CN113166265B - 抗紧密连接蛋白18.2和抗4-1bb双特异性抗体及其用途 - Google Patents
抗紧密连接蛋白18.2和抗4-1bb双特异性抗体及其用途 Download PDFInfo
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Abstract
本发明提供了针对紧密连接蛋白18.2(CLDN18.2)和4‑1BB的双特异性和多特异性抗体。这些抗体在没有表达CLDN18.2的细胞的情况下,可以与4‑1BB结合,但不能激活4‑1BB信号。然而,在存在表达CLDN18.2的细胞的情况下,这些抗体可以触发CLDN18.2依赖的4‑1BB信号,从而导致对表达CLDN18.2的肿瘤细胞的有效免疫应答。
Description
相关申请的交叉引用
本申请主张PCT申请序列号PCT/CN2019/100162(于2019年8月12日提交)、PCT/CN2019/104508(于2019年9月5日提交)、PCT/CN2020/071954(于2020年1月14日提交)和PCT/CN2020/087968(于2020年4月30日提交)的权益,各申请的内容在此通过引用全部并入。
背景技术
Claudins(紧密连接蛋白)是形成紧密细胞连接的重要组成部分的一个蛋白质家族。Claudin-18剪接变异体2(CLDN18.2)是一种胃特异性膜蛋白。在健康组织中,CLDN18.2作为紧密连接的一个组成部分,在短寿命的胃粘膜分化细胞中限制性表达,抗体治疗的可及性有限。然而,它在多种上皮性肿瘤实体的原发灶和转移灶(包括胃腺癌、胰腺癌、食管癌和肺腺癌细胞)的异位表达显著。
4-1BB(CD137,肿瘤坏死因子受体超家族9)是TNF受体超家族(TNFRSF)的成员,其为一种共刺激分子,在免疫细胞(固有免疫细胞和适应性免疫细胞)激活后表达。4-1BB在调节多种免疫细胞的活性方面起着重要作用。4-1BB激动剂增强免疫细胞增殖、存活、细胞因子分泌和CD8 T细胞的细胞溶解活性。许多其他研究表明,激活4-1BB可增强免疫反应,消除小鼠肿瘤。因此,4-1BB可能是一种很有前途的肿瘤免疫靶分子。
发明概述
本发明提供了针对紧密连接蛋白18.2(CLDN18.2)和4-1BB的双特异性和多特异性抗体。在一些实施方案中,本技术的抗体包括“条件激动剂”抗4-1BB部分,其在抗CLDN18.2部分没有与细胞上表达的CLDN18.2蛋白结合的情况下不能激活4-1BB信号传导。
4-1BB信号激活是激动剂抗体的预期机制,例如乌托米卢单抗(utomilumab)(PF-05082566)和脲单抗(urelumab)(BMS-663513)。然而,本发明的抗体的抗4-1BB部分不需要这种活性。实际上,优选的是,本抗体的抗4-1BB部分在没有CLDN18.2结合的情况下不能独立地激活4-1BB。有趣的是,当抗CLDN18.2部分与细胞上的CLDN18.2蛋白结合时,这种CLDN18.2结合可以触发4-1BB信号激活。
与已知的抗4-1BB激动剂抗体(通常与靶毒性剂量限制相关)相比,本发明的抗体被认为更安全。在不表达CLDN18.2的组织(例如肝脏)中,由于它们不能激活4-1BB信号,所以不期望本发明的抗体触发细胞毒性免疫应答。相反,在表达和/或可获得CLDN18.2的肿瘤组织中,本发明的抗体可启动对肿瘤细胞的有效免疫应答。因此,与目前临床上正在开发的具有靶向/固有毒性的抗4-1BB抗体不同,本发明公开的抗体可在治疗癌症的同时是有效且安全的。
附图说明
图1A-C说明了在本发明中测试的三种不同的双特异性形式。
图2A-D显示了4-1BB和CLDN18.2结合的ELISA结果。
图3显示了基于细胞的4-1BB结合。
图4A-C显示了CLDN18.2的结合结果。
图5A-D显示了CLDN18.2依赖的4-1BB信号激活。
图6A-E显示了在CLDN18.2表达细胞存在下的PBMC反应。
图7A-D显示了在CLDN18.2表达细胞存在下的CD8+T反应。
图8A-B显示了抗CLDN18.2-4-1BB抗体在同基因小鼠模型中的体内效力及其对肿瘤浸润淋巴细胞影响的体外分析。
图9A-C显示了C-1A10双特异性抗体在同基因小鼠模型中的体内效力。
图10显示了C-1A10和D-1A10在同基因小鼠模型中的剂量依赖性抗肿瘤功效。
图11A-D显示了D-1A10在同基因小鼠模型中的药代动力学和药效学关系。
发明详述
定义
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。
在本发明中,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。它可能以包括化学合成的任何方式产生。
本发明中关于细胞、核酸所使用的术语“分离的”,例如“分离的”DNA或RNA是指分别与存在于大分子的天然来源中的其它DNA或RNA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。
在本发明中,术语“重组”涉及多肽或多聚核苷酸,意指非天然存在的多肽或多聚核苷酸的形式,不受限制的实施例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”是指两个肽之间或两个核酸分子之间的序列相似性。可以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。术语“不相关的”或“非同源的”序列表示与本发明公开的序列之一有小于40%的同一性,但优选小于25%的同一性。
多聚核苷酸或多聚核苷酸区域(或多肽或多肽区域)与另一序列有具有一定百分比(例如,60%、65%、70%、75%、80%、85%、90%、95%、98%或者99%)的“序列同一性”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Current Protocols in Molecular Biology中所述的软件程序。优选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。特别地,程序是BLASTN和BLASTP,两者使用下列默认参数:Genetic code=standard;filter=none;strand=both;cutoff=60;expect=10;Matrix=BLOSUM62;Descriptions=50sequences;sort by=HIGHSCORE;Databases=non-redundant;GenBank+EMBL+DDBJ+PDB+GenBank CDS translations+SwissProtein+SPupdate+PIR。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。
在本发明中,“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及其任何抗原结合片段或其单链。因此术语“抗体”包括分子中含有具有与抗原结合的生物学活性的免疫球蛋白分子的至少一部分的任何蛋白质或肽。包括但不局限的该实施例包括重链或轻链或其配体结合部分的互补决定区(CDR)、重链或轻链可变区、重链或轻链恒定区、框架(FR)区或其任何部分、或结合蛋白的至少一部分。
在本发明中,术语“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“抗体片段”包括适体、镜像异构体和双价抗体。术语“抗体片段”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,这些区域与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。ScFv分子是本领域中已知的,例如在美国专利5,892,019中有相关描述。
术语“抗体”包括可以在生物化学上区分的各种广泛种类的多肽。本领域技术人员将会理解,重链的类别包括gamma、mu、alpha、delta或epsilon(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。免疫球蛋白亚类(同种型),例如IgG1、IgG2、IgG3、IgG4、IgG5等已被充分表征并且赋予的功能特异性也已知。本领域普通技术人员容易想到这些种类和同种型中的每一种改变形式,因此都在本发明公开的保护范围内,所有的免疫球蛋白种类都显然在本发明公开的保护范围内,后面的讨论通常针对免疫球蛋白分子的IgG种类。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。这四条链典型地通过二硫键以“Y”构型连接,其中轻链从“Y”口开始并延续通过可变区包围重链。
本发明公开的抗体、抗原结合多肽、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、表位结合片段例如Fab、Fab'和F(ab')2、Fd、Fvs、单链Fvs(scFv)、单链抗体,二硫键连接的Fvs(sdFv),包含VK或VH结构域的片段,由Fab表达文库产生的片段和抗独特型(抗Id)抗体(包括例如本发明公开的LIGHT抗体的抗Id抗体)。本发明公开的免疫球蛋白或抗体分子可以是免疫球蛋白的任何类型(例如IgG、IgE、IgM、IgD、IgA和IgY)或种类(例如,IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或者亚类。
轻链可以分为kappa或lambda(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。
轻链和重链都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,轻链(V解)和重链(VH)链部分的可变区决定了抗原识别和特异性。相反地,轻链(CK)和重链(CH1、CH2或CH3)的恒定区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CK结构域实际上分别包含重链和轻链的羧基端。
如上所述,可变区使得抗体能够选择性识别和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)的子集结合形成了限定三维抗原结合位点的可变区。该抗体四级结构形成存在于Y的每个臂末端的抗原结合位点。更具体地说,抗原结合位点由VH和VK链中各自的三个CDR定义(即CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3)。在某些情况下,例如某些来源于骆驼科动物的免疫球蛋白分子或基于骆驼科动物免疫球蛋白改造的免疫球蛋白分子,完整的免疫球蛋白分子可以仅由重链组成,没有轻链。例如参见Hamers-Casterman et al.,Nature 363:446-448(1993)。
在天然存在的抗体中,假设抗体在含水环境中呈现其三维构型时,存在于每个抗原结合域中的六个“互补决定区”或“CDR”是特异性地定位以形成抗原结合结构域的短的、非连续的氨基酸序列。抗原结合结构域中被称为“构架”区域的剩余其它氨基酸显示出较小的分子间可变性。构架区大部分采用β-折叠构象,CDR形成与之连接的环状结构,或在某些情况下形成β折叠结构的一部分。因此,框架区通过形成支架从而通过链间非共价相互作用使CDR定位在正确的方位上。特定位置的CDR形成的抗原结合域界定了与免疫反应性抗原上的表位互补的表面,该互补表面促进抗体和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都可以容易地鉴定出包含CDR和框架区的氨基酸,因为其已经被精确定义(参见"Sequences of Proteins of Immunological Interest,"Kabat,E.,et al.,U.S.Department of Health and Human Services,(1983)和Chothiaand Lesk,J.Mol.Biol.,196:901-917(1987))。
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。一个具体的例子是使用“互补决定区”(“CDR”)一词来描述在重链和轻链多肽的可变区内发现的非连续的抗原结合位点。这一特定区域在Kabat et al.,U.S.Dept.of Health and Human Services,“Sequences ofProteins of Immunological Interest"(1983)和Chothia等在J.Mol.Biol.196:901-917(1987)有相关描述,其通过引用全部并入本文。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都在本发明所定义和使用的术语的范围内。包含以上引用的每个参考文献所定义的CDR的适量的氨基酸残基在下表中被列出进行比较。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。本领域技术人员可以常规地根据抗体的可变区氨基酸序列确定出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等人还定义了适用于任何抗体的可变区序列的编号系统。本领域普通技术人员可以毫无疑义地将该“Kabat编号”系统应用到任何可变区序列,而不依赖于序列本身以外的任何实验数据。本发明所使用的“Kabat编号”是指由Kabat et al.,U.S.Dept.ofHealth and Human Services在“Sequence of Proteins of Immunological Interest"(1983)提出的编号系统。
除上述表格之外,Kabat编号系统按如下述方式介绍CDR区:CDR-H1在大约第31个氨基酸(即第一个半胱氨酸残基之后的大约9个残基)开始,包括大约5-7个氨基酸,并在下一个色氨酸残基处结束。CDR-H2在CDR-H1结束后的第15个残基处开始,包括大约16-19个氨基酸残基,并在下一个精氨酸或赖氨酸残基处结束。CDR-H3从CDR-H2结束后的大约第33个氨基酸残基开始;包括3-25个氨基酸;并以序列W-G-X-G结束,其中X指任何氨基酸。CDR-L1大约从第24个残基开始(即在半胱氨酸残基之后);包括约10-17个残基;并在下一个色氨酸残基处结束。CDR-L2从CDR-L1结束后的大约第16个残基开始,包括大约7个残基。CDR-L3在CDR-L2结束后的大约第33个残基(即在半胱氨酸残基之后)开始;包括大约7-11个残基并且以序列F或W-G-X-G结束,其中X指任何氨基酸。
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。在另一实施例中,可变区可以是软骨鱼纲(condricthoid)来源(例如来自鲨鱼)。
在本发明中,术语“重链恒定区”包括来源于免疫球蛋白重链的氨基酸序列。包含重链恒定区的多肽包括CH1结构域、铰链(例如上、中和/或下铰链区)结构域、CH2结构域、CH3结构域,或变体或片段中的至少一种。例如,本发明公开的抗原结合多肽可以包括含有CH1结构域的多肽链;包含CH1结构域、至少一部分铰链区以及CH2结构域的多肽链;包含CH1结构域和CH3结构域的多肽链;包含CH1结构域以及至少一部分铰链区以及CH3结构域的多肽链;或包含CH1结构域、至少一部分铰链区以及CH2结构域和CH3结构域的多肽链。在另一实施方案中,本发明公开的多肽包括包含CH3结构域的多肽链。此外,本发明中使用的抗体可能缺少至少一部分CH2结构域(例如全部或部分CH2结构域)。如上所述,本领域普通技术人员应当理解,重链恒定区可以被修饰从而使得它们天然存在的免疫球蛋白分子的氨基酸序列发生变化。
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,多肽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。在另一实施例中,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。在另一实施例中,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“轻链恒定区”包括来自抗体轻链的氨基酸序列。较佳地,轻链恒定区包含恒定κ结构域或恒定λ结构域中的至少一个。
“轻链-重链对”是指可通过轻链的CL结构域和重链的CH1结构域之间的二硫键形成二聚体的轻链和重链的集合。
如上所述,各种免疫球蛋白种类的恒定区的亚基结构和三维构型是众所周知的。在本发明中,术语“VH结构域”包括免疫球蛋白重链的氨基末端可变结构域,术语“CH1结构域”包括免疫球蛋白重链的第一个(大部分氨基末端)恒定区。CH1结构域与VH结构域相邻,并且是免疫球蛋白重链分子铰链区的氨基端。
在本发明中,术语“CH2结构域”包括使用常规编号方案时,从抗体的约第244个残基延伸至第360个残基的部分重链分子(第244至360个残基,Kabat编号系统;第231-340个残基,EU编号系统;参见Kabat et al.,U.S.Dept.of Health and Human Services,“Sequence of Proteins of Immunological Interest"(1983))。CH2结构域是独特的,因为该结构域不与其它结构域紧密配对,而是在完整的天然IgG分子的两个CH2结构域之间插入两个N-连接的分支碳水化合物链。还有文献记载,CH3结构域从CH2结构域开始延伸到IgG分子的C-末端,大约包含108个残基。
在本发明中,术语“铰链区”包括连接CH1结构域和CH2结构域的部分重链分子。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。铰链区可以被细分为三个不同的结构域:上、中和下铰链结构域(Roux et al.,J.Immunol161:4083(1998))。
“特异性结合”或“对……具有特异性,”通常是指抗体通过其抗原结合结构域与表位结合,并且该结合需要抗原结合结构域和表位之间具有互补性。根据这个定义,当抗体通过其抗原结合结构域与该表位结合时比它结合到随机的、不相关的表位更容易,其被称为“特异性结合”该表位。术语“特异性”在本发明中用于限定特定抗体与特定表位结合的相对亲和力。例如,可以认为抗体“A”比抗体“B”对特定表位具有更高的特异性,或者可以认为抗体“A”以比结合相关表位“D”更高的特异性结合表位“C”。
在本发明中,术语“治疗”是指治疗性治疗和预防性或防治性措施,其目的是预防或减缓(减少)不良的生理改变或紊乱,例如癌症的进程。有益的或期望的临床结果包括但不限于以下无论是可检测还是不可检测的结果,包括症状的缓解、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、疾病状态的改善或缓和,以及减轻(无论是部分还是全部)。“治疗”还意指与不接受治疗时预期的生存期限相比所延长的生存期限。需要治疗的包括那些已经患有病症或紊乱的人,以及那些容易患有病症或紊乱的人,或者那些需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”通常指需要诊断、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、家养动物、农场动物和动物园、运动或宠物动物如狗、猫、豚鼠、兔子、大鼠、小鼠、马、牛、奶牛等。
在本发明中,诸如“需要治疗的患者”或“需要治疗的受试者”等短语包括从施用本发明公开的抗体或组合物用于检测、诊断过程和/或治疗中受益的受试者,例如哺乳动物受试者。
抗紧密连接蛋白18.2抗4-1BB抗体
4-1BB是一种在活化的T细胞和自然杀伤(NK)细胞上表达的可诱导共刺激受体。4-1BB三聚体通过4-1BB配体(41BBL)三聚体聚集在T细胞上触发信号级联,导致抗凋亡分子、细胞因子分泌和增强效应器功能的上调。在NK细胞上,4-1BB信号可增强抗体依赖性细胞介导的细胞毒性。靶向4-1BB的激动性单克隆抗体已被开发,利用4-1BB信号传导进行癌症免疫治疗。多种诱导和自发肿瘤模型的临床前研究结果表明,用激动剂抗体靶向4-1BB可导致肿瘤清除和持久的抗肿瘤免疫。
两种激动剂抗体脲鲁单抗(urelumab)和乌托米卢单抗(utomilumab)目前正在进行临床试验。脲鲁单抗有很强的疗效,但有炎症性肝毒性。肝毒性似乎是针对性的,因此很难从疗效中分离出来。乌托米卢单抗相对安全,但也不太有效。
本实验性示例测试了一对抗4-1BB抗体,这些抗体因其不能独立激活4-1BB信号而被特别选择。在它们的单特异性形式中,它们可以单独与4-1BB结合或与细胞表面的4-1BB结合。然而,它们在细胞表面上的4-1BB结合不会导致4-1BB信号激活(例如,参见实施例3和图5)。
有趣的是,当这些条件激动剂4-1BB抗体之一的结合片段1A10并入进一步具有抗CLDN18.2部分的双特异性抗体中时,所得的双特异性抗体能够以CLDN18.2结合依赖性方式有效地激活4-1BB信号传导(参见实施例3和图5)。值得注意的是,这些测试的双特异性抗体使用N297A IgG1 Fc使FcγR药物治疗的4-1BB丧失兴奋。因此,4-1BB信号的激活只能归因于与CLDN18.2结合。
抗4-1BB激动剂抗体的靶向毒性归因于抗体在4-1BB兴奋中缺乏选择性。然而,可以容易地认识到本技术的抗体在克服此限制上的能力。在一个组织,如肝脏,CLDN18.2不表达或不容易获取,抗体将是安全的,因为它们不能激活4-1BB介导的细胞毒性。相比之下,在CLDN18.2过度表达或可获得的肿瘤组织中,抗体经历CLDN18.2结合依赖性4-1BB信号活化,导致4-1BB介导的免疫细胞活化,从而治疗肿瘤。
因此,根据本发明的一个实施方案,其提供一种抗体,所述抗体包括具有特异性结合CLDN18.2蛋白的抗紧密连接蛋白18.2(CLDN18.2)单元和具有特异性结合4-1BB蛋白的抗4-1BB单元。在优选实施方案中,在缺乏所述抗CLDN18.2单元结合所述CLDN18.2蛋白的情况下,所述抗4-1BB单元结合到所述4-1BB蛋白时不能激活4-1BB信号。
抗4-1BB部分缺乏4-1BB激动可以通过许多不同的方法实现。表明4-1BB在细胞表面的聚集是其激活的必要条件。因此,在一些实施方案中,在缺乏所述抗CLDN18.2单元结合所述CLDN18.2蛋白的情况下,所述抗4-1BB单元与细胞上的所述4-1BB蛋白的结合不会导致所述4-1BB蛋白的聚集。
4-1BB蛋白有四个细胞外富含半胱氨酸的虚拟重复序列(CRD)结构域,即CRD1、CRD2、CRD3和CRD4(见下表中的氨基酸序列和CRD区域)。脲鲁单抗与N端的CDR1结合,并以4-1BB配体(4-1BBL)依赖性方式激活4-1BB聚集。在一些实施方案中,本公开抗体的抗4-1BB单元不与CDR1结合。在一些实施方案中,本公开抗体的抗4-1BB单元结合到CDR2。在一些实施方案中,本公开抗体的抗4-1BB单元结合到CDR3。在一些实施方案中,本公开抗体的抗4-1BB单元结合到CDR4。
在某些情况下,4-1BB聚集可通过抗4-1BB抗体的效应器功能介导。因此,在一些实施方案中,本发明的抗体具有降低的或没有效应器功能的Fc片段。在一些实施方案中,这种效应器功能为抗体依赖性细胞介导的细胞毒性(ADCC)、补体依赖的细胞毒性(CDC)或抗体依赖性细胞吞噬作用(ADCP)。
可以使用本领域已知的技术改变抗体的效应器功能。在一些实施方案中,抗体的Fc片段以一种方式被突变或制造以减少或消除其与FcγR的结合。在一些实施方案中,Fc片段减少或不与FcγRI(CD64)结合;在一些实施方案中,Fc片段减少或不与FcγRIIA(CD32)结合;在一些实施方案中,Fc片段减少或不结合FcγRIIB(CD32);在一些实施方案中,Fc片段减少或不结合FcγRIIIA(CD16a);并且在一些实施方案中,Fc片段减少或不结合FcγRIIIB(CD16b)。在一些实施方案中,Fc片段减少或不结合到C1q(C1复合物的第一亚组分)。
在一些实施方案中,Fc片段包括一个或多个突变以减少或消除与FcγR或C1q结合。此类突变的非限制性实例包括IgG1 Fc片段中的L235E突变、IgG1 Fc片段中的L234A和/或L235A突变、IgG1 Fc片段中的P329G或P329A突变、IgG4 Fc片段中的F234A和/或L235A或L235E突变、IgG2 Fc片段中的H268Q、V309L、A330S和/或P331S突变以及V234A,IgG2 Fc片段中V234A、G237A、P238S、H268A、V309L、A330S和/或P331S突变(EU编号)。
抗体的效应器功能也可以通过减少或抑制Fc片段(例如,糖基化Fc片段)的糖基化来降低。在一些实施方案中,可以通过使用不能使抗体糖基化的细胞系来实现这种减少或抑制。在一些实施方案中,Fc片段被突变。
此类突变的非限制性示例包括N297处的突变(例如N297A、N297G和N297Q)(EU编号)。在一些实施方案中,突变为N297A。
抗体形式和序列实例
在实验实例中,测试了三种不同的双特异性抗体形式。其中,图1A的形式表现出比图1B和图1C更高的活性。这些数据表明本发明的抗体的合适形式可以使用Fab片段作为抗CLDN18.2部分。在一些实施方案中,所述形式包括用于抗4-1BB部分的单链片段(scFv)。在一些实施方案中,抗4-1BB部分不在Fab和Fc片段之间。
在一些实施方案中,抗CLDN18.2单元包括Fab片段,优选一对Fab片段。在一些实施方案中,抗4-1BB单元包括Fab片段,优选一对Fab片段。在一些实施方案中,抗4-1BB单元包括scFv,优选一对scFv片段。
在一些实施方案中,抗CLDN18.2单元位于抗4-1BB单元的N端。在一些实施方案中,Fc片段位于抗CLDN18.2单元和抗4-1BB单元之间。
抗CLDN18.2单元和抗4-1BB单元也提供了示例CDR序列和VH/VL序列。在一些实施方案中,抗4-1BB单元包含含有CDRH1、CDRH2和CDRH3的重链可变区(VH)和含有CDRL1、CDRL2和CDRL3的轻链可变区(VL),其中:所述CDRH1包含如SEQ ID NO:1所示的氨基酸序列或对SEQ ID NO:1进行一个或两个氨基酸取代的氨基酸序列;所述CDRH2包含如SEQ ID NO:2所示的氨基酸序列或对SEQ ID NO:2进行一个或两个氨基酸取代的氨基酸序列;所述CDRH3包含如SEQ ID NO:3、56、57、58或59所示的氨基酸序列,或对SEQ ID NO:3、56、57、58或59进行一个或两个氨基酸取代的氨基酸序列;所述CDRL1包含如SEQ ID NO:4或60所示的氨基酸序列,或对SEQ ID NO:4或60进行一个或两个氨基酸取代的氨基酸序列;所述CDRL2包含如SEQID NO:5或61所示的氨基酸序列,或对SEQ ID NO:5或61进行一个或两个氨基酸取代的氨基酸序列;所述CDRL3包含如SEQ ID NO:6或62所示的氨基酸序列,或对SEQ ID NO:6或62进行一个或两个氨基酸取代的氨基酸序列。
表A抗4-1BB单元实例的CDR序列
在一些实施方案中,所述CDRH1包含如SEQ ID NO:1所示的氨基酸序列;所述CDRH2包含如SEQ ID NO:2所示的氨基酸序列;所述CDRH3包含如SEQ ID NO:3、56、57、58或59所示的氨基酸序列;所述CDRL1包含如SEQ ID NO:4或60所示的氨基酸序列;所述CDRL2包含如SEQ ID NO:5或61所示的氨基酸序列;所述CDRL3包含如SEQ ID NO:6或62所示的氨基酸序列。
在一些实施方案中,抗4-1BB单元包含重链可变区(VH)以及轻链可变区(VL),所述重链可变区包含选自由SEQ ID NO:24、46-51和63-69组成的组中的氨基酸序列,所述轻链可变区包含选自由SEQ ID NO:25、52-53和70-74组成的组中的氨基酸序列。
表B.抗4-1BB单元实例的VH/VL序列
在一些实施方案中,抗CLDN18.2单元包含含有CDRH1、CDRH2和CDRH3的重链可变区(VH)和包含CDRL1、CDRL2和CDRL3的轻链可变区(VL),其中(a)所述CDRH1包含如SEQ ID NO:7所示的氨基酸序列;所述CDRH2包含如SEQ ID NO:8所示的氨基酸序列;所述CDRH3包含如SEQ ID NO:9所示的氨基酸序列;所述CDRL1包含如SEQ ID NO:10所示的氨基酸序列;所述CDRL2包含如SEQ ID NO:11所示的氨基酸序列;所述CDRL3包含如SEQ ID NO:12所示的氨基酸序列。
在一些实施方案中,抗CLDN18.2单元包含含有CDRH1、CDRH2和CDRH3的重链可变区(VH)和含有CDRL1、CDRL2和CDRL3的轻链可变区(VL),其中(b)所述CDRH1包含如SEQ ID NO:13所示的氨基酸序列;所述CDRH2包含如SEQ ID NO:14所示的氨基酸序列;所述CDRH3包含如SEQ ID NO:15所示的氨基酸序列;所述CDRL1包含如SEQ ID NO:16所示的氨基酸序列;所述CDRL2包含如SEQ ID NO:17所示的氨基酸序列;所述CDRL3包含如SEQ ID NO:18所示的氨基酸序列。
在一些实施方案中,抗CLDN18.2单元包含含有CDRH1、CDRH2和CDRH3的重链可变区(VH)和含有CDRL1、CDRL2和CDRL3的轻链可变区(VL),其中(c)所述CDRH1包含如SEQ ID NO:19所示的氨基酸序列;所述CDRH2包含如SEQ ID NO:20所示的氨基酸序列;所述CDRH3包含如SEQ ID NO:21所示的氨基酸序列;所述CDRL1包含如SEQ ID NO:22所示的氨基酸序列;所述CDRL2包含如SEQ ID NO:11所示的氨基酸序列;所述CDRL3包含如SEQ ID NO:23所示的氨基酸序列。
表C抗CLDN18.2单元实例的CDR序列
在一些实施方案中,所述抗CLDN18.2单元的VH包含选自由SEQ ID NO:26、28和30组成的组中的氨基酸序列,且所述抗CLDN18.2单元的VL包含选自由SEQ ID NO:27、29和31组成的组中的氨基酸序列。
在一些实施方案中,提供采用如图1A所示形式的双特异性抗体。在一些实施方案中,提供包含两个第一多肽和两个第二多肽的抗体,每个第一多肽从N端到C端依次包含重链可变区(VH)、CH1、CH2、CH3和对4-1BB蛋白具有特异性的单链片段(scFv);其中每个第二多肽包含轻链可变区(VL)和CL;其中每个VH与一个所述VL配对并且对紧密连接蛋白18.2(CLDN18.2)蛋白具有特异性;其中,在缺乏VH/VL对结合到CLDN18.2蛋白的情况下,所述scFv在结合到4-1BB蛋白时不能激活4-1BB信号。
此处的VH/VL对构成抗CLDN18.2单元,scFv构成抗4-1BB单元。CH2-CH3/CH2-CH3对构成Fc片段。上述关于抗CLDN18.2单元、抗4-1BB单元和Fc片段的各种实施方案也可适用于此处。
下表提供了第一多肽(重组分)和第二多肽(轻组分)的非限制性示例。在一些实施方案中,每个第一多肽包含如SEQ ID NO:40所示的氨基酸序列,并且每个第二多肽包含如SEQ ID NO:41所示的氨基酸序列。
在一些实施方案中,每个第一多肽包含如SEQ ID NO:42所示的氨基酸序列,每个第二多肽包含如SEQ ID NO:43所示的氨基酸序列。
在一些实施方案中,每个第一多肽包含如SEQ ID NO:44所示的氨基酸序列,每个第二多肽包含如SEQ ID NO:45所示的氨基酸序列。
表D.双特异性抗体实例的肽链
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表D2双特异性抗体实例的整合序列
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本领域的普通技术人员还应理解,本文所公开的抗体可进行修饰,使其在氨基酸序列上与从中衍生的天然存在的结合多肽不同。例如,衍生自指定蛋白质的多肽或氨基酸序列可以相似,例如,与起始序列具有一定的百分比同源性,例如,它可以与起始序列有60%、70%、75%、80%、85%、90%、95%、98%或99%的同源性。
在某些实施方案中,所述抗体包含通常不与抗体相关联的氨基酸序列或一个或多个部分。下面更详细地描述示例性修改。例如,本发明的抗体可包含柔性连接体序列,或可经修饰以添加功能部分(例如,PEG、药物、毒素或标签)。
本发明公开的抗体、变体或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、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经典的氨基酸。
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多肽的存在。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。
抗体还可以使用荧光发射金属元素例如152Eu或其它镧系元素来可检测地标记。这些金属元素可以使用如二乙基三胺五乙酸(DTPA)或乙二胺四乙酸(EDTA)这样的金属螯合基团连接到抗体上。用于将各种基团缀合至抗体的技术是众所周知的,参见例如Arnon etal.,“Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”,inMonoclonal Antibodies And Cancer Therapy、Reisfeld et al.(eds.),pp.243-56(AlanR.Liss,Inc.(1985)、Hellstrom et al.,“Antibodies For Drug Delivery”,inControlled Drug Delivery(2nd Ed.)、Robinson et al.,(eds.),Marcel Dekker,Inc.,pp.623-53(1987)、Thorpe,“Antibody Carriers Of Cytotoxic Agents In CancerTherapy:A Review”,in Monoclonal Antibodies'84:Biological And ClinicalApplications,Pinchera et al.(eds.),pp.475-506(1985)、“Analysis,Results,AndFuture Prospective Of The Therapeutic Use Of Radiolabeled Antibody In CancerTherapy”,in Monoclonal Antibodies For Cancer Detection And Therapy、Baldwin etal.(eds.),Academic Press pp.303-16(1985)和Thorpe et al.,“The Preparation AndCytotoxic Properties Of Antibody-Toxin Conjugates”,Immunol.Rev.(52:119-58(1982))。
编码抗体的多核苷酸和制备抗体的方法
本发明还公开了编码本发明所述抗体、变体及其衍生物的分离的多核苷酸或核酸分子。本发明公开的多聚核苷酸可以编码在相同的多聚核苷酸分子上或在分离的多聚核苷酸分子上的抗原结合多肽、变体或衍生物的整个重链和轻链可变区。此外,本发明公开的多聚核苷酸可以编码在相同的多聚核苷酸分子上或在分离的多聚核苷酸分子上的抗原结合多肽、变体或衍生物的部分重链和轻链可变区。
制备抗体的方法是本领域公知的并且在本发明中有所描述。在某些实施方案中,本发明公开的抗原结合多肽的可变区和恒定区都是全人源的。可以使用本领域中公开的技术和本发明所述的技术制备全人源抗体。例如,针对特定抗原的全人源抗体可以通过将抗原施用于转基因动物中来制备,所述转基因动物已经被改良过以响应抗原攻击而产生此类抗体,但其内源基因座已被禁用。可用于制备这种抗体的示例性技术参见美国专利6,150,584;6,458,592;6,420,140,其全部内容通过引用并入本文。
治疗方法
在本发明中,本发明的抗体、变体或衍生物可用于某些治疗和诊断方法中。
本发明将进一步描述基于抗体的疗法,将本发明所述的抗体施用于患者例如动物、哺乳动物和人,从而治疗本文所述的一种或多种紊乱或病症。本发明的治疗性化合物包括但不限于本发明所述抗体(包括本发明所述的变体和衍生物)和编码本发明所述抗体(包括本发明所述的变体和衍生物)的核酸或多聚核苷酸。
在一些实施方案中,提供了治疗需要其的患者的癌症的方法。在一个实施方案中,所述方法需要向患者施用有效量的本发明抗体。在一些实施方案中,患者中至少一个癌细胞(例如基质细胞)过度表达紧密连接蛋白18.2。
在本发明中还提供了细胞疗法,例如嵌合抗原受体(CAR)T细胞疗法。可以使用合适的细胞与本发明所述的抗PD-L1抗体接触(或者可选地,工程改造以表达本发明所述抗PD-L1抗体)。通过这样的接触或工程改造,细胞可以被引入需要治疗的癌症患者体内。癌症患者可能具有本文所述的任何类型的癌症。细胞(例如T细胞)包括但并不限制以下类型例如肿瘤浸润T淋巴细胞、CD4+T细胞、CD8+T细胞及其组合。
在一些实施方案中,细胞从癌症患者自身体内分离出来。在一些实施方案中,细胞由供体或细胞库提供。当细胞从癌症患者中分离出来时,可以将免疫反应不良反应降至最低。
非限制性癌症示例包括膀胱癌、乳腺癌、结直肠癌、子宫内膜癌、食管癌、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,癌症是胃癌、胰腺癌、食管癌、卵巢癌和肺癌中的一种或多种。
可以用本发明所述抗体或变体或其衍生物来治疗、预防、诊断和/或预测与细胞存活率增加相关的其他疾病或病症,包括但不限于恶性肿瘤和/或相关紊乱的进程或转移,所述紊乱包括白血病{包括急性白血病[例如急性淋巴细胞性白血病、急性骨髓性白血病(包括成髓细胞性、早幼粒细胞性、粒单核细胞性、单核细胞性和红白血病)]和慢性白血病[例如慢性髓细胞性(粒细胞性)白血病和慢性淋巴细胞性白血病]}、真性红细胞增多症、淋巴瘤(例如霍奇金淋巴瘤和非霍奇金淋巴瘤)、多发性骨髓瘤、瓦尔登斯特伦氏巨球蛋白血症、重链病,以及实体瘤,包括但不限于肉瘤和癌症如纤维肉瘤、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、尤因瘤、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、维尔姆斯氏瘤、宫颈癌、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突胶质细胞瘤、脑膜瘤、黑色素瘤、成神经细胞瘤和成视网膜细胞瘤。
对于任何特定患者的具体剂量和治疗方案将取决于各种因素,包括所使用的特定抗体及其变体或衍生物、患者的年龄和体重、一般健康状况、性别和饮食,以及给药时间、排泄频率、药物组合,以及所治疗的特定疾病的严重程度。由包括在本领域普通技术人员范围内的医疗护理人员对这些因素进行判断。所述剂量还将取决于待治疗的个体患者、给药途径、制剂类型、所用化合物的特性、疾病的严重程度以及所需的效果。所用剂量可以通过本领域熟知的药理学和药代动力学原理确定。
抗体及其变体的施用方法包括但不限于真皮内、肌肉、腹腔、静脉、皮下、鼻腔、硬脊膜外和口服注射。抗原结合多肽或组合物可以通过任何方便的途径施用,例如通过输注或推注,通过上皮或皮肤粘膜(例如口腔粘膜、直肠和肠粘膜等)吸收,并且可以与其他生物活性剂共同施用。因此,含有本发明的抗原结合多肽的药物组合物可以口服给药、直肠给药、肠胃外给药、脑池内给药、阴道内给药、腹腔内给药、外敷(如通过粉末,软膏,滴剂或透皮贴剂)、口腔给药或通过口服或鼻腔喷雾给药。
本发明使用的术语“肠胃外”是指包括静脉内、肌肉内、腹腔内、胸骨内、皮下和关节内注射和输注的施用方式。
施用方式可以是全身施用或局部施用。此外,可能需要通过任何合适的途径将本发明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连接到如贮液囊(可以是Ommaya贮液囊)来辅助注射。也可以通过肺部给药,例如通过使用吸入器或喷雾器,以及使用雾化的制剂。
可能需要将本发明的抗体多肽或组合物局部施用于需要治疗的区域;可以通过但不限于以下方式:手术期间局部输注,例如与手术后伤口敷料联合的局部应用,通过注射,通过导管,借助栓剂或借助植入物来实现,所述植入物是多孔的、无孔的或凝胶状的材料,包括膜(例如硅橡胶膜)或纤维。优选地,当施用本发明的蛋白质(包括抗体)时,必须注意使用不吸收蛋白质的材料。
可以通过标准的临床技术确定本发明抗体的剂量,该剂量将有效治疗、抑制和预防炎症、免疫或恶性疾病、紊乱或病症。此外,可以任选地采用体外实验来帮助确定最佳剂量范围。制剂使用的准确剂量也取决于给药途径和疾病、紊乱或病症的严重程度,且应根据医师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测试系统得到的剂量反应曲线推测出来。
作为一般建议,本发明的抗原结合多肽施用于患者的剂量通常为0.1mg至100mg/每kg患者体重,0.1mg至20mg/每kg病人的体重,或1mg到10mg/每kg病人的体重。通常,由于对外源多肽的免疫应答,人抗体在人体内的半衰期比其他物种的抗体长。因此,较低剂量的人抗体和较少的给药频率通常是可行的。此外,可以通过例如脂质化等修饰来增强抗体的摄取和组织穿透能力(例如进入脑内),从而减少本发明抗体的施用的剂量和频率。
在其他实施方案中,本发明的组合物与细胞因子联合施用。可以与本发明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。
在其他实施方案中,本发明的组合物与其它治疗或预防方案,例如放射性疗法联合施用。
组合物
本发明还提供了药物组合物。这样的组合物包含有效剂量的抗体和可接受的载体。在一些实施方案中,组合物还包含第二抗癌剂(例如免疫检查点抑制剂)。
在一个具体实施方案中,术语“药学上可接受的”是指由联邦或州政府的监管机构批准的或在美国药典或其他公认的药典中列出的用于动物,特别是用于人类的药物。此外,“药学上可接受的载体”通常将是任何类型的无毒固体、半固体或液体填充剂、稀释剂、包封材料或制剂助剂。
术语“载体”是指施用于治疗的稀释剂、佐剂、赋形剂或载体。这此类药物载体可以是无菌液体,如水和油,包括石油、动植物或合成来源的油,如花生油、大豆油、矿物油、芝麻油等。当药物组合物静脉内给药时,水是优选的载体。盐水溶液和葡萄糖水溶液和甘油溶液也可用作液体载体,特别是用于注射溶液。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、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。如有需要,组合物还可以含有少量的润湿剂或乳化剂,或pH缓冲剂如乙酸盐、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,以及调节张力的试剂如氯化钠或右旋葡萄糖也是可以预见的。这些组合物可以采取溶液、悬液、乳剂、片剂、丸剂、胶囊、散剂、缓释制剂等形式。该组合物可以用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,例如药物等级的甘露糖醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。合适的药物载体的实例在E.W.Martin的Remington's Pharmaceutical Sciences中有描述,在此通过引用并入本发明。此类组合物将含有临床有效剂量的抗原结合多肽,优选以纯化后的形式,连同合适数量的载体,以提供适合于患者的给药形式。该制剂应该适用于给药模式。亲本制剂可以封装在安瓿瓶、一次性注射器或由玻璃或塑料制成的多剂量小瓶中。
在一个实施方案中,根据常规步骤将组合物配制成适合静脉内注射于人体的药物组合物。具有代表性地是,用于静脉内给药的组合物是在无菌等渗水性缓冲液中的溶液。必要时,组合物还可包含增溶剂和局部麻醉剂如利多卡因,从而缓解注射部位的疼痛。一般而言,有效成分以单位剂量形式单独供给或混在一起供给,如以干燥的冻干粉末或无水浓缩物的形式装在可指示活性剂份量的密封容器(如安瓿瓶或小袋)中。在通过输注施用组合物的情况下,可以用含有无菌药用级水或盐水的输液瓶来分装组合物。在通过注射施用组合物的情况下,可以使用注射用的无菌水或盐水的安瓿瓶,使得可以在施用之前混合有效成分。
本发明的化合物可以配制成中性的或盐的形式。药学上可接受的盐包括衍生自如盐酸、磷酸、乙酸、草酸、酒石酸等的与阴离子形成的盐,以及衍生自如钠、钾、铵、钙、氢氧化铁、异丙胺、三乙胺、2-乙氨基乙醇、组氨酸、普鲁卡因等的与阳离子形成的盐。
具体实施方式
实施例1:抗CLDN18.2/4-1BB双特异性抗体的产生
选择三种先前鉴定的抗CLDN18.2抗体4F11E2、72C1B6A3和120B7B2,以及一种抗4-1BB抗体1A10(序列见下表),以产生全长IgG X单链抗体形式的抗CLDN18.2-4-1BB双特异性抗体(结构如图1A所示)。抗紧密连接蛋白18.2部分位于完整的IgG部分中,而抗4-1BB为一个位于Fc片段C端的scFv。双特异性抗体包括一个具有N297A突变的IgG1主链,以便使Fcγ丧失功能。
表1抗体序列
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4F11E2和1A10序列也用于产生两种不同形式的双特异性抗体,分别如图1B和图1C所示。在图1B的形式中,抗紧密连接蛋白18.2部分也采用Fab形式,而抗4-1BB部分插入在抗紧密连接蛋白18.2Fab和Fc片段之间作为scFab片段存在。此处也使用了IgG1(N297A)。
表2图1B形式的抗体
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在图1C的形式中,抗紧密连接蛋白18.2部分以全IgG1形式存在,而抗-4-1BB部分位于Fc的C端的scFab片段。
表3图1C形式的抗体
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在初步测试中,图1B和1C形式的双特异性抗体在4-1BB结合方面优于图1A形式的双特异性抗体。因此,只有形式图1A的那些进行了如下所示的附加测试。此外,E-1A10的效力略低于C-1A10和D-1A10,因此也未纳入进一步研究。
实施例2抗CLDN18.2/4-1BB双特异性抗体的抗原结合
本实施例使用基于蛋白和基于细胞的分析来评估实施例1的双特异性抗体对CLDN18.2和4-1BB的结合活性。
2.1 ELISA结合4-1BB
简单来说,用100μl经PBS稀释的、浓度为0.5μg/ml的人4-1BB-His蛋白在4℃过夜包被微量滴定板,然后用100μl/孔的1%BSA封闭微量滴定板。将从100nM起进行三倍稀释的抗体加入每个孔中,并在室温下孵育2小时。用PBS/吐温洗涤平板,然后在室温下用山羊抗人IgG抗体与辣根过氧化物酶(HRP)共孵育30分钟。洗涤后,用TMB底物显影,并用分光光度计在OD450nm处用进行分析。如图2A所示,抗CLDN18.2-4-1BB抗体(C-1A10和D-1A10)显示出与抗4-1BB单克隆抗体(1A10和脲单抗(BMUR))相同程度的结合。
2.2 ELISA结合CLDN18.2
为了检测CLDN18.2的结合,CLDN18.2蛋白在病毒样颗粒(VLP)中表达以模拟天然构象。同样,用100μl经PBS稀释的浓度为3μg/ml的CLDN18.2 VLP在4℃过夜包被微量滴定板,然后用300μl/孔3%BSA封闭微量滴定板。将从100nM起进行三倍稀释的抗体添加到每个孔中,并在37℃下孵育2小时。用PBS/吐温洗涤平板,然后在室温下用山羊抗人IgG抗体与辣根过氧化物酶(HRP)共孵育30分钟。洗涤后,用TMB底物显影,并用分光光度计在OD450nm处用进行分析。如图2B所示,抗CLDN18.2-4-1BB抗体(C-1A10和D-1A10)显示出比抗CLDN18.2单克隆抗体(I-MAB362)更强的结合。同时,在相同的实验条件下,还检测了与CLDN18.1蛋白的结合。如图2C所示,没有抗体显示与CLDN18.1的交叉反应。
2.3 ELISA结合双抗原
为了进一步证明抗CLDN18.2-4-1BB抗体可以同时结合CLDN18.2和4-1BB,进行了DACE(双抗原捕获ELISA)试验。简单地说,用100μl经PBS稀释的3μg/ml的CLDN18.2 VLP在4℃下过夜包被微量滴定板。然后,将从100nM起进行三倍稀释的抗体添加到每个孔中,并在37℃下孵育2小时。洗涤后,将平板与浓度为1μg/ml的100μl人4-1BB-生物素蛋白在37℃下孵育1小时,然后在室温下与链霉亲和素HRP再孵育30分钟。洗涤后,用TMB底物显影,并用分光光度计在OD450nm处用进行分析。如图2D所示,D-1A10可以同时与hCLDN18.2和4-1BB结合。相反,CLDN18.2单抗72C1B6A3在本试验中无信号。
2.4基于细胞与4-1BB的结合
为了评估抗原结合特性,通过FACS分析抗CLDN18.2-4-1BB抗体与表达4-1BB的HEK293的结合。每个孔中的1×105HEK293-4-1BB细胞总数与用FACS缓冲液(PBS中含2%FBS)连续稀释的抗体在4℃下孵育30分钟。经FACS缓冲液洗涤后,将PE结合的抗人IgG抗体添加到每个孔中,并在4℃下孵育30分钟。洗涤后用FACS Caliber测定PE的MFI。如图3所示,所测试的抗CLDN18.2-4-1BB抗体(C-1A10和D-1A10)显示出与4-1BB的浓度依赖性结合能力,其与单克隆抗体(1A10和BMUR)相当。
2.5基于细胞与CLDN18.2结合
为了评价其与CLDN18.2的结合能力,制备了稳定表达人CLDN18.2的CHO-K1细胞系。然后用流式细胞术对CHO-C18.2细胞系进行高表达(CHO-K1C18.2高)和低表达(CHO-K1-C18.2低)的分类。CHO-K1-C18.2细胞与用FACS缓冲液连续稀释的抗体在4℃孵育30分钟。经FACS缓冲液洗涤后,加入PE偶联抗人IgG抗体,于4℃孵育30分钟。FACS法测定PE的MFI。如图4A和4B所示,抗CLDN18.2-4-1BB抗体以浓度依赖性方式与CLDN18.2表达的细胞结合;同时,两种双特异性抗体的结合力均强于临床试验中的抗CLDN18.2单克隆抗体IMAB362。
SNU620是一种内源性表达CLDN18.2的胃癌细胞系。如图4C所示,抗CLDN18.2-4-1BB双特异性抗体也可与SNU620结合。
实施例3抗CLDN18.2/4-1BB双特异性抗体的功能活性
3.1基于细胞系的CLDN18.2-4-1BB双特异性抗体的功能鉴定
为了测试双特异性抗体促进4-1BB信号的能力,使用了商业化的4-1BB分析。在本试验中,GloResponseTM NFκB-luc2/4-1BB-Jurkat细胞系(Promega,cat#CS196004)为效应细胞,以表达或不表达CLDN18.2或SNU620的CHO-K1为靶细胞。GloResponseTM NFκB-luc2/4-1BB-Jurkat细胞系经基因修饰以稳定表达4-1BB和响应元件下游的荧光素酶。荧光素酶的表达是在抗体与4-1BB受体结合时诱导的。简而言之,将密度为每孔2.5×104个细胞的效应细胞与2.5×104个靶细胞混合在白色96孔板中。将6倍连续稀释的抗体添加到白色96孔板中,最终浓度范围为16.7nM至0.28fm。在37℃孵育6小时后,通过添加荧光素酶底物获得荧光,并用酶标仪(PHERAstar)测量。用GraphPad软件进行四参数对数曲线分析。
如图5所示,BMUR单克隆抗体可以剂量依赖性地增强41BB性能,而1A10单克隆抗体在相同的实验环境中没有激动剂活性。抗CLDN18.2-4-1BB双特异性抗体D-1A10和C-1A10的活性依赖于CLDN18.2的表达。
3.2双特异性抗体促进人外周血单个核细胞(PBMC)免疫应答的活性
为了检测双特异性抗体对刺激的人外周血单个核细胞反应的能力,使用细胞因子产生分析。以0.5g/ml人抗CD3抗体刺激人外周血单个核细胞作为效应细胞。以CHO-K1表达的CLDN18.2为靶细胞。人外周血单个核细胞(1×105)与CHO-K1-CLDN18.2或对照CHO-K1细胞(2.5×104)在人抗CD3抗体存在下共培养。将连续稀释的双特异性抗体添加到混合培养物中,最终浓度从20nM开始。48小时后,在培养基中使用IL-2(人)LANCE Ultra TR-FRET检测试剂盒和IFN-γ(人)LANCE Ultra TR-FRET检测试剂盒(PerkinElmer)对IL2和IFN-γ水平进行测定。如图6所示,在CLDN18.2表达细胞的情况下,只有双特异性抗体才能激活PBMC反应。
为了进一步证明双特异性抗体的活性与CLDN18.2水平相关,将来自一个供体的人PBMC与不同的胃腺癌(GA)PDX衍生细胞共培养,其证明表达不同水平的C18.2。将连续稀释的双特异性抗体添加到混合培养物中,最终浓度从20nM开始。48小时后,使用IL-2(人)LANCE Ultra TR-FRET检测试剂盒(PerkinElmer)测量培养基中的IL-2水平。如图6D和6E所示,双特异性抗体D-1A10的活性与CLDN18.2水平相关。即使在CLDN18.2低至中表达肿瘤中,D-1A10也能有效激活T细胞。
3.3促进人CD8+T细胞应答的双特异性抗体的活性
为了进一步测试双特异性抗体激活人CD8+T细胞的能力,我们使用从PBMCs分离的人CD8+T细胞作为效应细胞。以CHO-K1表达的CLDN18.2或SNU620为靶细胞。分离的CD8+T细胞(7.5×104)与靶细胞(2.5×104)在人抗CD3抗体存在下共培养。将连续稀释的双特异性抗体添加到混合培养物中,最终浓度从20nM开始。IL2和IFN水平-γ在共培养48小时后,使用IL-2(人)LANCE Ultra TR-FRET检测试剂盒和IFN-γ(人)LANCE Ultra TR-FRET检测试剂盒(PerkinElmer)对培养基中的IL-2进行检测。如图7所示,在存在过表达C18.2的CHO-K1(图7A-7B)或内源性表达C18.2的SNU620(图7C-7D)的情况下,双特异性抗体C-1A10和D-1A10都能增加激活的CD8+T细胞的IL2和IFN-γ的产生。
实施例4抗CLDN18.2-4-1BB双特异性抗体对肿瘤生长的抑制作用
使用表达人4-1BB胞外区的人源化小鼠。小鼠结肠腺癌细胞(MC38)表达人CLDN18.2。人源化小鼠(h4-1BB)皮下植入MC38-hCLDN18.2细胞。小鼠每3天腹腔注射5次以下抗体:同型对照(10mg/kg)、抗CLDN18.2抗体(10mg/kg)、抗4-1BB抗体(10mg/kg)、抗CLDN18.2(10mg/kg)和抗4-1BB(10mg/kg)的组合,以及抗CLDN18.2-4-1BB双特异性抗体(13.3mg/kg)。在实验期间,每周两次用卡尺测量肿瘤体积。如图8所示,由双特异性抗体诱导的肿瘤生长抑制显著大于在使用每种靶向单克隆抗体组合中观察到的。为进一步了解抗体的作用机制,收集肿瘤浸润淋巴细胞和外周血淋巴细胞,用流式细胞仪检测CD3+T细胞百分率。结果表明,双特异性抗体能特异性增加肿瘤微环境中CD3+T细胞的数量,而对外周血无影响。
在同一动物模型的另一重复实验中,进一步证明了其体内疗效。图9A显示了各组动物的肿瘤生长曲线。实验结束时,抗CLDN18.2-4-1BB抗体(C-1A10)对肿瘤生长的抑制率达105%。双特异性组7只小鼠中有6只在第一次治疗后第25天无瘤。
此外,本实施例在第一次肿瘤接种后35天在对侧边用第二剂量的MC38-hCLDN18.2肿瘤细胞再激发所有抗CLDN18.2-4-1BB抗体(C-1A10)治疗的动物,并监测肿瘤生长且不给予额外治疗。结果表明,随着肿瘤细胞在幼鼠中继续生长,所有BsAb处理的小鼠对肿瘤再激发具有抵抗力,并且在研究结束前被认为是无肿瘤的(图9B),这表明目前的双特异性抗体可以再次诱导MC38肿瘤的长期保护性免疫记忆。同样,在一个卫星组(N=3/组)中,小鼠接受同样的治疗,在第二剂量抗体后3天提取肿瘤,以量化肿瘤浸润淋巴细胞(TILs)。BsAb治疗组的CD45+、CD8+TILs细胞百分率明显高于对照组。相反,其对外周血淋巴细胞没有影响(图9C)。
为进一步评价抗CLDN18.2-4-1BB双特异性抗体的抗肿瘤效果,对植入MC38-hCLDN18.2抗体的4-1BB人源化小鼠给予不同浓度的双特异性抗体。小鼠每3天腹腔注射4次以下抗体:同型对照(10mg/kg)、C-1A10(13.3mg/kg)、C-1A10(2.6mg/kg)、C-1A10(0.5mg/kg)、D-1A10(13.3mg/kg)、D-1A10(2.6mg/kg)、D-1A10(0.5mg/kg)。在实验期间,每周两次用卡尺测量肿瘤体积。如图10所示,C-1A10和D-1A10均能以剂量依赖性的方式抑制肿瘤生长。
为了解人源化小鼠模型中抗CLDN18.2-4-1BB的药代动力学(PK)和药效学关系,对荷瘤-人源化小鼠单次给予3种不同浓度的D-1A10。在不同时间点测定血清浓度。如图11所示,总的来说,它显示了剂量依赖性PK曲线。体内药效与剂量水平相关。体外TIL分析表明CD8+细胞和CD45+细胞呈剂量依赖性增加。
实施例5附加条件激动剂全人抗4-1BB抗体的检测
以下抗4-1BB抗体具有高亲和力结合4-1BB的能力,并且在结合时不会激活4-1BB信号。
表4其他的抗4-1BB抗体
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表4中VH的CDRs
表5抗4-1BB scFv的VH和VL
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5.1 ELISA法测定抗原结合
为了评估抗原结合活性,对抗体进行ELISA试验。简单地说,以100μl/孔、在PBS中的0.1μg/ml的人4-1BB-Fc蛋白在4℃过夜包被微量滴定板,然后用100μl/孔5%牛血清白蛋白封闭微量滴定板。将从10μg/ml起的5倍稀释的抗体加入每个孔中,并在常温下培养1-2小时。用PBS/吐温洗涤平板,然后在常温下与结合有辣根过氧化物酶(HRP)的山羊抗人IgG抗体孵育1小时。洗涤后,用TMB底物显影平板,并用分光光度计在OD 450-630nm下分析。所检测的抗4-1BB抗体具有4-1BB结合能力。
5.2 FACS测定细胞结合
为了评估抗原结合特性,通过FACS分析候选抗体与哺乳动物表达的4-1BB的结合。简而言之,4-1BB-Jurkat细胞与抗体一起孵育。用FACS缓冲液(PBS中1%BSA)洗涤后,在每个孔中加入FITC-抗人IgG抗体,并在4℃孵育1小时。用FACS Caliber分析FITC的MFI。所检测的抗4-1BB抗体对细胞表面表达的4-1BB具有结合能力,并且能有效地与哺乳动物细胞表达的4-1BB结合。
5.3 4-1BB的蛋白质动力学
为了探索抗体的结合动力学,本实施例使用生物分子相互作用分析仪(Octet Red96)进行亲和性排序。如表5所示,所测试的抗4-1BB抗体具有较高的4-1BB结合亲和力。
表5结合动力学
本发明并不受所描述的旨在作为本发明各个方面的单个说明的具体实施例范围的限制,并且在功能上等同的任何组合物或方法均在本发明的保护范围内。对本领域技术人员而言显而易见的是,在不脱离本发明的精神或范围的情况下,可以对本发明的方法和组合物进行各种修改和变化。因此,落入本发明所附的权利要求及其等同物范围内的修改和变化均属于本发明保护的范围。
在本说明书中提及的所有出版物和专利申请通过引用全部并入本文,其程度与每个单独的出版物或专利申请通过引用被明确地和单独地指示参入本文相同。
SEQUENCE LISTING
<110> 天境生物科技(上海)有限公司
ABL生物有限公司
<120> 抗紧密连接蛋白18.2和抗4-1BB双特异性抗体及其用途
<130> P21113909CP
<150> PCT/CN2019/100162
<151> 2019-08-12
<150> PCT/CN2019/104508
<151> 2019-09-05
<150> PCT/CN2020/071954
<151> 2020-01-14
<150> PCT/CN2020/087968
<151> 2020-04-30
<160> 74
<170> PatentIn version 3.5
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Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ala
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Ser Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ile Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 30
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 30
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Ile Ile Gln Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Gln Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Tyr Phe Gly Asn Ala Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 31
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 31
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ala
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Tyr Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 32
<211> 330
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 32
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 Ala 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 Glu Glu
225 230 235 240
Met 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> 33
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 33
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> 34
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 34
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 35
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 35
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 36
<211> 103
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 36
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
100
<210> 37
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 37
Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser
1 5 10 15
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
20 25 30
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro
35 40 45
Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn
50 55 60
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
65 70 75 80
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
85 90 95
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
100 105
<210> 38
<211> 64
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 38
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
1 5 10 15
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
20 25 30
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
50 55 60
<210> 39
<211> 255
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 39
Met Gly Asn Ser Cys Tyr Asn Ile Val Ala Thr Leu Leu Leu Val Leu
1 5 10 15
Asn Phe Glu Arg Thr Arg Ser Leu Gln Asp Pro Cys Ser Asn Cys Pro
20 25 30
Ala Gly Thr Phe Cys Asp Asn Asn Arg Asn Gln Ile Cys Ser Pro Cys
35 40 45
Pro Pro Asn Ser Phe Ser Ser Ala Gly Gly Gln Arg Thr Cys Asp Ile
50 55 60
Cys Arg Gln Cys Lys Gly Val Phe Arg Thr Arg Lys Glu Cys Ser Ser
65 70 75 80
Thr Ser Asn Ala Glu Cys Asp Cys Thr Pro Gly Phe His Cys Leu Gly
85 90 95
Ala Gly Cys Ser Met Cys Glu Gln Asp Cys Lys Gln Gly Gln Glu Leu
100 105 110
Thr Lys Lys Gly Cys Lys Asp Cys Cys Phe Gly Thr Phe Asn Asp Gln
115 120 125
Lys Arg Gly Ile Cys Arg Pro Trp Thr Asn Cys Ser Leu Asp Gly Lys
130 135 140
Ser Val Leu Val Asn Gly Thr Lys Glu Arg Asp Val Val Cys Gly Pro
145 150 155 160
Ser Pro Ala Asp Leu Ser Pro Gly Ala Ser Ser Val Thr Pro Pro Ala
165 170 175
Pro Ala Arg Glu Pro Gly His Ser Pro Gln Ile Ile Ser Phe Phe Leu
180 185 190
Ala Leu Thr Ser Thr Ala Leu Leu Phe Leu Leu Phe Phe Leu Thr Leu
195 200 205
Arg Phe Ser Val Val Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
210 215 220
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
225 230 235 240
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
245 250 255
<210> 40
<211> 715
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<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 Thr Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Thr Ser Gly Glu Ser Pro Ile Tyr Phe Thr Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Tyr Gly Asn Ser Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
465 470 475 480
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
485 490 495
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
500 505 510
Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
515 520 525
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
530 535 540
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu
545 550 555 560
Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
580 585 590
Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
595 600 605
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
610 615 620
Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu
625 630 635 640
Trp Val Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala Asp
645 650 655
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
660 665 670
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
675 680 685
Tyr Cys Ala Arg Asp Ala Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr
690 695 700
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
705 710 715
<210> 41
<211> 220
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 41
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Leu Leu Asn Ala
20 25 30
Gly Asn Arg Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 42
<211> 716
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 42
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr
20 25 30
Pro Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Asn Phe His Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Tyr Gly Tyr Pro Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly
465 470 475 480
Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn
485 490 495
Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
500 505 510
Leu Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe
515 520 525
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu
530 535 540
Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser
545 550 555 560
Leu Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
580 585 590
Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
595 600 605
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
610 615 620
Ser Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu
625 630 635 640
Glu Trp Val Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala
645 650 655
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
660 665 670
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
675 680 685
Tyr Tyr Cys Ala Arg Asp Ala Gln Arg Asn Ser Met Arg Glu Phe Asp
690 695 700
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
705 710 715
<210> 43
<211> 220
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 43
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ala
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Ser Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ile Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 44
<211> 714
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 44
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Ile Ile Gln Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Phe Ile Asn Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Gln Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Tyr Phe Gly Asn Ala Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
450 455 460
Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln Arg
465 470 475 480
Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Tyr
485 490 495
Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile
500 505 510
Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly
515 520 525
Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser
530 535 540
Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu Ser
545 550 555 560
Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gly Gly
565 570 575
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
580 585 590
Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
595 600 605
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
610 615 620
Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp
625 630 635 640
Val Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala Asp Ser
645 650 655
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
660 665 670
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
675 680 685
Cys Ala Arg Asp Ala Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr Trp
690 695 700
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
705 710
<210> 45
<211> 220
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 45
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ala
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Tyr Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 46
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 46
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile 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 Gly Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 47
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 47
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile 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 Ala Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 48
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 48
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile 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 Ala Gln Arg Gln Ser Met Arg Glu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 49
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 49
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile 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 Gly Gln Arg Gln Ser Met Arg Glu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 50
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 50
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile 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 Ala Gln Arg Asn Ala Met Arg Glu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 51
<211> 127
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 51
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Pro Asp Asp Gly Asn 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 Ala Ala Val Tyr Tyr Cys
85 90 95
Ala Lys His Gly Gly Gln Lys Pro Thr Thr Lys Ser Ser Ser Ala Tyr
100 105 110
Gly Met Asp Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 52
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 52
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Arg
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 53
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 53
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 54
<211> 973
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 54
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Thr Ser Gly Glu Ser Pro Ile Tyr Phe Thr Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Tyr Gly Asn Ser Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly
260 265 270
Asn Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr
325 330 335
Ser Leu Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser
355 360 365
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
370 375 380
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro
385 390 395 400
Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn
405 410 415
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
420 425 430
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
435 440 445
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser Gly Ser Gly Ser Gly Ser
450 455 460
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Gly Gly Gly
465 470 475 480
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
485 490 495
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser Gly Ser Gly Ser
500 505 510
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Glu Val Gln Leu Leu Glu
515 520 525
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
530 535 540
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Asp Met Ser Trp Val Arg
545 550 555 560
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Trp Ile Ser Tyr Ser
565 570 575
Gly Gly Ser Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
580 585 590
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
595 600 605
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Gln Arg
610 615 620
Asn Ser Met Arg Glu Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
625 630 635 640
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
645 650 655
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
660 665 670
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
675 680 685
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
690 695 700
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
705 710 715 720
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
725 730 735
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
740 745 750
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
755 760 765
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
770 775 780
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
785 790 795 800
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
805 810 815
Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu
820 825 830
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
835 840 845
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
850 855 860
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
865 870 875 880
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
885 890 895
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
900 905 910
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
915 920 925
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
930 935 940
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
945 950 955 960
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
965 970
<210> 55
<211> 968
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 55
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Thr Ser Gly Glu Ser Pro Ile Tyr Phe Thr Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Tyr Gly Asn Ser Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
465 470 475 480
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
485 490 495
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
500 505 510
Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
515 520 525
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
530 535 540
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu
545 550 555 560
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln
565 570 575
Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
580 585 590
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
595 600 605
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys
610 615 620
Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr
625 630 635 640
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
645 650 655
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
660 665 670
Thr Val Ala Pro Thr Glu Cys Ser Gly Ser Gly Ser Gly Ser Gly Ser
675 680 685
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Gly Gly Gly Ser Gly
690 695 700
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
705 710 715 720
Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
725 730 735
Gly Ser Gly Ser Gly Ser Gly Ser Glu Val Gln Leu Leu Glu Ser Gly
740 745 750
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
755 760 765
Ser Gly Phe Thr Phe Ser Ser Tyr Asp Met Ser Trp Val Arg Gln Ala
770 775 780
Pro Gly Lys Gly Leu Glu Trp Val Ser Trp Ile Ser Tyr Ser Gly Gly
785 790 795 800
Ser Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
805 810 815
Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala
820 825 830
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Gln Arg Asn Ser
835 840 845
Met Arg Glu Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
850 855 860
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
865 870 875 880
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
885 890 895
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
900 905 910
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
915 920 925
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
930 935 940
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
945 950 955 960
Lys Lys Val Glu Pro Lys Ser Cys
965
<210> 56
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 56
Asp Gly Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr
1 5 10
<210> 57
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 57
Asp Ala Gln Arg Gln Ser Met Arg Glu Phe Asp Tyr
1 5 10
<210> 58
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 58
Asp Gly Gln Arg Gln Ser Met Arg Glu Phe Asp Tyr
1 5 10
<210> 59
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 59
Asp Ala Gln Arg Asn Ala Met Arg Glu Phe Asp Tyr
1 5 10
<210> 60
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 60
Gly Tyr Asp Met Ser
1 5
<210> 61
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 61
Val Ile Tyr Pro Asp Asp Gly Asn Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 62
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 62
His Gly Gly Gln Lys Pro Thr Thr Lys Ser Ser Ser Ala Tyr Gly Met
1 5 10 15
Asp Gly
<210> 63
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 63
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile 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 Gly Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 64
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 64
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile 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 Ala Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 65
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 65
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile 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 Ala Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 66
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 66
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile 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 Ala Gln Arg Gln Ser Met Arg Glu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 67
<211> 127
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 67
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Pro Asp Asp Gly Asn 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 Ala Ala Val Tyr Tyr Cys
85 90 95
Ala Lys His Gly Gly Gln Lys Pro Thr Thr Lys Ser Ser Ser Ala Tyr
100 105 110
Gly Met Asp Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 68
<211> 127
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 68
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Pro Asp Asp Gly Asn 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 Lys His Gly Gly Gln Lys Pro Thr Thr Lys Ser Ser Ser Ala Tyr
100 105 110
Gly Met Asp Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 69
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 69
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Arg
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 70
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 70
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Arg
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 71
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 71
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 72
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 72
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 73
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 73
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Arg
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 74
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 74
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu
100 105 110
Claims (34)
1.一种包含两个第一多肽和两个第二多肽的抗体,其特征在于,每个第一多肽从N端到C端依次包含重链可变区(VH)、CH1、CH2、CH3和对4-1BB蛋白具有特异性的单链片段(scFv);
其中每个第二多肽包括轻链可变区(VL)和CL;
其中每个VH与一个所述VL配对并且对紧密连接蛋白18.2(CLDN18.2)蛋白具有特异性;并且
所述scFv包含含有CDRH1、CDRH2和CDRH3的重链可变区(VH),以及含有CDRL1、CDRL2和CDRL3的轻链可变区(VL),其中:
所述CDRH1的氨基酸序列如SEQ ID NO:1所示;
所述CDRH2的氨基酸序列如SEQ ID NO:2所示;
所述CDRH3的氨基酸序列如SEQ ID NO:3、56、57、58或59所示;
所述CDRL1的氨基酸序列如SEQ ID NO:4所示;
所述CDRL2的氨基酸序列如SEQ ID NO:5所示;和
所述CDRL3的氨基酸序列如SEQ ID NO:6所示。
2.如权利要求1所述的抗体,其特征在于,所述scFv包含含有CDRH1、CDRH2和CDRH3的重链可变区(VH),以及含有CDRL1、CDRL2和CDRL3的轻链可变区(VL),其中:
所述CDRH1的氨基酸序列如SEQ ID NO:1所示;
所述CDRH2的氨基酸序列如SEQ ID NO:2所示;
所述CDRH3的氨基酸序列如SEQ ID NO:3所示;
所述CDRL1的氨基酸序列如SEQ ID NO:4所示;
所述CDRL2的氨基酸序列如SEQ ID NO:5所示;和
所述CDRL3的氨基酸序列如SEQ ID NO:6所示。
3.如权利要求1所述的抗体,其特征在于,所述scFv包含含有CDRH1、CDRH2和CDRH3的重链可变区(VH),以及含有CDRL1、CDRL2和CDRL3的轻链可变区(VL),其中:
所述CDRH1的氨基酸序列如SEQ ID NO:1所示;
所述CDRH2的氨基酸序列如SEQ ID NO:2所示;
所述CDRH3的氨基酸序列如SEQ ID NO:56所示;
所述CDRL1的氨基酸序列如SEQ ID NO:4所示;
所述CDRL2的氨基酸序列如SEQ ID NO:5所示;和
所述CDRL3的氨基酸序列如SEQ ID NO:6所示。
4.一种包含两个第一多肽和两个第二多肽的抗体,其特征在于,每个第一多肽从N端到C端依次包含重链可变区(VH)、CH1、对4-1BB蛋白具有特异性的单链片段(scFab)、CH2和CH3;
其中每个第二多肽包括轻链可变区(VL)和CL;
其中每个VH与一个所述VL配对并且对紧密连接蛋白18.2(CLDN18.2)蛋白具有特异性;并且
所述scFab包含含有CDRH1、CDRH2和CDRH3的重链可变区(VH),以及含有CDRL1、CDRL2和CDRL3的轻链可变区(VL),其中:
所述CDRH1的氨基酸序列如SEQ ID NO:1所示;
所述CDRH2的氨基酸序列如SEQ ID NO:2所示;
所述CDRH3的氨基酸序列如SEQ ID NO:3、56、57、58或59所示;
所述CDRL1的氨基酸序列如SEQ ID NO:4所示;
所述CDRL2的氨基酸序列如SEQ ID NO:5所示;和
所述CDRL3的氨基酸序列如SEQ ID NO:6所示。
5.如权利要求4所述的抗体,其特征在于,所述scFab包含含有CDRH1、CDRH2和CDRH3的重链可变区(VH),以及含有CDRL1、CDRL2和CDRL3的轻链可变区(VL),其中:
所述CDRH1的氨基酸序列如SEQ ID NO:1所示;
所述CDRH2的氨基酸序列如SEQ ID NO:2所示;
所述CDRH3的氨基酸序列如SEQ ID NO:3所示;
所述CDRL1的氨基酸序列如SEQ ID NO:4所示;
所述CDRL2的氨基酸序列如SEQ ID NO:5所示;和
所述CDRL3的氨基酸序列如SEQ ID NO:6所示。
6.如权利要求4所述的抗体,其特征在于,所述scFab包含含有CDRH1、CDRH2和CDRH3的重链可变区(VH),以及含有CDRL1、CDRL2和CDRL3的轻链可变区(VL),其中:
所述CDRH1的氨基酸序列如SEQ ID NO:1所示;
所述CDRH2的氨基酸序列如SEQ ID NO:2所示;
所述CDRH3的氨基酸序列如SEQ ID NO:56所示;
所述CDRL1的氨基酸序列如SEQ ID NO:4所示;
所述CDRL2的氨基酸序列如SEQ ID NO:5所示;和
所述CDRL3的氨基酸序列如SEQ ID NO:6所示。
7.一种包含两个第一多肽和两个第二多肽的抗体,其特征在于,每个第一多肽从N端到C端依次包含重链可变区(VH)、CH1、CH2、CH3和对4-1BB蛋白具有特异性的单链片段(scFab);
其中每个第二多肽包括轻链可变区(VL)和CL;
其中每个VH与一个所述VL配对并且对紧密连接蛋白18.2(CLDN18.2)蛋白具有特异性;并且
所述scFab包含含有CDRH1、CDRH2和CDRH3的重链可变区(VH),以及含有CDRL1、CDRL2和CDRL3的轻链可变区(VL),其中:
所述CDRH1的氨基酸序列如SEQ ID NO:1所示;
所述CDRH2的氨基酸序列如SEQ ID NO:2所示;
所述CDRH3的氨基酸序列如SEQ ID NO:3、56、57、58或59所示;
所述CDRL1的氨基酸序列如SEQ ID NO:4所示;
所述CDRL2的氨基酸序列如SEQ ID NO:5所示;和
所述CDRL3的氨基酸序列如SEQ ID NO:6所示。
8.如权利要求7所述的抗体,其特征在于,所述scFab包含含有CDRH1、CDRH2和CDRH3的重链可变区(VH),以及含有CDRL1、CDRL2和CDRL3的轻链可变区(VL),其中:
所述CDRH1的氨基酸序列如SEQ ID NO:1所示;
所述CDRH2的氨基酸序列如SEQ ID NO:2所示;
所述CDRH3的氨基酸序列如SEQ ID NO:3所示;
所述CDRL1的氨基酸序列如SEQ ID NO:4所示;
所述CDRL2的氨基酸序列如SEQ ID NO:5所示;和
所述CDRL3的氨基酸序列如SEQ ID NO:6所示。
9.如权利要求7所述的抗体,其特征在于,所述scFab包含含有CDRH1、CDRH2和CDRH3的重链可变区(VH),以及含有CDRL1、CDRL2和CDRL3的轻链可变区(VL),其中:
所述CDRH1的氨基酸序列如SEQ ID NO:1所示;
所述CDRH2的氨基酸序列如SEQ ID NO:2所示;
所述CDRH3的氨基酸序列如SEQ ID NO:56所示;
所述CDRL1的氨基酸序列如SEQ ID NO:4所示;
所述CDRL2的氨基酸序列如SEQ ID NO:5所示;和
所述CDRL3的氨基酸序列如SEQ ID NO:6所示。
10.如权利要求1-9任一项所述的抗体,其特征在于,在缺乏所述抗CLDN18.2单元结合所述CLDN18.2蛋白的情况下,所述抗4-1BB单元与细胞上的所述4-1BB蛋白的结合不会导致所述4-1BB蛋白的聚集。
11.如权利要求1-9任一项所述的抗体,其特征在于,其进一步包含具有降低的效应器功能的Fc片段。
12.如权利要求11所述的抗体,其特征在于,所述CH2和CH3构成具有降低的效应器功能的Fc片段。
13.如权利要求11所述的抗体,其特征在于,所述效应器功能为抗体依赖性细胞介导的细胞毒性(ADCC)、补体依赖的细胞毒性(CDC)或抗体依赖性细胞吞噬作用(ADCP)。
14.如权利要求13所述的抗体,其特征在于,所述Fc片段减少或没有结合FcγR或C1q。
15.如权利要求14所述的抗体,其特征在于,所述Fc片段具有一个或多个突变以减少或消除与FcγR或C1q结合。
16.如权利要求15所述的抗体,其特征在于,所述Fc片段选自由以下组成的组:
具有L235E突变的IgG1 Fc片段,
具有L234A和/或L235A突变的IgG1 Fc片段,
具有P329G或P329A突变的IgG1 Fc片段,
具有F234A和/或L235A或L235E突变的IgG4 Fc片段,
具有H268Q、V309L、A330S和/或P331S突变的IgG2 Fc片段,以及
具有V234A、G237A、P238S、H268A、V309L、A330S和/或P331S突变的IgG2 Fc片段(EU编号)。
17.如权利要求11所述的抗体,其特征在于,所述Fc片段为经糖基化的。
18.如权利要求17所述的抗体,其特征在于,所述Fc片段包含消除糖基化的突变。
19.如权利要求18所述的抗体,其特征在于,所述突变位于N297处,任选为N297A、N297G或N297Q。
20.如权利要求11所述的抗体,其特征在于,所述Fc片段包含N297A的突变,或者L234A和L235A突变的组合。
21.如权利要求1-9任一项所述的抗体,其特征在于,所述抗4-1BB单元包含重链可变区(VH)和轻链可变区(VL),其中
(a)所述抗4-1BB单元的VH的氨基酸序列如SEQ ID NO:24所示;和所述抗4-1BB单元的VL的氨基酸序列如SEQ ID NO:25所示;
或者
(b)所述抗4-1BB单元的VH的氨基酸序列如SEQ ID NO:46所示;和所述抗4-1BB单元的VL的氨基酸序列如SEQ ID NO:52所示;
或者
(c)所述抗4-1BB单元的VH的氨基酸序列如SEQ ID NO:47所示;和所述抗4-1BB单元的VL的氨基酸序列如SEQ ID NO:52所示;
或者
(d)所述抗4-1BB单元的VH的氨基酸序列如SEQ ID NO:48所示;和所述抗4-1BB单元的VL的氨基酸序列如SEQ ID NO:52所示;
或者
(e)所述抗4-1BB单元的VH的氨基酸序列如SEQ ID NO:49所示;和所述抗4-1BB单元的VL的氨基酸序列如SEQ ID NO:53所示;
或者
(f)所述抗4-1BB单元的VH的氨基酸序列如SEQ ID NO:50所示;和所述抗4-1BB单元的VL的氨基酸序列如SEQ ID NO:53所示;
或者
(g)所述抗4-1BB单元的VH的氨基酸序列如SEQ ID NO:63所示;和所述抗4-1BB单元的VL的氨基酸序列如SEQ ID NO:69所示;
或者
(h)所述抗4-1BB单元的VH的氨基酸序列如SEQ ID NO:64所示;和所述抗4-1BB单元的VL的氨基酸序列如SEQ ID NO:70所示;
或者
(i)所述抗4-1BB单元的VH的氨基酸序列如SEQ ID NO:65所示;和所述抗4-1BB单元的VL的氨基酸序列如SEQ ID NO:71所示;
或者
(j)所述抗4-1BB单元的VH的氨基酸序列如SEQ ID NO:66所示;和所述抗4-1BB单元的VL的氨基酸序列如SEQ ID NO:72所示。
22.权利要求1-9任一项所述的抗体,其特征在于,所述抗CLDN18.2单元包含含有CDRH1、CDRH2和CDRH3的重链可变区(VH),以及含有CDRL1、CDRL2和CDRL3的轻链可变区(VL),其中:
(a)所述CDRH1的氨基酸序列如SEQ ID NO:7所示;
所述CDRH2的氨基酸序列如SEQ ID NO:8所示;
所述CDRH3的氨基酸序列如SEQ ID NO:9所示;
所述CDRL1的氨基酸序列如SEQ ID NO:10所示;
所述CDRL2的氨基酸序列如SEQ ID NO:11所示;和
所述CDRL3的氨基酸序列如SEQ ID NO:12所示,
或者
(b)所述CDRH1的氨基酸序列如SEQ ID NO:13所示;
所述CDRH2的氨基酸序列如SEQ ID NO:14所示;
所述CDRH3的氨基酸序列如SEQ ID NO:15所示;
所述CDRL1的氨基酸序列如SEQ ID NO:16所示;
所述CDRL2的氨基酸序列如SEQ ID NO:17所示;和
所述CDRL3的氨基酸序列如SEQ ID NO:18所示,
或者
(c)所述CDRH1的氨基酸序列如SEQ ID NO:19所示;
所述CDRH2的氨基酸序列如SEQ ID NO:20所示;
所述CDRH3的氨基酸序列如SEQ ID NO:21所示;
所述CDRL1的氨基酸序列如SEQ ID NO:22所示;
所述CDRL2的氨基酸序列如SEQ ID NO:11所示;和
所述CDRL3的氨基酸序列如SEQ ID NO:23所示。
23.如权利要求22所述的抗体,其特征在于,
(a)所述抗CLDN18.2单元的VH的氨基酸序列如SEQ ID NO:26所示;和所述抗CLDN18.2单元的VL的氨基酸序列如SEQ ID NO:27所示;或者
(b)所述抗CLDN18.2单元的VH的氨基酸序列如SEQ ID NO:28所示;和所述抗CLDN18.2单元的VL的氨基酸序列如SEQ ID NO:29所示;或者
(c)所述抗CLDN18.2单元的VH的氨基酸序列如SEQ ID NO:30所示;和所述抗CLDN18.2单元的VL的氨基酸序列如SEQ ID NO:31所示。
24.如权利要求1所述的抗体,其特征在于,每一个所述第一多肽包含如SEQ ID NO:40所示的氨基酸序列,并且每一个所述第二多肽包含如SEQ ID NO:41所示的氨基酸序列。
25.如权利要求1所述的抗体,其特征在于,每一个所述第一多肽包含如SEQ ID NO:42所示的氨基酸序列,并且每一个所述第二多肽包含如SEQ ID NO:43所示的氨基酸序列。
26.如权利要求1所述的抗体,其特征在于,每一个所述第一多肽包含如SEQ ID NO:44所示的氨基酸序列,且每一个所述第二多肽包含如SEQ ID NO:45所示的氨基酸序列。
27.如权利要求4所述的抗体,其特征在于,每一个所述第一多肽包含如SEQ ID NO:54所示的氨基酸序列,且每一个所述第二多肽包含如SEQ ID NO:41所示的氨基酸序列。
28.如权利要求7所述的抗体,其特征在于,每一个所述第一多肽包含如SEQ ID NO:55所示的氨基酸序列,且每一个所述第二多肽包含如SEQ ID NO:41所示的氨基酸序列。
29.一种或多种编码如权利要求1-28任一项所述的抗体的多核苷酸。
30.一种组合物,其包含如权利要求1-28任一项所述的抗体和医学上可接受的载体。
31.如权利要求1-28任一项所述的抗体在制备用于治疗癌症的药物中的用途。
32.如权利要求31所述的用途,其特征在于,与相应的正常细胞相比,所述癌症的特征为癌细胞过表达CLDN18.2。
33.如权利要求31或32所述的用途,其特征在于,所述癌症为上皮肿瘤,或所述癌症选自由膀胱癌、乳腺癌、结直肠癌、子宫内膜癌、食管癌、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组成的组。
34.如权利要求31或32所述的用途,其特征在于,所述癌症选自由胃癌、胰腺癌、食管癌、肺癌和卵巢癌组成的组。
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KR20210082482A (ko) | 2021-07-05 |
PE20211147A1 (es) | 2021-06-28 |
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