CN114195893A - 抗整联蛋白抗体或抗原结合片段及其应用 - Google Patents
抗整联蛋白抗体或抗原结合片段及其应用 Download PDFInfo
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Abstract
本发明提供了一种抗整联蛋白抗体或抗原结合片段,所述抗体或抗原结合片段特异性结合αvβ8,还提供上述抗体或抗原结合片段在制备用于治疗或改善αvβ8相关疾病的药物中的应用,或在制备用于诊断αvβ8相关疾病的试剂盒中的应用。
Description
技术领域
本发明属于生物技术领域,尤其涉及抗αvβ8抗体或抗原结合片段及其应用。
背景技术
多功能细胞因子转化生长因子β(TGFβ)超家族蛋白广泛参与多种生物生理过程,对内皮细胞、***、上皮细胞以及免疫细胞等有着重要的生物学功能。TGFβ一般会和前肽(LAP)非共价结合,保持无活性的状态。该前肽被称为是TGFβ的潜伏相关结构域(latencyassociated domain,LAP)。TGFβ要想发挥作用,必须先经过一个活化的过程,从无活性的复合物中释放出来。该复合物一般包含:有活性的TGFβ二聚体,LAP以及LTBP(潜伏TGFβ结合蛋白,如GARP)。
TGFβ有3种不同的异构体,分别是TGFβ1、2和3。对于免疫***,TGFβ能调控调节性T细胞的功能以及免疫前体细胞的动态平衡。关于ECM重塑,TGFβ的信号可以促进成纤维细胞群体和ECM聚沉。在肿瘤微环境中,由于生理失调,TGFβ信号会促进肿瘤血管的生成,改变基质环境,以及抑制免疫***的活性。此外,TGFβ信号的增强,还会导致心血管狭窄和肾小球硬化等疾病。
整联蛋白(integrin)属于细胞表面受体,一般包含两个非共价结合的α亚基和β亚基,主要参与细胞与细胞间以及细胞与胞外基质(ECM)间的粘附和信号传导,在器官的发育和组织损伤中,为细胞的生长、迁移以及分化,提供粘附等作用。整连蛋白的结合特异性一般有α亚基和β亚基决定,目前已确认出18种α亚基以及8种β亚基,共24种不同的α亚基和β亚基组合(F.G.Giancotti,et.al.,Science,285,1028-1032,1999)。
αvβ8是整联蛋白超家族中的一员。αvβ8能够通过和L-TGFβ结合,使得TGFβ从其前体(Latent TGF-beta,L-TGFβ)被释放出来,从而导致TGFβ1和TGFβ3的成熟活化(Mu等(2002)J.Cell Biol.159:493)。αvβ8分布于上皮细胞、神经元组织以及间叶细胞等。而且Treg细胞能通过表达αvβ8,来激活TGFβ,从而抑制免疫活性。
综上所述,有必要提供一种抗体,通过与αvβ8结合后,阻断αvβ8与L-TGFβ结合,进而局部抑制TGFβ信号传导,其可以用于有效地和安全地治疗涉及TGFβ的疾病和障碍,包括,例如,癌症、纤维化和炎症。
发明内容
本发明提供了能特异性结合αvβ8的抗体或抗原结合片段。在一些实施方案中,本发明提供的抗体或抗原结合片段为分离的抗体或抗原结合片段。在一些实施方案中,本发明提供了能特异性结合人αvβ8或猴αvβ8的抗体或抗原结合片段。本发明的抗αvβ8抗体与αvβ8特异性结合后,能够阻断αvβ8和L-TGFβ的结合,从而局部抑制TGFβ的信号,在减少副作用的同时,治疗TGFβ信号相关的疾病。
在一些实施方案中,本发明提供的抗体或抗原结合片段包含:
(a)VH CDR1,其包含SEQ ID NO:5所示的氨基酸序列,
(b)VH CDR2,其包含SEQ ID NO:6所示的氨基酸序列,
(c)VH CDR3,其包含SEQ ID NO:7所示的氨基酸序列,
(d)VH CDR1,其包含SEQ ID NO:44所示的氨基酸序列,
(e)VH CDR2,其包含SEQ ID NO:45所示的氨基酸序列,和/或
(f)VH CDR3,其包含SEQ ID NO:46所示的氨基酸序列。
在一些实施方案中,所述VH CDR3为10-20个氨基酸组成,且其中包含片段RGDL。
在一些实施方案中,所述VH CDR3包含SEQ ID NO:8-25所示的任一氨基酸序列。
在一些实施方案中,所述VH CDR3包含SEQ ID NO:12或14所示的氨基酸序列。
在一些实施方案中,所述抗体或抗原结合片段特异性结合αvβ8,所述抗体或抗原结合片段包含:
(a)VH CDR1,其包含SEQ ID NO:5所示的氨基酸序列,
(b)VH CDR2,其包含SEQ ID NO:6所示的氨基酸序列,
(c)VH CDR3,其包含SEQ ID NO:8-25所示的任一氨基酸序列,
(d)VH CDR1,其包含SEQ ID NO:44所示的氨基酸序列,
(e)VH CDR2,其包含SEQ ID NO:45所示的氨基酸序列,以及
(f)VH CDR3,其包含SEQ ID NO:46所示的氨基酸序列。
在一些实施方案中,所述抗体或抗原结合片段包含如SEQ ID NO:5所示的VHCDR1,如SEQ ID NO:6所示的VH CDR1,如SEQ ID NO:12或14所示的VH CDR3,如SEQ ID NO:44所示的VL CDR1,如SEQ ID NO:45所示的VL CDR2,以及如SEQ ID NO:46所示的VL CDR3。
在一些实施方案中,所述抗体或抗原结合片段的重链可变区包含SEQ ID NO:26-43所示的任一氨基酸序列,或与SEQ ID NO:26-43所示的任一氨基酸序列至少有90%序列同源性的氨基酸序列,或与SEQ ID NO:26-43所示的任一氨基酸序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中,所述抗体或抗原结合片段的重链可变区包含SEQ ID NO:30或32所示的氨基酸序列,或与SEQ ID NO:30或32所示的氨基酸序列至少有90%序列同源性的氨基酸序列,或与SEQ ID NO:30或32所示的氨基酸序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中,所述抗体或抗原结合片段的轻链可变区包含SEQ ID NO:4所示的氨基酸序列,或与SEQ ID NO:4所示的氨基酸序列至少有90%序列同源性的氨基酸序列,或与SEQ ID NO:4所示的氨基酸序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中,所述抗体或抗原结合片段的重链可变区包含SEQ ID NO:30所示的氨基酸序列,轻链可变区包含SEQ ID NO:4所示的氨基酸序列。
在一些实施方案中,所述抗体或抗原结合片段的重链可变区包含SEQ ID NO:32所示的氨基酸序列,轻链可变区包含SEQ ID NO:4所示的氨基酸序列。
在一些实施方案中,抗体或抗原结合片段还包含重链恒定区、轻链恒定区、Fc区或其组合。在一些实施方案中,轻链恒定区是κ或λ链恒定区。在一些实施方案中,抗体或其片段是IgG、IgM、IgA、IgE或IgD其中一种同种型。在一些实施方案中,同种型是IgG1、IgG2、IgG3或IgG4。在一些实施方案中,同种型是IgG1。在一些实施方案中,抗体或抗原结合片段是鼠源抗体、嵌合抗体或人源化抗体。
在一些实施方案中,Fc是变体Fc区。在一些实施方案中,相对于亲本Fc区,变体Fc区具有一个或多个氨基酸修饰,如取代、缺失或***。在一些实施方案中,相对于亲本Fc区活性,Fc区的氨基酸修饰改变了效应功能活性。在一些实施方案中,变体Fc区可以具有改变的(即,增加的或降低的)抗体依赖性细胞毒性(ADCC)、补体介导的细胞毒性(CDC)、吞噬作用、调理作用或细胞结合。在一些实施方案中,相对于亲本Fc区,Fc区氨基酸修饰可以改变变体Fc区对FcγR(Fcγ受体)的亲和力。在一些实施方案中,所述Fc区来源于IgG1。
在一些实施方案中,所述抗体或抗原结合片段为分离的抗体或抗原结合片段。在一些实施方案中,所述抗体或抗原结合片段为scFV、Fab、F(ab)2或IgG1。在一些实施方案中,所述抗体或抗原结合片段为单克隆抗体。
在一些实施方案中,所述抗体或抗原结合片段的重链恒定区包含SEQ ID NO:47所示的氨基酸序列,或与SEQ ID NO:47所示的氨基酸序列至少有90%序列同源性的氨基酸序列,或与SEQ ID NO:47中任一项所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列;和/或所述抗体或抗原结合片段的轻链恒定区包含SEQ ID NO:48所示的氨基酸序列,或与SEQ ID NO:48所示的氨基酸序列至少有90%序列同源性的氨基酸序列,或与SEQ ID NO:48所示的氨基酸序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中,所述抗体或抗原结合片段的重链包含SEQ ID NO:49或50所示的氨基酸序列,或与SEQ ID NO:49或50所示的氨基酸序列至少有90%序列同源性的氨基酸序列,或与SEQ ID NO:49或50所示的氨基酸序列相比具有一个或多个保守氨基酸取代的氨基酸序列;和/或所述抗体或抗原结合片段的轻链包含SEQ ID NO:51所示的氨基酸序列,或与SEQ ID NO:51所示的氨基酸序列至少有90%序列同源性的氨基酸序列,或与SEQ ID NO:51所示的氨基酸序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中,所述抗体或抗原结合片段特异性结合αvβ3。在一些实施方案中,所述抗体或抗原结合片段特异性结合αvβ8和αvβ3。在一些实施方案中,所述抗体或抗原结合片段特异性结合αvβ8、αvβ6和αvβ3。
在一些实施方案中,所述抗体或抗原结合片段与αvβ8的亲和力数值KD≤100nM。在一些实施方案中,所述抗体或抗原结合片段与αvβ8的亲和力数值KD≤30nM。在一些实施方案中,所述抗体或抗原结合片段与αvβ3的亲和力数值KD≤100nM。在一些实施方案中,所述抗体或抗原结合片段与αvβ3的亲和力数值KD≤30nM。在一些实施方案中,所述抗体或抗原结合片段与αvβ8的亲和力数值KD≤100nM,与αvβ3的亲和力数值KD≤100nM。在一些实施方案中,所述抗体或抗原结合片段与αvβ8的亲和力数值KD≤30nM,与αvβ3的亲和力数值KD≤30nM。在一些实施方案中,所述抗体或抗原结合片段与αvβ8的亲和力数值KD≤26.3nM,与αvβ3的亲和力数值KD≤22nM。在一些实施方案中,所述抗体或抗原结合片段与αvβ8的亲和力数值KD≤14.6nM,与αvβ3的亲和力数值KD≤5.18nM。在一些实施方案中,所述抗体或抗原结合片段与αvβ8的亲和力数值KD≤14.6nM,与αvβ6的亲和力数值KD≤31.9nM,与αvβ3的亲和力数值KD≤5.18nM。
在一些实施方案中,所述抗体或抗原结合片段为分离的抗体或抗原结合片段。
另一方面,本发明还提供一种编码上述抗体或抗原结合片段的核酸分子。在一些实施方案中,所述核酸分子为分离的核酸分子。
另一方面,本发明还提供一种包含上述核酸分子的载体或宿主细胞。在一些实施方案中,所述宿主细胞为分离的宿主细胞。在一些实施方案中,所述宿主细胞为CHO细胞、HEK细胞(如HEK293F细胞)、BHK细胞、Cos1细胞、Cos7细胞、CV1细胞或鼠L细胞。
另一方面,本发明提供了一种组合物,所述组合物包含上述的抗体或抗原结合片段,以及药学上可接受的载体。
另一方面,本发明提供了制备本文所述的抗体或抗原结合片段的方法,包含在培养基中培养上述宿主细胞以产生抗体或抗原结合片段。
另一方面,本发明提供了上述的抗体或抗原结合片段或上述的组合物在制备用于治疗或改善TGFβ相关疾病的药物中的应用,或在制备用于诊断TGFβ相关疾病的试剂盒中的应用。
在一些实施方案中,所述TGFβ相关疾病包括癌症或自身免疫性疾病。
另一方面,本发明还提供一种在有需要的患者中治疗或改善TGFβ相关疾病的方法,所述方法包括向所述患者施用有效剂量的上述抗体或抗原结合片段。
在一些实施方案中,所述方法还包括向所述患者施用一种或多种治疗剂。
本发明提供的抗体或其抗原结合片段,能够特异性的识别并结合αvβ8,阻断αvβ8与L-TGFβ结合,从而局部抑制TGFβ的信号,在减少副作用的同时,治疗TGFβ信号相关的疾病。
附图说明
图1为酵母抗体克隆与αvβ8抗原结合情况。
图2为抗αvβ8的抗体和CHO细胞表面的αvβ8抗原的结合情况。
图3为抗αvβ8抗体阻断αvβ8与其配体L-TGFβ的结合实验。
图4为抗αvβ8抗体的细胞生物活性检测结果。
具体实施方式
定义
除非另作说明,否则下列的每一个术语应当具有下文所述的含义。
在本领域中使用和/或接受的术语有两个或多个定义的情况下,除非明确地对立指出,否则本文使用的术语的定义包括所有这些含义。
“约”指相关技术领域技术人员容易知道的相应数值的常规误差范围。在一些实施方式中,本文中提到“约”指所描述的数值以及其±10%、±5%或±1%的范围。
应当注意的是,术语“一种”实体是指一种或多种该实体,例如“一种抗体”应当被理解为一种或多种抗体,因此,术语“一种”(或“一个”)、“一种或多种”和“至少一种”可以在本文中互换使用。
术语“多肽”旨在涵盖单数的“多肽”以及复数的“多肽”,并且是指由通过酰胺键(也称为肽键)线性连接的单体(氨基酸)组成的分子。术语“多肽”是指两个或更多个氨基酸的任何单条链或多条链,并且不涉及产物的特定长度。因此,“多肽”的定义中包括肽、二肽、三肽、寡肽、“蛋白质”、“氨基酸链”或用于指两个或多个氨基酸链的任何其他术语,并且术语“多肽”可以用来代替上述任何一个术语,或者与上述任何一个术语交替使用。术语“多肽”也意在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、蛋白水解切割或非天然发生的氨基酸修饰。多肽可以源自天然生物来源或通过重组技术产生,但其不必从指定的核酸序列翻译所得。它可以包括化学合成等任何方式产生。
“氨基酸”是指含有氨基和羧基两种官能团化合物,比如α-氨基酸。两个或多个氨基酸可以通过酰胺键(也称为肽键)组成多肽。单个氨基酸由三个核苷酸(所谓的密码子或碱基三联体)组成的核酸编码。每一个氨基酸由至少一个密码子编码。相同氨基酸由不同密码子编码称为“遗传密码的简并性”。氨基酸包括天然氨基酸和非天然氨基酸。天然氨基酸包括丙氨酸(三字母代码:Ala,一字母代码:A)、精氨酸(Arg,R)、天冬酰胺(Asn,N)、天冬氨酸(Asp,D)、半胱氨酸(Cys,C)、谷氨酰胺(Gln,Q)、谷氨酸(Glu,E)、甘氨酸(Gly,G)、组氨酸(His,H)、异亮氨酸(Ile,I)、亮氨酸(Leu,L)、赖氨酸(Lys,K)、甲硫氨酸(Met,M)、苯丙氨酸(Phe,F)、脯氨酸(Pro,P)、丝氨酸(Ser,S)、苏氨酸(Thr,T)、色氨酸(Trp,W)、酪氨酸(Tyr,Y)和缬氨酸(Val,V)。
“保守氨基酸取代”是指一个氨基酸残基被另一个含有化学性质(例如电荷或疏水性)相似的侧链(R基团)的氨基酸残基所取代。一般而言,保守氨基酸取代不大会在实质上改变蛋白质的功能性质。含有化学性质相似侧链的氨基酸类别的实例包括:1)脂族侧链:甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸;2)脂族羟基侧链:丝氨酸和苏氨酸;3)含酰胺的侧链:天冬酰胺和谷氨酰胺;4)芳族侧链:苯丙氨酸、酪氨酸和色氨酸;5)碱性侧链:赖氨酸、精氨酸和组氨酸;6)酸性侧链:天冬氨酸和谷氨酸。本发明中“轻链可变区、重链可变区、轻链和重链的保守氨基酸取代”的氨基酸数目为约1个、约2个、约3个、约4个、约7个、约9个、约11个、约20个、约22个、约24个、约28个、约31个、约33个、约36个、约39个、约43个、约45个保守氨基酸取代,或这些数值中的任何两个之间的范围(包括终点)或其中任何值。
本发明中关于细胞、核酸、多肽、抗体等所使用的术语“分离的”,例如“分离的”DNA、RNA、多肽、抗体是指分别于细胞天然环境中的其它组分如DNA或RNA中的一种或多种所分离的分子。本发明使用的术语“分离的”还指当通过重组DNA技术产生时基本上不含细胞材料、病毒材料或细胞培养基的核酸或肽,或化学合成时的化学前体或其他化学品。此外,“分离的核酸”意在包括不以天然状态存在的核酸片段,并且不会以天然状态存在。术语“分离的”在本发明中也用于指从其他细胞蛋白质或组织分离的细胞或多肽。分离的多肽意在包括纯化的和重组的多肽。分离的多肽、抗体等通常通过至少一个纯化步骤制备。在一些实施方案中,分离的核酸、多肽、抗体等的纯度至少为约50%、约60%、约70%、约80%、约90%、约95%、约99%,或这些数值中的任何两个值之间的范围(包括终点)或其中任何值。
在本发明中,术语“重组”涉及多肽或多聚核苷酸,意指天然不存在的多肽或多聚核苷酸的形式,可以通过组合产生通常并不存在的多聚核苷酸或多肽。
“同源性”或“同一性”或“相似性”是指两个多肽之间或两个核酸分子之间的序列相似性。通过比较每个序列中可以比对的位置来确定同源性。当被比较的序列中的位置被相同的碱基或氨基酸占据时,则分子在该位置是同源的。序列之间的同源程度是由序列共有的匹配或同源位置的数目组成的一个函数。
多聚核苷酸或多聚核苷酸区域(或多肽或抗体序列)与另一序列有具有一定百分比(例如90%、95%、98%或者99%)的“序列同一性”或“序列同源性”是指当序列比对时,所比较的两个序列中该百分比的碱基(或氨基酸)相同。可以使用本领域已知的软件程序来确定该比对和同源性百分比或序列同一性,比如Ausubel et al.eds.(2007)在CurrentProtocols in Molecular Biology中所述的软件程序。在一些实施方案中,使用默认参数进行比对。其中一种比对程序是使用默认参数的BLAST。生物学上等同的多聚核苷酸是具有上述指定百分比的同源性并编码具有相同或相似生物学活性的多肽的多聚核苷酸。
多聚核苷酸是由四个核苷酸碱基的特定序列组成:腺嘌呤(A)、胞嘧啶(C)、鸟嘌呤(G)、胸腺嘧啶(T),或当多聚核苷酸是RNA时胸腺嘧啶换为尿嘧啶(U)。“多聚核苷酸序列”可以以多聚核苷酸分子的字母表示。该字母表示可以被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,例如用于功能基因组学和同源性搜索。
术语“多聚核苷酸”和“寡核苷酸”可互换使用,是指任何长度的核苷酸的聚合形式,无论是脱氧核糖核苷酸还是核糖核苷酸或其类似物。多聚核苷酸可以具有任何三维结构并且可以执行已知或未知的任何功能。比如: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、核糖酶、cDNA、dsRNA、siRNA、miRNA、重组多聚核苷酸、分支的多聚核苷酸、质粒、载体、任何序列的分离的DNA和、任何序列的分离的RNA。多聚核苷酸可以包含修饰的核苷酸,例如甲基化的核苷酸和核苷酸类似物。对核苷酸的结构修饰可以在组装多聚核苷酸之前或之后进行。核苷酸的序列可以被非核苷酸组分中断。聚合后可以进一步修饰多聚核苷酸。这个术语也指双链和单链分子。除另有说明或要求外,本公开的任何多聚核苷酸包括双链形式和已知或预测构成双链形式的两种可互补单链形式中的每一种。
术语“编码”应用于多核苷酸时,是指被称为“编码”多肽的多核苷酸,在其天然状态或当通过本领域技术人员公知的方法操作时,经转录和/或翻译可以产生该多肽和/或其片段。
在本发明中,“抗体”或“抗原结合片段”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或其任何抗原结合片段或其单链。因此术语“抗体”包括分子中含有与抗原结合的具有生物学活性的免疫球蛋白分子的部分或整体的蛋白质或肽。包括但不限于重链或轻链或其配体结合部分的互补决定区(CDR)、重链可变区(VH)、轻链可变区(VL)、重链恒定区(CH)、轻链恒定区(CL)、框架区(FR)或其任何部分。CDR区包括轻链的CDR区(VL CDR1-3)和重链的CDR区(VH CDR1-3)。
“单克隆抗体”(mAb)是由相同的免疫细胞制备的抗体,所述免疫细胞是单一亲本细胞的所有克隆。单克隆抗体可以具有单价亲和力,因为它们结合相同的表位(抗体识别的抗原部分)。相反,多克隆抗体与多个表位结合,并且通常由几种不同的浆细胞分泌。单克隆抗体可以通过杂交瘤、重组、转基因或本领域技术人员已知的其他技术制备。
抗体重链的类别包括γ、μ、α、δ、ε,其中还有一些亚类(例如γ1-γ4)。该链的性质决定了抗体的“种类”分别为IgG、IgM、IgA、IgG或IgE。其中一些可进一步分成免疫球蛋白亚类(同种型),例如IgG1、IgG2、IgG3、IgG4等。轻链的类别包括κ、λ。每个重链可以与κ或λ轻链结合。一般来说,当由杂交瘤、B细胞或基因工程宿主细胞生产免疫球蛋白时,其轻链和重链通过共价键结合,两条重链的“尾巴”部分通过共价二硫键或非共价键结合。在重链中,氨基酸序列从Y构型的叉状末端的N末端延伸至每条链底部的C末端。免疫球蛋白κ轻链可变区为Vκ;免疫球蛋白λ轻链可变区为Vλ。本发明通常用的VL为Vκ。虽然某些讨论针对免疫球蛋白分子的IgG种类,所有的免疫球蛋白种类都在本发明公开的保护范围内。关于IgG,标准的免疫球蛋白分子包含分子量约23,000道尔顿的两条相同的轻链多肽和分子量约为53,000-70,000的两条相同的重链多肽。轻链和重链都可分成结构和功能同源性的区域。
术语“恒定的”和“可变的”根据功能被使用。就这点而言,应理解,VL和VH决定了抗原识别和特异性。VL和VH上的抗原结合位点能够识别抗原决定簇并且与抗原特异性的结合。抗原结合位点由VH和VL中各自的三个CDR定义(即VH CDR1、VH CDR2、VH CDR3、VL CDR1、VL CDR2和VL CDR3)。CL和CH(CH1、CH2或CH3)赋予重要的生物学性质,如分泌、经胎盘移动、Fc受体结合、补体结合等。按照惯例,恒定区的编号随着它们变得更远离抗体的抗原结合位点或氨基末端而增加。N端部分是可变区,C端部分是恒定区;CH3和CL结构域实际上分别包含重链和轻链的羧基端。
在本发明中,抗体的重链恒定区可以来源于不同的免疫球蛋白分子。例如,抗体的重链恒定区可以包括源自IgG1分子的CH1结构域和源自IgG3分子的铰链区。在一些实施方案中,重链恒定区可以包括部分源自IgG1分子和部分源自IgG3分子的铰链区。在一些实施方案中,部分重链可以包括部分源自IgG1分子和部分源自IgG4分子的嵌合铰链区。
在本发明中,术语“铰链区”包括连接CH1结构域和CH2结构域的部分重链结构。所述铰链区包含约25个残基并且是有韧性的,从而使得两个N端抗原结合区能够独立移动。
在本发明中,术语“二硫键”包括两个硫原子之间形成的共价键。半胱氨酸包含可以与第二个硫醇基团形成二硫键或桥接的硫醇基团。在大多数天然存在的IgG分子中,CH1和CL区通过二硫键连接,两条重链通过两个二硫键相连接。
在本发明中,术语“片段”、“抗体片段”或“抗原结合片段”是抗体的一部分,例如F(ab')2、F(ab)2、Fab'、Fab、Fv、scFv等。不管其结构如何,抗体片段与被完整抗体识别的同一抗原结合。术语“抗原结合片段”包括适体、镜像异构体和双价抗体,还包括通过与特定抗原结合形成复合物起抗体作用的任何合成或基因工程蛋白质。
“单链可变片段”或“scFv”是指免疫球蛋白的VH和VL的融合蛋白。在一些方面,这些区域与约10个至约25个氨基酸的短接头肽连接。接头可以富含甘氨酸以增加柔韧性,以及富含丝氨酸或苏氨酸以增加溶解性,并且可以连接VH的N端和VL的C端,反之亦然。尽管该蛋白质被除去了恒定区和引入了接头,但其保留了原始免疫球蛋白的特异性。
本发明公开的抗体、抗原结合片段、变体或衍生物包括但不限于多克隆、单克隆、多特异性,全人源、人源化、灵长类化,或嵌合抗体、单链抗体、表位结合片段。
本文所用术语“表位”包括任意能够特异性结合免疫球蛋白或其片段或T细胞受体的蛋白决定区。表位决定区通常由分子的化学活性表面基团(如氨基酸或糖侧链)组成且通常有特定的三维结构性质以及特定的电荷性质。当解离常数小于等于1μM(例如小于等于100nM、小于等于10nM或小于等于1nM)时,即可称抗体特异性结合抗原。
根据Kabat和Chothia定义的CDR包括相互比较时的氨基酸残基的重叠或子集。尽管如此,应用任一定义来指代抗体或其变体的CDR都在本发明范围内。包含特定CDR的确切残基编号将根据CDR的序列和大小而变化。本领域技术人员通常可以根据抗体的可变区氨基酸序列确定出CDR包含哪些特定的残基。
Kabat等人还定义了适用于任何抗体的可变区序列的编号***。本领域普通技术人员可以不依赖于序列本身以外的其他实验数据将该“Kabat编号”***应用到任何可变区序列。“Kabat编号”是指由Kabat et al.,U.S.Dept.of Health and Human Services在“Sequence of Proteins of Immunological Interest”(1983)提出的编号***。抗体还可以用EU编号***。
本发明公开的抗体可以来源于任何动物,包括鸟类和哺乳动物。较佳地,抗体是人源、鼠源、驴源、兔源、山羊源、豚鼠源、骆驼源、美洲驼源、马源或鸡源抗体。在一些实施方案中,可变区可以是软骨鱼纲来源(例如来自鲨鱼)。
在本发明中,术语“嵌合抗体”被认为是指抗体的可变区从第一个物种中获得或衍生,而其恒定区(在本发明中可以是完整的、部分的或修饰过的)来源于第二个物种的任何抗体。在一些实施方案中,可变区来自非人源(例如小鼠或灵长类动物),而恒定区是人源。
“特异性结合”通常是指抗体或抗原结合片段与特定抗原通过其抗原结合结构域与表位互补性结合形成相对稳定的复合物。“特异性”可以用抗体或抗原结合片段与特定抗原或表位结合的相对亲和力表达。例如,如果抗体“A”比抗体“B”与同一抗原的相对亲和力大,可以认为抗体“A”比抗体“B”对该抗原具有更高的特异性。特异性结合可以用平衡解离常数(KD)来描述,较小的KD意味着较紧密的结合。确定两个分子是否特异性结合的方法是本领域内众所周知的,并包括例如平衡透析、表面等离子共振、生物膜层光学干涉测量法等。“特异性结合”αvβ8蛋白的抗体包括与αvβ8蛋白平衡解离常数KD小于或等于约30nM、小于或等于约26nM、小于或等于约15nM的抗体。
“治疗”是指治疗性治疗和预防性或防治性措施,其目的是预防、减缓、改善或停止不良的生理改变或紊乱,例如疾病的进程,包括但不限于以下无论是可检测还是不可检测的结果,症状的缓解、疾病程度的减小、疾病状态的稳定(即不恶化)、疾病进展的延迟或减缓、疾病状态的改善、缓和、减轻或消失(无论是部分还是全部)、延长与不接受治疗时预期的生存期限等。需要治疗的患者包括已经患有病症或紊乱的患者,容易患有病症或紊乱的患者,或者需要预防该病症或紊乱的患者,可以或预期从施用本发明公开的抗体或药物组合物用于检测、诊断过程和/或治疗中受益的患者。
“患者”指需要诊断、预后或治疗的任何哺乳动物,包括人类、狗、猫、兔子、鼠、马、牛等。
在本发明中,诸如“需要治疗的患者”包括从施用本发明公开的抗体或组合物中用于检测、诊断过程、预防和/或治疗中受益的患者,例如哺乳动物患者。
术语“细胞因子”是由一种细胞群释放的,作为细胞间介质作用于另一细胞的蛋白质的通称。此类细胞因子的例子有淋巴因子、单核因子、白介素(IL)(诸如IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-11、IL-12、IL-15)、肿瘤坏死因子(诸如TNF-α或TNF-β)及其它多肽因子(包括LIF和kit配体(KL)和γ-干扰素)。如本文中使用的,术语细胞因子包括来自天然来源或来自重组细胞培养物的蛋白质及天然序列细胞因子的生物学活性等效物。生物学活性等效物包括通过人工合成产生的小分子实体,及其药剂学可接受的衍生物和盐。
如本文所用,术语“标记”或“经标记的”是指掺入可检测标记,例如,通过掺入放射性标记的氨基酸,或者附着于可标记的亲和素(例如,含有荧光标记或可由光学方法或量热法检测的具有酶活性的链霉亲和素)检测的生物素基部分的多肽。在某些情况下,标记物或标记也可为治疗性的。标记多肽和糖蛋白的各种方法是本领域已知的并且可以使用。用于多肽的标记物的示例包括但不限于以下项:放射性同位素或放射性核素(例如3H、14C、15N、35S、90Y、99Tc、111In、125I、131I)、荧光标记物(例如FITC、罗丹明、镧系磷光体)、酶标记物(例如辣根过氧化酶、β-半乳糖苷酶、荧光素酶、碱性磷酸酶)、化学发光标记、生物素酰基、被二级报告基因识别的预定多肽表位(例如亮氨酸拉链对序列、二级抗体结合位点、金属结合结构域、表位标签)。
抗αvβ8抗体
本发明的抗体具有结合αvβ8的能力。在一些实施方案中,本发明的抗体具有结合人αvβ8或猕猴αvβ8的能力。
在一些实施方案中,本发明的抗体αvβ8抗体或其抗原结合片段包含重链可变区(VH),其中所述的VH包含互补决定区VH CDR1、VH CDR 2和VH CDR3。其中VH CDR1包含与SEQID NO:5所示的氨基酸序列具有至少50%、60%、70%、80%或90%同一性或者100%同一性的氨基酸序列,VH CDR2包含与SEQ ID NO:6所示的氨基酸序列具有至少50%、60%、70%、80%或90%同一性或者100%同一性的氨基酸序列,且VH CDR3包含与SEQ ID NO:7所示的氨基酸序列具有至少50%、60%、70%、80%或90%同一性或者100%同一性的氨基酸序列。
在一些实施方案中,VH CDR3含有10-20个氨基酸,其中包含序列RGDL(SEQ ID NO:7)。在一些实施方案中,VH CDR3含有16-18个氨基酸,其中包含序列RGDL。在一些实施方案中,VH CDR3包含SEQ ID NO:8-25所示的任一氨基酸序列。在一些实施方案中,VH CDR3包含SEQ ID NO:12所示的氨基酸序列。在一些实施方案中,VH CDR3包含SEQ ID NO:14所示的氨基酸序列。
在一些实施方案中,本发明的抗αvβ8抗体或其抗原结合片段包含轻链可变区(VL),其中所述VL包含互补决定区域(CDR)VL CDR1、VL CDR2和VL CDR3,其中VL CDR1包含与SEQ ID NO:44所示的氨基酸序列具有至少50%、60%、70%、80%或90%同一性或者100%同一性的氨基酸序列,VL CDR2包含与SEQ ID NO:45所示的氨基酸序列具有至少50%、60%、70%、80%或90%同一性或者100%同一性的氨基酸序列,VL CDR3包含与SEQID NO:46所示的氨基酸序列具有至少50%、60%、70%、80%或90%同一性或者100%同一性的氨基酸序列。
在一些实施方案中,本发明的抗αvβ8抗体或其抗原结合片段的VH CDR1包含如SEQID NO:5所示的氨基酸序列,VH CDR2包含如SEQ ID NO:6所示的氨基酸序列,VH CDR3包含如SEQ ID NO:12所示的氨基酸序列;VL CDR1包含如SEQ ID NO:44所示的氨基酸序列,VLCDR2包含如SEQ ID NO:45所示的氨基酸序列,VL CDR3包含如SEQ ID NO:46所示的氨基酸序列。
在一些实施方案中,本发明的抗体αvβ8抗体或其抗原结合片段的VH CDR1包含如SEQ ID NO:5所示的氨基酸序列,VH CDR2包含如SEQ ID NO:6所示的氨基酸序列,VH CDR3包含如SEQ ID NO:14所示的氨基酸序列;VL CDR1包含如SEQ ID NO:44所示的氨基酸序列,VL CDR2包含如SEQ ID NO:45所示的氨基酸序列,VL CDR3包含如SEQ ID NO:46所示的氨基酸序列。
本发明抗体或其抗原结合片段中CDR可以是表1中各CDR对应的任一氨基酸序列的示例性组合。
表1CDR序列
在一些实施方案中,本发明的抗αvβ8抗体或其抗原结合片段包含轻链可变区VL,其包含与SEQ ID NO:4所示的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性或者100%同一性的氨基酸序列。
在一些实施方案中,本发明的抗αvβ8抗体或其片段包含重链可变区VH,其包含与SEQ ID NO:26-43的任一氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性或者100%同一性的氨基酸序列。
在一些实施方案中,本发明的抗体包含如SEQ ID NO:47所示的重链恒定区(CH),以及如SEQ ID NO:48所示的轻链恒定区(CL)。
在一些实施方案中,抗体1包含如SEQ ID NO:26所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体2包含如SEQ ID NO:27所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体3包含如SEQ ID NO:28所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体4包含如SEQ ID NO:29所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体9包含如SEQ ID NO:30所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体13包含如SEQ ID NO:31所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体16包含如SEQ ID NO:32所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体21包含如SEQ ID NO:33所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体22包含如SEQ ID NO:34所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体23包含如SEQ ID NO:35所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体24包含如SEQ ID NO:36所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体25包含如SEQ ID NO:37所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体27包含如SEQ ID NO:38所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体28包含如SEQ ID NO:39所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体29包含如SEQ ID NO:40所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体30包含如SEQ ID NO:41所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体31包含如SEQ ID NO:42所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,抗体32包含如SEQ ID NO:43所示的VH,如SEQ ID NO:4所示的VL,如SEQ ID NO:47所示的CH,如SEQ ID NO:48所示的CL。
在一些实施方案中,公开了抗αvβ8抗体、抗原结合片段、变体或衍生物。变体是指对抗体或其抗原结合片段中的一个或多个氨基酸残基进行删除和/或替换,或***一个或多个氨基酸残基而得到的抗体或其抗原结合片段。衍生物包括被修饰的衍生物,即通过任何类型的分子与抗体的共价连接进行修饰,其中共价连接不会阻止抗体与表位结合。包括但不限制以下实例,抗体可以通过例如糖基化、乙酰化、聚乙二醇化、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、连接至细胞配体或其他蛋白质等。众多化学修饰中的任一种修饰可以通过现有技术进行,包括但不限于特异性化学裂解、乙酰化、甲酰化、衣霉素的代谢合成等。此外,抗体可以含有一个或多个非自然的氨基酸。
在一些实施方案中,抗体可以与治疗剂、药物前体、肽、蛋白质、酶、病毒、脂类、生物反应调节剂、药剂或PEG缀合。
抗体可以与治疗剂缀合或融合,所述治疗剂可包括可检测标记,如放射性标记、免疫调节剂、激素、酶、寡核苷酸、光敏治疗剂或诊断剂、可以是药物或毒素的细胞毒性剂、超声增强剂、非放射性标记物及其组合物,和本领域已知的其它此类试剂。
抗体可通过将其偶联至化学发光化合物来被可检测地标记。然后通过检测在化学反应过程中出现的发光从而确定化学发光标记的抗原结合片段的存在。特别有用的化学发光标记化合物的实例包括鲁米诺、异鲁米诺、芳香吖啶酯、咪唑、吖啶盐和草酸酯。
在一些实施方案中,本发明的抗体还涵盖抗αvβ8抗体的氨基酸序列的变体,以及与上文所述的任何抗体结合相同表位的抗体。
在一些实施方案中,本发明的抗αvβ8抗体还涵盖其抗体片段;在一些实施方案中,选自以下的抗体片段:Fab、Fab'-SH、Fv、scFv或(Fab’)2片段。
在一些实施方案中,本发明提供了编码以上任何抗αvβ8抗体或其片段的核酸。在一个实施方案中,提供包含所述核酸的载体。在一个实施方案中,载体是表达载体。表达载体包括质粒、逆转录病毒、YAC、EBV衍生的附加体等等。在一个实施方案中,提供包含所述载体的宿主细胞。在一个实施方案中,所述宿主细胞是真核的。在另一个实施方案中,宿主细胞选自酵母细胞、哺乳动物细胞(例如CHO细胞或293F细胞)或适用于制备抗体或其抗原结合片段的其它细胞。
在一些实施方案中,编码抗αvβ8抗体或其片段的核酸序列可根据抗αvβ8抗体或其片段的氨基酸序列通过本领域常规的方法获得。
在一些实施方案中,所述抗体是嵌合、人源化或全人源的。在一些实施方案中,所述抗体或其片段能激活T细胞,促进其增殖或分泌炎性因子。在一些实施方案中,所述抗体或其片段是一种IgG同种型,所述IgG同种型选自IgG1同种型、IgG2同种型、IgG3同种型和/或IgG4同种型组成的组。在一些实施方案中,所述抗体或其抗原结合片段是选自IgG1的IgG同种型。
本发明还包括与本文所述抗αvβ8抗体结合同一表位的抗体。例如,本发明的抗体特异性结合包括人αvβ8上一个或多个氨基酸残基的表位。
本领域技术人员将认识到,只需要通过查明待测抗体是否阻止已知抗体与αvβ8结合,而无需进行过多实验就可以确定抗体是否与本文所述抗体结合同一表位。如果受试抗体与本公开抗体竞争,则两种抗体可能结合至相同或相近的表位。
一种用于确定抗体是否具有本文所述抗体的特异性的替代方法是将本文所述抗体与通常该抗体对其有反应的可溶αvβ8蛋白质一起预温育,然后加入测试的抗体以确定测试的抗体与αvβ8结合的能力是否受到抑制。如果测试的抗体受到抑制,则其具有与本公开的抗体相同、或功能相同的表位特异性。
在一些实施方案中,本发明的抗体,可以使用例如下文所提供实施例中描述的方法制备。在一些实施方案中,还可通过使用Trioma技术,人B细胞杂交瘤技术(参见Kozbor等人,1983,Immunol Today 4:72),以及EBV杂交瘤技术(参见Cole等人,1985,In:MonoclonalAntibodies and Cancer Therapy,Alan R.Liss,Inc.,第77-96页)等来制备产生。
使用常规重组DNA技术,可将本发明的抗体的一个或多个CDR***框架区,例如***到人类框架区以构建人源化非全人源抗体。框架区可以是天然存在的或共有的框架区,优选人类框架区(参见Chothia et al.,J.Mol.Biol.278:457-479(1998),其列出一系列人类框架区)。一些多核苷酸可以编码产生含框架区和CDR组合的能与目标抗原的至少一个表位特异性结合的抗体。在框架区内可以进行一个或多个氨基酸取代,可以选择能够改善抗体与其抗原结合的氨基酸取代。另外,可用此法进行参与链间二硫键形成的一个或多个可变区中半胱氨酸残基的取代或缺失,从而产生缺少一个或多个链间二硫键的抗体分子。本领域技术范围内的对多核苷酸进行的其他改变也涵盖于本发明中。
此外,抗体可以通过使用常规重组DNA技术制备。通过使用本领域技术人员公知的重组DNA技术可以选择、构建和培养生产抗体的载体及细胞系。这些技术在各种实验室手册和主要出版物中均有描述,例如Recombinant DNA Technology for Production ofProtein Therapeutics in Cultured Mammalian Cells,D.L.Hacker,F.M.Wurm,inReference Module in Life Sciences,2017,其全部内容包括补充内容通过引用并入全文。
在一些实施方案中,可以按常规方法根据本文所述抗体氨基酸序列设计合成编码抗体的DNA,将其置入表达载体中,然后转染宿主细胞,在培养基中培养被转染的宿主细胞产生抗体。表达抗体载体包括至少一个启动子元件,抗体编码序列,转录终止信号和polyA尾。其他元件包括增强子,Kozak序列及***序列两侧RNA剪接的供体和受***点。可以通过SV40的前期和后期启动子,来自逆转录病毒的长末端重复序列如RSV、HTLV1、HIVI及巨细胞病毒的早期启动子来获得高效的转录,也可应用其它一些细胞的启动子如肌动蛋白启动子。合适的表达载体可包括pYD、pIRES1neo、pRetro-Off、pRetro-On、PLXSN、Plncx、pCHO1.0、pcDNA3.1(+/-)、pcDNA/Zeo(+/-)、pcDNA3.1/Hygro(+/-)、PSVL、PMSG、pRSVcat、pSV2dhfr、pBC12MI和pCS2等。常使用的哺乳动物细胞包括293细胞,Cos1细胞,Cos7细胞,CV1细胞,鼠L细胞和CHO细胞等。
在一些实施方案中,***基因片段需含有筛选标记,常见的筛选标记包括二氢叶酸还原酶,谷氨酰胺合成酶,新霉素抗性,潮霉素抗性等筛选基因,以便于转染成功的细胞的筛选分离。将构建好的质粒转染到宿主细胞,经过选择性培养基培养,转染成功的细胞大量生长,产生想要获得的目的蛋白。
抗体可以通过公知的技术纯化,例如利用蛋白A或蛋白G进行亲和层析,免疫亲和色谱等。例如D.Wilkinson(The Scientist,由The Scientist,Inc.,Philadelphia Pa.出版,第14卷,第8期(2000),第25-28页)讨论了免疫球蛋白的纯化。
此外,本发明的抗αvβ8抗体能够同时特异性的结合αvβ3。现在已经有许多证据表明进展性肿瘤生长依赖于血管发生、新血管的形成,它们提供给肿瘤以营养和氧气,带走废物和作为肿瘤向远处转移的导管(Gastl et al.,Oncol.54:177-184)。最近的研究进一步确定了整联蛋白在血管发生过程中的作用。整联蛋白是异二聚的跨膜蛋白,它们在细胞与细胞外基质(ECM)的粘附中起关键作用,通过细胞内信号传递介导细胞存活、增殖和迁移。在血管发生过程中,许多在活化的内皮细胞表面表达的整联蛋白调节关键的粘附性相互作用,许多ECM蛋白调节不同的生物学时间,如细胞迁移、增殖和分化。整联蛋白αVβ3介导血管发生过程中的独立途径。针对αvβ3的抗体阻断碱性成纤维细胞生长因子(bFGF)诱导的血管发生。αvβ3可表达于多种不同组织来源的恶性肿瘤,包括上皮性肿瘤、淋巴细胞源性肿瘤和以黑色素瘤为代表的神经外胚叶来源的肿瘤。并且αvβ3可促进肿瘤侵袭和转移、抑制肿瘤细胞凋亡。本发明的抗αvβ8抗体,既能够与整联蛋白αvβ8结合,又能够与整联蛋白αvβ3结合。抗αvβ8抗体结合两个靶点后,从不同途径发挥抗肿瘤作用,可能进一步提高抗体的抗肿瘤活性。
除了αvβ8,整联蛋白αvβ6也能够结合LAP,也会使得TGF-β从其前体(Latent TGF-beta)被释放出来,从而导致TGF-β1和3的成熟活化(Mu等(2002)J.Cell Biol.159:493)。在一些实施方案中,本发明提供的抗αvβ8抗体除了与αvβ8有较高的亲和力外,还能与αvβ6有较高的亲和力,进一步发挥抗体抑制TGFβ信号传导的作用,更有效地和安全地用于治疗涉及TGFβ的疾病和障碍,包括,例如,癌症、纤维化和炎症。
针对抗αvβ8抗体或其抗原结合片段的使用
在一些实施方案中,提供一种在有需要的患者中治疗或改善TGFβ相关疾病的方法,所述方法包括向所述患者施用有效剂量的本文所述的抗体或抗原结合片段。在一些实施方案中,提供本文抗体或抗原结合片段在制备用于治疗或改善TGFβ相关疾病的药物中的应用。本文所述抗αvβ8抗体可以治疗的疾病或病症包括血液癌症和/或实体瘤。
血液癌症包括例如白血病、淋巴瘤和骨髓瘤。在一些实施方案中,白血病包括急性淋巴细胞性白血病(ALL);急性骨髓性白血病(AML);慢性淋巴细胞性白血病(CLL);慢性骨髓性白血病(CML);骨髓性增生疾病/肿瘤(MPDS)。淋巴瘤包括霍奇金淋巴瘤、无痛性和侵袭性非霍奇金淋巴瘤、伯基特淋巴瘤和滤泡性淋巴瘤(小细胞和大细胞)。骨髓瘤包括多发性骨髓瘤(MM)、巨细胞骨髓瘤、重链骨髓瘤和轻链或本斯-琼斯骨髓瘤。实体瘤包括例如乳腺癌、卵巢癌、肺癌、胰腺癌、***癌、黑素瘤、结直肠癌、肺癌、头颈癌、膀胱癌、食道癌、肝癌和肾癌。
在一些实施方案中,本发明的抗体可以激活免疫应答,从而用于治疗感染。
感染是由致病因子侵入生物体组织、它们的繁殖以及宿主组织对这些生物体及它们产生的毒素的反应。感染可能由传染原引起,例如病毒、类病毒、朊病毒、细菌、线虫如寄生性蛔虫和蛲虫、节肢动物如蜱、螨虫、跳蚤和虱子、真菌如癣以及其他大寄生物如绦虫和其他蠕虫。在某一方面,传染原是细菌,如革兰氏阴性细菌。在某一方面,传染原是病毒,例如DNA病毒、RNA病毒和逆转录病毒。病毒的非限制性实例包括腺病毒、柯萨奇病毒、EB病毒、甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、单纯疱疹病毒1型、单纯疱疹病毒2型、巨细胞病毒、人疱疹病毒8型、HIV、流感病毒、麻疹病毒、腮腺炎病毒、人***瘤病毒、副流感病毒、脊髓灰质炎病毒、狂犬病毒、呼吸道合胞病毒、风疹病毒、水痘-带状疱疹病毒。
本发明的抗体还可以用于治疗由微生物引起的传染病,或者通过靶向结合微生物和免疫细胞杀灭微生物以实现消除微生物的目的。在某一方面,微生物是包括RNA和DNA病毒的病毒、***、革兰氏阴性细菌、原生动物或真菌。
本发明的抗体的治疗有效量涉及达到治疗目标所需的量。给药所需的量取决于抗体对其特异抗原的结合亲和力,疾病、紊乱或病症的严重程度、给药途径、在接受给药的对象中给予的抗体从自由体积耗尽的速率等。在一些实施方案中,本发明的抗体或抗体片段的治疗有效剂量的范围为从约0.01mg/kg到约100mg/kg。在一些实施方案中,本发明的抗体或抗体片段的治疗有效剂量的范围为从约0.1mg/kg到约30mg/kg。剂量频率范围可以是例如每周两次或至每三周一次。
在一些实施方案中,将抗αvβ8抗体给予经诊断具有一种或多种前述疾病(包括但不限于癌症或其他肿瘤病症)相关临床症状的患者。诊断后,给予抗αvβ8抗体以减轻或消除一种或多种前述疾病相关临床症状的效果。
在某些肿瘤样品中观察到αvβ8的过表达,并且具有αvβ8和/或αvβ3过表达的细胞的患者可能对使用本发明的抗αvβ8抗体的治疗有响应。因此,本发明的抗体也可以用于诊断和预后。
在一些实施方案中,包含细胞的样品可以从患者体内获得,该患者可以是癌症患者或待诊断的患者。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。在选择性地对样品进行预处理之后,可以在允许抗体与可能存在于样品中的αvβ8蛋白相互作用的条件下,将样品与本发明的抗体一起孵育,利用抗αvβ8抗体来检测样品中αvβ8蛋白的存在。
本发明的抗体还用于检测患者样品中的αvβ8,并因此可用于诊断。例如,本发明的抗αvβ8抗体用于体外试验(如ELISA)以检测患者样品中的αvβ8和/或αvβ3水平。
在一个实施方案中,本发明的抗αvβ8抗体固定在固体支持物(如微量滴定板的孔)上。固定的抗体作为捕捉抗体,捕捉测试样品中可能存在的任何αvβ8。在使固定的抗体接触患者样品前,清洗固相载体并使用封闭试剂(如牛奶蛋白或白蛋白)处理以避免分析物的非特异性吸附。随后使用可能含有抗原的测试样品或使用含有标准量抗原的溶液处理所述孔。这类样品是例如来自对象的血清样品,其可能具有被认为可诊断某一病变的循环抗原水平。洗去测试样品或标准品后,使用可检测标记的二抗处理固相支持物。标记的二抗用作检测抗体。测量可检测标记的水平,通过与标准样品所建立的标准曲线进行比较确定测试样品中αvβ8的浓度。
在一些实施方案中,使用本文所述的抗αvβ8抗体或其抗原结合片段时,抗体或其片段以药物组合物的形式存在。其中,药物组合物可以由抗αvβ8抗体或其抗原结合片段与药学上可接受的载体组成。如本文所用,术语“药学上可接受的载体”旨在包括与药物给药相容的任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延缓剂等。合适载体描述于最新版的Remington's Pharmaceutical Sciences中。此类载体或稀释剂包括但不限于水、盐水、林格氏溶液、葡萄糖溶液和/或5%的人血清白蛋白。
在一些实施方案中,含有抗αvβ8抗体的药物组合物与其预期施用途径相容。给药途径的示例包括肠胃外,例如静脉内、皮内、皮下、经口(例如吸入)、经皮(即局部的)、经粘膜和直肠给药。药物组合物可包括以下组分中的一种或多种:注射用无菌稀释剂,例如水、盐溶液、固定油、聚乙二醇类、甘油、丙二醇或其它合成溶剂;抑菌剂,例如苄醇或对羟基苯甲酸甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;螯合剂,例如乙二胺四乙酸(EDTA);缓冲剂,例如组氨酸盐酸盐、乙酸盐、柠檬酸盐或磷酸盐;渗透压调节剂,例如氯化钠或右旋糖;稳定剂,例如精氨酸、甲硫氨酸、海藻糖、蔗糖、山梨醇;表面活性剂,例如吐温20、吐温80。pH可用酸或碱进行调节,例如盐酸或氢氧化钠。可将药物组合物包装在安瓿、一次性注射器或玻璃或塑料制多剂量小瓶内。在一些实施方案中,适于注射用途的药物组合物包括无菌水性溶液(在此是水溶性的)或分散体以及用于即时制备无菌注射液或分散体的无菌粉末。使用时,组合物必须是无菌的并且应当为流动性达到易于注射的程度。其在制造和储存条件下必须是稳定的并且必须能防止微生物例如细菌和真菌的污染作用。注射用组合物的延长吸收可通过在所述组合物中包含延缓吸收的试剂例如单硬脂酸铝和明胶来达到。根据需要,可以通过将抗体以所需量掺入具有上文所列成分中的一种或多种组合(按需要)的合适溶剂中来制备无菌注射溶液,然后过滤消毒。也可以将前述的无菌溶液通过冷冻干燥获得粉末,用于在给药时制备无菌注射溶液。
在一些实施方案中,抗αvβ8抗体和其它治疗剂被制备为单个治疗组合物,并同时给予抗αvβ8抗体和其它治疗剂。或者,抗αvβ8抗体和其它治疗剂彼此独立,例如分别制备为独立的治疗组合物,并同时给予抗αvβ8抗体和其它治疗剂,或在治疗方案期间在不同时间给予抗αvβ8抗体和其它治疗剂。例如,在给予其它治疗剂前给予抗αvβ8抗体,在给予其它治疗剂后给予抗αvβ8抗体,或以交替的方案给予抗αvβ8抗体和其它治疗剂。本文中,以单个剂量或多个剂量给予抗αvβ8抗体和其它治疗剂。
本领域技术人员应理解本发明的抗体有多种用途。例如,本发明的抗体可用作治疗剂、用作诊断试剂盒中的试剂或用作诊断工具、或用作竞争实验中的试剂以生成治疗剂。
实施例
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径或已知方法得到。
实施例1:αvβ8抗原以及对照抗体的生产和纯化
1.1人源αvβ8抗原的制备:
从蛋白数据库Uniprot上,找到人αvβ8的两个亚基的氨基酸序列(ITGAV:P06756;ITGB8:P26012),其中人αvβ8的ITGAV和ITGB8两个亚基的胞外区的氨基酸序列分别是1到992和1到684位残基。并在两个亚基的胞外区的C端,分别加上酸性氨基酸长链(SEQ IN NO:1)和碱性氨基酸长链(SEQ IN NO:2)。这两段氨基酸有助于ITGAV和ITGB8两个亚基的稳定组装。通过酶切连接,把它们***到pCHO1.0质粒(购自Invitrogen公司,A13696-01),得到重组质粒。再把上述质粒通过PEI瞬转HEK293细胞,在培养7天后收集上清液,纯化得到αvβ8-his蛋白样品,用于下面各种实施例。
1.2对照抗体C6D4和264RAD的制备。
抗体C6D4的重链和轻链的序列见专利WO2018064478。抗体264RAD的重链和轻链的序列见专利CN103524619。通过酶切连接分别把重链和轻链的DNA连接到pCHO1.0质粒,得到用于表达全抗的重组质粒。根据制造商的说明书使用Freedom CHO-S试剂盒(购自Invitrogen),把上述重组质粒转入CHO-S细胞系,培养11天后,收集上清液,纯化得到C6D4和264RAD的抗体蛋白样品,用于下面各种实施例。
实施例2:抗人αvβ8抗体的制备
2.1抗体片段Fab制备
抗体片段Fab的VH如表2所示,其中下划线为CDR区;VL均如SEQ ID NO:4所示。通过人工合成得到编码上述序列的DNA(苏州金唯智生物科技有限公司),通过PCR同源重组连接分别把重链和轻链的DNA连接到酵母展示质粒pYD-VH-VL(质粒的构建参考文献SimonRosowski,Stefan Becker,et al.A novel one-step approach for the constructionof yeast surface display Fab antibody libraries.Microb.Cell Fact.(2018)17:3),然后电转入酵母,得到一批和αvβ8-his抗原结合的克隆株,其与αvβ8-his抗原结合流式分析结果如图1所示。测序结果VH如表2所示;VL均如SEQ ID NO:4所示。
SEQ ID NO:4如下(下划线为CDR):
DIQMTQSPSSLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK
表2:αvβ8结合的克隆的重链和轻链可变区的氨基酸序列
2.2IgG全抗的制备
制备IgG全抗。抗体的可变区如表2所示,抗体的恒定区为IgG1类型(重链恒定区如SEQ ID NO:47所示,轻链恒定区如SEQ ID NO:48所示)。设计合成编码上述抗体相应的重链和轻链的DNA片段,将其通过酶切连接到pCHO1.0质粒中,得到用于表达全抗的重组质粒。根据制造商的说明书使用Freedom CHO-S试剂盒(购自Invitrogen),把上述重组质粒转入CHO-S细胞系,培养11天后,收集上清液,通过Protein A纯化得到十八株抗体。
重链恒定区序列SEQ ID NO:47如下:
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
轻链恒定区序列SEQ ID NO:48如下:
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
抗体9的重链序列SEQ ID NO:49如下(下划线为可变区):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFT ISRDNSKNTLYLQMNSLRAEDTAVYYCARDRHWAVRGDLAVLQPKDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
抗体16的重链序列SEQ ID NO:50如下(下划线为可变区):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFT ISRDNSKNTLYLQMNSLRAEDTAVYYCARSALLPSRGDLPLRWVSDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
各抗体的轻链序列SEQ ID NO:3如下(下划线为可变区):
DIQMTQSPSSLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
实施例3:抗人αvβ8抗体的结合能力鉴定
3.1用ELISA测定抗人αvβ8抗体和αvβ8的结合以及特异性。
把αvβ8-his抗原以及αvβ1-his、αvβ3-his、αvβ5-his、αvβ6-his、α2bβ3-his、α5β1-his、α8β1-his(均购自ACRO公司),分别稀释于PBSAJ(PBS含0.1%BSA、1mM Mg2+以及1mM Ca2 +)中,按100ng/100μl/孔,过夜包板。第二天,洗板五遍后,分别孵育1h的20nM抗αvβ8抗体(抗体2、抗体4、抗体9、抗体13、抗体16、抗体21、抗体22、抗体23、抗体24、抗体25、抗体27、抗体28),该抗体稀释于PBSAJ。洗板8遍后,孵育1h anti-Kappa HRP。洗板8遍后,显色和终止反应,用酶标仪进行读数(结果如表3所示)。
表3:用ELISA测定抗αvβ8抗体的和整合素蛋白的结合
3.2抗αvβ8抗体的细胞表面抗原的结合能力。
通过转染带有的人αvβ8cDNA的pCMV载体产生过表达人αvβ8的CHO细胞(CHO-αvβ8细胞)。将CHO-αvβ8细胞(0.5×106个细胞)与20nM的抗人αvβ8抗体在PBSJ中混匀,并在冰上孵育40分钟。然后将细胞洗涤3次,并与anti-Fc PE荧光二抗在PBS(含0.2%BSA)中在冰上孵育25分钟。将细胞洗涤3次,在Accuri C6***(BD Biosciences)上进行流式细胞术分析,结果见图2。结果显示,所有的抗人αvβ8抗体都能明显结合CHO细胞上的αvβ8蛋白。
实施例4:抗αvβ8抗体阻断αvβ8与其配体L-TGFβ的结合
把4nM的L-TGFβ和10nM、30nM的抗αvβ8抗体(抗体9、抗体16)以及对照抗体C6D4和264RAD分别,同时孵育CHO-αvβ8细胞(0.5×106个细胞),所用的缓冲液是PBSAJ。孵育40分钟后,洗涤3遍,再孵育anti-Fc PE荧光二抗,孵育25分钟。将细胞洗涤3次,在Accuri C6***(BD Biosciences)上进行流式细胞术分析,结果见图3。结果显示抗体9和抗体16能够阻断αvβ8与其配体L-TGFβ的结合,且随着浓度的增加阻断效果增加,在30nM浓度下几乎完全阻断L-TGFβ和αvβ8的结合。
实施例5:通过BIACORE测定抗人αvβ8抗体的亲和力
按照BIACORE的使用说明书测定抗人αvβ8抗体的亲和力,具体流程为先用探针结合抗体,再检测40nM和10nM的αvβ8、αvβ6和αvβ3的结合和解离,从而计算出相应抗体的精确亲和力。其中所用的缓冲体系有两种,一种是HBS-P+电泳缓冲液(含有100μg/mL BSA、不含1mM Mg2+以及1mM Ca2+)。另一种是HBS-P电泳缓冲液(含有100μg/mL BSA,含1mM Mg2+以及1mM Ca2+),结果表4所示。结果表明,抗体9和αvβ8、αvβ3亲和力常数分别为26.3nM和22nM,抗体16号和αvβ8、αvβ6、αvβ3亲和力常分别为为14.6nM、31.9nM和5.18nM。
表4:用BIACORE精确测定抗人αvβ8抗体的亲和力。
实施例6:抗αvβ8抗体的细胞生物活性检测
此处使用的是TGFβ生物活性测定,参考的方法是Abe等人,Anal.Biochem.216:276-284(1994)。在生物体内,L-TGFβ通过二硫键和GARP蛋白组装在一起,并通过GARP展示在细胞膜上,当细胞膜上的αvβ8和L-TGFβ的RGDL位点结合时,通过机械作用,使得有活性的TGFβ从L-TGFβ中释放出来,从而激活下游信号通路。把GARP和L-TGFβ的cDNA(购自义翘神州)转入CHO中,得到过表达GARP和L-TGFβ的CHO细胞(命名为CHO-GARP-L-TGFβ)。把pGL6-PAI-1-lufiferas-reporter质粒(购自碧云天)电转入MLEC细胞中。在96孔板中,把CHO-αvβ8细胞(10万/100μL孔)和CHO-GARP-L-TGFβ细胞(10万/100μL孔),共同铺板,同时孵育100nM和300nM的抗人αvβ8抗体,以及100nM的C6D4、100nM和300nM的264RAD,并在培养基用添加(1mM Mg2+和1mM Ca2+)。然后孵育48小时。之后把MLEC按5万/100μL/孔进行铺板,再取100μL上述48小时后的细胞培养基上清,添加把MLEC细胞中,再孵育18小时。最每孔添加荧光反应物50μL(ONE-GloTM Luciferase Assay System,购自Promega公司),并用酶标仪进行读数,结果如图4。结果表明,抗体9和抗体16在100nM和300nM的浓度下,明显阻断TGFβ的释放,从而抑制其下游信号。
本文引用的所有出版物和专利文献都通过引用纳入本文,就好像每个所述出版物或文献都特定和单独表示通过引用纳入本文。对上述出版物和专利文献的引用并不表示承认上述任何内容是相关的在先技术,也并不表示承认其内容或日期。现在,本发明已以书面说明书方式描述,本领域技术人员应认识到可以多种实施方案实践本发明,而上文的说明书和实施例旨在说明而非限制本发明的权利要求。
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<213> 人工序列(Artificial Sequence)
<400> 10
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 11
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 12
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 13
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 14
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 15
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 16
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 17
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 18
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 19
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 20
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 21
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 22
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 23
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 24
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 25
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 26
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Gly Arg Val Gly Leu Arg Gly Asp Leu Pro Pro Gly Thr
100 105 110
Pro Val Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 27
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Val Ala Thr Gly Arg Gly Asp Leu Gly Ala His Gly
100 105 110
Arg Ile Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 28
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Arg Gln Asn Ala Leu Arg Gly Asp Leu Gln Pro Arg Phe
100 105 110
Thr Ser Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 29
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Met Gln Ser Arg Gly Asp Leu Pro Ala Trp Ala Ser Ser
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 30
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg His Trp Ala Val Arg Gly Asp Leu Ala Val Leu Gln
100 105 110
Pro Lys Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 31
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Met Phe Asn Gly Arg Arg Gly Asp Leu Pro Gln Gly Pro
100 105 110
Arg His Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 32
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ala Leu Leu Pro Ser Arg Gly Asp Leu Pro Leu Arg Trp
100 105 110
Val Ser Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 34
<211> 126
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Ala Thr Leu Val Arg Gly Asp Leu Gly Trp Leu His Glu
100 105 110
Asn Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 35
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asn Met Phe Pro Ser Arg Gly Asp Leu Ser Pro Leu Ala
100 105 110
Val Ala Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 36
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 36
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Leu Ser Gly Arg Gly Asp Leu Gly Trp Leu Ser Ser Pro
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 37
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 37
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Leu Leu Phe Phe Asp Arg Gly Asp Leu Pro Arg Gly His
100 105 110
Leu Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 38
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Leu Pro Gly Arg Gly Asp Leu Pro His Trp Thr Leu Ser
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 39
<211> 126
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Gly His Ala Gln Arg Gly Asp Leu Pro Arg Asn Ser Asp
100 105 110
Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 40
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 40
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Val Val Thr Ser Lys Arg Gly Asp Leu Ala Gly Gln Pro
100 105 110
Val Arg Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 41
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 41
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Ser Pro Ala Arg Gly Asp Leu Pro Ala Leu Arg Thr Ser
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 42
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 42
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Pro Leu Ala Ser Arg Gly Asp Leu Pro Ser Phe Ala Ser Ser
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 43
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 43
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Pro Phe Phe His Thr Arg Gly Asp Leu Ala Ser Ser Tyr
100 105 110
Leu Ser Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 44
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 44
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Pro Pro Ala Arg Gly Asp Leu Pro Asn Leu Ala Leu Ser
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 45
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 45
Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala
1 5 10
<210> 46
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 46
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 47
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 47
Gln Gln His Tyr Thr Thr Pro Pro Thr
1 5
<210> 47
<211> 330
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 47
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 48
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 48
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 49
<211> 457
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 49
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg His Trp Ala Val Arg Gly Asp Leu Ala Val Leu Gln
100 105 110
Pro Lys Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
115 120 125
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
130 135 140
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
145 150 155 160
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
165 170 175
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
180 185 190
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
195 200 205
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
210 215 220
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
225 230 235 240
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
245 250 255
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
260 265 270
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
275 280 285
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
290 295 300
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
305 310 315 320
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
325 330 335
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
340 345 350
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
355 360 365
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
370 375 380
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
385 390 395 400
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
405 410 415
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
420 425 430
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
435 440 445
Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 50
<211> 457
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 50
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ala Leu Leu Pro Ser Arg Gly Asp Leu Pro Leu Arg Trp
100 105 110
Val Ser Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
115 120 125
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
130 135 140
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
145 150 155 160
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
165 170 175
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
180 185 190
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
195 200 205
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
210 215 220
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
225 230 235 240
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
245 250 255
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
260 265 270
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
275 280 285
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
290 295 300
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
305 310 315 320
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
325 330 335
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
340 345 350
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
355 360 365
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
370 375 380
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
385 390 395 400
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
405 410 415
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
420 425 430
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
435 440 445
Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455
Claims (10)
1.一种抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段特异性结合αvβ8,所述抗体或抗原结合片段包含:
(a)VH CDR1,其包含SEQ ID NO:5所示的氨基酸序列,
(b)VH CDR2,其包含SEQ ID NO:6所示的氨基酸序列,
(c)VH CDR3,其包含SEQ ID NO:7所示的氨基酸序列,
(d)VH CDR1,其包含SEQ ID NO:44所示的氨基酸序列,
(e)VH CDR2,其包含SEQ ID NO:45所示的氨基酸序列,和/或
(f)VH CDR3,其包含SEQ ID NO:46所示的氨基酸序列。
2.如权利要求1所述的抗体或抗原结合片段,其特征在于,所述VH CDR3包含SEQ IDNO:8-25所示的任一氨基酸序列。
3.一种抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段特异性结合αvβ8,所述抗体或抗原结合片段包含:
(a)VH CDR1,其包含SEQ ID NO:5所示的氨基酸序列,
(b)VH CDR2,其包含SEQ ID NO:6所示的氨基酸序列,
(c)VH CDR3,其包含SEQ ID NO:8-25所示的任一氨基酸序列,
(d)VH CDR1,其包含SEQ ID NO:44所示的氨基酸序列,
(e)VH CDR2,其包含SEQ ID NO:45所示的氨基酸序列,以及
(f)VH CDR3,其包含SEQ ID NO:46所示的氨基酸序列。
4.如权利要求1-3任一项所述的抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段包含如SEQ ID NO:5所示的VH CDR1,如SEQ ID NO:6所示的VH CDR1,如SEQ ID NO:12或14所示的VH CDR3,如SEQ ID NO:44所示的VL CDR1,如SEQ ID NO:45所示的VL CDR2,以及如SEQ ID NO:46所示的VL CDR3。
5.如权利要求1-4任一项所述的抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段的重链可变区包含SEQ ID NO:26-43所示的任一氨基酸序列,或与SEQ ID NO:26-43所示的任一氨基酸序列至少有90%序列同源性的氨基酸序列;和/或所述抗体或抗原结合片段的轻链可变区包含SEQ ID NO:4所示的氨基酸序列,或与SEQ ID NO:4所示的氨基酸序列至少有90%序列同源性的氨基酸序列。
6.如权利要求1-5任一项所述的抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段的重链恒定区包含SEQ ID NO:47所示的氨基酸序列,或与SEQ ID NO:47所示的氨基酸序列至少有90%序列同源性的氨基酸序列;和/或所述抗体或抗原结合片段的轻链恒定区包含SEQ ID NO:48所示的氨基酸序列,或与SEQ ID NO:48所示的氨基酸序列至少有90%序列同源性的氨基酸序列。
7.如权利要求1-6任一项所述的抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段的重链包含SEQ ID NO:49或50所示的氨基酸序列,或与SEQ ID NO:49或50所示的氨基酸序列至少有90%序列同源性的氨基酸序列;和/或所述抗体或抗原结合片段的轻链包含SEQ ID NO:51所示的氨基酸序列,或与SEQ ID NO:51所示的氨基酸序列至少有90%序列同源性的氨基酸序列。
8.如权利要求1-7任一项所述的抗体或抗原结合片段,其特征在于,所述抗体或抗原结合片段特异性结合αvβ3和/或αvβ6。
9.一种组合物,其特征在于,所述组合物包含如权利要求1-8任一项所述的抗体或抗原结合片段,以及药学上可接受的载体。
10.如权利要求1-8任一项所述的抗体或抗原结合片段,或如权利要求9所述的组合物在制备用于治疗或改善TGFβ相关疾病的药物中的应用,或在制备用于诊断TGFβ相关疾病的试剂盒中的应用。
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