4环或所述β5链低至少10倍的亲和力与β1或β2结合。
5.根据前述任一项权利要求所述的抗体药物偶联物,其中所述抗体或其片段不与CLDN18.1蛋白结合,或以比与所述CLDN18.2蛋白低至少10倍的亲和力与所述CLDN18.1蛋白结合。
6.根据前述任一项权利要求所述的抗体药物偶联物,其中所述抗体或其片段以至少是对野生型CLDN18.2蛋白的亲和力的1%的亲和力结合CLDN18.2 M149L突变体。
7.根据前述任一项权利要求所述的抗体药物偶联物,其中所述抗体或其片段与选自由N45、Y46、G48、V54、R55、E56、S58、F60和E62组成的组中的至少一个氨基酸残基、以及选自由SEQ ID NO:30的Y169和G172组成的组中的至少一个氨基酸残基结合。
8.根据前述任一项权利要求所述的抗体药物偶联物,其中所述抗体或其片段包含轻链可变区和重链可变区,所述轻链可变区包含轻链互补决定区CDRL1、CDRL2和CDRL3,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,并且其中:
所述CDRL1包含选自SEQ ID NO:208-226、304-305和308-309的组的氨基酸序列;
所述CDRL2包含选自SEQ ID NO:227-233的组的氨基酸序列;
所述CDRL3包含选自SEQ ID NO:3、8、13、19、20和42-58的组的氨基酸序列;
所述CDRH1包含选自SEQ ID NO:234-254的组的氨基酸序列;
所述CDRH2包含选自SEQ ID NO:255-280、306、310和311的组的氨基酸序列;并且
所述CDRH3包含选自SEQ ID NO:281-303、307和312-314的组的氨基酸序列。
9.根据权利要求8所述的抗体药物偶联物,其中:
所述CDRL1包含SEQ ID NO:210、304或305的氨基酸序列;
所述CDRL2包含SEQ ID NO:227的氨基酸序列;
所述CDRL3包含SEQ ID NO:3、19或20的氨基酸序列;
所述CDRH1包含SEQ ID NO:253的氨基酸序列;
所述CDRH2包含SEQ ID NO:278或306的氨基酸序列;并且
所述CDRH3包含SEQ ID NO:303或307的氨基酸序列。
10.根据权利要求9所述的抗体药物偶联物,其中所述抗体或其片段包含轻链可变区,所述轻链可变区包含选自由SEQ ID NO:141、192-195和206-207组成的组的氨基酸序列,或与选自由SEQ ID NO:141、192-195和206-207组成的组的氨基酸序列具有至少90%序列同一性的肽。
11.根据权利要求9或10所述的抗体药物偶联物,其中所述抗体或其片段包含重链可变区,所述重链可变区包含选自由SEQ ID NO:171、188-191和205组成的组的氨基酸序列,或与选自由SEQ ID NO:171、188-191和205组成的组的氨基酸序列具有至少90%序列同一性的肽。
12.根据权利要求8所述的抗体药物偶联物,其中:
所述CDRL1包含SEQ ID NO:304的氨基酸序列;
所述CDRL2包含SEQ ID NO:227的氨基酸序列;
所述CDRL3包含SEQ ID NO:19的氨基酸序列;
所述CDRH1包含SEQ ID NO:253的氨基酸序列;
所述CDRH2包含SEQ ID NO:306的氨基酸序列;并且
所述CDRH3包含SEQ ID NO:307的氨基酸序列。
13.根据权利要求12所述的抗体药物偶联物,其中所述抗体或其片段包含轻链可变区和重链可变区,所述轻链可变区包含SEQ ID NO:206的氨基酸序列,所述重链可变区包含SEQ ID NO:205的氨基酸序列。
14.根据权利要求8所述的抗体药物偶联物,其中:
所述CDRL1包含SEQ ID NO:216、308或309的氨基酸序列;
所述CDRL2包含SEQ ID NO:227的氨基酸序列;
所述CDRL3包含SEQ ID NO:13的氨基酸序列;
所述CDRH1包含SEQ ID NO:246的氨基酸序列;
所述CDRH2包含SEQ ID NO:268、310或311的氨基酸序列;并且
所述CDRH3包含SEQ ID NO:294、312、313或314的氨基酸序列。
15.根据权利要求14所述的抗体药物偶联物,其中所述抗体或其片段包含轻链可变区,所述轻链可变区包含选自由SEQ ID NO:129、178-180和201-202组成的组的氨基酸序列,或与选自由SEQ ID NO:129、178-180和201-202组成的组的氨基酸序列具有至少90%序列同一性的肽。
16.根据权利要求14或15所述的抗体药物偶联物,其中所述抗体或其片段包含重链可变区,所述重链可变区包含选自由SEQ ID NO:159、175-177和196-200组成的组的氨基酸序列,或与选自由SEQ ID NO:159、175-177和196-200组成的组的氨基酸序列具有至少90%序列同一性的肽。
17.根据权利要求14所述的抗体药物偶联物,其中:
所述CDRL1包含SEQ ID NO:309的氨基酸序列;
所述CDRL2包含SEQ ID NO:227的氨基酸序列;
所述CDRL3包含SEQ ID NO:13的氨基酸序列;
所述CDRH1包含SEQ ID NO:246的氨基酸序列;
所述CDRH2包含SEQ ID NO:311的氨基酸序列;并且
所述CDRH3包含SEQ ID NO:294的氨基酸序列。
18.根据权利要求17所述的抗体药物偶联物,其中所述抗体或其片段包含轻链可变区和重链可变区,所述轻链可变区包含SEQ ID NO:202的氨基酸序列,所述重链可变区包含SEQ ID NO:197的氨基酸序列。
19.根据前述任一项权利要求所述的抗体药物偶联物,其中所述药物部分为细胞毒剂或细胞抑制剂。
20.根据权利要求19所述的抗体药物偶联物,其中所述药物部分为美登木素(maytansinoid)或澳瑞他汀。
21.根据权利要求20所述的抗体药物偶联物,其中所述药物部分包含DM1或DM4。
22.根据权利要求20所述的抗体药物偶联物,其中所述药物部分包含单甲基澳瑞他汀E(MMAE)或单甲基澳瑞他汀F(MMAF)。
23.根据前述任一项权利要求所述的抗体药物偶联物,其中所述药物部分通过接头连接至所述抗体或其片段。
24.根据权利要求23所述的抗体药物偶联物,其中所述接头在酸性条件下是可水解的。
25.一种在有需要的患者中治疗癌症的方法,包括将权利要求1-24任一项所述的抗体药物偶联物施用于所述患者。
26.权利要求1-24任一项所述的抗体药物偶联物在制备治疗癌症的药物中的用途。
27.根据权利要求25所述的方法或权利要求26所述的用途,其中所述癌症选自由膀胱癌、肝癌、结肠癌、直肠癌、子宫内膜癌、白血病、淋巴瘤、胰腺癌、小细胞肺癌、非小细胞肺癌、乳腺癌、尿道癌、头颈癌、胃肠癌、胃癌、食道癌、卵巢癌、肾癌、黑色素瘤、前列腺癌和甲状腺癌组成的组。
28.根据权利要求25所述的方法或权利要求26所述的用途,其中所述癌症为胃癌。
29.根据权利要求25所述的方法或权利要求26所述的用途,其中所述患者具有所述CLDN18.2蛋白的M149L突变体。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016165762A1 (en) * | 2015-04-15 | 2016-10-20 | Ganymed Pharmaceuticals Ag | Drug conjugates comprising antibodies against claudin 18.2 |
CN108473588A (zh) * | 2015-12-04 | 2018-08-31 | 艾伯维施特姆森特克斯有限责任公司 | 新颖抗密封蛋白抗体及使用方法 |
CN110240654A (zh) * | 2018-03-07 | 2019-09-17 | 复旦大学 | 结合cd73的抗体-药物偶联物 |
CN111788228A (zh) * | 2018-05-18 | 2020-10-16 | 礼新医药科技(上海)有限公司 | 抗密蛋白18.2抗体及其用途 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5892019A (en) | 1987-07-15 | 1999-04-06 | The United States Of America, As Represented By The Department Of Health And Human Services | Production of a single-gene-encoded immunoglobulin |
US6150584A (en) | 1990-01-12 | 2000-11-21 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US6130364A (en) | 1995-03-29 | 2000-10-10 | Abgenix, Inc. | Production of antibodies using Cre-mediated site-specific recombination |
US6420140B1 (en) | 1996-10-11 | 2002-07-16 | Abgenix, Inc. | Production of multimeric protein by cell fusion method |
EP1790664A1 (en) * | 2005-11-24 | 2007-05-30 | Ganymed Pharmaceuticals AG | Monoclonal antibodies against claudin-18 for treatment of cancer |
WO2013167153A1 (en) * | 2012-05-09 | 2013-11-14 | Ganymed Pharmaceuticals Ag | Antibodies useful in cancer diagnosis |
JP2019531084A (ja) * | 2016-07-08 | 2019-10-31 | カースゲン セラピューティクス カンパニー リミテッドCarsgen Therapeutics Co., Ltd. | 抗クローディンタンパク質18a2の抗体及びその応用 |
WO2018026742A1 (en) * | 2016-08-01 | 2018-02-08 | Askgene Pharma Inc. | Novel antibody-albumin-drug conjugates (aadc) and methods for using them |
US20220110973A1 (en) * | 2018-03-09 | 2022-04-14 | Cafa Therapeutics Limited | Method and composition for treating tumors |
BR112020014591A2 (pt) * | 2018-03-14 | 2020-12-01 | Beijing Xuanyi Pharmasciences Co., Ltd. | anticorpos anticlaudina 18.2 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016165762A1 (en) * | 2015-04-15 | 2016-10-20 | Ganymed Pharmaceuticals Ag | Drug conjugates comprising antibodies against claudin 18.2 |
CN108473588A (zh) * | 2015-12-04 | 2018-08-31 | 艾伯维施特姆森特克斯有限责任公司 | 新颖抗密封蛋白抗体及使用方法 |
CN110240654A (zh) * | 2018-03-07 | 2019-09-17 | 复旦大学 | 结合cd73的抗体-药物偶联物 |
CN111788228A (zh) * | 2018-05-18 | 2020-10-16 | 礼新医药科技(上海)有限公司 | 抗密蛋白18.2抗体及其用途 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023232080A1 (zh) * | 2022-06-01 | 2023-12-07 | 百奥泰生物制药股份有限公司 | 抗cldn18.2抗体及其抗体药物偶联物和用途 |
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