CN114040925B - 抗SIRPα单克隆抗体及其用途 - Google Patents
抗SIRPα单克隆抗体及其用途 Download PDFInfo
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Abstract
提供了对信号调节蛋白α(SIRPα)蛋白的变体1和变体2两者都具有结合特异性的抗体或其片段。该抗体和片段可以剂量依赖性地有效阻断SIRPα与CD47之间的相互作用,并有效诱导巨噬细胞介导的对表达CD47的肿瘤细胞的吞噬作用。
Description
背景技术
信号调节蛋白α(SIRPα)是信号调节蛋白(SIRP)家族的成员,也属于免疫球蛋白超家族。SIRP家族成员是已知参与受体酪氨酸激酶偶联信号传导过程的负调节的受体型跨膜糖蛋白。SIRPα可以被酪氨酸激酶磷酸化。已证明该PTP的磷酸化酪氨酸残基可以募集含有酪氨酸磷酸酶(PTP)的SH2结构域,并作为PTP的底物。SIRPα被发现参与由各种生长因子受体介导的信号转导。已证明CD47是一种配体。SIRPα与SIRP家族的其他几个成员具有非常高的相似性。SIRPα主要由髓细胞表达,也由干细胞或神经元表达。
SIRPα作为抑制性受体,与广泛表达的跨膜蛋白CD47相互作用,也称为“不要吃我”信号。这种相互作用消极地控制先天免疫细胞的效应功能,如宿主细胞吞噬作用。SIRPα在巨噬细胞膜上横向扩散并聚集在吞噬突触处,与CD47结合并发出“自我”信号,从而抑制巨噬细胞的细胞骨架密集型吞噬过程。
CD47连接后,SIRPα被磷酸化并募集磷酸酶,如SHP1和SHP2。胞外区含有三个免疫球蛋白超家族结构域——单个V集(V-set)和两个C1集(C1-set)的IgSF结构域。SIRPβ和γ具有相似的细胞外结构,但不同的胞质区产生不同类型的信号。
SIRPα识别CD47,这是一种区分活细胞和垂死细胞的抗吞噬信号。SIRPα的细胞外结构域与CD47结合,通过其细胞质结构域传递细胞内信号。CD47结合是通过SIRPα的NH2末端V样结构域介导的。胞质区含有四个ITIM,与配体结合后会被磷酸化。磷酸化介导了酪氨酸激酶SHP2的激活。SIRPα还与磷酸酶SHP1、衔接蛋白SCAP2和FYN结合蛋白结合。SHP磷酸酶向膜的募集导致肌球蛋白在细胞表面积累的抑制,并导致吞噬作用的抑制。
癌细胞高度表达CD47,激活SIRPα并抑制巨噬细胞介导的破坏。已证明拮抗癌细胞上CD47的SIRPα的高亲和力变体增加了癌细胞的吞噬作用。抗SIRPα抗体也已被证明可在单独或与其他癌症治疗的协同作用下帮助巨噬细胞减少癌症的生长和转移。
发明内容
本文发现的抗SIRPα抗体对变体v1和v2都具有高亲和力,可以剂量依赖性地有效阻断SIRPα与CD47之间的相互作用,并有效诱导巨噬细胞介导的对表达CD47的细胞的吞噬作用。相比之下,已知的抗SIRPα抗体只能识别变体1。
根据本公开的一个实施方案,提供了一种与野生型人信号调节蛋白α(SIRPα)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重链可变区和轻链可变区,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,所述轻链可变区包含互补决定区CDRL1、CDRL2和CDRL3,并且其中(a)所述CDRH1包含SEQ ID NO:15的氨基酸序列,所述CDRH2包含SEQ ID NO:16、21或22的氨基酸序列,所述CDRH3包含SEQ ID NO:17的氨基酸序列,所述CDRL1包含SEQ ID NO:18的氨基酸序列,所述CDRL2包含SEQ ID NO:19的氨基酸序列,并且所述CDRL3包含SEQ ID NO:20的氨基酸序列;(b)所述CDRH1包含SEQ ID NO:30的氨基酸序列,所述CDRH2包含SEQ ID NO:31、36、37或38的氨基酸序列,所述CDRH3包含SEQ IDNO:32的氨基酸序列,所述CDRL1包含SEQ ID NO:33的氨基酸序列,所述CDRL2包含SEQ IDNO:34的氨基酸序列,并且所述CDRL3包含SEQ ID NO:35的氨基酸序列;(c)所述CDRH1包含SEQ ID NO:47的氨基酸序列,所述CDRH2包含SEQ ID NO:48、53或54的氨基酸序列,所述CDRH3包含SEQ ID NO:49的氨基酸序列,所述CDRL1包含SEQ ID NO:50的氨基酸序列,所述CDRL2包含SEQ ID NO:51的氨基酸序列,并且所述CDRL3包含SEQ ID NO:52的氨基酸序列;(d)所述CDRH1包含SEQ ID NO:63的氨基酸序列,所述CDRH2包含SEQ ID NO:64的氨基酸序列,所述CDRH3包含SEQ ID NO:65的氨基酸序列,所述CDRL1包含SEQ ID NO:66的氨基酸序列,所述CDRL2包含SEQ ID NO:67的氨基酸序列,并且所述CDRL3包含SEQ ID NO:68的氨基酸序列;(e)所述CDRH1包含SEQ ID NO:77的氨基酸序列,所述CDRH2包含SEQ ID NO:78的氨基酸序列,所述CDRH3包含SEQ ID NO:79的氨基酸序列,所述CDRL1包含SEQ ID NO:80的氨基酸序列,所述CDRL2包含SEQ ID NO:81的氨基酸序列,并且所述CDRL3包含SEQ ID NO:82的氨基酸序列;(f)所述CDRH1包含SEQ ID NO:91的氨基酸序列,所述CDRH2包含SEQ ID NO:92的氨基酸序列,所述CDRH3包含SEQ ID NO:93的氨基酸序列,所述CDRL1包含SEQ ID NO:94的氨基酸序列,所述CDRL2包含SEQ ID NO:95的氨基酸序列,并且所述CDRL3包含SEQ IDNO:96的氨基酸序列;或者(g)所述CDRH1包含SEQ ID NO:103的氨基酸序列,所述CDRH2包含SEQ ID NO:104的氨基酸序列,所述CDRH3包含SEQ ID NO:105的氨基酸序列,所述CDRL1包含SEQ ID NO:106的氨基酸序列,所述CDRL2包含SEQ ID NO:107的氨基酸序列,并且所述CDRL3包含SEQ ID NO:108的氨基酸序列。
在一个实施方案中,本公开提供了一种与野生型人信号调节蛋白α(SIRPα)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重链可变区和轻链可变区,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,所述轻链可变区包含互补决定区CDRL1、CDRL2和CDRL3,并且其中所述CDRH1包含SEQ ID NO:15的氨基酸序列,所述CDRH2包含SEQ ID NO:16、21或22的氨基酸序列,所述CDRH3包含SEQ ID NO:17的氨基酸序列,所述CDRL1包含SEQ ID NO:18的氨基酸序列,所述CDRL2包含SEQ ID NO:19的氨基酸序列,并且所述CDRL3包含SEQ ID NO:20的氨基酸序列。
在一些实施方案中,所述重链可变区包含选自由SEQ ID NO:1和23-27组成的组的氨基酸序列,或与选自由SEQ ID NO:1和23-27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,所述轻链可变区包含选自由SEQ ID NO:2和28-29组成的组的氨基酸序列,或与选自由SEQ ID NO:2和28-29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,所述重链可变区包含SEQ ID NO:27的氨基酸序列,并且所述轻链可变区包含SEQ ID NO:29的氨基酸序列。
在另一实施方案中,提供了一种与野生型人信号调节蛋白α(SIRPα)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重链可变区和轻链可变区,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,所述轻链可变区包含互补决定区CDRL1、CDRL2和CDRL3,并且其中所述CDRH1包含SEQ ID NO:30的氨基酸序列,所述CDRH2包含SEQID NO:31、36、37或38的氨基酸序列,所述CDRH3包含SEQ ID NO:32的氨基酸序列,所述CDRL1包含SEQ ID NO:33的氨基酸序列,所述CDRL2包含SEQ ID NO:34的氨基酸序列,并且所述CDRL3包含SEQ ID NO:35的氨基酸序列。
在一些实施方案中,所述重链可变区包含选自由SEQ ID NO:3和39-44组成的组的氨基酸序列,或与选自由SEQ ID NO:3和39-44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,所述轻链可变区包含选自由SEQ ID NO:4和45-46组成的组的氨基酸序列,或与选自由SEQ ID NO:4和45-46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,所述重链可变区包含SEQ ID NO:43的氨基酸序列,并且所述轻链可变区包含SEQ ID NO:45的氨基酸序列。
又一个实施方案提供了一种与野生型人信号调节蛋白α(SIRPα)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重链可变区和轻链可变区,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,所述轻链可变区包含互补决定区CDRL1、CDRL2和CDRL3,并且其中所述CDRH1包含SEQ ID NO:47的氨基酸序列,所述CDRH2包含SEQID NO:48、53或54的氨基酸序列,所述CDRH3包含SEQ ID NO:49的氨基酸序列,所述CDRL1包含SEQ ID NO:50的氨基酸序列,所述CDRL2包含SEQ ID NO:51的氨基酸序列,并且所述CDRL3包含SEQ ID NO:52的氨基酸序列。
在一些实施方案中,所述重链可变区包含选自由SEQ ID NO:5和55-60组成的组的氨基酸序列,或与选自由SEQ ID NO:5和55-60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,所述轻链可变区包含选自由SEQ ID NO:6和61-62组成的组的氨基酸序列,或与选自由SEQ ID NO:6和61-62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,本公开的抗体或片段可以结合SIRPα变体1和变体2。在一些实施方案中,所述抗体或片段是人源化的。在一些实施方案中,本公开的抗体或片段进一步具有对第二靶蛋白的结合特异性。
在一些实施方案中,还提供了包含所述抗体或其片段以及药学上可接受的载体的组合物。在一些实施方案中,所述组合物进一步包含对肿瘤抗原具有特异性的第二抗体。在一些实施方案中,所述第二抗体是一种肿瘤调理抗体(tumor-opsonizing antibody)。
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所述抗体或其片段。
附图说明
图1显示了抗体与SIRPαv1和v2的交叉结合。
图2显示了抗体对SIRPαv1的结合亲和力。
图3显示了抗体对SIRPα与CD47相互作用的竞争。
图4显示了抗体对巨噬细胞介导的吞噬作用的诱导。
图5显示了抗体处理增加巨噬细胞介导的对肿瘤细胞的吞噬作用。
图6展示了动物扫描图像和图表,显示03-hz51与利妥昔单抗在Raji淋巴瘤肿瘤模型中完全抑制肿瘤生长的协同作用。
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(polypeptide)”以及复数“多肽(polypeptides)”,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。
“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。
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)。
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(VH)和轻链(VL)的可变区的融合蛋白。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部位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所述CDR和所述框架区的氨基酸,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),包含约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,包含约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,包含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),包含约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,包含约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),包含约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”包括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众所周知的。如本文所用,术语“VH结构域”包含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”包含免疫球蛋白重链的第一个(氨基最末端)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”包含重链分子的部分,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”包含将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.Immunol161:4083(1998))。
如本文所述的术语“二硫键”包含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,并且两条重链通过两个二硫键连接,使用Kabat编号系统对应于第239和第242位(第226或第229位,EU编号系统)。
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,目标结合区或位点来自非人类来源(例如小鼠或灵长类),并且恒定区是人类来源。
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“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。需要治疗的人包括已经患有该病症或紊乱的人,以及易于患有该病症或紊乱的人或要预防该病症或紊乱的人。
“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”的短语包括受试者,如哺乳动物受试者,他们将从例如用于检测、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。
抗SIRPα抗体
本公开提供了对变体v1和v2都具有高亲和力的抗SIRPα抗体和片段。变体1(hSIRPαV1)是欧洲人、非洲人、混血美国人和南亚人中的主要变体。变体2(hSIRPαV2)是东亚人中的主要变体。hSIRPαV1和hSIRPαV2的序列在细胞外Ig-样V-样(IgV)结构域内不同。本公开的抗体和片段识别两种变体的能力使它们能够在最广泛的患者群体中有效。
此外,本公开的抗体和片段表现出优异的结合亲和力,对巨噬细胞介导的吞噬作用的有效诱导,以及卓越的化学、制造和控制(CMC)可开发性。
因此,根据本公开的一个实施方案,提供了能够结合SIRPα的变体1和2的抗体及其抗原结合片段。示例抗体包括表1中所列的鼠类抗体,以及表2-8中的人源化抗体。还包括含有与本文所示相同的CDR的抗体。在一些实施方案中,所公开的抗体和片段包括与本文所示的抗体和片段结合相同表位结合的抗体和片段,以及与本公开的抗体和片段竞争结合SIRPα的抗体和片段。
根据本公开的一个实施方案,提供了一种抗体或其片段,其包含具有本文所公开的CDR区的重链和轻链可变结构域,以及它们的生物等效物。
在一个实施方案中,所述CDR是248G3F6的CDR,如表2B和表2D所例示。在一个实施方案中,所述CDRH1包含SEQ ID NO:15的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRH2包含SEQ ID NO:16、21或22的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRH3包含SEQ ID NO:17的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRL1包含SEQ ID NO:18的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRL2包含SEQ ID NO:19的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,以及所述CDRL3包含SEQ ID NO:20的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体。
一个实施方案提供了与野生型人信号调节蛋白α(SIRPα)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重链可变区和轻链可变区,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,所述轻链可变区包含互补决定区CDRL1、CDRL2和CDRL3,并且其中所述CDRH1包含SEQ ID NO:15的氨基酸序列,所述CDRH2包含SEQ ID NO:16的氨基酸序列,所述CDRH3包含SEQ ID NO:17的氨基酸序列,所述CDRL1包含SEQ ID NO:18的氨基酸序列,所述CDRL2包含SEQ ID NO:19的氨基酸序列,并且所述CDRL3包含SEQ IDNO:20的氨基酸序列。
一个实施方案提供了与野生型人信号调节蛋白α(SIRPα)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重链可变区和轻链可变区,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,所述轻链可变区包含互补决定区CDRL1、CDRL2和CDRL3,并且其中所述CDRH1包含SEQ ID NO:15的氨基酸序列,所述CDRH2包含SEQ ID NO:21的氨基酸序列,所述CDRH3包含SEQ ID NO:17的氨基酸序列,所述CDRL1包含SEQ ID NO:18的氨基酸序列,所述CDRL2包含SEQ ID NO:19的氨基酸序列,并且所述CDRL3包含SEQ IDNO:20的氨基酸序列。
一个实施方案提供了与野生型人信号调节蛋白α(SIRPα)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重链可变区和轻链可变区,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,所述轻链可变区包含互补决定区CDRL1、CDRL2和CDRL3,并且其中所述CDRH1包含SEQ ID NO:15的氨基酸序列,所述CDRH2包含SEQ ID NO:22的氨基酸序列,所述CDRH3包含SEQ ID NO:17的氨基酸序列,所述CDRL1包含SEQ ID NO:18的氨基酸序列,所述CDRL2包含SEQ ID NO:19的氨基酸序列,并且所述CDRL3包含SEQ IDNO:20的氨基酸序列。
在一些实施方案中,所述重链可变区包含选自由SEQ ID NO:1和23-27组成的组的氨基酸序列,或与选自由SEQ ID NO:1和23-27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,所述轻链可变区包含选自由SEQ ID NO:2和28-29组成的组的氨基酸序列,或与选自由SEQ ID NO:2和28-29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,所述重链可变区包含SEQ ID NO:27的氨基酸序列,并且所述轻链可变区包含SEQ ID NO:29的氨基酸序列。
在一个实施方案中,所述CDR是300A6A6的CDR,如表3B和表3D所例示。在一个实施方案中,所述CDRH1包含SEQ ID NO:30的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRH2包含SEQ ID NO:31、36、37或38的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRH3包含SEQ ID NO:32的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRL1包含SEQ ID NO:33的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRL2包含SEQ ID NO:34的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,以及所述CDRL3包含SEQ ID NO:35的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体。
在一个实施方案中,提供了与野生型人信号调节蛋白α(SIRPα)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重链可变区和轻链可变区,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,所述轻链可变区包含互补决定区CDRL1、CDRL2和CDRL3,并且其中所述CDRH1包含SEQ ID NO:30的氨基酸序列,所述CDRH2包含SEQID NO:31的氨基酸序列,所述CDRH3包含SEQ ID NO:32的氨基酸序列,所述CDRL1包含SEQID NO:33的氨基酸序列,所述CDRL2包含SEQ ID NO:34的氨基酸序列,并且所述CDRL3包含SEQ ID NO:35的氨基酸序列。
在一个实施方案中,提供了与野生型人信号调节蛋白α(SIRPα)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重链可变区和轻链可变区,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,所述轻链可变区包含互补决定区CDRL1、CDRL2和CDRL3,并且其中所述CDRH1包含SEQ ID NO:30的氨基酸序列,所述CDRH2包含SEQID NO:36的氨基酸序列,所述CDRH3包含SEQ ID NO:32的氨基酸序列,所述CDRL1包含SEQID NO:33的氨基酸序列,所述CDRL2包含SEQ ID NO:34的氨基酸序列,并且所述CDRL3包含SEQ ID NO:35的氨基酸序列。
在一个实施方案中,提供了与野生型人信号调节蛋白α(SIRPα)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重链可变区和轻链可变区,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,所述轻链可变区包含互补决定区CDRL1、CDRL2和CDRL3,并且其中所述CDRH1包含SEQ ID NO:30的氨基酸序列,所述CDRH2包含SEQID NO:37的氨基酸序列,所述CDRH3包含SEQ ID NO:32的氨基酸序列,所述CDRL1包含SEQID NO:33的氨基酸序列,所述CDRL2包含SEQ ID NO:34的氨基酸序列,并且所述CDRL3包含SEQ ID NO:35的氨基酸序列。
在一个实施方案中,提供了与野生型人信号调节蛋白α(SIRPα)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重链可变区和轻链可变区,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,所述轻链可变区包含互补决定区CDRL1、CDRL2和CDRL3,并且其中所述CDRH1包含SEQ ID NO:30的氨基酸序列,所述CDRH2包含SEQID NO:38的氨基酸序列,所述CDRH3包含SEQ ID NO:32的氨基酸序列,所述CDRL1包含SEQID NO:33的氨基酸序列,所述CDRL2包含SEQ ID NO:34的氨基酸序列,并且所述CDRL3包含SEQ ID NO:35的氨基酸序列。
在一些实施方案中,所述重链可变区包含选自由SEQ ID NO:3和39-44组成的组的氨基酸序列,或与选自由SEQ ID NO:3和39-44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,所述轻链可变区包含选自由SEQ ID NO:4和45-46组成的组的氨基酸序列,或与选自由SEQ ID NO:4和45-46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,所述重链可变区包含SEQ ID NO:43的氨基酸序列,并且所述轻链可变区包含SEQ ID NO:45的氨基酸序列。
在一个实施方案中,所述CDR是102A10F2的CDR,如表4B和表4D所例示。在一个实施方案中,所述CDRH1包含SEQ ID NO:47的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRH2包含SEQ ID NO:48、53或54的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRH3包含SEQ ID NO:49的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRL1包含SEQ ID NO:50的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRL2包含SEQ ID NO:51的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,以及所述CDRL3包含SEQ ID NO:52的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体。
在一个实施方案中,提供了与野生型人信号调节蛋白α(SIRPα)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重链可变区和轻链可变区,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,所述轻链可变区包含互补决定区CDRL1、CDRL2和CDRL3,并且其中所述CDRH1包含SEQ ID NO:47的氨基酸序列,所述CDRH2包含SEQID NO:48的氨基酸序列,所述CDRH3包含SEQ ID NO:49的氨基酸序列,所述CDRL1包含SEQID NO:50的氨基酸序列,所述CDRL2包含SEQ ID NO:51的氨基酸序列,并且所述CDRL3包含SEQ ID NO:52的氨基酸序列。
在一个实施方案中,提供了与野生型人信号调节蛋白α(SIRPα)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重链可变区和轻链可变区,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,所述轻链可变区包含互补决定区CDRL1、CDRL2和CDRL3,并且其中所述CDRH1包含SEQ ID NO:47的氨基酸序列,所述CDRH2包含SEQID NO:53的氨基酸序列,所述CDRH3包含SEQ ID NO:49的氨基酸序列,所述CDRL1包含SEQID NO:50的氨基酸序列,所述CDRL2包含SEQ ID NO:51的氨基酸序列,并且所述CDRL3包含SEQ ID NO:52的氨基酸序列。
在一个实施方案中,提供了与野生型人信号调节蛋白α(SIRPα)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重链可变区和轻链可变区,所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,所述轻链可变区包含互补决定区CDRL1、CDRL2和CDRL3,并且其中所述CDRH1包含SEQ ID NO:47的氨基酸序列,所述CDRH2包含SEQID NO:54的氨基酸序列,所述CDRH3包含SEQ ID NO:49的氨基酸序列,所述CDRL1包含SEQID NO:50的氨基酸序列,所述CDRL2包含SEQ ID NO:51的氨基酸序列,并且所述CDRL3包含SEQ ID NO:52的氨基酸序列。
在一些实施方案中,所述重链可变区包含选自由SEQ ID NO:5和55-60组成的组的氨基酸序列,或与选自由SEQ ID NO:5和55-60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,所述轻链可变区包含选自由SEQ ID NO:6和61-62组成的组的氨基酸序列,或与选自由SEQ ID NO:6和61-62组成的组的氨基酸序列具有至少90%序列同一性的肽。
在一个实施方案中,所述CDR是62D2H6的CDR,如表5B和表5D所例示。在一个实施方案中,所述CDRH1包含SEQ ID NO:63的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRH2包含SEQ ID NO:64的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRH3包含SEQ ID NO:65的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRL1包含SEQ ID NO:66的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRL2包含SEQ ID NO:67的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,以及所述CDRL3包含SEQ ID NO:68的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体。
在一些实施方案中,所述重链可变区包含选自由SEQ ID NO:7和69-72组成的组的氨基酸序列,或与选自由SEQ ID NO:7和69-72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,所述轻链可变区包含选自由SEQ ID NO:8和73-76组成的组的氨基酸序列,或与选自由SEQ ID NO:8和73-76组成的组的氨基酸序列具有至少90%序列同一性的肽。
在一个实施方案中,所述CDR是211F8E11的CDR,如表6B和表6D所例示。在一个实施方案中,所述CDRH1包含SEQ ID NO:77的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRH2包含SEQ ID NO:78的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRH3包含SEQ ID NO:79的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRL1包含SEQ ID NO:80的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRL2包含SEQ IDNO:81的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,以及所述CDRL3包含SEQ ID NO:82的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体。
在一些实施方案中,所述重链可变区包含选自由SEQ ID NO:9和83-86组成的组的氨基酸序列,或与选自由SEQ ID NO:9和83-86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,所述轻链可变区包含选自由SEQ ID NO:10和87-90组成的组的氨基酸序列,或与选自由SEQ ID NO:10和87-90组成的组的氨基酸序列具有至少90%序列同一性的肽。
在一个实施方案中,所述CDR是217D11E5的CDR,如表7B和表7D所例示。在一个实施方案中,所述CDRH1包含SEQ ID NO:91的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRH2包含SEQ ID NO:92的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRH3包含SEQ ID NO:93的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRL1包含SEQ ID NO:94的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRL2包含SEQ IDNO:95的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,以及所述CDRL3包含SEQ ID NO:96的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体。
在一些实施方案中,所述重链可变区包含选自由SEQ ID NO:11和97-100组成的组的氨基酸序列,或与选自由SEQ ID NO:11和97-100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,所述轻链可变区包含选自由SEQ ID NO:12和101-102组成的组的氨基酸序列,或与选自由SEQ ID NO:12和101-102组成的组的氨基酸序列具有至少90%序列同一性的肽。
在一个实施方案中,所述CDR是234B7D5的CDR,如表8B和表8D所例示。在一个实施方案中,所述CDRH1包含SEQ ID NO:103的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRH2包含SEQ ID NO:104的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRH3包含SEQ ID NO:105的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRL1包含SEQ ID NO:106的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,所述CDRL2包含SEQ ID NO:107的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体,以及所述CDRL3包含SEQ ID NO:108的氨基酸序列或其具有一个、两个或三个缺失、添加、取代或其组合的变体。
在一些实施方案中,所述重链可变区包含选自由SEQ ID NO:13和109-112组成的组的氨基酸序列,或与选自由SEQ ID NO:13和109-112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,所述轻链可变区包含选自由SEQ ID NO:14和113-118组成的组的氨基酸序列,或与选自由SEQ ID NO:14和113-118组成的组的氨基酸序列具有至少90%序列同一性的肽。
所述含有这些CDR区的抗体,无论是小鼠的、人源化的还是嵌合的,都具有有效的SIRPα结合和抑制活性。如实施例5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可称为亲和力成熟或去风险化的CDR。
表2B、3B和4B中提供了去风险化的CDR的非限制性实例。修饰的CDR可以包含具有一个、两个或三个氨基酸的添加、缺失和/或取代的CDR。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”是指其中的所述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A.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B.保守的氨基酸取代
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,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,抗体可以包含一个或多个非典型氨基酸。
在一些实施方案中,所述抗体可以与治疗剂、前药、肽、蛋白质、酶、病毒、脂质、生物反应调节剂、药物制剂或PEG缀合。
所述抗体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制剂。
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众所周知的,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Controlled DrugDelivery(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:Biological And Clinical Applications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))。
双功能分子与联合疗法
先天免疫系统的一个重要组成部分是巨噬细胞。巨噬细胞通过吞噬肿瘤细胞来抑制肿瘤生长。肿瘤细胞可以通过在其细胞表面上调“不要吃我”的信号CD47以逃避巨噬细胞的监视。CD47是普遍表达的,但在各种肿瘤类型中上调。通过与各种配体相互作用,CD47在调节细胞运动、粘附、迁移和血小板激活方面发挥作用。SIRPα是免疫球蛋白超家族的另一个成员,主要表达在神经元和髓细胞表面,包括巨噬细胞、粒细胞、单核细胞和树突状细胞。CD47/SIRPα轴是已知的肿瘤细胞逃避免疫的主要途径。
靶向CD47的制剂可以启动抗体调理作用,并激活抗体依赖性细胞毒性(ADCC)或抗体依赖性细胞吞噬作用(ADCP),这有助于破坏肿瘤细胞。然而,由于CD47的普遍表达可能导致红细胞毒性和其他血液学不良反应,因为血细胞上存在该抗原。靶向SIRPα的分子或同时靶向SIRPα和CD47的双特异性制剂可以通过拥有功能性的Fc结构域而被设计为引发ADCC和ADCP效应。
由于与CD47相比,SIRPα的表达更受限制,这些分子不会像仅靶向CD47的分子具有那么多的血液学事件。因此,抗SIRPα抗体可以比抗CD47抗体更安全。另一种选择是开发同时针对CD47/SIRPα轴和另一种肿瘤抗原的双特异性制剂。这些制剂可以是双特异性抗体、融合蛋白和联合疗法。
肿瘤抗原的实例,特别是可以触发肿瘤调理作用的抗原包括但不限于CD19、CD20、EGFR、HER2、CD3、CD16、PD1、PD-L1、LAG3、TIM3、CTLA4、VISTA、CSFR1、A2AR、CD73、CD39、CD40、CEA、HER2、VEGFR、TIGIT、紧密连接蛋白18.2、CD24、GPC3、Il13RA2、4-1BB、CCR8和CMET。
还提供了不同形式的双特异性抗体。在一些实施方案中,抗SIRPα片段和第二片段中的每一个都独立地选自Fab片段、单链可变片段(scFv)或单域抗体。在一些实施方案中,所述双特异性抗体进一步包括Fc片段。
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众所周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挑战时产生这种抗体,但其内源性基因座已失效。可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,本公开的所述抗体、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的核酸或多核苷酸(包括如本文所述的变体及其衍生物)。
本公开的抗体也可以用于治疗或抑制癌症。如前文所提供的,SIRPα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SIRPα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。在一些实施方案中,患者体内的至少有一种癌细胞(例如基质细胞)过表达SIRPα。
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SIRPα抗体接触(或者替代性地被改造以表达本公开的抗SIRPα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、脑血管瘤、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众所周知的药理学和药代动力学原理确定。
抗体、变体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。抗原结合多肽或组合物可以通过任何方便的途径给药,例如通过输液或推注,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。
本文所用术语“肠胃外”是指给药方式,包括静脉内、肌内、腹膜内、胸腔内、皮下和关节内注射和输液。
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液、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的量。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,本公开的抗原结合多肽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,本公开的组合物与其他治疗或预防方案例如放射疗法联合施用。
诊断方法
在某些肿瘤样本中观察到SIRPα的过表达,并且具有SIRPα过表达的细胞的患者可能对用本公开的抗SIRPα抗体的治疗有反应。因此,本公开的抗体也可用于诊断和预后目的。
样本优选地包括可以从患者获得的细胞,所述患者可以是癌症患者或需要诊断的患者。所述细胞是肿瘤组织或肿瘤块、血液样本、尿液样本或来自患者的任何样本的细胞。在对样本进行任选的预处理后,可以在允许抗体与所述样本中可能存在的SIRPα蛋白相互作用的条件下将所述样本与本公开的抗体进行孵育。利用抗SIRPα抗体的优势,可以使用如ELISA等方法检测样本中SIRPα蛋白的存在。
样本中SIRPα蛋白的存在(任选地数量或浓度)可用于癌症的诊断,作为患者适合用抗体治疗的指示,或作为患者对癌症治疗有(或无)反应的指示。对于预后方法,可以在癌症治疗开始后的某些阶段进行一次、两次或更多次检测以指示治疗的进展。
组合物
本公开还提供了药物组合物。该药物组合物包括有效量的抗体,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;还设想了用于调整涨度的试剂,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'sPharmaceutical Sciences)》中描述了合适的药物载体的实例,通过引入并入本文。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中。当所述组合物通过输液给药时,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,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。
具体实施方式
实施例1:产生针对人SIRPα的鼠单克隆抗体
用人SIRPa蛋白免疫不同品系的小鼠,并相应地产生杂交瘤。进行八次融合以产生足够数量的杂交瘤克隆。选择SIRPa v1/v2阳性结合物并进行亚克隆。随后,对大约30种纯化的抗体进行体外结合和功能筛选,鉴定出结合亲和力最高、功能效力最强的先导抗体。该先导抗体是人源化的。
下表提供了先导鼠抗体的VH/VL序列。
表1.先导鼠抗体的VH/VL序列
实施例2.SIRPa v1和v2的交叉结合
本实施例检测了小鼠抗SIRPα单克隆抗体与重组人SIRPα变体1和变体2蛋白的ELISA结合的剂量反应(0.5μg/ml@100μl)。重组人SIRPαv1或v2蛋白(百英生物)在PBS中以0.5μg/ml的浓度包被到微量滴定板上,室温下保持2小时。抗原包被后,用含有1%BSA的PBS/0.05%吐温(PBST)在室温下封闭孔1小时。
用PBST洗涤孔后,将不同浓度的抗SIRPα抗体加入孔中并在室温下孵育1小时。为了检测结合抗体,加入HRP缀合的抗小鼠Fc的二抗(Jackson Immuno Research),然后加入荧光底物(罗氏)。在所有孵育步骤之间,用PBST洗涤板的孔3次。在TECAN Spectrafluor读板器中测量荧光。
结果如图1所示。两种测试的抗体248G3F6和300A6A6对变体1和2都表现出纳克级的亲和力。
使用Biacore 8K系统通过人抗体捕获方法进行抗体与变体1的结合动力学检测。根据制造商的说明,将抗小鼠Fc IgG固定在CM5传感器芯片上。注射测试抗体并通过固定化的抗人Fc IgG捕获。分别注射连续浓度的抗原,并分别记录每个浓度抗原分析物的结合曲线。
检测系统通过注射10mM的甘氨酸-盐酸pH1.5,持续30秒而再生。运行缓冲液为HBS-EP+(10mM HEPES,pH 7.4,150mM NaCl,3mM EDTA和0.05%P20)。检测温度为25℃,并且结合和解离时间分别为180秒和600秒。使用Biacore K8评估软件1.0,根据1:1结合模型对Biacore数据进行拟合,计算出结合速率常数(ka)和解离速率常数(kd)以及平衡常数(KD)。
结果如图2所示,并且总结于下表。两种测试的抗体都表现出优异的结合亲和力。
样本 | ka(1/Ms) | kd(1/s) | KD(M) |
248G3F6 | 1.87E+05 | 3.74E-04 | 2.00E-09 |
300A6A6 | 1.31E+05 | 1.48E-04 | 1.13E-09 |
实施例3.与CD47的竞争
本实施例测试了抗SIRPα抗体与CD47竞争结合SIRPα的能力。
将重组CD47-Fc融合蛋白(Acrobiosystems)在PBS中以1μg/ml的浓度包被到微量滴定板上,4℃保持2小时。用含有1%BSA的PBST在室温下封闭1小时后,在没有或有不同浓度的抗SIRPα抗体的情况下,在室温下加入1μg/mL的SIRPα-His蛋白保持1小时。随后洗板三次并与HRP缀合的抗组氨酸二抗在室温下孵育1小时。洗涤后,每孔加入TMB溶液保持30分钟,用2M H2SO4终止反应,并在490nm处测量OD值。
如图3所示,248G3F6和300A6A6均有效且剂量依赖性地抑制CD47与SIRPα的结合。
实施例4.巨噬细胞介导的吞噬作用的诱导
本实施例测试了抗SIRPα抗体诱导巨噬细胞介导的吞噬作用的能力。
从人血中分离出PBMC,将单核细胞分化为巨噬细胞6天。刮取单核细胞衍生的巨噬细胞(MDM)并重新铺在24孔培养皿中,使其粘附24小时。将内源性表达CD47的人肿瘤细胞系Raji转染人PD-L1使其表面过表达人PD-L1。选择该PD-L1过表达的Raji细胞作为靶细胞并用1μM CFSE标记10分钟,然后以肿瘤细胞与吞噬细胞为5:1的比例加入MDM中。
在培养体系中加入抗SIRPα抗体和抗PD-L1抗体。孵育3小时后,用PBS洗去未被吞噬的靶细胞,刮掉剩余的吞噬细胞,用巨噬细胞标记物C76抗体染色,并通过流式细胞术分析。通过对C76+细胞设门,然后评估CFSE+细胞的百分比来测量吞噬作用。
图4显示了通过抗SIRPα抗体与抗PD-L1抗体的组合处理对表达PD-L1的肿瘤细胞的吞噬结果。抗PD-L1抗体与任一抗SIRPα抗体的组合表现出最高的吞噬作用(右侧的两个柱)。
实施例5.小鼠单克隆抗体的人源化
使用鼠抗体可变区基因来产生人源化单克隆抗体。在该过程的第一步中,将单克隆抗体的VH和VL的氨基酸序列与人Ig基因序列的现有数据库进行比较,以找到整体上最匹配的人类种系Ig基因序列。
人源化抗体的氨基酸序列提供如下。
人源化的序列
A.248G3F6
表2A.248G3F6-VH的人源化
表2B.CDR序列
CDR | 序列 | SEQ ID NO: |
CDR-H1 | DTYMH | 15 |
CDR-H2 | RIDPADGDTKYNPKFQD | 16 |
CDR-H3 | GNYVN | 17 |
CDR-H2(v4) | RIDPAEGDTKYNPKFQD | 21 |
CDR-H2(v5) | RIDPADADTKYNPKFQD | 22 |
表2C.248G3F6-VL的人源化
表2D.CDR序列
CDR | 序列 | SEQ ID NO: |
CDR-L1 | RASSSVSSSYLY | 18 |
CDR-L2 | STSNLAS | 19 |
CDR-L3 | HQWYSYPRT | 20 |
表2E.人源化抗体
VL | VL v1 | VL v2 | |
VH | HSP210-02-Chi | ||
VH v1 | HSP210-02-hz11 | HSP210-02-hz12 | |
VH v2 | HSP210-02-hz21 | HSP210-02-hz22 | |
VH v3 | HSP210-02-hz31 | HSP210-02-hz32 | |
VH v4 | HSP210-02-hz41 | HSP210-02-hz42 | |
VH v5 | HSP210-02-hz51 | <![CDATA[<u>HSP210-02-hz52</u>]]> |
B.300A6A6
表3A.300A6A6-VH的人源化
表3B.CDR序列
CDR | 序列 | SEQ ID NO: |
CDR-H1 | SNYIH | 30 |
CDR-H2 | WIYPGDGDTNYNQKFNG | 31 |
CDR-H3 | NYGGIWFAY | 32 |
CDR-H2(v4) | WIYPGEGDTNYNQKFNG | 36 |
CDR-H2(v5) | WIYPGDADTNYNQKFNG | 37 |
CDR-H2(v6) | WIYPGDGDTNYNQKFQG | 38 |
表3C.300A6A6-VL的人源化
表3D.CDR序列
CDR | 序列 | SEQ ID NO: |
CDR-L1 | QASQDIGNKLI | 33 |
CDR-L2 | YVTNLPG | 34 |
CDR-L3 | LQYKQNPLT | 35 |
表3E.人源化抗体
VL | VL v1 | VL v2 | |
VH | HSP210-03-Chi | ||
VH v1 | HSP210-03-hz11 | HSP210-03-hz12 | |
VH v2 | HSP210-03-hz21 | HSP210-03-hz22 | |
VH v3 | HSP210-03-hz31 | HSP210-03-hz32 | |
VH v4 | HSP210-03-hz41 | HSP210-03-hz42 | |
VH v5 | <![CDATA[<u>HSP210-03-hz51</u>]]> | HSP210-03-hz52 | |
VH v6 | HSP210-03-hz61 | HSP210-03-hz62 |
C.102A10F2
表4A.102A10F2-VH的人源化
表4B.CDR序列
CDR | 序列 | SEQ ID NO: |
CDR-H1 | TYDIGMG | 47 |
CDR-H2 | HIWWNDREYYNSALQS | 48 |
CDR-H3 | IDYFGSGQAWFTY | 49 |
CDR-H2(v5) | <![CDATA[HIWWNDREYY<u>S</u>SALQS]]> | 53 |
CDR-H2(v6) | <![CDATA[HIWWNDREYYN<u>P</u>ALQS]]> | 54 |
表4C.102A10F2-VL的人源化
表4D.CDR序列
CDR | 序列 | SEQ ID NO: |
CDR-L1 | SSSSTISSTYLH | 50 |
CDR-L2 | GTSNLAS | 51 |
CDR-L3 | QQGSRIPFT | 52 |
表3E.人源化抗体
VL | VL v1 | VL v2 | |
VH | HSP210-01-Chi | ||
VH v1 | HSP210-01-hz11 | HSP210-01-hz12 | |
VH v2 | HSP210-01-hz21 | HSP210-01-hz22 | |
VH v3 | HSP210-01-hz31 | HSP210-01-hz32 | |
VH v4 | HSP210-01-hz41 | HSP210-01-hz42 | |
VH v5 | HSP210-01-hz51 | HSP210-01-hz52 | |
VH v6 | HSP210-01-hz61 | HSP210-01-hz62 |
D.62D2H6
表5A.62D2H6-VH的人源化
表5B.CDR序列
CDR | 序列 | SEQ ID NO: |
CDR-H1 | DYYMH | 63 |
CDR-H2 | RIDPEDGETKYAPKFQG | 64 |
CDR-H3 | SWAY | 65 |
表5C.62D2H6-VL的人源化
表5D.CDR序列
表5E.人源化抗体
VL | VL v1 | VL v2 | VL v3 | VL v4 | |
VH | 嵌合体 | ||||
VH v1 | hz11 | ||||
VH v2 | hz22 | hz24 | |||
VH v3 | hz33 | ||||
VH v4 | hz42 | hz44 |
E.211F8E11
表6A.211F8E11-VH的人源化
表6B.CDR序列
CDR | 序列 | SEQ ID NO: |
CDR-H1 | DTYMH | 77 |
CDR-H2 | RIDPANVNTIYDPKFQG | 78 |
CDR-H3 | VGAYDGYDFDY | 79 |
表6C.211F8E11-VL的人源化
表6D.CDR序列
CDR | 序列 | SEQ ID NO: |
CDR-L1 | RASESVDNYGNSFMH | 80 |
CDR-L2 | RASNLES | 81 |
CDR-L3 | QQNNEDPLT | 82 |
表6E.人源化抗体
VL | VL v1 | VL v2 | VL v3 | VL v4 | |
VH | 嵌合体 | ||||
VH v1 | hz11 | ||||
VH v2 | hz22 | hz24 | |||
VH v3 | hz33 | ||||
VH v4 | hz42 | hz44 |
F.217D11E5
表7A.217D11E5-VH的人源化
表7B.CDR序列
CDR | 序列 | SEQ ID NO: |
CDR-H1 | SYVMH | 91 |
CDR-H2 | YINPYNDGTKYNEKFKG | 92 |
CDR-H3 | SYYDYDGSFDY | 93 |
表7C.217D11E5-VL的人源化
表7D.CDR序列
CDR | 序列 | SEQ ID NO: |
CDR-L1 | KASQDVTTAVA | 94 |
CDR-L2 | SASYRYT | 95 |
CDR-L3 | QQHYSTPWT | 96 |
表7E.人源化抗体
VL | VL v1 | VL v2 | |
VH | 嵌合体 | ||
VH v1 | hz11 | ||
VH v2 | hz21 | hz22 | |
VH v3 | |||
VH v4 | hz41 | hz42 |
G.234B7D5
表8A.234B7D5-VH的人源化
表8B.CDR序列
CDR | 序列 | SEQ ID NO: |
CDR-H1 | DTYIH | 103 |
CDR-H2 | RIDPADGDTKHNPKFHD | 104 |
CDR-H3 | GNYVN | 105 |
表7C.234B7D5-VL的人源化
表8D.CDR序列
表8E.人源化抗体
VL | VL v1 | VL v2 | VL v3 | VL v4 | VL v5 | VL v6 | |
VH | 嵌合体 | ||||||
VH v1 | hz11 | ||||||
VH v2 | hz22 | hz24 | hz26 | ||||
VH v3 | hz33 | ||||||
VH v4 | hz42 | hz44 | hz46 |
实施例6.人源化抗体的检测
本实施例测试了一些人源化抗体用于阻断SIRPα和CD47之间相互作用的能力。
将重组CD47-Fc融合蛋白(Acrobiosystems)在PBS中以1μg/ml的浓度包被到微量滴定板上,4℃保持16小时。用含有1%BSA的PBST在室温下封闭1小时后,在没有或有不同浓度的抗SIRPα抗体的情况下,在室温下加入1μg/mL的SIRPα-His蛋白保持1小时。随后洗板三次并与HRP缀合的抗组氨酸二抗在室温下孵育1小时。洗涤后,每孔加入TMB溶液保持30分钟,用2M H2SO4终止反应,并在490nm处测量OD值。
表2E(248G3F6)、3E(300A6A6)和4E(102A10F2)所列出的所有抗体都经过测试并表现出高IC50(表9)。
表9.人源化抗体阻断SIRPα与CD47相互作用的活性
实施例7.巨噬细胞介导的肿瘤细胞吞噬作用的增加
本实施例测试了一些人源化抗体增加巨噬细胞介导的肿瘤细胞吞噬作用的能力。
从人血中分离出PBMC,并使用标准方案将单核细胞分化为巨噬细胞。刮取单核细胞衍生的巨噬细胞(MDM)并重新铺在24孔培养皿中,使其粘附24小时。选择内源性表达CD47的人肿瘤细胞系Raji作为靶细胞并用1μM CFSE标记10分钟,然后以肿瘤细胞与吞噬细胞为5:1的比例加入MDM中,并以指定浓度加入不同浓度的抗SIRPα抗体。孵育3小时后,用PBS洗去未被吞噬的靶细胞,刮掉剩余的吞噬细胞,用C76抗体染色,并通过流式细胞术分析。通过对C76+细胞设门,然后评估CFSE+细胞的百分比来测量吞噬作用。
结果显示在图5中。在测试的抗体中,02-hz52(248G3F6)和03-hz51(300A6A6)表现出最高的活性,其他所有抗体也表现出极好的活性。
实施例8.对SIRPαv1和v2的结合亲和力
本实施例中测试了人源化抗体02-hz52(248G3F6)和03-hz51(300A6A6)对SIRPαv1和v2的结合亲和力。
使用Biacore 8K系统通过人抗体捕获方法进行抗体与抗原的结合动力学检测。根据制造商的说明,将抗小鼠Fc IgG固定在CM5传感器芯片上。注射测试抗体并通过固定化的抗人Fc IgG捕获。然后分别注射连续浓度的人SIRPαv1蛋白或SIRPαv2蛋白,并分别记录每个浓度抗原分析物的结合曲线。检测系统通过注射10mM的甘氨酸-盐酸pH1.5,持续30秒而再生。运行缓冲液为HBS-EP+(10mM HEPES,pH 7.4,150mM NaCl,3mM EDTA和0.05%P20)。检测温度为25℃,并且结合和解离时间分别为180秒和600秒。使用Biacore K8评估软件1.0,根据1:1结合模型对Biacore数据进行拟合,计算出结合速率常数(ka)和解离速率常数(kd)以及平衡常数(KD)。
检测结果示于表10A-B。
表10A.对SIRPαv1的结合亲和力
样本 | ka(1/Ms) | kd(1/s) | KD(M) |
02-hz52 | 7.04E+05 | 2.98E-04 | 4.23E-10 |
03-hz51 | 8.05E+05 | 8.04E-04 | 9.99E-10 |
表10B.对SIRPαv2的结合亲和力
样本 | ka(1/Ms) | kd(1/s) | KD(M) |
02-hz52 | 3.33E+05 | 2.47E-03 | 7.40E-09 |
03-hz51 | 3.31E+05 | 1.00E-03 | 3.03E-09 |
实施例9.可开发性研究
测试了与人IgG4重链恒定区和κ轻链恒定区融合的抗体02-hz52(248G3F6)和03-hz51(300A6A6)的可开发性。两种抗体均不含游离半胱氨酸。检测结果表明,两种抗体均可纯化达到临床级纯度,具有合适的Tm、酸/碱峰比、疏水性和pI。结果列于表11。
表10A.对SIRPαv1的结合亲和力
实施例10.体内测试
本实施例测试了人源化抗体03-hz51(300A6A6)在小鼠中单独或与利妥昔单抗联合使用的功效。
将重悬于PBS中的Raji-Luc细胞以1×105个细胞/0.2mL以及0.2mL/头的体积接种到B-NDG-hSIRPα人源化小鼠的尾静脉中。接种第三天用小动物成像设备测量肿瘤成像信号值。当平均成像信号强度达到1.35×106p/秒时,根据肿瘤成像信号值和动物体重将动物分组,平均分配到4个实验中。每个实验组6只小鼠。
利妥昔单抗在10mg/kg的剂量水平对Raji-Luc淋巴瘤表现出显著的抑制作用,没有临床不良症状。03-hz51与利妥昔单抗(10mg/kg+0.1mg/kg)联用对Raji-Luc淋巴瘤显示出显著的抑制作用。数据显示03-hz51与利妥昔单抗在Raji淋巴瘤肿瘤模型中完全抑制肿瘤生长方面具有协同作用。
***
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引用而并入相同。
序列表
<110> 礼新医药科技(上海)有限公司
<120> 抗SIRPα单克隆抗体及其用途
<130> FSP1V213968JW
<150> PCT/CN2019/127915
<151> 2019-12-24
<160> 118
<170> PatentIn version 3.5
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<220>
<223> 合成的
<400> 20
His Gln Trp Tyr Ser Tyr Pro Arg Thr
1 5
<210> 21
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 21
Arg Ile Asp Pro Ala Glu Gly Asp Thr Lys Tyr Asn Pro Lys Phe Gln
1 5 10 15
Asp
<210> 22
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 22
Arg Ile Asp Pro Ala Asp Ala Asp Thr Lys Tyr Asn Pro Lys Phe Gln
1 5 10 15
Asp
<210> 23
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 23
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 Phe Asn Phe Glu Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asp Gly Asp Thr Lys Tyr Asn Pro Lys Phe
50 55 60
Gln Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asn Tyr Val Asn Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 24
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 24
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 Phe Asn Phe Glu Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asp Gly Asp Thr Lys Tyr Asn Pro Lys Phe
50 55 60
Gln Asp Arg Val Thr Met Thr Val Asp Thr Ser Thr Asn 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
Val Arg Gly Asn Tyr Val Asn Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 25
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 25
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 Phe Asn Phe Glu Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asp Gly Asp Thr Lys Tyr Asn Pro Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Val Asp Thr Ser Thr Asn 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
Val Arg Gly Asn Tyr Val Asn Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 26
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 26
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 Phe Asn Phe Glu Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Glu Gly Asp Thr Lys Tyr Asn Pro Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Val Asp Thr Ser Thr Asn 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
Val Arg Gly Asn Tyr Val Asn Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 27
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 27
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 Phe Asn Phe Glu Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asp Ala Asp Thr Lys Tyr Asn Pro Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Val Asp Thr Ser Thr Asn 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
Val Arg Gly Asn Tyr Val Asn Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 28
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 28
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Trp Tyr Ser Tyr Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 29
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 29
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Val Tyr Phe Cys His Gln Trp Tyr Ser Tyr Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 30
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 30
Ser Asn Tyr Ile His
1 5
<210> 31
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 31
Trp Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gln Lys Phe Asn
1 5 10 15
Gly
<210> 32
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 32
Asn Tyr Gly Gly Ile Trp Phe Ala Tyr
1 5
<210> 33
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 33
Gln Ala Ser Gln Asp Ile Gly Asn Lys Leu Ile
1 5 10
<210> 34
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 34
Tyr Val Thr Asn Leu Pro Gly
1 5
<210> 35
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 35
Leu Gln Tyr Lys Gln Asn Pro Leu Thr
1 5
<210> 36
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 36
Trp Ile Tyr Pro Gly Glu Gly Asp Thr Asn Tyr Asn Gln Lys Phe Asn
1 5 10 15
Gly
<210> 37
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 37
Trp Ile Tyr Pro Gly Asp Ala Asp Thr Asn Tyr Asn Gln Lys Phe Asn
1 5 10 15
Gly
<210> 38
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 38
Trp Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gln Lys Phe Gln
1 5 10 15
Gly
<210> 39
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 39
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Asn
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Asn Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr 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 Asn Tyr Gly Gly Ile Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 40
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 40
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Asn
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Asn Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr 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 Ile Asn Tyr Gly Gly Ile Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 41
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 41
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Asn
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Asn Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Thr 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 Ile Asn Tyr Gly Gly Ile Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 42
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 42
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Asn
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Glu Gly Asp Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Asn Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Thr 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 Ile Asn Tyr Gly Gly Ile Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 43
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 43
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Asn
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Ala Asp Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Asn Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Thr 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 Ile Asn Tyr Gly Gly Ile Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 44
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 44
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Asn
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Thr 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 Ile Asn Tyr Gly Gly Ile Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 45
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 45
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Gly Asn Lys
20 25 30
Leu Ile Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Val Thr Asn Leu Pro Gly Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Lys Gln Asn Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 46
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 46
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Gly Asn Lys
20 25 30
Leu Ile Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
His Tyr Val Thr Asn Leu Pro Gly Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Ser Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Lys Gln Asn Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 47
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 47
Thr Tyr Asp Ile Gly Met Gly
1 5
<210> 48
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 48
His Ile Trp Trp Asn Asp Arg Glu Tyr Tyr Asn Ser Ala Leu Gln Ser
1 5 10 15
<210> 49
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 49
Ile Asp Tyr Phe Gly Ser Gly Gln Ala Trp Phe Thr Tyr
1 5 10
<210> 50
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 50
Ser Ser Ser Ser Thr Ile Ser Ser Thr Tyr Leu His
1 5 10
<210> 51
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 51
Gly Thr Ser Asn Leu Ala Ser
1 5
<210> 52
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 52
Gln Gln Gly Ser Arg Ile Pro Phe Thr
1 5
<210> 53
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 53
His Ile Trp Trp Asn Asp Arg Glu Tyr Tyr Ser Ser Ala Leu Gln Ser
1 5 10 15
<210> 54
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 54
His Ile Trp Trp Asn Asp Arg Glu Tyr Tyr Asn Pro Ala Leu Gln Ser
1 5 10 15
<210> 55
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 55
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Asn Thr Tyr
20 25 30
Asp Ile Gly Met Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile Trp Trp Asn Asp Arg Glu Tyr Tyr Asn Ser Ala
50 55 60
Leu Gln Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ile Asp Tyr Phe Gly Ser Gly Gln Ala Trp Phe Thr Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 56
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 56
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Asn Thr Tyr
20 25 30
Asp Ile Gly Met Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile Trp Trp Asn Asp Arg Glu Tyr Tyr Asn Ser Ala
50 55 60
Leu Gln Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Thr Gln Val
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Val Arg Ile Asp Tyr Phe Gly Ser Gly Gln Ala Trp Phe Thr Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 57
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 57
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Asn Thr Tyr
20 25 30
Asp Ile Gly Met Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Ala His Ile Trp Trp Asn Asp Arg Glu Tyr Tyr Asn Ser Ala
50 55 60
Leu Gln Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Thr Gln Val
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Val Arg Ile Asp Tyr Phe Gly Ser Gly Gln Ala Trp Phe Thr Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 58
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 58
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Asp Ile Gly Met Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Ala His Ile Trp Trp Asn Asp Arg Glu Tyr Tyr Asn Ser Ala
50 55 60
Leu Gln Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Thr Gln Val
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Val Arg Ile Asp Tyr Phe Gly Ser Gly Gln Ala Trp Phe Thr Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 59
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 59
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Asn Thr Tyr
20 25 30
Asp Ile Gly Met Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Ala His Ile Trp Trp Asn Asp Arg Glu Tyr Tyr Ser Ser Ala
50 55 60
Leu Gln Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Thr Gln Val
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Val Arg Ile Asp Tyr Phe Gly Ser Gly Gln Ala Trp Phe Thr Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 60
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 60
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Asn Thr Tyr
20 25 30
Asp Ile Gly Met Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Ala His Ile Trp Trp Asn Asp Arg Glu Tyr Tyr Asn Pro Ala
50 55 60
Leu Gln Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Thr Gln Val
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Val Arg Ile Asp Tyr Phe Gly Ser Gly Gln Ala Trp Phe Thr Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 61
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 61
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ser Ser Ser Thr Ile Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ser Arg Ile Pro
85 90 95
Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 62
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 62
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ser Ser Ser Thr Ile Ser Ser Thr
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Ser Gly Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Gly Ser Arg Ile Pro
85 90 95
Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 63
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 63
Asp Tyr Tyr Met His
1 5
<210> 64
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 64
Arg Ile Asp Pro Glu Asp Gly Glu Thr Lys Tyr Ala Pro Lys Phe Gln
1 5 10 15
Gly
<210> 65
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 65
Ser Trp Ala Tyr
1
<210> 66
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 66
Ser Ala Ser Ser Ser Val Ser Ser Ser Tyr Leu Tyr
1 5 10
<210> 67
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 67
Ser Thr Ser Asn Leu Ala Ser
1 5
<210> 68
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 68
His Gln Trp Ser Ser Tyr Pro Arg Thr
1 5
<210> 69
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 69
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Val Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Glu Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp 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 Thr Ser Trp Ala Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
100 105 110
Ser
<210> 70
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 70
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Glu Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asn 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
Ser Arg Ser Trp Ala Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
100 105 110
Ser
<210> 71
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 71
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 Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Glu Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Trp Ala Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
100 105 110
Ser
<210> 72
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 72
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 Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Glu Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Asn 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
Ser Arg Ser Trp Ala Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
100 105 110
Ser
<210> 73
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 73
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Trp Ser Ser Tyr Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 74
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 74
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Val Tyr Phe Cys His Gln Trp Ser Ser Tyr Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 75
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 75
Glu Ile Val Met Thr Gln Ser Pro Pro Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Trp Ser Ser Tyr Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 76
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 76
Glu Ile Val Met Thr Gln Ser Pro Pro Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Ala Ala Val Tyr Phe Cys His Gln Trp Ser Ser Tyr Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 77
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 77
Asp Thr Tyr Met His
1 5
<210> 78
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 78
Arg Ile Asp Pro Ala Asn Val Asn Thr Ile Tyr Asp Pro Lys Phe Gln
1 5 10 15
Gly
<210> 79
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 79
Val Gly Ala Tyr Asp Gly Tyr Asp Phe Asp Tyr
1 5 10
<210> 80
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 80
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Ser Phe Met His
1 5 10 15
<210> 81
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 81
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 82
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 82
Gln Gln Asn Asn Glu Asp Pro Leu Thr
1 5
<210> 83
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 83
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Val Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asn Val Asn Thr Ile Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp 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 Thr Val Gly Ala Tyr Asp Gly Tyr Asp Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 84
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 84
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asn Val Asn Thr Ile Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asn 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 Val Gly Ala Tyr Asp Gly Tyr Asp Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 85
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 85
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 Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asn Val Asn Thr Ile Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Gly Ala Tyr Asp Gly Tyr Asp Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 86
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 86
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 Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asn Val Asn Thr Ile Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Asn 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 Val Gly Ala Tyr Asp Gly Tyr Asp Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 87
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 87
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 Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 88
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 88
Asp Ile Val Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 89
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 89
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 90
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 90
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Asn Asn
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 91
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 91
Ser Tyr Val Met His
1 5
<210> 92
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 92
Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 93
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 93
Ser Tyr Tyr Asp Tyr Asp Gly Ser Phe Asp Tyr
1 5 10
<210> 94
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 94
Lys Ala Ser Gln Asp Val Thr Thr Ala Val Ala
1 5 10
<210> 95
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 95
Ser Ala Ser Tyr Arg Tyr Thr
1 5
<210> 96
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 96
Gln Gln His Tyr Ser Thr Pro Trp Thr
1 5
<210> 97
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 97
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 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 Ser Tyr Tyr Asp Tyr Asp Gly Ser Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 98
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 98
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ser Asp Lys 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 Ser Tyr Tyr Asp Tyr Asp Gly Ser Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 99
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 99
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Tyr Tyr Asp Tyr Asp Gly Ser Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 100
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 100
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 Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Ser Asp Lys Ser Thr 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 Ser Tyr Tyr Asp Tyr Asp Gly Ser Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 101
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 101
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Thr Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 102
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 102
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Thr Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 103
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 103
Asp Thr Tyr Ile His
1 5
<210> 104
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 104
Arg Ile Asp Pro Ala Asp Gly Asp Thr Lys His Asn Pro Lys Phe His
1 5 10 15
Asp
<210> 105
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 105
Gly Asn Tyr Val Asn
1 5
<210> 106
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 106
Arg Ala Ser Ser Ser Val Thr Ser Ser Tyr Leu Tyr
1 5 10
<210> 107
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 107
Ser Ala Ser Asn Leu Ala Ser
1 5
<210> 108
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 108
His Gln Trp Tyr Ser Tyr Pro Arg Thr
1 5
<210> 109
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 109
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Val Ser Gly Phe Asn Phe Glu Asp Thr
20 25 30
Tyr Ile His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asp Gly Asp Thr Lys His Asn Pro Lys Phe
50 55 60
His Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp 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 Thr Gly Asn Tyr Val Asn Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 110
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 110
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Phe Asn Phe Glu Asp Thr
20 25 30
Tyr Ile His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asp Gly Asp Thr Lys His Asn Pro Lys Phe
50 55 60
His Asp Arg Val Thr Ile Thr Val Asp Thr Ser Thr Asn 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
Val Arg Gly Asn Tyr Val Asn Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 111
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 111
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 Phe Asn Phe Glu Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asp Gly Asp Thr Lys His Asn Pro Lys Phe
50 55 60
His Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asn Tyr Val Asn Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 112
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 112
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 Phe Asn Phe Glu Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asp Gly Asp Thr Lys His Asn Pro Lys Phe
50 55 60
His Asp Arg Val Thr Met Thr Val Asp Thr Ser Thr Asn 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
Val Arg Gly Asn Tyr Val Asn Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 113
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 113
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Thr Ser Ser
20 25 30
Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Ser Ala Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Trp Tyr Ser Tyr Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 114
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 114
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Thr Ser Ser
20 25 30
Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Ser Ala Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Val Tyr Phe Cys His Gln Trp Tyr Ser Tyr Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 115
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 115
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Thr Ser Ser
20 25 30
Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Ser Ala Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Trp Tyr Ser Tyr Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 116
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 116
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Thr Ser Ser
20 25 30
Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Ser Ala Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Val Tyr Phe Cys His Gln Trp Tyr Ser Tyr Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 117
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 117
Glu Ile Val Met Thr Gln Ser Pro Pro Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Thr Ser Ser
20 25 30
Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Ser Ala Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Trp Tyr Ser Tyr Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 118
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 118
Glu Ile Val Met Thr Gln Ser Pro Pro Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Thr Ser Ser
20 25 30
Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Ser Ala Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Ala Ala Val Tyr Phe Cys His Gln Trp Tyr Ser Tyr Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
Claims (12)
1.一种与野生型人信号调节蛋白α(SIRPα)蛋白具有结合特异性的抗体或其抗原结合片段,其中所述抗体或其片段包含重链可变区(VH)和轻链可变区(VL),所述重链可变区包含重链互补决定区CDRH1、CDRH2和CDRH3,所述轻链可变区包含轻链互补决定区CDRL1、CDRL2和CDRL3,其中:
(a)根据Kabat系统定义,VH CDR1、VH CDR2和VH CDR3分别为SEQ ID NO:43的第31-35位氨基酸、第50-65位氨基酸和第95-102位氨基酸,并且VL CDR1、VL CDR2和VL CDR3分别为SEQ ID NO:45的第24-34位氨基酸、第50-56位氨基酸和第89-97位氨基酸;或者
(b)根据Chothia系统定义,VH CDR1、VH CDR2和VH CDR3分别为SEQ ID NO:43的第26-32位氨基酸、第52-58位氨基酸和第95-102位氨基酸,并且VL CDR1、VL CDR2和VL CDR3分别为SEQ ID NO:45的第26-32位氨基酸、第50-52位氨基酸和第91-96位氨基酸。
2.根据权利要求1所述的抗体或其抗原结合片段,其中,根据Kabat系统定义,VH CDR1、VH CDR2和VH CDR3分别为SEQ ID NO:43的第31-35位氨基酸、第50-65位氨基酸和第95-102位氨基酸,并且VL CDR1、VL CDR2和VL CDR3分别为SEQ ID NO:45的第24-34位氨基酸、第50-56位氨基酸和第89-97位氨基酸。
3.根据权利要求1所述的抗体或其抗原结合片段,其中,根据Chothia系统定义,VHCDR1、VH CDR2和VH CDR3分别为SEQ ID NO:43的第26-32位氨基酸、第52-58位氨基酸和第95-102位氨基酸,并且VL CDR1、VL CDR2和VL CDR3分别为SEQ ID NO:45的第26-32位氨基酸、第50-52位氨基酸和第91-96位氨基酸。
4.根据权利要求1所述的抗体或其抗原结合片段,其中所述重链可变区的氨基酸序列如SEQ ID NO:43所示,并且所述轻链可变区的氨基酸序列如SEQ ID NO:45所示。
5.根据权利要求1-4任一项所述的抗体或其抗原结合片段,其进一步具有与第二靶蛋白的结合特异性。
6.一种组合物,包括权利要求1-5任一项所述的抗体或其抗原结合片段,以及药学上可接受的载体。
7.根据权利要求6所述的组合物,进一步包括对肿瘤抗原具有特异性的第二抗体。
8.根据权利要求7所述的组合物,其中所述第二抗体是肿瘤调理抗体。
9.权利要求1-5任一项所述的抗体或其抗原结合片段在制备用于治疗癌症的药物中的应用。
10.根据权利要求9所述的应用,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。
11.根据权利要求9所述的应用,其中所述药物进一步包括靶向触发肿瘤调理的蛋白质的第二抗体。
12.根据权利要求11所述的应用,其中所述蛋白选自由CD19、CD20、EGFR、HER2、CD3、CD16、PD1、PD-L1、LAG3、TIM3、CTLA4、VISTA、CSFR1、A2AR、CD73、CD39、CD40、CEA、VEGFR、TIGIT、紧密连接蛋白18.2、CD24、GPC3、Il13RA2、4-1BB、CCR8和CMET组成的组。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101880324A (zh) * | 2010-05-25 | 2010-11-10 | 中国人民解放军第二军医大学 | 一种抗人SIRPα的单克隆抗体及其细胞株、制备方法和应用 |
WO2015138600A2 (en) * | 2014-03-11 | 2015-09-17 | The Board Of Trustees Of The Leland Stanford Junior University | Anti sirp-alpha antibodies and bi-specific macrophage enhancing antibodies |
WO2018190719A2 (en) * | 2017-04-13 | 2018-10-18 | Aduro Biotech Holdings, Europe B.V. | Anti-sirp alpha antibodies |
WO2019023347A1 (en) * | 2017-07-26 | 2019-01-31 | Forty Seven, Inc. | ANTI-SIRP-ALPHA ANTIBODIES AND ASSOCIATED METHODS |
CN110325549A (zh) * | 2016-12-09 | 2019-10-11 | 艾利妥 | 抗SIRPα抗体及其使用方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10611842B2 (en) * | 2016-08-03 | 2020-04-07 | The Board Of Trustees Of The Leland Stanford Junior University | Disrupting FC receptor engagement on macrophages enhances efficacy of anti-SIRPα antibody therapy |
WO2018210793A2 (en) * | 2017-05-16 | 2018-11-22 | Synthon Biopharmaceuticals B.V. | ANTI-SIRPα ANTIBODIES |
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101880324A (zh) * | 2010-05-25 | 2010-11-10 | 中国人民解放军第二军医大学 | 一种抗人SIRPα的单克隆抗体及其细胞株、制备方法和应用 |
WO2015138600A2 (en) * | 2014-03-11 | 2015-09-17 | The Board Of Trustees Of The Leland Stanford Junior University | Anti sirp-alpha antibodies and bi-specific macrophage enhancing antibodies |
CN106456749A (zh) * | 2014-03-11 | 2017-02-22 | 小利兰·斯坦福大学托管委员会 | 抗SIRPα抗体和双特异性巨噬细胞增强型抗体 |
CN110325549A (zh) * | 2016-12-09 | 2019-10-11 | 艾利妥 | 抗SIRPα抗体及其使用方法 |
WO2018190719A2 (en) * | 2017-04-13 | 2018-10-18 | Aduro Biotech Holdings, Europe B.V. | Anti-sirp alpha antibodies |
WO2019023347A1 (en) * | 2017-07-26 | 2019-01-31 | Forty Seven, Inc. | ANTI-SIRP-ALPHA ANTIBODIES AND ASSOCIATED METHODS |
Non-Patent Citations (4)
Title |
---|
A Phase 1 study Evaluating BI 765063, a first in class selective myeloid sirpa inhibitor,as stand-alone and in combination with BI754091,a programmed death-1(PD-1) inhibitor,in patients with advanced solid tumours.;Jean-Pierre Delord等;《blood》;20191113;第134卷;全文 * |
Discovery of high affinity,pan-allelic,and pan-mammalian reactive antibodies against the myeloid checkpoint receptor SIRPα.;Janet Sim等;《MABS》;20190731;第11卷(第6期);全文 * |
SIRPα及其配体CD47在巨噬细胞吞噬过程中的作用;黄丽芳等;《南昌大学学报(医学版)》;20161028(第05期);全文 * |
天然免疫检查点CD47-SIRPα在恶性肿瘤中的研究进展;查莉等;《肿瘤防治研究》;20180825(第08期);全文 * |
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