CN112996815B - 人pd-l1抗体 - Google Patents
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- CN112996815B CN112996815B CN202080005962.XA CN202080005962A CN112996815B CN 112996815 B CN112996815 B CN 112996815B CN 202080005962 A CN202080005962 A CN 202080005962A CN 112996815 B CN112996815 B CN 112996815B
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Abstract
本发明提供全人抗PD‑L1抗体或其片段。在各种实施例中,所述抗体或其片段包括VH CDR1、VH CDR2、VH CDR3、VL CDR1、VL CDR2及VL CDR3,其分别选自由如SEQ ID NO:35‑42、SEQID NO:43‑51、SEQ ID NO:52‑66、SEQ ID NO:67‑79、SEQ ID NO:80‑88及SEQ ID NO:89‑102所示的序列或其各自的变体组成的组。本发明还提供了使用所述抗体或其片段治疗和诊断诸如癌症和传染病等疾病的方法。
Description
背景技术
程序性死亡配体1(PD-L1),也称为分化簇274(CD274)或B7同源物1(B7-H1),针对其的抗体被用于癌症治疗和其他临床应用。PD-L1是一种40kDa的1型跨膜蛋白,被认为在妊娠、组织移植、自身免疫性疾病和肝炎等疾病状态下对免疫系统起着重要的抑制作用。PD-L1与PD-1或B7.1的结合传递了一种抑制信号,这种抑制信号可减少淋巴结处CD8+T细胞的增殖,并且所述结合还能够使得PD-1通过凋亡控制淋巴结中外来抗原特异性T细胞的积聚,而凋亡通过Bcl-2基因的下调来进一步介导。
除癌症治疗外,PD-L1的抑制性还有望在治疗感染性疾病中发挥作用。在胞内感染小鼠模型中,单核细胞增生李斯特菌(L.monocytogenes)能够诱导T细胞、NK细胞和巨噬细胞中PD-L1蛋白的表达。PD-L1阻断剂(例如,使用阻断抗体)能够导致被感染小鼠的死亡率增加。阻断剂减少了巨噬细胞中TNFα和一氧化氮的产生和NK细胞中颗粒酶B的产生,并降低了对单核细胞增生李斯特菌抗原特异性的CD8 T细胞(而非CD4 T细胞)的增殖。这些证据表明PD-L1在胞内感染中起着正性共刺激分子的作用。
发明内容概述
本发明提供一种对人PD-L1蛋白具有高亲和力的抗PD-L1抗体,并且该抗体可有效阻断PD-L1与其受体PD-1之间的相互作用。所鉴定的抗体是全人抗体,并且预期在临床应用中具有比人源化抗体更好的性能。
本发明的一个实施方案提供一种抗PD-L1抗体或其片段。在一些实施方案中,抗体或其抗原结合片段包含VH CDR1,其含有选自如SEQ ID NO:35-42所示的氨基酸序列及其具有一个或两个氨基酸取代的变体;VH CDR2,其含有选自如SEQ ID NO:43-51所示的氨基酸序列及其具有一个或两个氨基酸取代的变体;VH CDR3,其含有选自如SEQ ID NO:52-66所示的氨基酸序列及其具有一个或两个氨基酸取代的变体;VL CDR1,其含有选自如SEQ IDNO:67-79所示的氨基酸序列及其具有一个或两个氨基酸取代的变体,VL CDR2,其含有选自如SEQ ID NO:80-88所示的氨基酸序列及其具有一个或两个氨基酸取代的变体,以及包含选自如SEQ ID NO:89-102所示的氨基酸序列的VL CDR3及其具有一个或两个氨基酸取代的变体。
在一个实施方案中,所述VH CDR1包含如SEQ ID NO:37所示的氨基酸序列,所述VHCDR2包含如SEQ ID NO:46、135、136、137、142或143所示的氨基酸序列,所述VH CDR3包含如SEQ ID NO:63所示的氨基酸序列,所述VL CDR1包含如SEQ ID NO:76所示的氨基酸序列,所述VL CDR2包含如SEQ ID NO:83所示的氨基酸序列,以及所述VL CDR3包含如SEQ ID NO:97所示的氨基酸序列。在一个特定实施方案中,所述VH CDR2包含如SEQ ID NO:46所示的氨基酸序列。
在示例抗体或片段中,VH包含如SEQ ID NO:23、124、126、127、128、130、140或145所示的氨基酸序列,且所述VL包含如SEQ ID NO:24或125所示的氨基酸序列,以及它们的变体。例如,所述VH包含如SEQ ID NO:124所示的氨基酸序列或与SEQ ID NO:124具有至少95%序列同源性的第一氨基酸序列(同时保留所述CDRs),且所述VL包含如SEQ ID NO:125所示的氨基酸序列或与SEQ ID NO:125具有至少95%序列同源性的第二氨基酸序列(同时保留所述CDRs)。
本发明还提供了一种组合物,其包含所述抗体或其片段以及药学上可接受的载体。本发明还提供一种或多种编码所述抗体或其片段的多核苷酸、包含一种或多种编码所述抗体或其片段的多核苷酸的分离的细胞。
本发明还提供了治疗方法和用途。在其中一个实施方案中提供了在有需求的患者中治疗癌症或感染的方法,包括向患者施用有效剂量的本发明公开的抗体或其片段。在一些实施方案中,所述癌症是实体瘤。在一些实施方案中,所述癌症是膀胱癌、肝癌、结肠癌、直肠癌、子宫内膜癌、白血病、淋巴瘤、胰腺癌、小细胞肺癌、非小细胞肺癌、乳腺癌、尿道癌、头颈癌、胃肠癌、胃癌、食道癌、卵巢癌、肾癌、黑色素瘤、前列腺癌和甲状腺癌。在一些实施方案中,所述癌症可以是膀胱癌、肝癌、胰腺癌、非小细胞肺癌、乳腺癌、尿道癌、结肠直肠癌、头颈癌、鳞状细胞癌、梅克尔细胞癌、胃肠癌、胃癌、食道癌、卵巢癌、肾癌和小细胞肺癌。在一些实施方案中,该方法还包括向患者施用第二种癌症治疗剂。在一些实施方案中,所述感染是病毒感染、细菌感染、真菌感染或寄生虫感染。
附图说明
图1显示测试抗体与PD-L1的结合图。
图2显示抗体阻断PD1/PDL1介导的NF-AT荧光素酶活性的活性。
图3显示所有测试抗体在荧光素酶抑制下剂量依赖性逆转PD1/PDL1介导的NF。
图4显示突变抗体的功能测试结果。
图5显示B12-01与Tecentriq和阿维单抗(avelumab)的基于细胞的亲和力测试结果。
图6显示B12-01对PD-L1具有亚纳摩尔级别的亲和力。
图7显示B12-01与人PD-L1和食蟹猴PD-L1的结合能力相当。
图8显示B12-01有效阻断PD1蛋白与细胞表面PDL1的结合。
图9显示B12-01在体外显著促进人T细胞活化。
图10显示B12-01抑制肿瘤生长的体内功效。
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。
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。
术语“等价的核酸或多聚核苷酸”是指具有与核酸或其互补物的核苷酸序列具有一定程度的同源性或序列同一性的核苷酸序列的核酸。双链核酸的同源物意指包括具有与其或其互补序列具有一定同源性的核苷酸序列的核酸。一方面,核酸的同源物能够与核酸或其互补物杂交。同样地,“等价的多肽”是指与参考多肽的氨基酸序列具有一定同源性或序列同一性的多肽。在某些方面,序列同一性为至少约70%、75%、80%、85%、90%、95%、98%或99%。在某些方面,与参考的多肽或多聚核苷酸相比,等价的多肽或多聚核苷酸具有1、2、3、4或5个添加、缺失、取代及其组合。在某些方面,等价的序列保留参考序列的活性(例如表位结合)或结构(例如盐桥)。
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。
“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PD-L1抗体
本发明提供了对人PD-L1蛋白具有高亲和力的抗PD-L1抗体。测试抗体表现出有效的结合和抑制活性,并可用于治疗和诊断用途。
如实验实施例所示,从噬菌体文库中获得许多全人抗PD-L1抗体,包括B01-B17。其中一些抗体表现出良好的结合活性。例如,B04、B05、B06、B07、B10、B11、B12、B13、B14和B16可剂量依赖性地阻断PD1/PD-L1介导的NFAF荧光素酶活性。其中B06、B12和B16作用最强。
本发明的抗体与市场上和临床开发中的现有产品相比具有较好的优势。使用的参考抗体包括阿特珠单抗(atezolizumab,TecentriqTM),一种完全人源化的、Fc工程改造的IgG1同种型单克隆抗体,和阿维单抗(avelumab,BavencioTM),一种完全人源化的单克隆抗体。atezolizumab已被批准用于治疗转移性非小细胞肺癌(NSCLC)、扩展期小细胞肺癌和三阴性乳腺癌。在美国和欧洲,avelumab已被批准用于治疗梅克尔细胞癌。atezolizumab和avelumab是目前市场上领先的PD-L1抗体。
如实施例1所示,相当多的测试抗体,包括B07、B12、B13和B16,表现出比atezolizumab更高(或至少相当)的PD-L1结合亲和力(图1)。与atezolizumab和avelumab相比,对B12的一个变体B12-01进一步测试。与B12相比,B12-01在VH的C端有一个丝氨酸取代,在VL的N端有一个常规的DIQM伸展。
如实施例5所示,在基于细胞的亲和力测定中,B12-01优于atezolizumab和avelumab(图5)。B12-01比atezolizumab更有效是令人惊讶的,因为即使是比atezolizumab开发较晚的avelumab,也被认为(并由此证明)比atezolizumab更有效。
同样在实施例5中,在可开发性试验中,B12-01表现出比atezolizumab更高的亲水性,这表明B12-01具有更高的水溶性。因此,B12-01的这种特性在配方开发过程中有更高的灵活性。更进一步,如实施例7所示,B12-01对食蟹猴PD-L1具有跨物种反应性,这在动物模型的临床前研究中是有利的。
因此,根据本发明的一个实施例,提供了一种包含来自这些新鉴定抗体的CDR区域的抗体。这种CDR序列列在下表A中。
表A抗体B01-B17的CDR序列(Kabat)
LCDR1 | SEQ ID NO: | LCDR2 | SEQ ID NO: | LCDR3 | SEQ ID NO: | |
B01 | RASQSISSYLN | 67 | AASSLQS | 80 | QQSYSTPPT | 89 |
B02 | RASQTISRYLN | 68 | ATSSLQS | 81 | QQSYSTPTT | 90 |
B03 | RASQSIDTWLA | 69 | NASTLKS | 82 | QQSYSTPLT | 91 |
B04 | RASESISSWLA | 70 | KASSLES | 83 | QQSYSTPPT | 89 |
B05 | RASQSISSWLA | 71 | KASSLES | 83 | QQTYSLPLT | 92 |
B06 | RASQGISSYLA | 72 | AASTLQS | 84 | QQYLSVPYT | 93 |
B07 | RASQSISTWLA | 73 | KASSLES | 83 | QQSYSIPLT | 94 |
B08 | RASESISRWLA | 74 | AASNLES | 85 | QQAESFPS | 95 |
B09 | RASQSISSYLN | 67 | AASSLQS | 80 | QQSYSTPLT | 91 |
B10 | RASQSISDWLA | 75 | KASSLES | 83 | QQSFSTPFT | 96 |
B11 | RASQSISSYLN | 67 | AASSLQS | 80 | QQSYSTPLT | 91 |
B12 | RASRGISSWLA | 76 | KASSLES | 83 | QQSSSIPLT | 97 |
B13 | RASQSISSWLA | 71 | KASSLQS | 86 | QQSYSTPFT | 98 |
B14 | RASQGISSWLA | 77 | AASSLQS | 80 | QQANSFPFT | 99 |
B15 | RASQFISKYVN | 78 | GASILET | 87 | QQTHSTPRGV | 100 |
B16 | RASQSISSWLA | 71 | KASSLES | 83 | QHSNSLPLT | 101 |
B17 | QASQDISNYLN | 79 | DASNLET | 88 | QQYDNLPPFT | 102 |
可以设想,可以在这些CDR序列之间设计小的改变(例如,一个氨基酸的添加、删除或替换),以保持抗体的活性,甚至改善它们。这种修饰的CDR序列被称为CDR变体。
如实施例4所示,具有所有测试CDR变体的突变抗体表现出与原始抗体相当的活性。因此,这些CDR变体也在本发明的范围内。在一些实施方案中,变体具有一个或多个替换,例如D>E、S>A、G>A、N>Q、DS>ES、DS>DA、DG>DA、NS>NA或NS>QS。下面提供了一些例子。
表B代表性的CDR变体
HCDR1 | Sequence | SEQ ID NO: |
原始 | DSWIH | 38 |
变体 | ESWIH | 132 |
HCDR2 | Sequence | SEQ ID NO: |
原始 | WISPYGGSTYYADSVKG | 47 |
变体 | WISPYGGSTYYADAVKG | 133 |
WISPYGGSTYYAESVKG | 134 |
HCDR2 | Sequence | SEQ ID NO: |
原始 | NIKQDGSEKYYVDSVKG | 46 |
变体 | NIKQDGSEKYYVESVKG | 135 |
NIKQDASEKYYVDSVKG | 136 | |
NIKQDASEKYYVESVKG | 137 | |
NIKQEGSEKYYVDSVKG | 143 | |
NIKQEGSEKYYVDAVKG | 144 |
LCDR3 | Sequence | SEQ ID NO: |
原始 | QHSNSLPLT | 101 |
变体 | QHSNALPLT | 138 |
QHSQSLPLT | 139 |
在一个实施方案中,抗PD-L1抗体或其片段包括VH CDR1,其包含选自如SEQ IDNO:35-42所示的氨基酸序列及其具有一个或多个氨基酸取代的变体(例如,SEQ ID NO:132);VH CDR2,其包含选自如SEQ ID NO:43-51所示的氨基酸序列及其具有一个或多个氨基酸取代的变体(例如,SEQ ID NO:133-137和143-144);VH CDR3,其包含选自如SEQ IDNO:52-66所示的氨基酸序列及其具有一个或多个氨基酸取代的变体;VL CDR1,其包含选自如SEQ ID NO:67-79所示的氨基酸序列及其具有一个或多个氨基酸取代的变体;VL CDR2,其包含选自如SEQ ID NO:80-88所示的氨基酸序列及其具有一个或多个氨基酸取代的变体;以及VL CDR3,其包含选自如SEQ ID NO:89-102所示的氨基酸序列及其具有一个或多个氨基酸取代的变体(例如,SEQ ID NO:138-139)。
在一些实施方案中,所述VH CDR1包含选自如SEQ ID NO:35-42(或变体,例如SEQID NO:132)所示的氨基酸序列,所述VH CDR2包含选自如SEQ ID NO:43-51(或变体,例如SEQ ID NO:133-137和143-144)所示的氨基酸序列,所述VH CDR3包含选自如SEQ ID NO:52-66所示的氨基酸序列,所述VL CDR1包含选自如SEQ ID NO:67-79所示的氨基酸序列,所述VL CDR2包含选自如SEQ ID NO:80-88所示的氨基酸序列,以及所述VL CDR3包含选自如SEQ ID NO:89-102(或变体,例如SEQ ID NO:138-139)所示的氨基酸序列。
在一些实施方案中,所述CDR序列选自B04、B05、B06、B07、B10、B11、B12、B13、B14或B16。在一些实施方案中,所述VH CDR1包含选自如SEQ ID NO:37-38和40(或变体,例如SEQID NO:132)所示的氨基酸序列,所述VH CDR2包含选自如SEQ ID NO:45-47和49(或变体,例如SEQ ID NO:133-137和143-144)所示的氨基酸序列,所述VH CDR3包含选自如SEQ ID NO:54-58和61-64所示的氨基酸序列,所述VL CDR1包含选自如SEQ ID NO:67、70-73和75-77所示的氨基酸序列,所述VL CDR2包含选自如SEQ ID NO:80、83-84和86所示的氨基酸序列,以及所述VL CDR3包含选自如SEQ ID NO:89、91-94、96-99和101(或变体,如SEQ ID NO:138-139)所示的氨基酸序列。
在一些实施方案中,所述CDR序列选自B06、B12或B16。在一些实施方案中,所述VHCDR1包含选自如SEQ ID NO:37-38(或变体,例如SEQ ID NO:132)所示的氨基酸序列,所述VH CDR2包含选自如SEQ ID NO:46-47(或变体,例如SEQ ID NO:133-137和143-144)所示的氨基酸序列,所述VH CDR3包含选自如SEQ ID NO:57和63所示的氨基酸序列,所述VLCDR1包含选自如SEQ ID NO:71-72和76所示的氨基酸序列,所述VL CDR2包含选自如SEQ ID NO:83-84所示的氨基酸序列,所述VL CDR3包含选自如SEQ ID NO:93、97和101(或变体,如SEQID NO:138-139)所示的氨基酸序列。
本发明的抗体或片段的CDR序列可以从表A中所列的B01-B17的特定抗体中选择。例如,所述VH CDR1可以为SEQ ID NO:35,所述VH CDR2可以为SEQ ID NO:45,所述VH CDR3可以为SEQ ID NO:55,所述VL CDR1可以为SEQ ID NO:70,所述VL CDR2可以为SEQ ID NO:83,并且所述VL CDR3可以为SEQ ID NO:92(例如B01)。代表性的抗体或片段包括如SEQ IDNO:1所示的VH和如SEQ ID NO:2所示的VL。表A和表1提供了其他CDR序列和VH/VL序列。
在一个实施方案中,所述VH CDR1包含如SEQ ID NO:38(或变体,例如SEQ ID NO:132)所示的氨基酸序列,所述VH CDR2包含如SEQ ID NO:47(或变体,例如SEQ ID NO:133-134)所示的氨基酸序列,所述VH CDR3包含如SEQ ID NO:57所示的氨基酸序列,所述VLCDR1包含如SEQ ID NO:72所示的氨基酸序列,所述VL CDR2包含如SEQ ID NO:84所示的氨基酸序列,以及所述VL CDR3包含如SEQ ID NO:93所示的氨基酸序列(例如B06)。代表性的抗体或片段包括如SEQ ID NO:11(或变体,例如SEQ ID NO:121-123)所示的VH和如SEQ IDNO:12所示的VL。
在一个实施方案中,所述VH CDR1包含如SEQ ID NO:37所示的氨基酸序列,所述VHCDR2包含如SEQ ID NO:46(或诸如SEQ ID NO:135-137或143-144的变体)所示的氨基酸序列,所述VH CDR3包含如SEQ ID NO:63所示的氨基酸序列,所述VL CDR1包含如SEQ ID NO:76所示的氨基酸序列,所述VL-CDR2包含如SEQ ID NO:83所示的氨基酸序列,以及所述VLCDR3包含如SEQ ID NO:97所示的氨基酸序列(例如B12)。代表性的抗体或片段包括如SEQID NO:23(或诸如SEQ ID NO:124、126、127、128、130、140或145的变体)所示的VH和如SEQID NO:24(或诸如SEQ ID NO:125的变体)所示的VL。
本发明的一个实施方案提供了抗体或其抗原结合片段,其中该抗体或其片段对人程序性死亡配体1(PD-L1)蛋白具有特异性,并且包含含有VH CDR1、VH CDR2和VH CDR3的重链可变区(VH)和含有VL CDR1、VL CDR2和VL CDR3的轻链可变区(VL),其中:所述VH CDR1包含如SEQ ID NO:37所示的氨基酸序列,所述VH CDR2包含如SEQ ID NO:46所示的氨基酸序列,所述VH CDR3包含如SEQ ID NO:63所示的氨基酸序列,所述VL CDR1包含如SEQ ID NO:76所示的氨基酸序列,所述VL CDR2包含如SEQ ID NO:83如的氨基酸序列,以及所述VLCDR3包含如SEQ ID NO:97所示的氨基酸序列。
在一些实施方案中,所述VH包含如SEQ ID NO:124所示的氨基酸序列或与SEQ IDNO:124具有至少95%(或至少90%、85%)序列同源性的第一氨基酸序列,并且所述VL包含如SEQ ID NO:125所示的氨基酸序列或与所述SEQ ID:125具有至少95%(或至少90%、85%)序列同源性的第二氨基酸序列。
在一个实施方案中,所述VH CDR1包含如SEQ ID NO:37所示的氨基酸序列,所述VHCDR2包含如SEQ ID NO:46(或变体,例如SEQ ID NO:135-137或143-144)所示的氨基酸序列,所述VH CDR3包含如SEQ ID NO:63所示的氨基酸序列,所述VL CDR1包含如SEQ ID NO:71所示的氨基酸序列,所述VL-CDR2包含如SEQ ID NO:83所示的氨基酸序列,所述VL CDR3包含如SEQ ID NO:101(或变体,如SEQ ID NO:138-139的变体)所示的氨基酸序列(例如B16)。代表性的抗体或片段包括如SEQ ID NO:31(或变体,如SEQ ID NO:124、126、127、128、130、140和145)所示的VH和如SEQ ID NO:32(或变体,如SEQ ID NO:129和131)所示的VL。
表A提供了依据Kabat系统的CDR序列。Chothia系统对于VH CDR1和CDR2通常具有不同的序列。如下表C所示。
表C根据Chothia系统的CDR序列和变体
HCDR1 | SEQ ID NO: | HCDR2 | SEQ ID NO: | HCDR3 | SEQ ID NO: | |
B01 | GFTLSSH | 103 | HQDASL | 112 | GDNQFDN | 52 |
B02 | GFTFSTY | 104 | AASGDY | 113 | DRSSGYYLSPNDAFDI | 53 |
B03 | GFSFSSY | 105 | KEDGSE | 114 | VVRFNDAFDI | 54 |
B04 | GFTFSSY | 106 | KQDGSE | 115 | TMLWDDAFDI | 55 |
B05 | GFTFSSY | 106 | KQDGSE | 115 | GGYYGDDDAFDI | 56 |
B06 | GFTFSDS | 107 | SPYGGS | 116 | RHWPGGFDY | 57 |
B07 | GFTFSSY | 106 | KQDGSE | 115 | VCGYDDAFDI | 58 |
B08 | GFTFSDH | 108 | SSSSSY | 117 | GRVGATNRFGMDV | 59 |
B09 | GFTFSSY | 106 | KQDGSE | 115 | EDFWSGYQDV | 60 |
B10 | GFTFSSY | 106 | KQDGSE | 115 | ATVKYGGDDAFDI | 61 |
B11 | GGTFSSY | 109 | IPIFGT | 118 | RTDSYGYSDAFDI | 62 |
B12 | GFTFSSY | 106 | KQDGSE | 115 | VALWDDAFDI | 63 |
B13 | GFTFSSY | 106 | KQDGSE | 115 | STVKYGADDAFDI | 64 |
B14 | GFSFSSY | 105 | KEDGSE | 114 | VVRFNDAFDI | 54 |
B15 | GFTFSVY | 110 | SNGDGDI | 119 | AARSGYYNDY | 65 |
B16 | GFTFSSY | 106 | KQDGSE | 115 | VALWDDAFDI | 63 |
B17 | GFTFSSN | 111 | GGGGVN | 120 | GEKGYSNSCIDY | 66 |
HCDR1 | 序列 | SEQ ID NO: |
原始 | GFTFSDS | 107 |
变体 | GFTFSES | 141 |
HCDR2 | 序列 | SEQ ID NO: |
原始 | KQDGSE | 115 |
变体 | KQDASE | 142 |
LCDR3 | 序列 | SEQ ID NO: |
原始 | QHSNSLPLT | 101 |
变体 | QHSNALPLT | 138 |
QHSQSLPLT | 139 |
在一个实施方案中,抗PD-L1抗体或其片段包括VH CDR1,其包含选自如SEQ IDNO:103-111所示的氨基酸序列及其具有一个或多个氨基酸取代的变体(例如SEQ ID NO:141);VH CDR2,其包含选自如SEQ ID NO:112-120所示的氨基酸序列及其具有一个或多个氨基酸取代(例如SEQ ID NO:142)的变体;VH CDR3,其包含选自如SEQ ID NO:52-66所示的氨基酸序列及其具有一个或多个氨基酸取代的变体;VL CDR1,其包含选自如SEQ ID NO:67-79所示的氨基酸序列及其具有一个或多个氨基酸取代的变体;VL CDR2,其包含选自如SEQ ID NO:80-88所示的氨基酸序列及其具有一个或多个氨基酸取代的变体;以及VLCDR3,其包含选自如SEQ ID NO:89-102所示的氨基酸序列及其具有一个或多个氨基酸取代的变体(例如SEQ ID NO:138-139)。
在一些实施方案中,所述VH CDR1包含选自如SEQ ID NO:103-111(或变体,例如SEQ ID NO:141)所示的氨基酸序列,所述VH CDR2包含选自如SEQ ID NO:112-120(或变体,例如SEQ ID NO:142)所示的氨基酸序列,所述VH CDR3包含选自如SEQ ID NO:52-66所示的氨基酸序列,所述VL CDR1包含选自如SEQ ID NO:67-79所示的氨基酸序列,所述VL CDR2包含选自如SEQ ID NO:80-88所示的氨基酸序列,并且所述VL CDR3包含选自如SEQ ID NO:89-102(或变体,例如SEQ ID NO:138-139)所示的氨基酸序列。
在一些实施方案中,所述CDR序列选自B04、B05、B06、B07、B10、B11、B12、B13、B14或B16。在一些实施方案中,所述VH CDR1包含选自如SEQ ID NO:105-107和109(或变体,例如SEQ ID NO:141)所示的氨基酸序列,所述VH CDR2包含选自如SEQ ID NO:114-116和118(或变体,例如SEQ ID NO:142)所示的氨基酸序列,所述VH CDR3包含选自如SEQ ID NO:54-58和61-64所示的氨基酸序列,所述VL CDR1包含选自如SEQ ID NO:67、70-73和75-77所示的氨基酸序列,所述VL CDR2包含选自如SEQ ID NO:80、83-84和86所示的氨基酸序列,所述VLCDR3包含选自如SEQ ID NO:89、91-94、96-99和101(或变体,例如SEQ ID NO:138-139)所示的氨基酸序列。
在一些实施方案中,所述CDR序列选自B06、B12或B16。在一些实施方案中,所述VHCDR1包含选自如SEQ ID NO:106-107(或变体,例如SEQ ID NO:141)所示的氨基酸序列,所述VH CDR2包含选自如SEQ ID NO:115-116(或变体,例如SEQ ID NO:142)所示的氨基酸序列,所述VH CDR3包含选自如SEQ ID NO:57和63所示的氨基酸序列,所述VL CDR1包含选自如SEQ ID NO:71-72和76所示的氨基酸序列,所述VL CDR2包含选自如SEQ ID NO:83-84所示的氨基酸序列,所述VL CDR3包含选自如SEQ ID NO:93、97和101(或变体,如SEQ ID NO:138-139)所示的氨基酸序列。
本发明的抗体或片段的CDR序列可以从表A中所列的B01-B17的特定抗体中选择。例如,所述VH CDR1可以为SEQ ID NO:35,所述VH CDR2可以SEQ ID NO:45,所述VH CDR3可以为SEQ ID NO:55,所述VL CDR1可以为SEQ ID NO:70,所述VL CDR2可以为SEQ ID NO:83,并且所述VL CDR3可以为SEQ ID NO:92(例如B01)。代表性的抗体或片段包括如SEQ ID NO:1所示的VH和如SEQ ID NO:2所示的VL。表A和表1提供了其他CDR序列和VH/VL序列。
在一个实施方案中,所述VH CDR1包含如SEQ ID NO:107(或变体,例如SEQ ID NO:141)所示的氨基酸序列,所述VH CDR2包含如SEQ ID NO:116所示的氨基酸序列,所述VHCDR3包含如SEQ ID NO:57所示的氨基酸序列,所述VL CDR1包含如SEQ ID NO:72所示的氨基酸序列,所述VL CDR2包含如SEQ ID NO:84所示的氨基酸序列,并且所述VL CDR3包含如SEQ ID NO:93所示的氨基酸序列(例如B06)。代表性的抗体或片段包括如SEQ ID NO:11(或变体,例如SEQ ID NO:121-123)所示的VH和如SEQ ID NO:12所示的VL。
在一个实施方案中,所述VH CDR1包含如SEQ ID NO:106所示的氨基酸序列,所述VH CDR2包含如SEQ ID NO:115(或变体,例如SEQ ID NO:142)所示的氨基酸序列,所述VHCDR3包含如SEQ ID NO:63所示的氨基酸序列,所述VL CDR1包含如SEQ ID NO:76所示的氨基酸序列,所述VL CDR2包含如SEQ ID NO:83所示的氨基酸序列,并且所述VL CDR3包含如SEQ ID NO:97所示的氨基酸序列(例如B12)。代表性的抗体或片段包括如SEQ ID NO:23(或变体,如SEQ ID NO:124、126、127、128、130、140和145所示)所示的VH和如SEQ ID NO:24(或变体,例如SEQ ID NO:125)所示的VL。
在一个实施方案中,所述VH CDR1包含如SEQ ID NO:106所示的氨基酸序列,所述VH CDR2包含如SEQ ID NO:115(或变体,例如SEQ ID NO:142)所示的氨基酸序列,所述VHCDR3包含如SEQ ID NO:63所示的氨基酸序列,所述VL CDR1包含如SEQ ID NO:71所示的氨基酸序列,所述VL CDR2包含如SEQ ID NO:83所示的氨基酸序列,并且所述VL CDR3包含如SEQ ID NO:101(或变体,例如SEQ ID NO:138-139)所示的氨基酸序列(例如B16)。代表性的抗体或片段包括如SEQ ID NO:31(或变体,例如SEQ ID NO:124、126、127、128、130、140或145)所示的VH和如SEQ ID NO:32(或变体,例如SEQ ID NO:129和131)所示的VL。
在一些实施方案中,还提供抗PD-L1抗体和抗原结合片段,其与本文公开的任何抗体竞争结合到人PD-L1。在一些实施方案中,还提供与本文公开的任何抗体结合到相同表位的抗PD-L1抗体和抗原结合片段。在一些实施方案中,还提供抗PD-L1抗体和抗原结合片段,其包括本文公开的抗体的VH CDR1、CDR2和CDR3以及VL CDR1、CDR2和CDR3。
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%的相同。在一些实施方案中,修饰的抗体或片段保留指定的CDR序列。
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)。
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。
癌症治疗
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。
本发明所述抗体还可用于治疗或抑制癌症。PD-L1可以在肿瘤细胞中过表达。肿瘤来源的PD-L1可以结合免疫细胞上的PD-1,从而限制抗肿瘤T细胞的免疫。在小鼠肿瘤模型中使用靶向PD-L1的小分子抑制剂或单克隆抗体的结果表明,靶向PD-L1的疗法是有效控制肿瘤生长重要的替代方法和现实途径。正如在实施方案中所证实的,抗PD-L1抗体能激活适应性免疫应答机制,从而提高癌症患者的存活率。
因此,在一些实施方案中提供了用于治疗有此需要的患者的癌症的方法。在一个实施方案中,该方法需要向患者施用有效剂量的本发明所述抗体。在一些实施方案中,患者体内的至少一种癌细胞(例如基质细胞)会表达、过表达或诱导表达PD-L1。例如,PD-L1的诱导表达可以通过施用肿瘤疫苗或放射疗法来完成。
表达PD-L1蛋白的肿瘤包括膀胱癌、非小细胞肺癌、肾癌、乳腺癌、尿道癌、结肠癌、头颈癌、鳞状细胞癌、梅克尔(Merkel)细胞癌、胃肠道癌、胃癌、食道癌、卵巢癌、肾癌和小细胞肺癌。因此,本发明公开的抗体可用于治疗任何一种或多种此类癌症。
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。
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/或相关疾病紊乱的进程或转移,所述疾病紊乱包括白血病{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、甲状腺癌、子宫内膜癌、黑色素瘤、前列腺癌、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。
治疗感染
如在实验实施例中所证实的,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、人乳头瘤病毒、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、革兰氏阳性细菌、革兰氏阴性细菌、原生动物或真菌。
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。
通常在进行体外测试用于治疗感染性或恶性疾病、紊乱或病症的方法,包括施用本发明所述抗体、变体或衍生物,然后在可接受的动物模型中体内测试期望的治疗性或预防性活性,最后施用于人体。合适的动物模型(包括转基因动物)是本领域普通技术人员所公知的。例如,用于证明本发明所述抗原结合多肽的治疗用途的体外测定包括抗原结合多肽对细胞系或患者组织样品的影响。抗原结合多肽对细胞系和/或组织样品的作用可以利用本领域技术人员已知的技术进行检测,例如本发明其他部分公开的技术。根据本发明的内容,可用于确定是否施用特异性抗原结合多肽的体外测定实验包括体外细胞培养实验,其中患者组织样品在培养物中培养,并暴露于或以其他方式施用化合物,并观察这种化合物对组织样品的影响。
诊断方法
在某些肿瘤样品中观察到PD-L1的过表达,并且具有PD-L1过表达的细胞的患者可能对使用本发明的抗PD-L1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。
优选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希望诊断的患者。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PD-L1蛋白相互作用的条件下,将样品与本发明的抗体一起孵育。可以使用诸如ELISA的方法,利用抗PD-L1抗体来检测样品中PD-L1蛋白的存在。
样品中PD-L1蛋白的存在(任意的含量或浓度)可以用于诊断癌症,其可以作为患者适用抗体治疗的指示,或作为患者已经(或没有)对癌症治疗作出反应的指示。对于预后方法,可以在开始癌症治疗时在特定阶段进行一次、两次或更多次地检测,以指示治疗的进展。
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。
实施例
实施例1全人源初始噬菌体文库淘选和筛选
本实施例显示了从噬菌体文库中筛选全人抗PD-L1抗体。
抗原:人PDL1胞外结构域(ECD)avi-His-生物素标记蛋白(B3568B,Biointron)。
全人源初始噬菌体文库的制备:噬菌体文库是利用噬菌体载体构建的,噬菌体载体由从健康人外周血单个核细胞扩增的抗体基因片段组成。其构建了Fab噬菌体库。文库大小为2×1011。
针对PDL1 ECD蛋白的噬菌体文库溶液的淘选。噬菌体文库首先用BSA包被的链霉亲和素免疫磁珠(Dynabeads)进行阴性筛选。所得噬菌体与PDL1-ECD-avi-his生物素蛋白孵育,并用Kingfihser磁珠系统洗涤。粘合剂用胰蛋白酶洗脱。随后检测洗脱的噬菌体(产量1)结合抗原的效价,并与大肠杆菌共培养。共有三轮的淘选和筛选。产量2和产量3的效价显著提高。
从产量2和产量3中择优挑选出单克隆,然后在96孔板中培养。对培养上清进行IgG浓度和抗原结合效价的测定。选取277个阳性克隆进行测序。序列后分析鉴定出128个独特序列。对所有克隆进行ELISA结合分析。确定了17个最好的序列,见下表。确定了17个最好的结合序列,见下表1。
表1候选抗体序列
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实施例2PDL1抗体的结合特性分析
对17个独特克隆进行表征并转化为全长IgG。用重组人PD-L1(Sino-Biological,Cat#:10084-H08H)检测其结合性能。
为了评估抗原结合活性,对抗体进行ELISA试验。简单地说,用1μg/ml的人PD-L1蛋白的PBS包被微量滴定板,100μl/孔并在4℃下过夜,然后用100μl/孔的1%BSA封闭。将从10μg/ml起进行4倍稀释的人源化抗体添加到每个孔中,并在室温下培养1-2小时。用PBS/吐温洗涤平板,然后在室温下与山羊-抗人IgG抗体与辣根过氧化物酶(HRP)共培养1小时。洗涤后,用TMB底物显影,并用分光光度计在OD450nm处进行分析。如图1所示,所有抗体均表现出与人PD-L1的结合效果。特别是B03、B04、B05、B06、B07、B10、B12、B13、B14和B16与人PD-L1具有良好的结合。在这些结合剂中,B04、B06、B07、B12和B16与(Atezolizumab)(一种参考抗PD-L1抗体)相当或更好。
实施例3基于细胞的PDL1抗体的功能分析
为了测试抗PDL1抗体刺激T细胞反应的能力,使用表达hPD-1的Jurkat细胞来检测。Jurkat是一种人T细胞白血病细胞系,其在TCR刺激下能激活NF-AT活化荧光素酶的表达。在此次实验中,通过慢病毒转染了人PD-1基因的Jurkat细胞为应答细胞。Raji-PD-L1细胞作为抗原呈递细胞(APC)。葡萄球菌肠毒素(SE)被用来激发TCR信号。在这个系统中,外源性表达的huPDL1可以抑制Jurkat细胞中SE刺激的NF-AT荧光素酶活性,而抗PDL1抗体可以逆转NF-AT荧光素酶的活性。
简而言之,在SE刺激下,将APC(2.5×104)与表达PD-1的Jurkat T细胞(1×105)共培养。在培养开始时加入抗PDL1抗体。6小时后,评估所得细胞的荧光素酶活性。如图2所示,抗体B04、B05、B06、B07、B10、B11、B12、B13、B14和B16剂量依赖性地阻断PD1/PDL1介导的NF-AT荧光素酶活性。
为了进一步评估PDL1阻断抗体的功能,从而进一步评估了所选抗体(B04、B06、B07、B10、B12、B16)在更大剂量的Jurkat PD1试验中的功能。如图3所示,所有这些抗体剂量依赖性地逆转了PD1/PDL1介导的NF-AT荧光素酶抑制。其中B06、B07、B12和B16为最有效的抗体。
实施例4翻译后修饰(PTM)去除设计
在人抗体序列的CDR区域中通常存在翻译后修饰(PTM)位点。序列分析还发现,在DS或DG中天冬氨酸(Asp)可能发生异构化,在B06、B12或B16位点中发现脱酰胺位点。制备并测试了一些这样的氨基酸取代(表2)。所测试的序列还包括治疗性抗体的框架区域中的某些常规的改变,例如,在VH的C-末端的丝氨酸和在VL的N-末端的DIQM延伸。
表2突变抗体序列
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为了测试突变的抗PDL1抗体刺激T细胞应答的功能效力,如上所述使用hPD-1表达的Jurkat细胞分析。如图4所示,代表性突变体都具有相当的功能效力,证明了这些突变在降低抗体翻译后修饰可能性方面的前景。
实施例5与参考抗体的比较
B12的一种修饰变体B12-01作为代表与已知参考PD-L1抗体进行比较。参考抗体包括atezolizumab(TecentriqTM),一种完全人源化的、Fc工程改造的IgG1同种型单克隆抗体,和avelumab(BavencioTM),一种完全人源化的单克隆抗体。
通过慢病毒转染了人PD-1基因的Jurkat细胞为应答细胞。Raji-PD-L1细胞作为抗原呈递细胞(APC)。葡萄球菌肠毒素(SE)用来激发TCR信号。在这个系统中,外源性表达的huPDL1可以抑制Jurkat细胞中SE刺激的NF-AT荧光素酶活性,而抗PDL1抗体可以逆转NF-AT荧光素酶活性。
在SE刺激下,将APC与表达PD-1的Jurkat T细胞共培养。在培养开始时加入抗PDL1抗体。6小时后,评估所得细胞的荧光素酶活性。
结果如图5所示。在基于细胞的试验中,B12-01的亲和力显著高于avelumab(EC50:0.098nM vs.0.27nM),也优于Tecentriq(EC50:0.098nM vs.0.12nM)。
接下来,分析B12-01的中试开发特性,包括纯度(排阻色谱法(SEC))、等电点(pI)、熔点(Tm)和亲水性(疏水作用色谱法(HIC)),并与参考抗体Tecentriq的特性进行比较。结果见下表3。
表3可开发性比较
样本ID# | B12-01 | Tecentriq |
SEC(%单体) | 93.79 | 99.61 |
pI | 8.8 | 8.6 |
酸(%) | 35.6 | 38.7 |
主要(%) | 58.7 | 47.7 |
基础(%) | 5.7 | 13.6 |
Tm pH=7.5(℃) | 68.5/78.0 | 59.5/81.5 |
HIC(NH4)2SO4(M) | 1.01 | 0.41 |
有趣的是,结果表明B12-01具有比Tecentriq更高的亲水性。亲水性的差异可归因于其氨基酸组成的不同,说明B12-01的水溶性比Tecentriq高。该特性将在随后的CMC阶段的配方开发过程中提供更大的灵活性。
实施例6Biacore测定结合亲和力
在本实施例中,用Biacore T200评估B12-01与His标记的人PD-L1的亲和力。
通过蛋白质A芯片捕获分析物B12-01。以10μL/min的流速将人PD-L1蛋白(25nM-1.56nM)注入捕获的分析物上。使配体结合120s并解离600s。数据显示B12-01对PD-L1具有亚纳摩尔级别的亲和力(9.48×10-10M,图6)。
实施例7跨物种反应性
本实施例检测了抗体与来自不同物种的PDL1蛋白质的结合活性。
人、食蟹猴、大鼠和小鼠PDL1-His蛋白在4℃下以0.5μg/ml包被过夜。将B12-01以1:3的比例从10μg/ml开始连续稀释,并在常温下与各种PDL1抗原孵育1小时。洗涤平板,然后与HRP结合的小鼠抗人IgG Fc抗体孵育,随后与TMB底物显色,并在OD 450nm下通过分光光度计分析。如图7所示,B12-01显示出与人PD-L1和食蟹猴PD-L1相当的结合能力。未观察到B12-01与大鼠或小鼠PDL1的特异性结合。
实施例8阻断PD1-PDL1相互作用
本实施例使用基于Raji-PDL1细胞的阻断试验来评估PDL1抗体阻断PD1蛋白与其细胞配体PDL1结合的能力。
将高表达人PDL1的Raji细胞以每孔1×105细胞的浓度接种到96孔板中。B12-01抗体和同型对照IgG用FACS缓冲液从10μg/mL(1:3,10剂量)连续稀释,并与细胞在冰上孵育30分钟。洗涤后,稀释的生物素化Avi-和His-标记的人PD1蛋白(3μg/mL)与抗体细胞复合物在冰上孵育30分钟,然后进行链霉亲和素-PE抗体检测。用流式细胞仪测定荧光强度,用Flowjo软件分析平均荧光强度(MFI)。数据显示B12-01抗体具有显著的阻断PD1蛋白与细胞表面PDL1结合的能力(图8)。
实施例9对T细胞活化的体外作用
本实施例使用原代人混合淋巴细胞反应(MLR)分析评估PDL1抗体对T细胞活化的体外功能。
简单地说,从一个供体的人外周血单个核细胞中分离CD14+单核细胞,并用GM-CSF和IL-4刺激7天以分化为未成熟树突状细胞(imDC)。另一供体(1×105/孔)的人外周血单个核细胞(PBMC)中的2×105/ml CD4+T细胞与imDCs(1×104/孔)在PDL1抗体存在下共培养5天。ELISA法测定上清液中IFN-γ的浓度。通过检测培养基中的IFNγ水平,结果表明,B12-01显著促进了人类T细胞的活化(图9)。
实施例10 PDL1抗体的体内疗效
本实施例采用人PDL1胞外结构域(ECD)转基因小鼠来评估PDL1抗体的体内疗效。
将表达人PDL1的小鼠结肠腺癌细胞MC38(MC38-hPD-L1)皮下植入人源化hPDL1小鼠体内。当平均肿瘤体积约100mm3时将小鼠分为两组,每3天腹腔注射B12-01抗体或同型IgG对照组10mg/kg,共6次。实验期间每周两次用卡尺测量肿瘤体积。结果显示,与IgG组相比,B12-01能有效抑制肿瘤生长(图10)。
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
<120> 人PD-L1抗体
<130> P21112737CP
<150> PCT/CN2019/084468
<151> 2019-04-26
<160> 145
<170> PatentIn version 3.5
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20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 9
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 9
Glu Val Gln Leu Val Glu Thr Gly Arg Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser 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 Gly Gly Tyr Tyr Gly Asp Asp Asp Ala Phe Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ala
115 120
<210> 10
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 10
Asn Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Tyr Ser Leu Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Arg Val Gly Ile Lys
100 105
<210> 11
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 12
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 12
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Leu Ser Val Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 13
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 13
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
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser 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 Val Cys Gly Tyr Asp Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ala
115
<210> 14
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 14
Asn Ile Gln Met Thr His Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Ser Ile Ser Thr Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ile Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 15
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 15
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 Val Gly Ser Gly Phe Thr Phe Ser Asp His
20 25 30
Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser 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 Gly Arg Val Gly Ala Thr Asn Arg Phe Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ala
115 120
<210> 16
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 16
Asp Ile Gln Met Ile Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Ile Ser Arg Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Glu Ser Phe Pro Ser
85 90 95
Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 17
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 17
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
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser 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 Glu Asp Phe Trp Ser Gly Tyr Gln Asp Val Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ala
115
<210> 18
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 18
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 19
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 19
Gln Val Gln Leu Val Gln 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
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Gly Ala Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Ala Thr Val Lys Tyr Gly Gly Asp Asp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ala
115 120
<210> 20
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 20
Asn Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asp Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Phe Ser Thr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 21
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 21
Glu Val Gln Leu Leu Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Thr Asp Ser Tyr Gly Tyr Ser Asp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ala
115 120
<210> 22
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 22
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 23
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 23
Gln 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
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser 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 Val Ala Leu Trp Asp Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ala
115
<210> 24
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 24
Asn Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Arg Ala Ser Arg Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile
35 40 45
Ser Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ile Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 25
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 25
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
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser 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 Phe Cys
85 90 95
Ala Arg Ser Thr Val Lys Tyr Gly Ala Asp Asp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Ala Met Val Thr Val Ser Ala
115 120
<210> 26
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 26
Asn Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 27
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 27
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Glu Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser 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 Val Val Arg Phe Asn Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ala
115
<210> 28
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 28
Asn Ile Gln Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 29
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 29
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Val Tyr
20 25 30
Tyr Met Ala Trp Ile Arg Gln Ala Pro Gly Glu Gly Leu Glu Trp Ile
35 40 45
Ser Tyr Thr Ser Asn Gly Asp Gly Asp Ile Thr Tyr Tyr Ala Asp Ser
50 55 60
Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu
65 70 75 80
Leu Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Val Arg Ala Ala Arg Ser Gly Tyr Tyr Asn Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 30
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 30
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Thr Cys Arg Ala Ser Gln Phe Ile Ser Lys Tyr
20 25 30
Val Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile
35 40 45
Tyr Gly Ala Ser Ile Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Phe Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr His Ser Thr Pro Arg
85 90 95
Gly Val Phe Gly Gln Gly Thr Arg Val Glu Val Lys
100 105
<210> 31
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 31
Gln Val Gln Leu Leu Asp 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
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser 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 Val Ala Leu Trp Asp Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ala
115
<210> 32
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 32
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His Ser Asn Ser Leu Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 33
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 33
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 Asn
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Val Gly Gly Gly Gly Val 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 Gly Glu Lys Gly Tyr Ser Asn Ser Cys Ile Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 34
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 34
Asn Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Pro
85 90 95
Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 35
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 35
Ser His Trp Leu Ala
1 5
<210> 36
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 36
Thr Tyr Ile Ile Asn
1 5
<210> 37
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 37
Ser Tyr Trp Met Ser
1 5
<210> 38
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 38
Asp Ser Trp Ile His
1 5
<210> 39
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 39
Asp His Tyr Met Asp
1 5
<210> 40
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 40
Ser Tyr Ala Ile Ser
1 5
<210> 41
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 41
Val Tyr Tyr Met Ala
1 5
<210> 42
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 42
Ser Asn Ala Met Ser
1 5
<210> 43
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 43
Ser Ile His Gln Asp Ala Ser Leu Glu Phe Tyr Val Asp Ser Val Glu
1 5 10 15
Gly
<210> 44
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 44
Ser Val Ala Ala Ser Gly Asp Tyr Ala Tyr Tyr Ala Asn Ser Val Lys
1 5 10 15
Gly
<210> 45
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 45
Asn Ile Lys Glu Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val Lys
1 5 10 15
Gly
<210> 46
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 46
Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val Lys
1 5 10 15
Gly
<210> 47
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 47
Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 48
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 48
Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 49
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 49
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 50
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 50
Tyr Thr Ser Asn Gly Asp Gly Asp Ile Thr Tyr Tyr Ala Asp Ser Val
1 5 10 15
Lys Asp
<210> 51
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 51
Ala Val Gly Gly Gly Gly Val Asn Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 52
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 52
Gly Asp Asn Gln Phe Asp Asn
1 5
<210> 53
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 53
Asp Arg Ser Ser Gly Tyr Tyr Leu Ser Pro Asn Asp Ala Phe Asp Ile
1 5 10 15
<210> 54
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 54
Val Val Arg Phe Asn Asp Ala Phe Asp Ile
1 5 10
<210> 55
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 55
Thr Met Leu Trp Asp Asp Ala Phe Asp Ile
1 5 10
<210> 56
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 56
Gly Gly Tyr Tyr Gly Asp Asp Asp Ala Phe Asp Ile
1 5 10
<210> 57
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 57
Arg His Trp Pro Gly Gly Phe Asp Tyr
1 5
<210> 58
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 58
Val Cys Gly Tyr Asp Asp Ala Phe Asp Ile
1 5 10
<210> 59
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 59
Gly Arg Val Gly Ala Thr Asn Arg Phe Gly Met Asp Val
1 5 10
<210> 60
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 60
Glu Asp Phe Trp Ser Gly Tyr Gln Asp Val
1 5 10
<210> 61
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 61
Ala Thr Val Lys Tyr Gly Gly Asp Asp Ala Phe Asp Ile
1 5 10
<210> 62
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 62
Arg Thr Asp Ser Tyr Gly Tyr Ser Asp Ala Phe Asp Ile
1 5 10
<210> 63
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 63
Val Ala Leu Trp Asp Asp Ala Phe Asp Ile
1 5 10
<210> 64
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 64
Ser Thr Val Lys Tyr Gly Ala Asp Asp Ala Phe Asp Ile
1 5 10
<210> 65
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 65
Ala Ala Arg Ser Gly Tyr Tyr Asn Asp Tyr
1 5 10
<210> 66
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 66
Gly Glu Lys Gly Tyr Ser Asn Ser Cys Ile Asp Tyr
1 5 10
<210> 67
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 67
Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn
1 5 10
<210> 68
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 68
Arg Ala Ser Gln Thr Ile Ser Arg Tyr Leu Asn
1 5 10
<210> 69
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 69
Arg Ala Ser Gln Ser Ile Asp Thr Trp Leu Ala
1 5 10
<210> 70
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 70
Arg Ala Ser Glu Ser Ile Ser Ser Trp Leu Ala
1 5 10
<210> 71
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 71
Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala
1 5 10
<210> 72
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 72
Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala
1 5 10
<210> 73
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 73
Arg Ala Ser Gln Ser Ile Ser Thr Trp Leu Ala
1 5 10
<210> 74
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 74
Arg Ala Ser Glu Ser Ile Ser Arg Trp Leu Ala
1 5 10
<210> 75
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 75
Arg Ala Ser Gln Ser Ile Ser Asp Trp Leu Ala
1 5 10
<210> 76
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 76
Arg Ala Ser Arg Gly Ile Ser Ser Trp Leu Ala
1 5 10
<210> 77
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 77
Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
1 5 10
<210> 78
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 78
Arg Ala Ser Gln Phe Ile Ser Lys Tyr Val Asn
1 5 10
<210> 79
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 79
Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 80
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 80
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 81
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 81
Ala Thr Ser Ser Leu Gln Ser
1 5
<210> 82
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 82
Asn Ala Ser Thr Leu Lys Ser
1 5
<210> 83
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 83
Lys Ala Ser Ser Leu Glu Ser
1 5
<210> 84
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 84
Ala Ala Ser Thr Leu Gln Ser
1 5
<210> 85
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 85
Ala Ala Ser Asn Leu Glu Ser
1 5
<210> 86
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 86
Lys Ala Ser Ser Leu Gln Ser
1 5
<210> 87
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 87
Gly Ala Ser Ile Leu Glu Thr
1 5
<210> 88
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 88
Asp Ala Ser Asn Leu Glu Thr
1 5
<210> 89
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 89
Gln Gln Ser Tyr Ser Thr Pro Pro Thr
1 5
<210> 90
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 90
Gln Gln Ser Tyr Ser Thr Pro Thr Thr
1 5
<210> 91
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 91
Gln Gln Ser Tyr Ser Thr Pro Leu Thr
1 5
<210> 92
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 92
Gln Gln Thr Tyr Ser Leu Pro Leu Thr
1 5
<210> 93
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 93
Gln Gln Tyr Leu Ser Val Pro Tyr Thr
1 5
<210> 94
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 94
Gln Gln Ser Tyr Ser Ile Pro Leu Thr
1 5
<210> 95
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 95
Gln Gln Ala Glu Ser Phe Pro Ser
1 5
<210> 96
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 96
Gln Gln Ser Phe Ser Thr Pro Phe Thr
1 5
<210> 97
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 97
Gln Gln Ser Ser Ser Ile Pro Leu Thr
1 5
<210> 98
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 98
Gln Gln Ser Tyr Ser Thr Pro Phe Thr
1 5
<210> 99
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 99
Gln Gln Ala Asn Ser Phe Pro Phe Thr
1 5
<210> 100
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 100
Gln Gln Thr His Ser Thr Pro Arg Gly Val
1 5 10
<210> 101
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 101
Gln His Ser Asn Ser Leu Pro Leu Thr
1 5
<210> 102
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 102
Gln Gln Tyr Asp Asn Leu Pro Pro Phe Thr
1 5 10
<210> 103
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 103
Gly Phe Thr Leu Ser Ser His
1 5
<210> 104
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 104
Gly Phe Thr Phe Ser Thr Tyr
1 5
<210> 105
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 105
Gly Phe Ser Phe Ser Ser Tyr
1 5
<210> 106
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 106
Gly Phe Thr Phe Ser Ser Tyr
1 5
<210> 107
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 107
Gly Phe Thr Phe Ser Asp Ser
1 5
<210> 108
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 108
Gly Phe Thr Phe Ser Asp His
1 5
<210> 109
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 109
Gly Gly Thr Phe Ser Ser Tyr
1 5
<210> 110
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 110
Gly Phe Thr Phe Ser Val Tyr
1 5
<210> 111
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 111
Gly Phe Thr Phe Ser Ser Asn
1 5
<210> 112
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 112
His Gln Asp Ala Ser Leu
1 5
<210> 113
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 113
Ala Ala Ser Gly Asp Tyr
1 5
<210> 114
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 114
Lys Glu Asp Gly Ser Glu
1 5
<210> 115
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 115
Lys Gln Asp Gly Ser Glu
1 5
<210> 116
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 116
Ser Pro Tyr Gly Gly Ser
1 5
<210> 117
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 117
Ser Ser Ser Ser Ser Tyr
1 5
<210> 118
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 118
Ile Pro Ile Phe Gly Thr
1 5
<210> 119
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 119
Ser Asn Gly Asp Gly Asp Ile
1 5
<210> 120
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 120
Gly Gly Gly Gly Val Asn
1 5
<210> 121
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 121
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 122
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 122
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 Glu Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 123
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 123
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Glu Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ala Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 124
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 124
Gln 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
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser 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 Val Ala Leu Trp Asp Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 125
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 125
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Arg Ala Ser Arg Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile
35 40 45
Ser Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Ile Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 126
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 126
Gln 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
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Glu Gly Ser Glu Lys Tyr Tyr Val Asp Ser 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 Val Ala Leu Trp Asp Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 127
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 127
Gln 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
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Ala Ser Glu Lys Tyr Tyr Val Asp Ser 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 Val Ala Leu Trp Asp Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 128
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 128
Gln 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
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Glu Ser 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 Val Ala Leu Trp Asp Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 129
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 129
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His Ser Asn Ala Leu Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 130
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 130
Gln 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
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Ala Ser Glu Lys Tyr Tyr Val Glu Ser 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 Val Ala Leu Trp Asp Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 131
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 131
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His Ser Gln Ser Leu Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 132
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 132
Glu Ser Trp Ile His
1 5
<210> 133
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 133
Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ala Val Lys
1 5 10 15
Gly
<210> 134
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 134
Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Glu Ser Val Lys
1 5 10 15
Gly
<210> 135
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 135
Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Glu Ser Val Lys
1 5 10 15
Gly
<210> 136
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 136
Asn Ile Lys Gln Asp Ala Ser Glu Lys Tyr Tyr Val Asp Ser Val Lys
1 5 10 15
Gly
<210> 137
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 137
Asn Ile Lys Gln Asp Ala Ser Glu Lys Tyr Tyr Val Glu Ser Val Lys
1 5 10 15
Gly
<210> 138
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 138
Gln His Ser Asn Ala Leu Pro Leu Thr
1 5
<210> 139
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 139
Gln His Ser Gln Ser Leu Pro Leu Thr
1 5
<210> 140
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 140
Gln 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
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Glu Gly Ser Glu Lys Tyr Tyr Val Asp Ala 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 Val Ala Leu Trp Asp Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 141
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 141
Gly Phe Thr Phe Ser Glu Ser
1 5
<210> 142
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 142
Lys Gln Asp Ala Ser Glu
1 5
<210> 143
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 143
Asn Ile Lys Gln Glu Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val Lys
1 5 10 15
Gly
<210> 144
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 144
Asn Ile Lys Gln Glu Gly Ser Glu Lys Tyr Tyr Val Asp Ala Val Lys
1 5 10 15
Gly
<210> 145
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 145
Gln Val Gln Leu Leu Asp 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
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser 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 Val Ala Leu Trp Asp Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
Claims (12)
1.一种抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段对人程序性死亡配体1(PD-L1)蛋白具有特异性,并且包含含有VH CDR1、VH CDR2和VH CDR3的重链可变区(VH)和含有VL CDR1、VL CDR2和VL CDR3的轻链可变区(VL),其中:
所述VH CDR1的氨基酸序列如SEQ ID NO:37所示,
所述VH CDR2的氨基酸序列如SEQ ID NO:46、143或144所示,
所述VH CDR3的氨基酸序列如SEQ ID NO:63所示,
所述VL CDR1的氨基酸序列如SEQ ID NO:76所示,
所述VL CDR2的氨基酸序列如SEQ ID NO:83所示,以及
所述VL CDR3的氨基酸序列如SEQ ID NO:97所示。
2.如权利要求1所述的抗体或其抗原结合片段,其特征在于,
所述VH CDR1的氨基酸序列如SEQ ID NO:37所示,
所述VH CDR2的氨基酸序列如SEQ ID NO:46所示,
所述VH CDR3的氨基酸序列如SEQ ID NO:63所示,
所述VL CDR1的氨基酸序列如SEQ ID NO:76所示,
所述VL CDR2的氨基酸序列如SEQ ID NO:83所示,以及
所述VL CDR3的氨基酸序列如SEQ ID NO:97所示。
3.如权利要求1所述的抗体或其抗原结合片段,其特征在于,
所述VH包含如SEQ ID NO:126或140所示的氨基酸序列,且所述VL包含如SEQ ID NO:125所示的氨基酸序列。
4.如权利要求2所述的抗体或其抗原结合片段,其特征在于,
所述VH包含如SEQ ID NO:124所示的氨基酸序列,且所述VL包含如SEQ ID NO:125所示的氨基酸序列;或者
所述VH包含如SEQ ID NO:23所示的氨基酸序列,且所述VL包含如SEQ ID NO:24所示的氨基酸序列。
5.如权利要求1-4任一项所述的抗体或其抗原结合片段,其特征在于,其进一步包含重链恒定区、轻链恒定区、Fc区或其组合。
6.如权利要求1-4任一项所述的抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段为全人抗体。
7.一种双特异性抗体,其包含如权利要求1-6任一项所述的抗原结合片段,其为第一抗原结合片段,
和对非PD-L1的抗原具有特异性的第二抗原结合片段。
8.一种组合物,其包含如权利要求1-6任一项所述的抗体或其抗原结合片段以及药学上可接受的载体。
9.一种编码如权利要求1-6任一项所述的抗体或其抗原结合片段的多核苷酸。
10.一种分离的细胞,其包含编码如权利要求1-6任一项所述的抗体或其抗原结合片段的多核苷酸。
11.如权利要求1-6任一项所述的抗体或其抗原结合片段或如权利要求8所述的组合物在制备用于治疗癌症的药物中的用途,其中所述癌症为实体瘤。
12.如权利要求11所述的用途,其特征在于,所述癌症选自由膀胱癌、肝癌、子宫内膜癌、淋巴瘤、胰腺癌、小细胞肺癌、非小细胞肺癌、乳腺癌、尿道癌、头颈癌、胃肠道癌、食道癌、卵巢癌、肾癌、黑色素瘤和前列腺癌组成的组。
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PCT/CN2020/087019 WO2020216379A1 (en) | 2019-04-26 | 2020-04-26 | Human pd-l1 antibodies |
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