CN114901365A - 肿瘤特异性密蛋白18.2抗体 - Google Patents
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- CN114901365A CN114901365A CN202080090043.7A CN202080090043A CN114901365A CN 114901365 A CN114901365 A CN 114901365A CN 202080090043 A CN202080090043 A CN 202080090043A CN 114901365 A CN114901365 A CN 114901365A
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Abstract
本发明提供肿瘤特异性抗CLDN18.2抗体或其片段。与表达CLDN18.2的健康组织相比,抗体或其片段对表达CLDN18.2的肿瘤组织展现出结合增加。此外,抗体不表现出与CLDN18.1的交叉反应性。本发明还提供核酸、载体、宿主细胞和医学用途。
Description
发明背景
紧密连接是连接相邻的上皮或内皮细胞以形成屏障,阻止分子在细胞之间通过,并有助于维持细胞和组织的极性的多蛋白复合物。紧密连接由三大组跨膜蛋白组成:密蛋白和闭合蛋白、细胞质斑块蛋白和带蛋白。它们还含有细胞骨架蛋白和信号传导蛋白,例如肌动蛋白、肌球蛋白II和PKCζ。这些蛋白质相互作用以维持紧密连接结构(Yu和Turner2008)。
密蛋白形成23种蛋白质的家族(Hewitt,Agarwal和Morin 2006)。密蛋白18是由CLDN18基因编码的人类蛋白质,可在上皮细胞中形成紧密连接股。人CLDN18可以在两个可变第一外显子的情况下可变剪接,产生两种蛋白质同种型(isoform)CLDN18.1(或密蛋白18.1)和CLDN18.2(或密蛋白18.2)。CLDN18.2在WO2000/015659中首次公开为Zsig28蛋白。这两种同种型的不同之处在于涵盖第一细胞外环的N端69个氨基酸。第一胞外域的跨度从氨基酸28到氨基酸80。在此范围内,CLDN18.1和CLDN18.2之间存在8个氨基酸差异。这两种不同的同种型在不同的组织中表达,CLDN18.1主要在肺组织中表达,而CLDN18.2显示出胃特异性(Niimi等人2001)。CLDN18.2在正常胃中的表达限于胃上皮的分化的短寿命细胞。CLDN18.2的表达已在各种肿瘤组织中得到进一步鉴定。例如,已发现CLDN18.2在胰腺、食管、卵巢和肺部的肿瘤中表达,与不同的组织学亚型相关(Sahin等人2008)。人CLDN18.2蛋白的氨基酸序列可来源于NCBI参考序列:NP_001002026.1。该序列也公开为SEQ ID NO:133。
鉴于CLDN18.2在正常组织中的受限表达模式以及其在人类癌症中的异位表达,其是上皮肿瘤抗体治疗的有吸引力的癌症靶标。已经对这种抗体疗法进行了许多研究。WO2004/047863鉴定了CLDN18的剪接变体并筛选了针对源自CLDN18.2的不同肽的抗体:肽DQWSTQDLYN(SEQ ID NO:57),CLDN18.2的N端胞外,与糖基化无关;肽NNPVTAVFNYQ(SEQ IDNO:58),CLDN18.2的N端胞外,大体上未糖基化;和肽STQDLYNNPVTAVF(SEQ ID NO:59),CLDN18.2的N端胞外域,未糖基化。其还公开了用在CLDN18.1和CLDN18.2同种型共同的C端胞外域中的泛CLDN18肽TNFWMSTANMYTG(SEQ ID NO:60)筛选的多克隆兔抗体。WO2005/113587公开了针对由肽序列定义的CLDN18.2特定表位的抗体:ALMIVGIVLGAIGLLV(SEQ IDNO:61)和RIGSMEDSAKANMTLTSGIMFIVS(SEQ ID NO:62)。WO2007/059997公开了通过用肽METDTLLLWVLLLWVPGSTGDAAQPARRARRTKLGTELGSTPVWWNSADGRMDQWSTQDLYNNPVTAVFNYQGLWRSCVRESSGFTECRGYFTLLGLPAMLQAVRAAIQHSGGRSRRARTKTHLRRGSE(SEQ ID NO:63)免疫获得的CLDN18.2特异性单克隆抗体,包括具有N-端和C-端延伸的CLDN18.2的第一胞外域。通过这种免疫获得的抗体通过补体依赖性细胞毒性(CDC)和抗体依赖性细胞介导的细胞毒性(ADCC)介导细胞杀伤。抗体IMAB362,也称为Claudiximab或Zolbetuximab,公开于WO2007/059997和WO2016/165762。IMAB362是源自鼠单克隆抗体的IgG1抗体,并且已经被嵌合以展示人IgG1恒定区供临床使用。WO2008/145338还公开了与第一胞外域内的重叠肽(MDQWSTQDLYNNPVT(SEQ ID NO:64)、LYNNPVTAVFNYQGL(SEQ ID NO:65)、VFNYQGLWRSCVRES(SEQ ID NO:66)、QGLWRSCVRESSGFT(SEQ ID NO:67)和RSCVRESSGFTECRG(SEQ ID NO:68))结合的抗体。为了产生靶向CLDN18.2的C-端部分的抗体以用于检测癌症组织切片的细胞中的CLDN18.2表达的诊断目的,WO2013/167259公开了与CLDN18.2的C-端表位结合的抗体。这两个表位的序列是TEDEVQSYPSKHDYV(SEQ ID NO:69)和EVQSYPSKHDYV(SEQ ID NO:70)。WO2013/174509提出了抗CLDN18.2抗体与稳定γδ T细胞的药剂或与稳定或增加CLDN18.2表达的药剂的组合。抗体可以与治疗部分如细胞毒素、药物(例如,免疫抑制剂)或放射性同位素缀合。WO2014/075788公开了使用结合CLDN18.2和CD3的双特异性抗体治疗癌症疾病的方法。WO2014/127906公开了稳定或增加CLDN18.2表达的组合剂。WO2016/166122公开了抗CLDN18.2单克隆抗体,该抗体可在CLDN18.2结合后高效内化,因此适用于抗体-药物缀合物(ADC)开发。此外,还公开了分别使用可切割的SPDB或缬氨酸-瓜氨酸接头将此类抗体与药物DM4和MMAE缀合。然而,尽管专利申请中公开了所有抗体,但目前只有WO2007/059997和WO2016/165762中公开的嵌合IMAB362在临床试验中得到测试。除了这些抗体和ADC,WO2018/006882还公开了基于抗CLDN18.2单克隆抗体的嵌合抗原受体(CAR)。WO2018/006882的抗体已经人源化,其序列在与Jiang等人2018(Jiang等人2018)相关的补充材料部分中公开。基于人源化抗体的CAR T细胞目前正在晚期胃腺癌和胰腺癌患者的I期临床试验(ClinicalTrials.gov标识符:NCT03159819)中进行测试。CN109762067公开了介导通过CDC和ADCC的细胞杀伤的其他抗CLDN18.2单克隆抗体。WO2019/173420公开了具有ADCC活性的抗CLDN18.2人源化单克隆抗体。WO2019/175617公开了相较于IMAB362结合不同的表位的抗CLDN18.2单克隆抗体。WO2019/219089公开了结合CLDN18.2突变体的单克隆抗体。
已描述CLDN18.2以不同的构象存在并含有潜在的细胞外N-糖基化位点(参见WO2007/059997第3页,第一段),这可能导致正常细胞和肿瘤细胞之间潜在不同的拓扑结构/差异糖基化(参见WO2007/059997第4页,第二段)。然而,报道的抗体无一优先靶向肿瘤细胞上表达的CLDN18.2。由于CLDN18.2不仅在肿瘤中表达,而且在健康组织即在胃组织中表达(Sahin等人2008),显然有益的是具有仅靶向肿瘤中表达的CLDN18.2的抗体,以避免经常与治疗性抗体对健康器官/组织的中靶作用相关的安全问题和副作用(Hansel等人2010),特别是如针对IMAB362报道(Sahin等人2018;Tureci等人2019)。
除了以高亲和力与靶标结合外,治疗性抗体还应在开发、生产、储存和临床应用(体内)期间保持其期望特性。翻译后修饰(PTM)可能会损害抗体的稳定性(Lu等人2019;Gervais 2016)。由于不受控制的PTM可能导致抗体的功效、活性、效力或稳定性低于期望,因此在开发治疗性抗体期间设计具有最小可能PTM的抗体非常重要。PTM还可以对生物仿制药的监管接受、技术转让或工艺和开发产生深远的影响。主要的修饰是氧化、脱酰胺和异构化。此外,IMAB362是仍具有延伸的小鼠序列的嵌合抗体,所述小鼠序列可能会导致某些患者产生抗药抗体,其例如在重复应用后可能会导致治疗效果下降。
因此,需要改进的对CLDN18.2特异性的抗体,用于治疗肿瘤患者。
定义
“抗体”,也称为“免疫球蛋白”(Ig),通常包含四条多肽链—两条重(H)链和两条轻(L)链,因此是多聚体蛋白质,或包含其等效的Ig同源物(例如,仅包含重链的骆驼科抗体,单结构域抗体(sdAb)或纳米抗体,其可以衍生自重链或轻链)。术语“抗体”包括基于抗体的结合蛋白、保留靶标结合能力的修饰抗体形式。术语“抗体”还包括保留Ig分子的基本表位结合特征的全长功能突变体、变体或衍生物(包括但不限于鼠的、嵌合的、人源化的和完全人的抗体),并且包括双重特异性、双特异性、多特异性和双可变结构域Ig。Ig分子可以是任何类别(例如,IgG、IgE、IgM、IgD、IgA和IgY)或亚类(例如,IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)和同种异型。Ig分子也可以发生突变,例如增强或降低对Fcγ受体或新生Fc受体(FcRn)的亲和力。
如本文所用,“抗体片段”涉及非全长的并表现出靶标结合的包含衍生自抗体的至少一条多肽链的分子。抗体片段能够与其相应的全长抗体结合相同的表位或靶标。抗体片段包括但不限于单独或任意组合的(i)Fab片段,其是由可变轻(VL)结构域、可变重(VH)结构域、恒定轻(CL)结构域和恒定重1(CH1)结构域组成的单价片段;(ii)F(ab')2片段,其是包含两个在铰链区通过二硫键连接的Fab片段的二价片段(F(ab')2片段的还原产生具有游离巯基的两个Fab'片段);(iii)Fab(Fa)片段的重链部分,其由VH和CH1结构域组成;(iv)可变片段(Fv)片段,其由抗体单臂的VL和VH结构域组成;(v)结构域抗体(dAb)片段,其包含单个可变结构域;(vi)分离的互补决定区(CDR);(vii)单链Fv片段(scFv);(viii)双抗体,其为二价双特异性抗体,其中VH和VL结构域在单个多肽链上表达,但使用的接头太短而无法使同一链上的两个结构域之间配对,从而迫使结构域与另一条链的互补结构域配对并产生两个抗原结合位点;(ix)线性抗体,其包含一对串联的Fv片段(VH-CH1-VH-CH1),与互补轻链多肽一起形成一对抗原结合区;(x)双重可变结构域免疫球蛋白;(xi)免疫球蛋白重链和/或轻链的其他非全长部分,或其突变体、变体或衍生物。
如本文所用,“基于抗体的结合蛋白”可代表在其他非免疫球蛋白或非抗体衍生组分的情况下含有至少一个抗体衍生的VH、VL或CH免疫球蛋白结构域的任何蛋白质。此类基于抗体的蛋白质包括但不限于(i)结合蛋白的Fc融合蛋白,包括具有全部或部分免疫球蛋白CH结构域的受体或受体组分,(ii)结合蛋白,其中VH和/或VL结构域与替代分子支架偶联,或(iii)分子,其中免疫球蛋白VH和/或VL和/或CH结构域以天然存在的抗体或抗体片段中通常找不到的方式组合和/或组装。
如本文所用,术语“修饰的抗体形式”涵盖抗体-药物缀合物(ADC)、聚环氧烷修饰的scFv、单抗体、双抗体、骆驼科抗体、结构域抗体、双特异性或三特异性抗体、IgA、或由J链和分泌组分连接的两种IgG结构、鲨鱼抗体、新大陆灵长类动物框架和非新大陆灵长类动物CDR、去除铰链区的IgG4抗体、具有工程改造进入CH3结构域中的两个额外结合位点的IgG、具有改变的Fc区以增强或降低对Fcγ受体的亲和力的抗体、包含CH3、VL和VH的二聚化构建体等。
Kabat编号方案(Martin和Allemn 2014)已经应用于公开的抗体。
在本说明书和权利要求书中使用术语“包含”时,其不排除其他元素。出于本发明的目的,认为术语“由……组成”是术语“包含……”的优选实施方案。如果在下文中将组限定为包括至少一定数量的实施方案,这也应理解为公开了优选地仅由这些实施方案组成的组。
除非另有明确说明,涉及单数名词时使用的不定冠词或定冠词例如“一”、“一个”或“该”,包括该名词的复数形式。
技术术语按其常识使用。如果将特定含义传达给某些术语,则将在以下使用该术语的上下文中给出术语的定义。
发明详述
本发明人惊奇地鉴定出如以下实施方案中进一步描述的新型抗CLDN18.2抗体,其展现出相较于表达CLDN18.2的健康胃细胞对表达CLDN18.2的肿瘤细胞的结合增加和/或具有改进的稳定性和/或在保留其改进的特性的情况下人源化。
因此,在本发明的一个实施方案中,本发明提供了结合CLDN18.2的抗体或其片段,其中该抗体或其片段展现出相较于表达CLDN18.2的健康组织对表达CLDN18.2的肿瘤组织的结合增加。在一个实施方案中,用于比较的健康细胞或组织是健康胃细胞或健康胃组织。
分别如实施例4和5中所示,本文提供的抗体或其片段对肿瘤组织的结合增加可以通过生物分析方法如流式细胞术(FC)或免疫组织化学(IHC)来显示。可以通过将表达CLDN18.2的A549细胞皮下注射到Balb/c小鼠中来生成表达CLDN18.2的肿瘤。表达CLDN18.2的A549细胞可以如实施例4中所示生成,并且可以在2019年12月6日保藏在DSMZ-DeutscheSammlung von Mikroorganismen und Zellkulturen GmbH Inhoffenstr.7B38124Braunschweig DE的保藏号DSM ACC3360下获得。健康组织(例如健康胃组织)也可以来源于携带肿瘤的小鼠。因此可以在肿瘤组织和从同一动物获得的健康组织上显示相较于健康组织对肿瘤组织的结合增加。
相较于在健康组织中表达的CLDN18.2,对在肿瘤组织中表达的CLDN18.2的结合增加可能是由于翻译后修饰,如CLDN18.2的差异糖基化或CLDN18.2的错误折叠。
流式细胞术(FC)可用作测试抗体结合的生物分析方法。CLDN18.2阳性细胞的百分比可以例如通过特异性抗CLDN18.2抗体的FC测量。另一种可能的结合读数可以例如是肿瘤细胞样品中CLDN18.2阳性细胞的百分比相对于从健康组织(如健康胃组织)获得的细胞样品中CLDN18.2阳性细胞的百分比的比率。与健康细胞(如健康胃细胞)相比,抗体对由表达CLDN18.2的A549细胞生成的表达CLDN18.2的肿瘤细胞的结合增加,可以通过>2、>5、≥10、优选地≥15、以及更优选地≥20的比率显示。
与健康细胞(如健康胃细胞)相比,抗体对由表达CLDN18.2的A549细胞生成的表达CLDN18.2的肿瘤细胞的结合增加,也可以通过显示相较于健康细胞(如健康胃细胞),抗体结合至少2倍更多、至少5倍更多、至少10倍更多、优选地至少15倍更多、优选地至少20倍更多的肿瘤细胞来描述。
免疫组织化学(IHC)可用作测试抗体结合的生物分析方法。优选地,用于IHC的组织样品应在切除后速冻,一旦解冻,就如例如实施例5所示固定在丙酮中。由于CLDN18.2是健康组织中的紧密连接蛋白,因此阳性CLDN18.2染色应导致在健康组织和/或肿瘤组织中的细胞-细胞界面处膜染色占主导的显现。因此,阴性CLDN18.2染色或弱染色应导致膜染色的缺乏。
在另一个实施方案中,本发明提供了抗体或其片段,当通过对过表达CLDN18.2的HEK293T细胞的流式细胞术(FC)滴定进行测量时,其以高于0.4μg/ml、高于0.5μg/ml、优选地高于0.6μg/ml、但不高于1μg/ml的半数最大有效浓度(EC50)值结合CLDN18.2。可以如实施例3中所述生成过表达CLDN18.2的HEK293T细胞。当通过对过表达CLDN18.2的HEK293T细胞的流式细胞术(FC)滴定进行测量时,本发明的抗体的EC50值可以是0.4至1μg/ml、0.5至1μg/ml或优选地0.6至1μg/ml。
或者,当通过对过表达CLDN18.2的HEK293T细胞的流式细胞术进行测量时,本发明抗体的EC50值可以与IMAB362的EC50值进行比较,其中本发明抗体的EC50值比IMAB362的EC50值至少高1.1倍、至少高1.2倍、优选地至少高1.5倍、更优选地至少高2倍、甚至更优选地至少高2.5倍,但比IMAB362的EC50值高不超过5倍。当通过对过表达CLDN18.2的HEK293T细胞的流式细胞术测量时,本发明抗体的EC50值可以比IMAB362的EC50值高1.1倍至高2.5倍、高1.2倍至高2.5倍、优选地高1.5倍至高2.5倍、或更优选地高2倍至高2.5倍。
在另一个实施方案中,本发明提供了抗体或其片段,当通过对PA-TU-8988S-High细胞的流式细胞术滴定进行测量时,其以高于0.6μg/ml、高于1μg/ml、优选地高于1.5μg/ml、更优选地高于2μg/ml但不高于3mg/ml的EC50值结合CLDN18.2。可以如实施例2中所述生成PA-TU-8988S-High细胞。当通过对PA-TU-8988S-High细胞的流式细胞术滴定进行测量时,本发明抗体的EC50值可以是0.6至3μg/ml、1至3mg/ml、优选地1.5至3μg/ml、或更优选地2至3μg/ml。
或者,当通过对PA-TU-8988S-High细胞的流式细胞术进行测量时,本发明抗体的EC50值可以与IMAB362的EC50值进行比较,其中本发明抗体的EC50值比IMAB362的EC50值至少高1.5倍、至少高2倍、优选地至少高3倍、更优选至少高4倍,但高不超过5倍。当通过流式细胞术对PA-TU-8988S-High细胞进行测量时,本发明抗体的EC50值可以比IMAB362的EC50值高1.5倍至高5倍、高2倍至高5倍、高3倍至高5倍、或高4倍至高5倍。
在另一个实施方案中,本发明提供了抗体或其片段,当通过对过表达CLDN18.2的HEK293T细胞的流式细胞术进行测量时,其以IMAB362的maxMFI值的+/-40%内的maxMFI值结合CLDN18.2。本发明还提供了抗体或其片段,当通过对PA-TU-8988S-High细胞的流式细胞术进行测量时,其以等于IMAB362的maxMFI值或比IMAB362的maxMFI值高至多2倍的maxMFI值结合CLDN18.2。
相较于表达CLDN18.2的健康组织对表达CLDN18.2的肿瘤组织的结合增加的抗体或其功能片段可以相较于不能区分表达CLDN18.2的健康组织与表达CLDN18.2的肿瘤组织的抗体具有治疗优势。肿瘤特异性抗体可以不导致通常与治疗性抗体在健康器官/组织中的中靶作用有关的安全问题和副作用(Hansel等人2010)。例如对于IMAB362,已经报道了这种不想要的效应(Sahin等人2018;Tureci等人2019)。
本发明还提供了结合CLDN18.2的抗体或其片段,其包含分别为SEQ ID NO:21、SEQID NO:22和SEQ ID NO:23的重链互补决定区(HCDR)HCDR1、HCDR2和HCDR3序列以及分别为SEQ ID NO:24、SEQ ID NO:25和SEQ ID NO:26的轻链CDR LCDR1、LCDR2和LCDR3序列。
本发明还提供了结合CLDN18.2的抗体或其片段,其包含SEQ ID NO:23的重链HCDR3序列和SEQ ID NO:26的轻链LCDR3序列。
相应的共有序列可以在表1中找到。应当理解,基于源自共有序列的CDR的任意组合并结合CLDN18.2的任何抗体或其片段是本发明的一部分。
表1:分离的抗体CDR共有序列
抗体结合或结合亲和力通常用平衡结合或解离常数(分别为Ka或Kd)表示,它们又是解离和结合速率常数(分别为koff和kon)的倒数比。因此,只要速率常数的比率保持不变,等效的亲和力可对应于不同的速率常数。结合亲和力和/或速率常数可以使用本领域熟知的或本文描述的技术来确定,如ELISA、流式细胞术滴定、等温滴定量热法(ITC)、Biacore(SPR)、生物层干扰量度法(biolayer inferometry)或荧光偏振。在一些情况下,由于抗原的性质,抗体的Ka或Kd可能难以测量。对于如密蛋白的整合膜蛋白而言,尤其如此(Hashimoto等人2018)。在这种情况下,整合膜蛋白可以表达为蛋白脂质体或脂质颗粒。此类脂质颗粒可固定在塑料上并用于ELISA测定以确定抗体与固定抗原的结合亲和力。因此,可以计算每个测试抗体或其功能片段的半数最大有效浓度(EC50)值,代替Ka或Kd值,反映其与抗原的结合亲和力(或结合强度)。下面的实施例2和图1举例说明了具有包含在表1的共有序列中的CDR的抗体的ELISA测定结合亲和力曲线。EC50值和最大结合值可用于定量抗体与CLDN18.2的结合。下面的实施例3涉及通过对表达CLDN18.2的细胞的流式细胞术,计算具有包含在表1的共有序列中的CDR的抗体的EC50值。
在另一个实施方案中,本发明提供了结合CLDN18.2的抗体或其片段,其包含分别为SEQ ID NO:21、SEQ ID NO:126和SEQ ID NO:23的重链CDR HCDR1、HCDR2和HCR3序列以及分别为SEQ ID NO:24、SEQ ID NO:25和SEQ ID NO:26的轻链CDR LCDR1、LCDR2和LCDR3序列。
在一个实施方案中,本发明涉及结合CLDN18.2的抗体或其片段,其包含:
a.分别为SEQ ID NO:1、SEQ ID NO:15和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ IDNO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;
b.分别为SEQ ID NO:1、SEQ ID NO:16和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ IDNO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;
c.分别为SEQ ID NO:1、SEQ ID NO:16和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:17、SEQID NO:14和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列;
d.分别为SEQ ID NO:1、SEQ ID NO:16和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:18、SEQID NO:19和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列;
e.分别为SEQ ID NO:12、SEQ ID NO:15和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ IDNO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;
f.分别为SEQ ID NO:1、SEQ ID NO:20和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQID NO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;
g.分别为SEQ ID NO:1、SEQ ID NO:20和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:18、SEQID NO:19和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列;
h.分别为SEQ ID NO:12、SEQ ID NO:20和SEQ ID NO:8的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ IDNO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;或
i.分别为SEQ ID NO:12、SEQ ID NO:20和SEQ ID NO:8的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:17、SEQID NO:14和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列。
在又一个实施方案中,本发明提供了结合CLDN18.2的抗体或其片段,其包含:
a.分别为SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ IDNO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;
b.分别为SEQ ID NO:1、SEQ ID NO:7和SEQ ID NO:8的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:9、SEQ IDNO:10和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列;或
c.分别为SEQ ID NO:12、SEQ ID NO:2和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:13、SEQID NO:14和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列。
在又一个实施方案中,本发明涉及结合CLDN18.2的抗体或其片段,其包含:
a.SEQ ID NO:27的VH序列和SEQ ID NO:28的VL序列;
b.SEQ ID NO:29的VH序列和SEQ ID NO:30的VL序列;
c.SEQ ID NO:31的VH序列和SEQ ID NO:32的VL序列。
在另一个实施方案中,本发明涉及结合CLDN18.2的抗体或其片段,其包含:
a.SEQ ID NO:33的VH序列;
b.SEQ ID NO:34的VH序列;
c.SEQ ID NO:35的VH序列;
d.SEQ ID NO:36的VH序列;或
e.SEQ ID NO:37的VH序列;
和
f.SEQ ID NO:38的VL序列;
g.SEQ ID NO:39的VL序列;
h.SEQ ID NO:40的VL序列;或
i.SEQ ID NO:41的VL序列。
在另一个实施方案中,本发明涉及结合CLDN18.2的抗体或其片段,其包含:
a.SEQ ID NO:33的VH序列和SEQ ID NO:38的VL序列;
b.SEQ ID NO:34的VH序列和SEQ ID NO:38的VL序列;
c.SEQ ID NO:34的VH序列和SEQ ID NO:39的VL序列;
d.SEQ ID NO:34的VH序列和SEQ ID NO:40的VL序列;
e.SEQ ID NO:35的VH序列和SEQ ID NO:38的VL序列;
f.SEQ ID NO:36的VH序列和SEQ ID NO:41的VL序列;
g.SEQ ID NO:36的VH序列和SEQ ID NO:40的VL序列;
h.SEQ ID NO:37的VH序列和SEQ ID NO:41的VL序列;
i.SEQ ID NO:37的VH序列和SEQ ID NO:38的VL序列;或
j.SEQ ID NO:37的VH序列和SEQ ID NO:39的VL序列。
在另一个实施方案中,本发明涉及结合CLDN18.2的抗体,其包含:
a.SEQ ID NO:46的重链序列和SEQ ID NO:51的轻链序列;
b.SEQ ID NO:47的重链序列和SEQ ID NO:51的轻链序列;
c.SEQ ID NO:47的重链序列和SEQ ID NO:52的轻链序列;
d.SEQ ID NO:47的重链序列和SEQ ID NO:53的轻链序列;
e.SEQ ID NO:48的重链序列和SEQ ID NO:51的轻链序列;
f.SEQ ID NO:47的重链序列和SEQ ID NO:54的轻链序列;
g.SEQ ID NO:49的重链序列和SEQ ID NO:53的轻链序列;
h.SEQ ID NO:50的重链序列和SEQ ID NO:54的轻链序列;
i.SEQ ID NO:50的重链序列和SEQ ID NO:51的轻链序列;或
j.SEQ ID NO:50的重链序列和SEQ ID NO:52的轻链序列。
所公开的抗体的恒定轻链区CL和恒定重链区CH1和Fc区可以分别具有SEQ ID NO:127和SEQ ID NO:128的氨基酸序列。
在优选的实施方案中,本发明涉及结合CLDN18.2的抗体,其包含SEQ ID NO:46的重链序列和SEQ ID NO:51的轻链序列。
在进一步优选的实施方案中,本发明涉及结合CLDN18.2的抗体,其由SEQ ID NO:46的重链序列和SEQ ID NO:51的轻链序列组成。
本发明还涉及具有与本发明抗体的氨基酸序列有至少80%同一性、至少85%同一性、至少90%同一性、至少95%同一性或至少98%同一性的氨基酸序列的抗体,相较于表达CLDN18.2的健康胃细胞,其表现出对表达CLDN18.2的肿瘤细胞的结合增加。
在一个实施方案中,本发明涉及结合CLDN18.2的抗体,其具有与包含以下的抗体有至少80%同一性、至少85%同一性、至少90%同一性、至少95%同一性或至少98%同一性的氨基酸序列:
a.SEQ ID NO:27的VH序列和SEQ ID NO:28的VL序列;
b.SEQ ID NO:29的VH序列和SEQ ID NO:30的VL序列;
c.SEQ ID NO:31的VH序列和SEQ ID NO:32的VL序列。
在进一步的实施方案中,本发明涉及结合CLDN18.2的抗体,其具有与包含以下的抗体有至少80%同一性、至少85%同一性、至少90%同一性、至少95%同一性或至少98%同一性的氨基酸序列:
a.SEQ ID NO:33的VH序列和SEQ ID NO:38的VL序列;
b.SEQ ID NO:34的VH序列和SEQ ID NO:38的VL序列;
c.SEQ ID NO:34的VH序列和SEQ ID NO:39的VL序列;
d.SEQ ID NO:34的VH序列和SEQ ID NO:40的VL序列;
e.SEQ ID NO:35的VH序列和SEQ ID NO:38的VL序列;
f.SEQ ID NO:36的VH序列和SEQ ID NO:41的VL序列;
g.SEQ ID NO:36的VH序列和SEQ ID NO:40的VL序列;
h.SEQ ID NO:37的VH序列和SEQ ID NO:41的VL序列;
i.SEQ ID NO:37的VH序列和SEQ ID NO:38的VL序列;或
j.SEQ ID NO:37的VH序列和SEQ ID NO:39的VL序列。
在又一个实施方案中,本发明涉及结合CLDN18.2的抗体,其具有与由SEQ ID NO:46的重链序列和SEQ ID NO:51的轻链序列组成的抗体有至少80%同一性、至少85%同一性、至少90%同一性、至少95%同一性或至少98%同一性的氨基酸序列。
在另一个实施方案中,抗体(或存在的抗体片段)的Fc结构域可以包含修饰或突变,如下表2中列出的修饰或突变。可以引入此类修饰或突变来调节抗体的Fc结构域的效应器活性。抗体的修饰还可以包括添加到抗体HC链和/或LC链的C端的肽标签。此类标签可以用于例如蛋白质纯化或蛋白质缀合。
在另一个实施方案中,本发明提供了结合CLDN18.2抗体或其片段,该抗体是IgA1、IgA2、IgD、IgE、IgG1、IgG2、IgG3、IgG4、合成IgG、IgM、F(ab)2、Fv、scFv、IgGACH2、F(ab')2、scFvCH3、Fab、VL、VH、scFv4、scFv3、scFv2、dsFv、Fv、scFv-Fc、(scFv)2、非消耗性(non-depleting)IgG、双抗体、二价抗体或其Fc工程化版本。在优选的实施方案中,抗体是IgG1类型的抗体。免疫球蛋白的Fc区与多种Fcγ受体(FcγR)和补体蛋白(例如,C1q)相互作用,并介导免疫效应器功能,如通过抗体依赖性细胞毒性(ADCC)、抗体依赖性细胞吞噬作用(ADCP)或补体依赖性细胞毒性(CDC)消除靶细胞。对于治疗方法,增强或沉默相关效应器功能可能是有益的。免疫球蛋白的类型(IgA、IgD、IgE、IgG、IgM)可以根据与Fc结构域相关的抗体的期望效应器功能来选择。也可以使用合成免疫球蛋白,如具有IgG2氨基酸118至260和IgG4氨基酸261至447的免疫球蛋白或具有来自IgG4的点突变(例如,H268Q/V309L/A30S/P331S)的IgG2变体。此类合成免疫球蛋白降低了抗体的效应器功能。Fc工程化免疫球蛋白也可以用于调节抗体效应器功能。表2显示了此类Fc工程化的实例。在具有改变的岩藻糖基化的生产细胞系中的表达也可以影响FcγR结合。
表2:调节抗体效应器功能的修饰的实例。除非另有说明,否则突变位于IgG1亚类上(Wang,Mathieu和Brezski 2018)。
也可以调节抗体的半衰期。Fc结构域在抗体的稳定性和血清半衰期中起着核心作用。对于治疗方法,抗体半衰期可通过使用缺少Fc结构域或具有截短Fc结构域的抗体片段来缩短,如F(ab)2、Fv、scFv、IgGACH2、F(ab')2、scFvCH3、Fab、VL、VH、scFv4、scFv3、scFv2、dsFv、Fv、scFv-Fc或(scFv)2。抗体也可以是双抗体或二价抗体的形式。双抗体或二价抗体可用于增加对靶标的亲和力,从而允许较低剂量。缺少Fc结构域或具有截短Fc结构域的功能片段也可用于开发其他治疗方法,如嵌合抗原受体T细胞(CAR T细胞)或双特异性T细胞接合剂(BiTE)。在CAR构建体中,一个VH结构域和一个VL结构域通常通过短肽接头连接以形成单链可变片段(scFv),并且scFv片段进一步连接到跨膜结构域和胞质内T细胞免疫受体的基于酪氨酸的激活基序(来自例如CD3ζ)和共刺激分子的其他结构域(来自例如CD28、4-1BB(CD127)或OX40)(Chang和Chen 2017)。scFv片段中使用的VH和VL结构域可以是表3中列出的抗体。BiTE通常由两种不同抗体的两个scFv的融合物组成。一个scFv结构域可以是表3中列出的结合CLDN18.2的分离的抗体,而另一个scFv结构域来自结合例如CD3、CD16、NKG2D、NKp46、CD2、CD28或CD25的抗体。可在Diego Ellerman(2019)的综述中找到用于T细胞重定向的BiTE抗体形式和其他双特异性抗体形式的充分指导。
在另一个实施方案中,本发明提供了结合CLDN18.2的抗体或其片段,该抗体具有SEQ ID NO:127的恒定轻链区(CL)和优选地具有降低的FcγR结合的SEQ ID NO:129的恒定重链区CH1以及Fc区,其在恒定重链区CH2中具有L234A/L235A突变。更优选地,本发明提供了抗体,该抗体具有SEQ ID NO:130的恒定重链区CH1和Fc区,其在恒定重链区CH1和Fc区中具有L234A/L235A/P329G突变,具有甚至进一步降低的FcγR结合。
在另一个优选的实施方案中,本发明涉及结合CLDN18.2的抗体或其片段,其包含SEQ ID NO:33的VH序列、SEQ ID NO:38的VL序列、SEQ ID NO:127的恒定轻链区(CL)以及具有L234A/L235A的SEQ ID NO:129的恒定重链区CH1和Fc区。
在另一个优选的实施方案中,本发明涉及结合CLDN18.2的抗体或其片段,其由SEQID NO:33的VH序列、SEQ ID NO:38的VL序列、SEQ ID NO:127的恒定轻链区(CL)以及具有L234A/L235A的SEQ ID NO:129的恒定重链区CH1和Fc区组成。
在另一个实施方案中,本发明提供了结合CLDN18.2的抗体或其片段,其中该抗体或其片段是人源化的。单克隆抗体的人源化是完善建立的。Handbook of TherapeuticAntibodies,第二版提供了单克隆抗体的人源化(Saldanha 2014)、用于分析此类抗体的生物信息学工具(Martin和Allemn 2014)以及治疗性抗体的开发和制备(Jacobi等人2014)的充分信息。
在另一个实施方案中,抗体或其片段是结合CLDN18.2的分离的抗体或分离的片段。
在另一个实施方案中,本发明提供了结合CLDN18.2的抗体或其片段,其中该抗体或其片段不结合CLDN18.1。因此,抗体不表现出与CLDN18.1的交叉反应性或交叉结合。抗体与靶蛋白的结合可以通过对表达靶蛋白的细胞的流式细胞术进行测试。测试抗体与其靶蛋白的特异性结合可以在直方图上可视化。此图在抗体特异性结合表达的靶蛋白时产生具有高荧光信号的峰,而在抗体不结合或仅非常弱地结合表达的靶蛋白时产生具有低荧光信号的峰。结合程度也可以用条形图表示,显示通过流式细胞术测量的最大平均荧光强度(maxMFI),高maxMFI反映强结合,低/无maxMFI反映无结合或非常弱的结合。比较同一实验设置中不同抗体的maxMFI值也可以表明抗体与靶标的亲和力,较高的maxMFI表示较低的解离率(off rate)和较高的亲和力。在实施例3以及图4和图5中可以找到此结合测定的实例。
在另一个实施方案中,本发明提供了结合CLDN18.2的抗体或其片段,该抗体与另一个部分结合。抗体或其片段与另一部分的结合可以是共价的或非共价的。该部分可以包括放射性同位素、荧光标签、组织学标志物、细胞毒素或细胞因子。该部分与抗体的共价结合可以通过本领域中已知的接头促进。
在又一个实施方案中,本发明涉及结合CLDN18.2的肿瘤特异性抗体或其片段,其中该抗体对翻译后脱酰胺化的易感性低于IMAB362。在另一个实施方案中,本发明涉及结合CLDN18.2的肿瘤特异性抗体或其片段,其中该抗体不经历翻译后脱酰胺化。翻译后修饰(PTM)是抗体开发以及抗体生产和储存中的重要问题。不受控制的PTM可能导致抗体具有较低的功效、活性、效力或稳定性。PTM可以是N-糖基化、赖氨酸糖基化和生物加工过程中来自细胞培养基的其他半胱氨酸、谷胱甘肽或其他含巯基的化合物加帽的半胱氨酸、或者由于通过共价二硫键连接的半胱氨酸形成二聚体和更高级的寡聚体。在PTM中,天冬酰胺(Asn,N)残基的脱酰胺化、天冬氨酸盐(天冬氨酸,Asp,D)残基的异构化和琥珀酰亚胺中间体的形成是在生产、储存期间或施用后体内的治疗性抗体的最常见的修饰反应。Asn的脱酰胺化和Asp的异构化取决于序列倾向、结构环境和储存条件,特别是溶液pH值和储存温度。这些修饰可能导致功能或生物活性降低或甚至丧失,特别是在受影响的残基参与靶标结合的情况下。Asn和Asp残基面临修饰的风险,特别是当它们位于结构柔性的区域(如CDR环)中时,以及满足某些其他结构的先决条件时,而已观察到框架区对修饰具有可比较的抗性。除了Asn和Asp残基的结构位置外,还鉴定了Asn脱酰胺和Asp异构化的典型基序。这些典型基序分别为NG、NS、NN、NT、NH、以及DG、DS、DD、DT和DH(Lu等人2019)。在计算机分析中,公开的抗体在VL结构域的CDR2的最后一个氨基酸和HC的CH2和CH3区(VL-CDR2(在位置62)、CH2(在位置282)、CH3(在位置403))中呈现DG Asp异构化基序。
Asp的异构化可以通过将抗体置于低pH(即pH 5.5)和加热(即40℃)两周来测试,而抗体的Asn脱酰胺化可以通过将抗体置于高pH(即pH 8.0)和加热(即40℃)一周,模拟生产和储存条件来测试。
发明人现已表明,尽管在这些苛刻条件下,所公开的抗体在它们的CDR中含有Asn和Asp,并且带有Asp-Gly(DG)Asp-异构化基序,但是令人惊讶地它们没有Asn脱酰胺化(参见表6)和Asp异构化(参见表7)并且它们与CLDN18.2的结合亲和力不受影响。另一方面,IMAB362在这种条件下显示出Asn脱酰胺化,诱导结合亲和力丧失(如表6和图10所示)。因此,本发明提供了结合CLDN18.2的分离的抗体或其片段,并且在生产、储存和临床应用(体内)期间与IMAB362相比不易受PTM影响,并且保证在生产、储存和临床应用(体内)期间维持的与CLDN18.2的结合亲和力。
本发明还提供了与本文所述抗体结合相同表位的抗体。在一个实施方案中,该抗体与包含SEQ ID NO:46的重链序列和SEQ ID NO:51的轻链序列的抗体结合相同的表位。
本发明进一步提供与本文所述抗体竞争结合的抗体。在一个实施方案中,该抗体与包含SEQ ID NO:46的重链序列和SEQ ID NO:51的轻链序列的抗体竞争结合。
本发明进一步提供竞争性抑制本文所述抗体与密蛋白18.2结合的抗体。在一个实施方案中,该抗体竞争性地抑制包含SEQ ID NO:46的重链序列和SEQ ID NO:51的轻链序列的抗体与密蛋白18.2的结合。
检测抗体与相同抗原的结合的合适方法包括定位抗原-抗体相互作用的方法。此方法已描述于Abbott 2014(Abbott,Damschroder和Lowe 2014)。检测竞争的合适方法包括通过表位分箱(binning)进行的竞争性测定,如Abdiche2009(Abdiche等人2009)中所述。检测竞争性抑制的合适方法包括ELISA测定。
根据一个实施方案,本发明提供了编码结合CLDN18.2的分离的肿瘤特异性抗体或其功能片段的核酸序列。核酸序列可以编码单独的CDR、编码VH和VL区、或编码抗体的整个重链和轻链。这些核酸序列可以在表3中找到。核酸序列还可以编码F(ab)2、Fv、scFv、IgGACH2、F(ab')2、scFvCH3、Fab、VL、VH、scFv4、scFv3、scFv2、dsFv、Fv、scFv-Fc、(scFv)2、非消耗性IgG、双抗体、二价抗体或其Fc工程化版本。编码的免疫球蛋白可以是IgA1、IgA2、IgD、IgE、IgG1、IdG2、IgG3、IgG4、合成IgG、IgM或其突变和Fc工程化版本。
在又一个实施方案中,核酸序列还可以编码结合CLDN18.2的CAR构建体。在Chang和Chen(2017)或June和Sadelain(2018)中可以找到关于构建CAR T细胞的充分指导。在一个实施方案中,本发明提供了T细胞,该T细胞经过基因工程改造以产生人工T细胞受体,例如嵌合抗原受体(CAR),其中人工T细胞受体包含本发明的结合CLDN18.2的抗体或其功能片段。
在又一个实施方案中,本发明提供特异性结合CLDN18.2的基于肿瘤特异性抗体的结合蛋白。此类结合蛋白可以至少包含公开的抗体的CLDN18.2结合结构域和另一个与抗体无关的蛋白质结构域。本发明还提供了结合CLDN18.2的修饰抗体形式。
本发明还提供了表达载体,其包含本发明的核酸或由于密码子简并性而导致的简并核酸。表达载体可以是用于在哺乳动物细胞、细菌、真菌或昆虫细胞中表达蛋白质的表达载体,并且选择用于携带包含编码抗体或其功能片段的核酸的表达载体的宿主细胞类型。在Green和Sambrook(Green和Sambrook 2012)中可以找到构建此类载体的充分指导。
在另一个实施方案中,本发明提供了包含本发明的核酸或表达载体的宿主细胞。宿主细胞可以是哺乳动物细胞或细胞系、细菌细胞、真菌细胞或昆虫细胞。
在另一个实施方案中,本发明涉及结合CLDN18.2的抗体或其片段、编码该抗体或其片段的核酸、包含该核酸的载体或包含该核酸或该载体的宿主细胞,用于治疗患有肿瘤疾病的受试者。
在另一个实施方案中,本发明涉及结合CLDN18.2的抗体或其片段、编码该抗体或其片段的核酸、包含该核酸的载体或包含该核酸或该载体的宿主细胞,用于治疗有形成赘生性疾病风险的受试者,和/或用于治疗被诊断患有赘生性疾病的受试者。
所公开的抗体或其片段可用作单一疗法。在一个优选的实施方案中,所公开的抗体或其片段与肿瘤疾病的既定护理标准结合使用。
肿瘤疾病可以是选自胰腺癌、胃癌、食道癌、卵巢癌和肺癌中的至少一种疾病。据了解,待治疗的赘生性疾病表达CLDN18.2。
在一个实施方案中,受试者是哺乳动物。在优选的实施方案中,受试者是人。
本发明的另一个实施方案提供了使用结合CLDN18.2的抗体或其功能片段治疗赘生性疾病的方法,所述赘生性疾病包括胰腺癌、胃癌、食道癌、卵巢癌或肺癌,其中该方法包括向有需要的受试者提供施用药学有效量的抗体或其功能片段。治疗方法可以是单一疗法或优选地与肿瘤疾病的既定护理标准的联合疗法。
人CLDN18.2蛋白的氨基酸序列可来源于NCBI参考序列:NP_001002026.1。该序列也公开为SEQ ID NO:133。
附图说明
图1:通过ELISA评估如指定的所选嵌合和人源化抗CLDN18.2抗体与含有CLDN18.2的脂质颗粒或空脂质颗粒的结合。A.嵌合抗体cCl1-1、cCl1-2、cCl1-3、IMAB362和仅二抗;B.人源化抗体hCl1a至hCl1j、嵌合cCl1-1、IMAB362和仅二抗。所有新生成的抗体都结合脂质体CLDN18.2。
图2:针对CLDN18.2表达水平对PA-TU-8988S细胞进行分选。A.用IMAB362染色的PA-TU-9888S的FC谱。B.通过FACS针对高表达CLDN18.2分选的PA-TU-8988S细胞的FC谱。
图3:生成过表达huCLDN18.2的HEK293T细胞。用编码huCLDN18.2以稳定表达CLDN18.2或编码huCLDN18.1以稳定表达CLDN18.1的质粒转染不内源性表达CLDN18.2的HEK293T细胞。在用IMAB362和泛CLDN18.1抗体或仅抗人IgG二抗染色后,通过FC分析表达。A.未转染的HEK293T细胞的FC谱。B.稳定表达CLDN18.1的转染HEK293T细胞的FC谱。C.稳定表达CLDN18.2的转染HEK293T细胞的FC谱。
图4:嵌合cCl1-1、cCl1-2和cCl1-3抗体与过表达CLDN18.1或CLDN18.2的前B细胞L11细胞的流式细胞术结合测定。嵌合抗体结合CLDN18.2而不结合CLDN18.1。IMAB362用作阳性结合对照。
图5:人源化hCl1a至hCl1j抗体对过表达CLDN18.1或CLDN18.2的HEK293T细胞的流式细胞术结合测定。人源化抗体结合CLDN18.2而不结合CLDN18.1。IMAB362和cCL1-1用作阳性结合对照。
图6:过表达CLDN18.2的A549细胞的FACS表达谱。用编码CLDN18.2的质粒稳定转染不表达内源性CLDN18.2的A549细胞,并使用IMAB362通过FACS分析CLDN18.2的表达。
图7:流式细胞术活细胞染色。该图表示由CLDN18.2抗体(cCl1-1、hCl1a、hCl1b、hCl1c、hCl1f和IMAB362)结合的分离的单细胞的百分比。单细胞从注射的过表达CLDN18.2的A549细胞引起的表达CLDN18.2的小鼠肿瘤中分离(实心条)或从表达CLDN18.2的小鼠健康胃中分离(空心条)。
图8:冷冻胃组织染色。表达CLDN18.2的小鼠健康胃组织的冷冻组织切片已用hCl1a(A)、hCl1b(B)、hCl1c(C)、hCl1f(D)或IMAB362(E)抗体染色。图片是代表性的IHC图像。
图9:从注射的过表达CLDN18.2的A549细胞引起的冷冻肿瘤组织的染色。表达CLDN18.2的小鼠肿瘤的冷冻组织切片已用hCl1a(A)、hCl1f(B)、IMAB362(C)或Abcam34H14L15泛CLDN18抗体染色。图片是代表性的IHC图像。
图10:脱酰胺化对IMAB362结合活性的影响。脱酰胺化后IMAB362对CLDN18.2的亲和力降低。
实施例
实施例1:嵌合和人源化抗体的生成
生成单克隆抗体的技术已经是完善建立的。Handbook of TherapeuticAntibodies,第二版(2014)提供了有关这些技术的充分信息,如通过免疫小鼠或大鼠产生单克隆抗体(Moldenhauer 2014)、单克隆抗体的人源化(Saldanha2014)、用于分析抗体的生物信息学工具(Martin和Allemn 2014)或治疗性抗体的开发和制备(Jacobi等人2014)。简而言之,通过用编码人CLDN18.2cDNA(huCLDN18.2)(NCBI参考序列:NM_001002026.3)的质粒对大鼠进行DNA免疫,生成针对CLDN18.2的单克隆抗体。通过流式细胞术(FC分析)和ELISA分析大鼠免疫血清对huCLDN18.2的特异性反应性。随后从免疫大鼠分离的淋巴细胞中生成杂交瘤克隆以获得嵌合抗体。三个克隆被鉴定为CLDN18.2特异性,从而产生了具有相似的CDR的名为cCl1-1、cCl1-2和cCl1-3的嵌合抗体(参见表3)。随后,将cCl1-1、cCl1-2和cCl1-3人源化,产生了10个人源化克隆,分别命名为hCl1a、hCl1b0、hCl1c、hCl1d、hCl1e、hCl1f、hCl1g、hCl1h、hCl1i和hCl1j抗体(参见表3)。
作为对照,使用WO2013/174509中公布的重链(SEQ ID NO:55)和轻链(SEQ ID NO:56)的序列合成IMAB362抗体,命名为单克隆抗体182-D1106-362,保藏号DSM ACC2810,于2006年10月26日保藏在DSMZ-Deutsche Sammlung von Mikroorganismen undZellkulturen GmbH Inhoffenstr.7B 38124Braunschweig DE。
表3:抗体核酸和氨基酸序列
进一步修饰实施例2至5中描述的抗体以在HC的C端含有RLPQTGG标签(SEQ ID NO:131)和/或在LC的C端含有GGGGSLPQTGG标签(SEQ ID NO:132)。在这种情况下,HC上的C端赖氨酸(K)被标签的Arg(R)取代。标签的添加没有改变抗体对CLDN18.2的亲和力和特异性。
实施例2:ELISA测定和FC滴定以确认嵌合和人源化抗体变体对CLDN18.2的结合
嵌合抗体和人源化抗体(hCl)对CLDN18.2的结合亲和力在ELISA测定中进行了测试,其中带有CLDN18.2的脂质颗粒作为抗原来源。CLDN18.2-脂质颗粒和空脂质颗粒(没有结合的抗原,作为阴性对照)用于以10U/ml的最终浓度包被96孔板。用PBS/0.05%Tween-20(PBS-T)洗涤并在37℃下用PBS-T/3%BSA封闭至少1小时后,起始浓度为2μg/ml的测试抗体的1:3连续稀释液添加到包被的孔中并在37℃下孵育至少1小时。通过结合HRP-山羊抗人二抗,以SIGMAFASTTM OPD作为过氧化物酶底物进行显影,通过加入2M H2SO4终止反应,然后在ELISA读板器上读取490nm处的OD,揭示了结合抗体的存在。代表性结合曲线显示于图1。本发明的所有测试抗体特异性结合含有CLDN18.2的脂质颗粒。有趣的是,与亲本嵌合cCl1-1抗体相比,嵌合抗体的人源化并未导致亲和力降低,如可以预期,并且对于10种抗体中的6种,甚至增加了其亲和力。
嵌合抗体和人源化抗体对CLDN18.2的结合也通过使用过表达CLDN18.2的PA-TU-8988S细胞(Creative Bioarray,目录号CSC-C0326)和HEK293T(ATCC,CRL-3216TM)细胞的FC滴定来测试。FC滴定允许测量测试抗体的半数最大有效浓度(EC50)。通过FACS选择表达高水平CLDN18.2的PA-TU-8988S细胞。本文中,这些细胞被命名为PA-TU-8988S-High细胞。基于IMAB362的FACS染色,PA-TU-8988S细胞群表达不同水平的CLDN18.2,具有高水平和中等水平的表达(参见图2A)。为了具有更同质的细胞群,细胞通过FACS分选以仅选择具有较高CLDN18.2表达的细胞。简而言之,将悬浮在FACS缓冲液(PBS,2%FCS)中的PA-TU-8988S细胞与2μg/ml的IMAB362在冰上孵育30分钟。在FACS缓冲液中洗涤后,将细胞与PE标记的Fcγ特异性IgG山羊抗人二抗(eBioscience)在冰上孵育30分钟。洗涤后,将染色的细胞重悬于FACS缓冲液中,通过FACSAriaTM仪器进行分析和分选,将中等表达细胞与高表达细胞分离(图2B)。在分选后,将收集的PA-TU-8988S-High细胞重悬于生长培养基中,扩增,并将冷冻等分保存于液氮中。如实施例3所述生成过表达CLDN18.2或CLDN18.1的HEK293T细胞,并通过流式细胞术分析CLDN18.2的表达(图3)。
为了量化抗体与CLDN18.2的结合,将250x103个细胞/孔的过表达CLDN18.2的HEK293T细胞或PA-TU-8988-High细胞接种到96-孔板中的FC缓冲液(PBS/2%FBS)中并通过离心沉降。IMAB362和待测的hCl抗体以20μg/ml稀释,然后按1:4连续稀释并在4℃下与分配的细胞孵育30分钟。在用FC缓冲液洗涤后,将PE偶联的抗人IgG二抗添加到细胞中,在4℃下再持续30分钟,然后用FC缓冲液进一步洗涤。然后将细胞重悬于100μl FC缓冲液中,并用FACSCaliburTM细胞分析仪(BD Biosciences,美国)进行测量。FC分析(参见图5和表4)表明,hCl抗体比IMAB362具有更高的EC50值,尽管其maxMFI值与IMAB362在相同的范围内。相似的maxMFI值可以指示IMAB362和hCl抗体的相似结合/解离速率。
表4:在过表达CLDN18.2的HEK293T细胞系和PA-TU-8988S-High细胞系上测量的所
有hCl和IMAB362抗体的最大MFI和EC50(μg/ml)。
实施例3:稳定表达hCLDN18.1和hCLDN18.2的前B细胞L11细胞和HEK293 T细胞的
生成;嵌合抗体和人源化抗体的结合特异性的测试。
前B细胞L11细胞系(Waldmeier等人2016)和HEK293T(ATCC CRL-3216TM)细胞系不内源性表达CLDN18.1或CLDN18.2。因此,为了测试抗体结合,将CLDN18.1和CLDN18.2在这些细胞系中重组过表达。通过用转座酶表达构建体(pcDNA3.1-hy-mPB),带有可转座的全长huCLDN18.1(pPB-Puro-huCLDN18.1)或huCLDN18.2(pPB-Puro-huCLDN18.2)以及嘌呤霉素抗性盒的构建体和携带EGFP的构建体作为转染对照(pEGFP-N3)(Waldmeier等人2016)电穿孔共转染细胞。电穿孔后,细胞在37℃的加湿培养箱中在生长培养基中恢复两天,对于L11细胞在7.5%CO2气氛的情况下,对于HEK293T细胞在5%CO2气氛的情况下。通过EGFP表达的FC分析来验证转染。然后通过将1μg/ml嘌呤霉素添加到培养物中来选择表达CLDN18.1或CLDN18.2的细胞,并进一步扩增以允许生成在含有10%DMSO的FCS中的冷冻原液。通过FC分析转染细胞中CLDN18.1和CLDN18.2的表达(参见图3)。简而言之,通过离心收集悬浮生长的经胰蛋白酶处理的HEK293T细胞和L11细胞,重悬于PBS/2%FCS中,并使用IMAB362作为一抗在冰上以2μg/ml的浓度对CLDN18.2染色30分钟,然后在PBS/2%FCS中洗涤,用抗人IgG(Fcγ特异性)PE山羊抗体(eBioscience)作为二抗在冰上染色30分钟。进一步洗涤后,使用FACSCaliburTM仪器分析重悬于冰冷FC缓冲液中的染色细胞(参见图4和图5)。未转染的亲本细胞不表达CLDN18.2,用作阴性对照。使用识别CLDN18.1和CLDN18.2的专有泛CLDN18抗体以类似方式分析CLDN18.1的表达(参见图3)。任何可用于流式细胞术测量的泛CLDN18抗体也适用,如OriGene Technologies提供的抗体抗密蛋白-18/CLDN18(C端)(目录号AP50944PU-N)、来自MyBioSource的CLDN18(C端)兔pAb(目录号MBS8555451)或来自ProSci的CLDN18抗体(目录号63-847)。
因此,使用稳定表达huCLDN18.1和huCLDN18.2的L11和HEK293T细胞来测试嵌合抗体cCl1-1、cCl1-2、cCl1-3和人源化抗体对CLDN18.2而非CLDN18.1的结合特异性。使用2μg/ml的抗体将细胞在冰上染色30分钟,然后在PBS/2%FCS中洗涤后,用抗人IgG(Fcγ特异性)PE山羊抗体(eBioscience)作为二抗冰上染色30分钟。所有三种嵌合抗体(图4)和人源化抗体(图5)均结合L11或HEK293T细胞表达的huCLDN18.2,而不结合huCLDN18.1。此外,人源化抗体与huCLDN18.2结合的亲和力与IMAB362相似,并且亲和力至少与cCl1-1一样好(图5)。
实施例4:通过对活体肿瘤组织和活体胃组织的流式细胞术测试人源化CLDN18.2
抗体结合活性
A549(ATCC CCL-185TM)细胞系不内源性表达CLDN18.1或CLDN18.2。为了测试抗体与CLDN18.2的结合,在A549细胞中表达CLDN18.2。通过用转座酶表达构建体(pcDNA3.1-hy-mPB)(Klose等人2017),带有可转座的全长huCldn18.2(pPB-Puro-huCldn18.1)以及嘌呤霉素表达盒的构建体和携带EGFP的构建体作为转染对照(pEGFP-N3)(Waldmeier等人2016)电穿孔共转染A549细胞。电穿孔后,让细胞在37℃、5%CO2气氛的加湿培养箱中的生长培养基中恢复两天。通过EGFP表达的FC分析来验证转染。然后通过将1μg/ml嘌呤霉素添加到培养物中来选择表达CLDN18.1或CLDN18.2的细胞,并进一步扩增以允许生成在含有10%DMSO的FCS中的冷冻原液。通过FC分析转染细胞中CLDN18.2的表达。简而言之,通过离心收集胰蛋白酶处理的A549细胞,重悬于PBS/2%FCS中并使用IMAB362作为一抗在冰上以2μg/ml的浓度对CLDN18.2染色30分钟,然后在PBS/2%FCS中洗涤后,用2.5μg/ml抗人IgG(Fcγ特异性)PE山羊抗体(eBioscience)作为二抗在冰上染色30分钟。进一步洗涤后,使用FACSCaliburTM仪器分析重悬于冰冷FC缓冲液中的染色细胞(参见图6)。未转染的亲本细胞不表达CLDN18.2,用作阴性对照。这些细胞于2019年12月6日保藏于DSMZ-Deutsche Sammlung vonMikroorganismen und Zellkulturen GmbH Inhoffenstr.7B 38124Braunschweig DE,可在保藏号DSM ACC3360下获得。
将在100μl 50%Matrigel中表达CLDN18.2的1x106 A549细胞皮下植入两只Balb/c小鼠,并在数周内监测肿瘤生长,直至肿瘤达到150-450mm3之间的期望大小。收集健康的胃组织和肿瘤组织用于FC分析。将收集的组织切成小块并用Miltenyi肿瘤分离试剂盒(MACS Miltenyi Biotec,德国)消化。将组织块与解离缓冲液(根据制造商说明制备)在6孔板中37℃下在持续的轻柔震荡运动下孵育30分钟。将样品重悬并通过70μm细胞过滤器(Corning,美国)过滤,然后用20ml FC缓冲液(PBS+2%FBS)洗涤。将细胞悬液离心(在4℃下400g 5分钟)并弃去上清液。如果需要,将细胞悬液通过过滤器并反复离心,将沉淀物重悬于5ml红细胞裂解缓冲液(Biolegend,美国)中,在冰上孵育4分钟。孵育后,加入25ml PBS,再次离心悬浮液(4℃下400g 5分钟)。将沉淀物重悬于FC缓冲液中(基于沉淀0.5-3ml)。将相等数量的细胞转移到96孔板中并进一步处理用于FC分析。用PBS洗涤板中的细胞并离心(在4℃下400g 2分钟)。将沉淀物重悬于50μl/孔的染色混合物中,该混合物由在PBS中稀释的所选抗体(4μg/ml的cCl1-1、hCl1a、hCl1b、hCl1c和hCl1f;2μg/ml的IMAB364)和AF488标记的AE1/AE3泛细胞角蛋白抗体(Thermo Fisher Scientific,美国)组成,并在冰上孵育25分钟。孵育后,细胞在PBS中洗涤两次并离心(在4℃下400g 2分钟)。将沉淀物重悬于50μl/孔的二次染色混合物(PBS+PE标记的抗人抗体)(Thermo Fisher Scientific,美国)中,并在冰上孵育25分钟。孵育后,细胞在PBS中再次洗涤两次。将沉淀物重悬于100μl含有DAPI的PBS中。将板保持在冰上直至FC分析。对于FC分析,通过前向散射和DAPI染色将活细胞与死细胞分离。然后对活细胞进行门控以确定是否存在细胞角蛋白(AF888阳性)和结合的CLDN18.2抗体(PE阳性细胞)。FC分析结果可以参见图7和表5。结果是从两只小鼠获得的数据的平均值。
所有测试的抗体(cCl1-1、hCl1a、hCl1b、hCl1c、hCl1f和IMAB364)结合相似百分比(约在20%和30%之间)的带有CLDN18.2的肿瘤细胞。然而,令人惊讶的是,只有IMAB362与带有CLDN18.2的健康胃细胞结合,而cCl1-1、hCl1a、hCl1b、hCl1c和hCl1f的结合几乎无法检测到,结合不到1%的健康胃细胞。源于注射的表达CLDN18.2的A549细胞的肿瘤细胞与健康胃细胞中表达的CLDN18.2之间的结合能力差异也表示为阳性肿瘤细胞%除以阳性胃细胞%的比率(参见表5中的最后一列)。对于IMAB362,该比率低于5,平均而言接近1,而对于测试的cCl1-1人源化克隆(hCl1a、hCl1b、hCl1c和hCl1f),该比率高于15,平均而言高于30。
表5:FC结合数据和所选抗体对健康胃细胞和肿瘤细胞的结合比率。
因此,与健康胃细胞相比,cCl1-1和测试的cCl1-1人源化克隆(hCl1a、hCl1b、hCl1c和hCl1f)显示出与肿瘤细胞的结合增加,因此是肿瘤特异性CLDN18.2抗体。相比之下,IMAB362无法区分带有CLDN18.2的肿瘤细胞和带有CLDN18.2的健康胃细胞。
实施例5:通过在冷冻组织样品上的免疫组织化学(IHC)测试人源化CLDN18.2抗体
从皮下植入1x106个表达CLDN18.2的A549细胞的Balb/c小鼠获得的表达CLDN18.2的新鲜胃和肿瘤组织样品在合适的组织模具中的OCT中速冻。在-20℃下用低温恒温器切割5-15μm厚的组织切片,在室温(RT)下转移到显微镜载玻片上,随后保持冷冻直至IHC染色。染色前,将载玻片放回室温并在预冷的丙酮(-20℃)中固定10分钟。在室温下蒸发丙酮后,将载玻片在TBS中冲洗并处理以封闭非特异性染色位点:将载玻片在0.3%H2O2中室温孵育15分钟,然后用TBS洗涤并在过氧化物酶封闭溶液(Agilent,美国)中室温下孵育60分钟。封闭后,对载玻片进行抗体染色处理:将载玻片与一抗(hCL1a、hCl1b、hCl1c、hCl1f、IMAB362和34H14L15泛CLDN18抗体(Abcam,美国))在室温下孵育120分钟,在TBS中洗涤,然后与HRP缀合的抗人抗体(或泛CLDN18抗体的抗兔抗体)在室温下孵育30分钟。根据制造商的说明,通过用DAB+底物Chromogen系统(Agilent,美国)处理载玻片,揭示与组织切片上的CLDN18.2或泛CLDN18结合的抗体。在随后的TBS洗涤后,载玻片在苏木精中复染,在dH2O中冲洗15分钟,在连续的95%和100%乙醇洗涤中脱水,然后在二甲苯中进一步清洁载玻片。最后,用盖玻片将载玻片安装在甘油封固剂(Agilent,美国)中。健康小鼠胃组织和小鼠肿瘤组织染色的代表性显微镜图像可以分别在图8和图9中找到。
图8显示了健康胃组织的代表性染色。在与hCL1a、hCl1b、hCl1c和hCl1f(分别为图A、B、C和D)共染色的组织中,仅可见细胞核的苏木精染色,而与IMAB362共染色的组织(图E)显示了膜CLDN18.2 DAB染色。因此,与表达CLDN18.2的健康胃组织结合的IMAB362相比,测试的cCl1-1的人源化克隆(hCL1a、hCl1b、hCl1c和hCl1f)不结合表达CLDN18.2的健康胃组织。此外,图9显示了肿瘤组织的代表性染色,图A、B、C和D分别是用hCl1a、hCl1f、IMAB362和Abcam 34H14L15泛CLDN18抗体染色的肿瘤组织的代表性图像。所有用测试抗体染色的肿瘤都显示出强烈的膜CLDN18.2 DAB染色。与IMAB362或泛CLDN18抗体类似,测试的cCl1-1的人源化克隆(hCL1a和hCl1f)结合表达CLDN18.2的小鼠肿瘤组织。因此,相较于表达CLDN18.2的健康胃组织,cCl1-1的人源化克隆表现出与表达CLDN18.2的肿瘤组织的结合增加。
实施例6:人源化抗体(hCl)变体和IMAB362的Asn脱酰胺化和Asp异构化倾向分析
Asn(N)残基的脱酰胺化和Asp(D)残基的异构化作用可能发生在生物制药制备、储存或临床应用(体内)过程中。脱酰胺化和异构化可能导致蛋白质结构、功能、活性、稳定性和免疫原性的潜在变化。因此,必须将其最小化和控制,特别是在监管环境中。可以在计算机上分析Asn脱酰胺化和Asp异构化基序的存在。最常见的Asn脱酰胺化基序是NG基序,而最常见的Asp异构化基序是DG基序。
这种计算机分析表明,所有的hCl抗体在VL的第二个CDR中都具有潜在的DG Asp异构化基序,并且hCl抗体或IMAB362无一在其CDR中具有潜在的NG脱酰胺化基序。为了验证计算机的预测,对hCl抗体和IMAB362在高pH或低pH和热条件下进行应激,以加速制备过程和长期储存期间可能发生的修饰。简而言之,用Amicon离心过滤器将抗体样品缓冲液交换为20mM磷酸钠缓冲液pH 8.0用于Asn脱酰胺化应激测试,或20mM柠檬酸盐缓冲液、pH 5.5用于Asp异构化应激测试,并将样品稀释至终浓度为3.0mg/ml。将30μl样品在具有加热防冷凝盖的加热块中于40℃下孵育1周(Asn-脱酰胺化)或2周(Asp-异构化)。应激处理和无应激处理的样品储存于-80℃。通过强阳离子交换(SCX)色谱分析样品的Asn脱酰胺化和Asp异构化。在SCX色谱图中,Asn的脱酰胺化导致主峰之前的峰面积(bM)增加,而在SCX色谱图中,Asp异构化导致主峰之后的峰面积(aM)增加(Du等人2012)。SCX色谱在MAbPac SCX-10柱(ThermoFisher Scientific,Basel,瑞士)上运行,缓冲液A为pH 4.0,缓冲液B为pH 11.0。流速为0.5ml/min,pH梯度为30-80%缓冲液B。将20μl缓冲液A中的10μg样品进样到柱中。通过280nm处的蛋白质吸光度进行样品检测。hCl抗体仅显示bM增加约27.9-32.2%(参见表6),这评定为不重要的。然而,IMAB362显示bM显著增加40.9%(参见表6),即使该抗体在可变结构域中没有NG基序。与本发明的抗CLDN18.2单克隆抗体相比,IMAB362在HC CDR3(氨基酸103-104)(SEQ ID NO:55)和LC CDR1(氨基酸31-32)(SEQ ID NO:56)位置具有两个NS基序。NS基序是脱酰胺化的第二最可能的基序。
表6:mAB的脱酰胺化应激测试,强阳离子交换(SCX)色谱
Asn-脱酰胺化应激测试对hCl1a、hCl1i和IMAB362与CLDN18.2的结合亲和力的影响在ELISA测定中进行了测试,其中带有CLDN18.2的脂质颗粒作为抗原来源。CLDN18.2脂质颗粒和空脂质颗粒(无抗原)用于在100mM碳酸钠,pH 9.6中以10U/ml的终浓度包被96孔板。用PBS/0.05%Tween-20(PBS-T)洗涤并在37℃下用PBS-T/3%BSA封闭至少1小时后,添加起始浓度2μg/ml的hCl抗体的1:3连续稀释液并在37℃下孵育至少1小时。通过结合HRP-山羊抗人二抗,以Sigma-Fast OPD作为过氧化物酶底物显色,通过添加2M H2SO4终止反应,并在ELISA读板器上以OD-490进行读数,揭示了结合抗体的存在。脱酰胺化应激测试后IMAB362EC50值高出1.8倍(无应激处理参考:EC50为51.5ng/ml,应激处理:EC50为95.09ng/ml)(参见图10)。这可能与脱酰胺化应激测试后SCX中40.9%的bM增加有关(参见表6)。确认SCXAsn脱酰胺化结果,在对hCl1a和hCl1i进行脱酰胺化应激测试后,未观察到抗原结合的显著差异(参见表6)。因此,脱酰胺化应激测试表明,与IMAB362相比,hCl抗体更不易于脱酰胺化和潜在的降低的靶结合,并且可以预见在制备、储存和临床应用(体内)期间更稳定,从而产生更均匀和活性的抗体/产品。
尽管所有hCl抗体在VL的第2个CDR和HC的CH2和CH3结构域中具有潜在的DG Asp异构化基序(VL-CDR2(位置62)、CH2(位置282)、CH3(位置403)),Asp异构化应激测试没有显示Asp异构化(参见表7),这与Du等人(Du等人2012)的预测相反。无应激处理的样品(IMAB362除外)的aM值已经明显较高。这可能是由于重链的赖氨酸剪切(clipping)变体。IMAB362是无应激处理样品中唯一没有高aM的抗体。IMAB362是唯一测试的不含C端Lys的抗CLDN18.2抗体,这意味着对于hCl抗体,C端Lys剪切是无应激处理和应激处理样品中aM增加的最可能原因。
表7:mAb的Asp异构化应激测试,强阳离子交换(SCX)色谱
本发明也通过以下实施方案来描述:
1.结合CLDN18.2的抗体或其片段,其中该抗体或其片段展现出与表达CLDN18.2的健康组织相比对表达CLDN18.2的肿瘤组织的结合增加。
2.结合CLDN18.2的抗体或其片段,其包含分别为SEQ ID NO:21、SEQ ID NO:22和SEQ ID NO:23的HCDR1、HCDR2和HCDR3序列,分别为SEQ ID NO:24、SEQ ID NO:25和SEQ IDNO:26的LCDR1、LCDR2和LCDR3序列。
3.实施方案1或2的抗体或其片段,其包含:
a.分别为SEQ ID NO:1、SEQ ID NO:15和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;
b.分别为SEQ ID NO:1、SEQ ID NO:16和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;
c.分别为SEQ ID NO:1、SEQ ID NO:16和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:17、SEQ ID NO:14和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列;
d.分别为SEQ ID NO:1、SEQ ID NO:16和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列;
e.分别为SEQ ID NO:12、SEQ ID NO:15和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;
f.分别为SEQ ID NO:1、SEQ ID NO:20和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;
g.分别为SEQ ID NO:1、SEQ ID NO:20和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列;
h.分别为SEQ ID NO:12、SEQ ID NO:20和SEQ ID NO:8的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;或
i.分别为SEQ ID NO:12、SEQ ID NO:20和SEQ ID NO:8的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:17、SEQ ID NO:14和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列。
4.实施方案1或2的抗体或其片段,其包含:
a.分别为SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;
b.分别为SEQ ID NO:1、SEQ ID NO:7和SEQ ID NO:8的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:9、SEQ ID NO:10和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列;或
c.分别为SEQ ID NO:12、SEQ ID NO:2和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列。
5.实施方案1或2的抗体或其片段,其包含:
a.SEQ ID NO:27的VH序列和SEQ ID NO:28的VL序列;
b.SEQ ID NO:29的VH序列和SEQ ID NO:30的VL序列;或
c.SEQ ID NO:31的VH序列和SEQ ID NO:32的VL序列。
6.实施方案1-3中任一项的抗体或其片段,其包含:
a.与SEQ ID NO:33的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VH序列;
b.与SEQ ID NO:34的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VH序列;
c.与SEQ ID NO:35的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VH序列;
d.与SEQ ID NO:36的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VH序列;或
e.与SEQ ID NO:37的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VH序列;
和
f.与SEQ ID NO:38的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VL序列;
g.与SEQ ID NO:39的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VL序列;
h.与SEQ ID NO:40的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VL序列;或
i.与SEQ ID NO:41的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VL序列。
7.实施方案1或2的抗体或其片段,其包含:
a.SEQ ID NO:33的VH序列;
b.SEQ ID NO:34的VH序列;
c.SEQ ID NO:35的VH序列;
d.SEQ ID NO:36的VH序列;或
e.SEQ ID NO:37的VH序列;
和
f.SEQ ID NO:38的VL序列;
g.SEQ ID NO:39的VL序列;
h.SEQ ID NO:40的VL序列;或
i.SEQ ID NO:41的VL序列。
8.实施方案1或2的抗体或其片段,其包含:
a.SEQ ID NO:33的VH序列和SEQ ID NO:38的VL序列;
b.SEQ ID NO:34的VH序列和SEQ ID NO:38的VL序列;
c.SEQ ID NO:34的VH序列和SEQ ID NO:39的VL序列;
d.SEQ ID NO:34的VH序列和SEQ ID NO:40的VL序列;
e.SEQ ID NO:35的VH序列和SEQ ID NO:38的VL序列;
f.SEQ ID NO:36的VH序列和SEQ ID NO:41的VL序列;
g.SEQ ID NO:36的VH序列和SEQ ID NO:40的VL序列;
h.SEQ ID NO:37的VH序列和SEQ ID NO:41的VL序列;
i.SEQ ID NO:37的VH序列和SEQ ID NO:38的VL序列;或
j.SEQ ID NO:37的VH序列和SEQ ID NO:39的VL序列。
9.实施方案1-3中任一项的抗体,其包含:
a.与SEQ ID NO:46的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:51的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
b.与SEQ ID NO:47的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:51的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
c.与SEQ ID NO:47的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:52的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
d.与SEQ ID NO:47的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:53的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
e.与SEQ ID NO:48的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:51的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
f.与SEQ ID NO:47的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:54的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
g.与SEQ ID NO:49的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:53的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
h.与SEQ ID NO:50的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:54的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
i.与SEQ ID NO:50的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:51的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
j.与SEQ ID NO:50的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:52的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列,
或其具有工程化Fc结构域的版本。
10.实施方案1或2的抗体,其包含:
a.SEQ ID NO:46的重链序列和SEQ ID NO:51的轻链序列;
b.SEQ ID NO:47的重链序列和SEQ ID NO:51的轻链序列;
c.SEQ ID NO:47的重链序列和SEQ ID NO:52的轻链序列;
d.SEQ ID NO:47的重链序列和SEQ ID NO:53的轻链序列;
e.SEQ ID NO:48的重链序列和SEQ ID NO:51的轻链序列;
f.SEQ ID NO:47的重链序列和SEQ ID NO:54的轻链序列;
g.SEQ ID NO:49的重链序列和SEQ ID NO:53的轻链序列;
h.SEQ ID NO:50的重链序列和SEQ ID NO:54的轻链序列;
i.SEQ ID NO:50的重链序列和SEQ ID NO:51的轻链序列;
j.SEQ ID NO:50的重链序列和SEQ ID NO:52的轻链序列,或其具有工程化Fc结构域的版本。
11.实施方案1至10中任一项的抗体或其片段,其中抗体或其片段是IgA1、IgA2、IgD、IgE、IgG1、IgG2、IgG3、IgG4、合成IgG、IgM、F(ab)2、Fv、scFv、IgGACH2、F(ab')2、scFvCH3、Fab、VL、VH、scFv4、scFv3、scFv2、dsFv、Fv、scFv-Fc、(scFv)2、非消耗性IgG、双抗体、二价抗体或其Fc工程化版本。
12.实施方案1至11中任一项的抗体或其片段,其中抗体或其片段是人源化的。
13.实施方案1至12中任一项的抗体或其片段,其中抗体或其片段不结合CLDN18.1。
14.实施方案1至13中任一项的抗体或其片段,其中抗体或其片段对翻译后脱酰胺化的敏感性低于IMAB362。
15.实施方案1至14中任一项的抗体或其片段,其中抗体或其片段在流式细胞术测量期间相较于表达CLDN18.2的健康组织细胞标记多至少2倍、多至少5倍、多至少10倍或多至少20倍的表达CLDN18.2的肿瘤细胞。
16.实施方案1至14中任一项的抗体或其片段,其中相较于表达CLDN18.2的健康组织细胞对表达CLDN18.2的肿瘤细胞的结合增加通过流式细胞术或通过免疫组织化学测量。
17.实施方案1至16中任一项的抗体或其片段,其中抗体或其片段以相较于IMAB362结合在HEK293T细胞或PA-TU-8988-High中表达的CLDN18.2的EC50值高至少1.1倍、高至少1.2倍、高至少1.5倍、高至少2倍或高至少2.5倍但高不超过3倍的EC50值结合在HEK293T细胞或PA-TU-8988-High细胞中表达的CLDN18.2。
18.实施方案17的抗体或其片段,其中结合通过流式细胞术(FC)滴定测量。
19.实施方案1至18中任一项的抗体或其片段,其中抗体或其片段是分离的。
20.编码实施方案1至19中任一项的抗体或其片段的核酸。
21.包含实施方案20的核酸的载体。
22.包含实施方案20的核酸或实施方案21的载体的宿主细胞。
23.实施方案1至19中任一项的抗体或其片段、实施方案20的核酸、实施方案21的载体或实施方案22的宿主细胞,用于治疗如下受试者:
a.患有赘生性疾病,
b.有风险形成赘生性疾病,和/或
c.被诊断为赘生性疾病。
24.用于实施方案23的抗体或其片段,其中赘生性疾病选自胰腺癌、胃癌、食道癌、卵巢癌和肺癌。
25.结合CLDN18.2的抗体或其片段,其中抗体或其片段
(i)与包含SEQ ID NO:46的重链序列和SEQ ID NO:51的轻链序列的抗体结合相同的表位;
(ii)与包含SEQ ID NO:46的重链序列和SEQ ID NO:51的轻链序列的抗体竞争结合;和/或
(iii)竞争性抑制包含SEQ ID NO:46的重链序列和SEQ ID NO:51的轻链序列的抗体与CLDN18.2的结合。
序列
SEQ ID NO:1 DYAMH
SEQ ID NO:2 WINTYTGKPTYADDFKG
SEQ ID NO:3 AVFYGYTMDA
SEQ ID NO:4 RASEDIYSNLA
SEQ ID NO:5 SVKRLQD
SEQ ID NO:6 LQGSNFPLT
SEQ ID NO:7 WINAYTGKPTYADDFKG
SEQ ID NO:8 AVYYGYTMDA
SEQ ID NO:9 RTSEDIYSNFA
SEQ ID NO:10 SVNRLQD
SEQ ID NO:11 LQGSKFPLT
SEQ ID NO:12 DYAMY
SEQ ID NO:13 RTSEDIYSNLA
SEQ ID NO:14 AIKRLQD
SEQ ID NO:15 WINTYTGKPTYAQKFQG
SEQ ID NO:16 WINTYTGKPTYSQKFQG
SEQ ID NO:17 RTSEDIYSNLA
SEQ ID NO:18 RTSEDIYSNFA
SEQ ID NO:19 SVNRLQD
SEQ ID NO:20 WINAYTGKPTYAQKFQG
SEQ ID NO:21 DYAMX
第5位的X是H或Y
SEQ ID NO:22 WINXYTGKPTYXXXFXG
第4位的X是T或A;
第12位的X是A或S;
第13位的X是D或Q;
第14位的X是D或K;
第16位的X是K或Q
SEQ ID NO:23 AVXYGYTMDA
第3位的X是F或Y
SEQ ID NO:24 RXSEDIYSNXA
第2位的X是A或T;
第10位的X是L或F
SEQ ID NO:25 XXXRLQD
第1位的X是S或A;
第2位的X是V或I;
第3位的X是K或N
SEQ ID NO:26 LQGSXFPLT
第5位的X是K或N
SEQ ID NO:27 cCl1-1 HC可变区
QIQLVQSGPELKKPGESVKISCKASGYTFTDYAMHWVKQAPGKGLKWMGWINTYTGKPTYADDFKGRFVFSLEASASTANLQISNLKNEDTATYFCARAVFYGYTMDAWGQGTSVTVSS
SEQ ID NO:28 cCl1-1 LC可变区
DIQMTQSPASLSASLGETISIACRASEDIYSNLAWYQQKSGKSPQLLIFSVKRLQDGVPSRFSGSGSGTQYSLKISGMQPEDEGDYFCLQGSNFPLTFGSGTKLEIK
SEQ ID NO:29 cCl1-2 HC可变区
QIQLVQSGPELKKPGESVKISCKTSGYTFTDYAMHWVKQGPGKGMKWMGWINAYTGKPTYADDFKGRFVLSLEASASTANLQISNLKNEDTATYFCARAVYYGYTMDAWGQGTSVIVSS
SEQ ID NO:30 cCl1-2 LC可变区
DIQMTQSPASLSASLGETISIECRTSEDIYSNFAWFQQKSGKSPQLLIYSVNRLQDGVPSRFSGSGSGTQYSLKISGMQPEDEGDYFCLQGSKFPLTFGSGTKLEIK
SEQ ID NO:31 cCl1-3 HC可变区
QIQLVQSGPELKKPGESVKISCKASGYTFTDYAMYWVKQVPGKGLRWMGWINTYTGKPTYADDFKGRFVFSLEASASTANLQISNLKNEDTATYFCARAVFYGYTMDAWGQGTSVTVSS
SEQ ID NO:32 cCl1-3 LC可变区
DIQMTQSPASLSASLGETISIACRTSEDIYSNLAWYQQKSGKSPQLLIFAIKRLQDGVPSRFSGSGSGTQYSLKISGMQPEDEGDYFCLQGSKFPLTFGSGTKLEIK
SEQ ID NO:33 hCL1a HC可变区
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYAMHWVRQAPGQRLEWMGWINTYTGKPTYAQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARAVFYGYTMDAWGQGTLVTVSS
SEQ ID NO:34 hCL1b,c和d HC可变区
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYAMHWVRQAPGQRLEWMGWINTYTGKPTYSQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARAVFYGYTMDAWGQGTLVTVSS
SEQ ID NO:35 hCL1e HC可变区
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYAMYWVRQAPGQRLEWMGWINTYTGKPTYAQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARAVFYGYTMDAWGQGTLVTVSS
SEQ ID NO:36 hCL1f和g HC可变区
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYAMHWVRQAPGQRLEWMGWINAYTGKPTYAQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARAVFYGYTMDAWGQGTLVTVSS
SEQ ID NO:37 hCL1h,i和j HC可变区
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYAMYWVRQAPGQRLEWMGWINAYTGKPTYAQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARAVYYGYTMDAWGQGTLVTVSS
SEQ ID NO:38 hCL1a,b,e和i LC可变区
DIQMTQSPSSLSASVGDRVTITCRASEDIYSNLAWYQQKPGKAPKLLIFSVKRLQDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQGSNFPLTFGQGTKVEIK
SEQ ID NO:39 hCL1c和j LC可变区
DIQMTQSPSSLSASVGDRVTITCRTSEDIYSNLAWYQQKPGKAPKLLIFAIKRLQDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQGSKFPLTFGQGTKVEIK
SEQ ID NO:40 hCL1d和g LC可变区
DIQMTQSPSSLSASVGDRVTITCRTSEDIYSNFAWYQQKPGKAPKLLIYSVNRLQDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQGSKFPLTFGQGTKVEIK
SEQ ID NO:41 hCL1f和h LC可变区
DIQMTQSPSSLSASVGDRVTITCRASEDIYSNLAWYQQKPGKAPKLLIYSVKRLQDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQGSNFPLTFGQGTKVEIK
SEQ ID NO:42 hCL3a,b和c HC可变区
QVQLQESGPGLVKPSETLSLTCAVSGYSVSSNYRWHWIRQPPGKGLEWIGYINIAGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARNPSITRAMDAWGQGTLVTVSS
SEQ ID NO:43 hCL3a LC可变区
DIQMTQSPSSLSASVGDRVTITCKSSQNIFKNLEWYQQKPGKAPKLLIYYTNNLQTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCYQYNSGPFTFGQGTKVEIK
SEQ ID NO:44 hCL3b LC可变区
DIQMTQSPSSLSASVGDRVTITCRSSQNIFKNLEWYQQKPGKAPKLLIYYTNNLQTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCYQYNSGPFTFGQGTKVEIK
SEQ ID NO:45 hCL3c LC可变区
DIQMTQSPSSLSASVGDRVTITCRSSQNIFKNLEWYQQKPGKAPKLLIYYTNNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCYQYNSGPFTFGQGTKVEIK
SEQ ID NO:46 hCL1a HC全长
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYAMHWVRQAPGQRLEWMGWINTYTGKPTYAQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARAVFYGYTMDAWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:47 hCL1b,c和d HC全长
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYAMHWVRQAPGQRLEWMGWINTYTGKPTYSQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARAVFYGYTMDAWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:48 hCL1e HC全长
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYAMYWVRQAPGQRLEWMGWINTYTGKPTYAQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARAVFYGYTMDAWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:49 hCL1f和g HC全长
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYAMHWVRQAPGQRLEWMGWINAYTGKPTYAQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARAVFYGYTMDAWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:50 hCL1h,i和j HC全长
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYAMYWVRQAPGQRLEWMGWINAYTGKPTYAQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARAVYYGYTMDAWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:51 hCL1a,b,e和i LC全长
DIQMTQSPSSLSASVGDRVTITCRASEDIYSNLAWYQQKPGKAPKLLIFSVKRLQDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQGSNFPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:52 hCL1c和j LC全长
DIQMTQSPSSLSASVGDRVTITCRTSEDIYSNLAWYQQKPGKAPKLLIFAIKRLQDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQGSKFPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:53 hCL1d和g LC全长
DIQMTQSPSSLSASVGDRVTITCRTSEDIYSNFAWYQQKPGKAPKLLIYSVNRLQDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQGSKFPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:54 hCL1f和h LC全长
DIQMTQSPSSLSASVGDRVTITCRASEDIYSNLAWYQQKPGKAPKLLIYSVKRLQDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQGSNFPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:55 IMAB362 HC全长
QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGNIYPSDSYTNYNQKFKDKATLTVDKSSSTAYMQLSSPTSEDSAVYYCTRSWRGNSFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:56 IMAB362 LC全长
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:57 DQWSTQDLYN
SEQ ID NO:58 NNPVTAVFNYQ
SEQ ID NO:59 STQDLYNNPVTAVF
SEQ ID NO:60 TNFWMSTANMYTG
SEQ ID NO:61 ALMIVGIVLGAIGLLV
SEQ ID NO:62 RIGSMEDSAKANMTLTSGIMFIVS
SEQ ID NO:63
METDTLLLWVLLLWVPGSTGDAAQPARRARRTKLGTELGSTPVWWNSADGRMDQWSTQDLYNNPVTAVFNYQGLWRSCVRESSGFTECRGYFTLLGLPAMLQAVRAAIQHSGGRSRRARTKTHLRRGSE
SEQ ID NO:64 MDQWSTQDLYNNPVT
SEQ ID NO:65 LYNNPVTAVFNYQGL
SEQ ID NO:66 VFNYQGLWRSCVRES
SEQ ID NO:67 QGLWRSCVRESSGFT
SEQ ID NO:68 RSCVRESSGFTECRG
SEQ ID NO:69 TEDEVQSYPSKHDYV
SEQ ID NO:70 EVQSYPSKHDYV
SEQ ID NO:71 gactacgcgatgcac
SEQ ID NO:72 tggatcaacacgtacacggggaagccgacatacgcggacgacttcaagggg
SEQ ID NO:73 gccgtcttctacggatatacgatggacgcg
SEQ ID NO:74
cagatccagctcgtccagagcgggccggagctgaagaagccgggggagagcgtgaagatctcgtgcaaggcgagcggatatacgttcacggactacgcgatgcactgggtcaagcaagcgccggggaaagggctgaagtggatggggtggatcaacacgtacacggggaagccgacatacgcggacgacttcaaggggcgattcgtgttctcgctggaggcgagcgcgagcacggcgaacctgcaaatctcgaacctgaagaacgaggacacggcgacgtacttctgcgcgcgggccgtcttctacggatatacgatggacgcgtgggggcagggtaccagcgtgacggtctcgagc
SEQ ID NO:75 cgggcgagcgaggacatctactcgaacctggcg
SEQ ID NO:76 tccgtcaagcggctgcaagac
SEQ ID NO:77 ctgcaagggagcaacttcccgctgacg
SEQ ID NO:78
gacatccagatgacgcagagcccggcgtcgctgagcgcgagcctgggggagacgatctcgatcgcgtgccgggcgagcgaggacatctactcgaacctggcgtggtatcaacagaagagcgggaagagcccgcagctgctgatcttctccgtcaagcggctgcaagacggcgtcccgagccgattctcggggagcgggagcgggacgcagtactcgctgaagatctcggggatgcagccggaggacgagggggactacttctgcctgcaagggagcaacttcccgctgacgttcgggtcgggtaccaaactcgagatcaaa
SEQ ID NO:79 tggatcaacgcgtacacggggaagccgacctacgcggacgacttcaagggg
SEQ ID NO:80 gccgtctactacggatatacgatggac
SEQ ID NO:81
cagatccagctcgtccagagcgggccggagctgaagaagccgggggagagcgtgaagatctcgtgcaagacgagcggatatacgttcacggactacgcgatgcactgggtcaagcaggggccagggaaagggatgaagtggatggggtggatcaacgcgtacacggggaagccgacctacgcggacgacttcaaggggcgattcgtgctgagcctggaggcgagcgcctcgacggcgaacctgcaaatctcgaacctgaagaacgaggacacggcgacgtacttctgcgcgcgggccgtctactacggatatacgatggacgcgtgggggcagggtaccagcgtgatcgtctcgagc
SEQ ID NO:82 cggacgagcgaggacatctactcgaacttcgcg
SEQ ID NO:83 tcagtcaaccggctgcaagac
SEQ ID NO:84 ctgcaagggagcaagttcccgctgacg
SEQ ID NO:85
gacatccagatgacgcagagcccggcgagcctgagcgcgagcctgggggagacgatctcgatcgagtgccggacgagcgaggacatctactcgaacttcgcgtggttccagcagaagagcgggaagagcccgcagctgctgatctactcagtcaaccggctgcaagacggcgtcccgagccgattctcggggagcgggagcgggacgcagtactcgctgaagatctcggggatgcagccggaggacgagggggactacttctgcctgcaagggagcaagttcccgctgacgttcgggagcggtaccaaactcgagatcaaa
SEQ ID NO:86 gactacgcgatgtac
SEQ ID NO:87 tggatcaacacgtacacggggaagccgacctacgcggacgacttcaagggg
SEQ ID NO:88
cagatccagctcgtccagagcgggccggagctgaagaagccgggggagagcgtgaagatctcgtgcaaggcgagcggatatacgttcacggactacgcgatgtactgggtcaagcaagtgccggggaaagggctgcgatggatggggtggatcaacacgtacacggggaagccgacctacgcggacgacttcaaggggcgattcgtgttctcgctggaggcgagcgcgagcacggcgaacctgcaaatctcgaacctgaagaacgaggacacggcgacgtacttctgcgcgcgggccgtcttctacggatatacgatggacgcgtgggggcagggtaccagcgtgacggtctcgagc
SEQ ID NO:89 cggacgagcgaggacatctactcgaacctggcg
SEQ ID NO:90 gcgatcaagcggctgcaagac
SEQ ID NO:91
gacatccagatgacgcagagcccggcgagcctgagcgcgagcctgggggagacgatctcgatcgcgtgccggacgagcgaggacatctactcgaacctggcgtggtatcaacagaagagcgggaagagcccgcagctgctgatcttcgcgatcaagcggctgcaagacggcgtcccgagccgattctcggggagcgggagcgggacgcagtactcgctgaagatctcggggatgcagccggaggacgagggggactacttctgcctgcaagggagcaagttcccgctgacgttcgggtcgggtaccaaactcgagatcaaa
SEQ ID NO:92 tggatcaatacatacacggggaagccgacttatgcgcaaaaattccaagga
SEQ ID NO:93 gcggtcttctacggatatacgatggatgcc
SEQ ID NO:94
caggtccaactagtccaaagcggggcggaagtcaagaagcccggagcatccgtcaaagtcagctgcaaggcgagcggatatacatttacggactacgcgatgcactgggtcaggcaagcccctgggcaaaggctcgaatggatgggatggatcaatacatacacggggaagccgacttatgcgcaaaaattccaaggaagagtcacaattacgcgggatacatccgcatctaccgcctacatggagctaagctcgctgcggagcgaggatacggcggtctactattgcgcccgagcggtcttctacggatatacgatggatgcctgggggcagggtaccctggtcacggtctcgagc
SEQ ID NO:95 agggcctccgaagacatctactccaacctggca
SEQ ID NO:96 agcgtcaaaagactacaagat
SEQ ID NO:97 ttgcaaggaagcaatttccccttgact
SEQ ID NO:98
gacattcaaatgacgcaaagcccatcatcgctgagcgcatcggtcggggatagagtcaccataacatgcagggcctccgaagacatctactccaacctggcatggtatcaacaaaaaccggggaaggctccgaagctgctgatatttagcgtcaaaagactacaagatggagtaccgagccgattttcgggaagcgggagcgggacggatttcacgctgaccatatcaagtttgcaaccggaggattttgcgacatactattgcttgcaaggaagcaatttccccttgactttcgggcaaggtaccaaggtcgagatcaaa
SEQ ID NO:99 gattatgcaatgcac
SEQ ID NO:100 tggattaacacctacacgggcaagcccacatactcccaaaaattccaagga
SEQ ID NO:101 gctgtattctatggatatacaatggatgcc
SEQ ID NO:102
caggtccaattagtccaaagcggggcggaagtcaagaagccgggggcgagcgtcaaagtctcatgcaaagcgagcggatacacatttacggattatgcaatgcactgggtcaggcaagcacccggacaaaggctggaatggatgggatggattaacacctacacgggcaagcccacatactcccaaaaattccaaggaagggtcacgataacgagagacacgagcgcgagcaccggaatggatgggatggattaacacctacacgggcaagcccacatactcccaaaaattccaaggaagggtcacgataacgagagacacgagcgcgagcaccgtaccctggtcaccgtctcgagc
SEQ ID NO:103 cgaacgagcgaggacatatactcaaaccttgca
SEQ ID NO:104 gcgataaagaggctgcaagac
SEQ ID NO:105 ttgcaaggctccaaatttcccctgaca
SEQ ID NO:106
gacatccaaatgactcaaagcccatcatcgctatcggcatcggtcggggatagagtcacgataacatgccgaacgagcgaggacatatactcaaaccttgcatggtatcaacaaaagccggggaaggccccgaagctactgatattcgcgataaagaggctgcaagacggagttccatcacgattttcgggatctggctcggggaccgattttacgctgactatatcatcgctgcaaccggaagattttgcaacatactactgcttgcaaggctccaaatttcccctgacattcggacaaggtaccaaggtcgagatcaaa
SEQ ID NO:107 cggacgagcgaggatatttattcgaactttgca
SEQ ID NO:108 cagtcaatcggctacaagat
SEQ ID NO:109
gacatccaaatgacgcaatcaccgagctcgctgagcgcatctgtcggggaccgtgtcacaatcacatgccggacgagcgaggatatttattcgaactttgcatggtatcaacaaaaaccgggcaaggctccgaaacttttgatttattcagtcaatcggctacaagatggcgtcccgagccgatttagcgggagcggatcgggaaccgactttacgctgacgatatcatcgctacaaccggaggacttcgcgacttattactgcctacaagggagcaaattcccgctgacattcggacaaggtaccaaggtcgagatcaaa
SEQ ID NO:110 gattacgcaatgtac
SEQ ID NO:111 tggataaatacctatacgggaaagccaacatacgcccaaaaattccaaggc
SEQ ID NO:112 gccgtcttttatggatatacgatggacgca
SEQ ID NO:113
caggtccaactggtccaatcgggggctgaagtcaaaaagccgggggcgagcgtcaaagtcagctgcaaagcatcgggatacacatttacggattacgcaatgtactgggtcaggcaagcacccggccaacgactggaatggatgggctggataaatacctatacgggaaagccaacatacgcccaaaaattccaaggccgcgtcacaataacgcgggacacgagcgcatcgacggcttatatggaactatcatcgctgcgatcggaagacacggcggtctattattgcgcacgcgccgtcttttatggatatacgatggacgcatgggggcagggtaccctggtcacggtctcgagc
SEQ ID NO:114 gactacgcaatgcac
SEQ ID NO:115 tggattaatgcctacacggggaagccgacctacgcacaaaaattccaagga
SEQ ID NO:116 gccgtcttctatggatatacgatggatgct
SEQ ID NO:117
caggtccaattggtccaaagcggggcggaggtcaagaagccgggggcgagcgtcaaagtctcatgcaaggcaagcggatatacatttacggactacgcaatgcactgggtccggcaagcccctgggcaacggctggaatggatgggatggattaatgcctacacggggaagccgacctacgcacaaaaattccaaggacgagtcacgattacgcgggatactagcgcgagcaccgcatatatggagctaagctcgctgcgatctgaggataccgctgtatactactgcgcgagagccgtcttctatggatatacgatggatgcttgggggcagggtaccctggtcacggtctcgagc
SEQ ID NO:118 cgagcttcggaggacatctatagcaacttggct
SEQ ID NO:119 agcgtcaaaaggctccaagac
SEQ ID NO:120 ctacaaggctctaacttcccattgaca
SEQ ID NO:121
gatatccaaatgacgcaatcaccatctagcctatcggcctctgtgggggaccgagtcaccatcacatgccgagcttcggaggacatctatagcaacttggcttggtatcaacaaaagccggggaaagcaccaaagctgctgatatatagcgtcaaaaggctccaagacggagtcccaagccgattctcgggctccggctccgggacggattttacgctgacaatttcgagcctgcaaccggaggactttgcaacctactattgcctacaaggctctaacttcccattgacatttgggcaaggtaccaaggtcgagatcaaa
SEQ ID NO:122 gactacgctatgtat
SEQ ID NO:123 tggattaatgcctacaccgggaagccgacttatgcgcaaaaatttcaagga
SEQ ID NO:124 gcggtctactatggatatacgatggacgca
SEQ ID NO:125
caggtccaactggttcaatctggagcggaagtcaagaagcccggagcatccgtcaaagtctcgtgcaaggcatctggatacacattcaccgactacgctatgtattgggtccggcaagcccccggacaacggctggaatggatgggatggattaatgcctacaccgggaagccgacttatgcgcaaaaatttcaaggaagggtcacgattacgcgggacacgagcgcctcaaccgcatacatggagctatcgagcctgcgaagcgaggacaccgcggtctactactgcgcgcgggcggtctactatggatatacgatggacgcatgggggcagggtaccctggtcacggtctcgagc
SEQ ID NO:126 WINXYTGKPTYXQKFQG
第4位的X是T或A;
第12位的X是A或S
[HC CDR2仅用于hCl1x,而不是嵌合克隆cCl1-1,2,3]
SEQ ID NO:127
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC[恒定轻链-CL结构域]
SEQ ID NO:128
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK[恒定重链-CH1+Fc结构域]
SEQ ID NO:129
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK[恒定重链中的L234A/L235A突变-CH1+Fc结构域]
SEQ ID NO:130
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK[恒定重链中的L236A/L236A/P329G突变-CH1+Fc结构域]
SEQ ID NO:131 RLPQTGG[分选酶标签]
SEQ ID NO:132 GGGGS-LPQTGG[分选酶标签]
SEQ ID NO:133 CLDN18.2
MAVTACQGLGFVVSLIGIAGIIAATCMDQWSTQDLYNNPVTAVFNYQGLWRSCVRESSGFTECRGYFTLLGLPAMLQAVRALMIVGIVLGAIGLLVSIFALKCIRIGSMEDSAKANMTLTSGIMFIVSGLCAIAGVSVFANMLVTNFWMSTANMYTGMGGMVQTVQTRYTFGAALFVGWVAGGLTLIGGVMMCIACRGLAPEETNYKAVSYHASGHSVAYKPGGFKASTGFGSNTKNKKIYDGGARTEDEVQSYPSKHDYV
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CN109762067
WO2000/015659
WO2004/047863
WO2005/113587
WO2007/059997
WO2008/145338
WO2013/167259
WO2013/174509
WO2014/075788
WO2014/127906
WO2016/166122
WO2016/165762
WO2018/006882
WO2019/173420
WO2019/175617
WO2019/219089
序列表
<110> 斯迪安生物技术公司
<120> 肿瘤特异性密蛋白18.2抗体
<130> S12411WO / SOTCLD-1904
<150> 19 219 359.7
<151> 2019-12-23
<150> 20 152 510.2
<151> 2020-01-17
<160> 133
<170> PatentIn 版本 3.5
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> cCl1-1, cCl1-2, hCl1a, hCl1b, hCl1c, hCl1d, hCl1f, hCl1g HCDR1
<400> 1
Asp Tyr Ala Met His
1 5
<210> 2
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> cCl1-1, cCl1-3 HCDR2
<400> 2
Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ala Asp Asp Phe Lys
1 5 10 15
Gly
<210> 3
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> cCl1-1, cCl1-3 , hCl1a, hCl1b, hCl1c, hCl1d, hCl1e, hCl1f, hCl1g
HCDR3
<400> 3
Ala Val Phe Tyr Gly Tyr Thr Met Asp Ala
1 5 10
<210> 4
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> cCl1-1, hCl1a, hCl1b, hCl1e, hCl1f, hCl1h, hCl1i LCDR1
<400> 4
Arg Ala Ser Glu Asp Ile Tyr Ser Asn Leu Ala
1 5 10
<210> 5
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> cCl1-1, hCl1a, hCl1b, hCl1e, hCl1f, hCl1h, hCl1i LCDR2
<400> 5
Ser Val Lys Arg Leu Gln Asp
1 5
<210> 6
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> cCl1-1, hCl1a, hCl1b, hCl1e, hCl1f, hCl1h, hCl1i LCDR3
<400> 6
Leu Gln Gly Ser Asn Phe Pro Leu Thr
1 5
<210> 7
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> cCl1-2 HCDR2
<400> 7
Trp Ile Asn Ala Tyr Thr Gly Lys Pro Thr Tyr Ala Asp Asp Phe Lys
1 5 10 15
Gly
<210> 8
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> cCl1-2, hCl1h, hCl1i, hCl1j HCDR3
<400> 8
Ala Val Tyr Tyr Gly Tyr Thr Met Asp Ala
1 5 10
<210> 9
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> cCl1-2 LCDR1
<400> 9
Arg Thr Ser Glu Asp Ile Tyr Ser Asn Phe Ala
1 5 10
<210> 10
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> cCl1-2 LCDR2
<400> 10
Ser Val Asn Arg Leu Gln Asp
1 5
<210> 11
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> cCl1-2, cCl1-3, hCl1c, hCl1d, hCl1g, hCl1j LCDR3
<400> 11
Leu Gln Gly Ser Lys Phe Pro Leu Thr
1 5
<210> 12
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> cCl1-3, hCl1e, hCl1h, hCl1i, hCl1j HCDR1
<400> 12
Asp Tyr Ala Met Tyr
1 5
<210> 13
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> cCl1-3 LCDR1
<400> 13
Arg Thr Ser Glu Asp Ile Tyr Ser Asn Leu Ala
1 5 10
<210> 14
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> cCl1-3, hCl1c, hCl1j LCDR2
<400> 14
Ala Ile Lys Arg Leu Gln Asp
1 5
<210> 15
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> hCl1a, hCl1e HCDR2
<400> 15
Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 16
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> hCl1b, hCl1c, hCl1d HCDR2
<400> 16
Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ser Gln Lys Phe Gln
1 5 10 15
Gly
<210> 17
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> hCl1c, hCl1j LCDR1
<400> 17
Arg Thr Ser Glu Asp Ile Tyr Ser Asn Leu Ala
1 5 10
<210> 18
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> hCl1d, hCl1g LCDR1
<400> 18
Arg Thr Ser Glu Asp Ile Tyr Ser Asn Phe Ala
1 5 10
<210> 19
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> hCl1d, hCl1g LCDR2
<400> 19
Ser Val Asn Arg Leu Gln Asp
1 5
<210> 20
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> hCl1f, hCl1g, hCl1h, hCl1i, hCl1j HCDR2
<400> 20
Trp Ile Asn Ala Tyr Thr Gly Lys Pro Thr Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 21
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> HCDR1共有序列
<220>
<221> 杂项特征
<222> (5)..(5)
<223> H或Y
<400> 21
Asp Tyr Ala Met Xaa
1 5
<210> 22
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> HCDR2共有序列
<220>
<221> 杂项特征
<222> (4)..(4)
<223> T或A
<220>
<221> 杂项特征
<222> (12)..(12)
<223> A或S
<220>
<221> 杂项特征
<222> (13)..(13)
<223> D或Q
<220>
<221> 杂项特征
<222> (14)..(14)
<223> D或K
<220>
<221> 杂项特征
<222> (16)..(16)
<223> K或Q
<400> 22
Trp Ile Asn Xaa Tyr Thr Gly Lys Pro Thr Tyr Xaa Xaa Xaa Phe Xaa
1 5 10 15
Gly
<210> 23
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> HCDR3共有序列
<220>
<221> 杂项特征
<222> (3)..(3)
<223> F或Y
<400> 23
Ala Val Xaa Tyr Gly Tyr Thr Met Asp Ala
1 5 10
<210> 24
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> LCDR1共有序列
<220>
<221> 杂项特征
<222> (2)..(2)
<223> A或T
<220>
<221> 杂项特征
<222> (10)..(10)
<223> L或F
<400> 24
Arg Xaa Ser Glu Asp Ile Tyr Ser Asn Xaa Ala
1 5 10
<210> 25
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> LCDR2共有序列
<220>
<221> 杂项特征
<222> (1)..(1)
<223> S或A
<220>
<221> 杂项特征
<222> (2)..(2)
<223> V或I
<220>
<221> 杂项特征
<222> (3)..(3)
<223> K或N
<400> 25
Xaa Xaa Xaa Arg Leu Gln Asp
1 5
<210> 26
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> LCDR3共有序列
<220>
<221> 杂项特征
<222> (5)..(5)
<223> K或N
<400> 26
Leu Gln Gly Ser Xaa Phe Pro Leu Thr
1 5
<210> 27
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> cCl1-1 HC可变区
<400> 27
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ala Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Val Phe Ser Leu Glu Ala Ser Ala Ser Thr Ala Asn
65 70 75 80
Leu Gln Ile Ser Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ala Val Phe Tyr Gly Tyr Thr Met Asp Ala Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 28
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> cCl1-1 LC可变区
<400> 28
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Glu Thr Ile Ser Ile Ala Cys Arg Ala Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Ser Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Phe Ser Val Lys Arg Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Ser Gly Met Gln Pro
65 70 75 80
Glu Asp Glu Gly Asp Tyr Phe Cys Leu Gln Gly Ser Asn Phe Pro Leu
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 29
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> cCl1-2 HC可变区
<400> 29
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ala Met His Trp Val Lys Gln Gly Pro Gly Lys Gly Met Lys Trp Met
35 40 45
Gly Trp Ile Asn Ala Tyr Thr Gly Lys Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Val Leu Ser Leu Glu Ala Ser Ala Ser Thr Ala Asn
65 70 75 80
Leu Gln Ile Ser Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ala Val Tyr Tyr Gly Tyr Thr Met Asp Ala Trp Gly Gln Gly
100 105 110
Thr Ser Val Ile Val Ser Ser
115
<210> 30
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> cCl1-2 LC可变区
<400> 30
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Glu Thr Ile Ser Ile Glu Cys Arg Thr Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Phe Ala Trp Phe Gln Gln Lys Ser Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Tyr Ser Val Asn Arg Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Ser Gly Met Gln Pro
65 70 75 80
Glu Asp Glu Gly Asp Tyr Phe Cys Leu Gln Gly Ser Lys Phe Pro Leu
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 31
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> cCl1-3 HC可变区
<400> 31
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ala Met Tyr Trp Val Lys Gln Val Pro Gly Lys Gly Leu Arg Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Val Phe Ser Leu Glu Ala Ser Ala Ser Thr Ala Asn
65 70 75 80
Leu Gln Ile Ser Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ala Val Phe Tyr Gly Tyr Thr Met Asp Ala Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 32
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> cCl1-3 LC可变区
<400> 32
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Glu Thr Ile Ser Ile Ala Cys Arg Thr Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Ser Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Phe Ala Ile Lys Arg Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Ser Gly Met Gln Pro
65 70 75 80
Glu Asp Glu Gly Asp Tyr Phe Cys Leu Gln Gly Ser Lys Phe Pro Leu
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 33
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> hCl1a HC可变区
<400> 33
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 Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ala Gln Lys Phe
50 55 60
Gln 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 Val Phe Tyr Gly Tyr Thr Met Asp Ala Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 34
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> hCl1b, hCl1c和hCl1d HC可变区
<400> 34
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 Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ser Gln Lys Phe
50 55 60
Gln 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 Val Phe Tyr Gly Tyr Thr Met Asp Ala Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 35
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> hCl1e HC可变区
<400> 35
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 Asp Tyr
20 25 30
Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ala Gln Lys Phe
50 55 60
Gln 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 Val Phe Tyr Gly Tyr Thr Met Asp Ala Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 36
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> hCl1f和hCl1g HC可变区
<400> 36
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 Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Ala Tyr Thr Gly Lys Pro Thr Tyr Ala Gln Lys Phe
50 55 60
Gln 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 Val Phe Tyr Gly Tyr Thr Met Asp Ala Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 37
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> hCl1h, hCl1i和hCl1j HC可变区
<400> 37
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 Asp Tyr
20 25 30
Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Ala Tyr Thr Gly Lys Pro Thr Tyr Ala Gln Lys Phe
50 55 60
Gln 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 Val Tyr Tyr Gly Tyr Thr Met Asp Ala Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 38
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> hCl1a, hCl1b, hCl1e和hCl1i LC可变区
<400> 38
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Phe Ser Val Lys Arg Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Asn Phe Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 39
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> hCl1c和hCl1j LC可变区
<400> 39
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 Thr Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Phe Ala Ile Lys Arg Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 40
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> hCl1d和hCl1g LC可变区
<400> 40
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 Thr Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Phe Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Val Asn Arg Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 41
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> hCl1f和hCl1h LC可变区
<400> 41
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Val Lys Arg Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Asn Phe Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 42
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> hCl3a, hCl1b和hCl1c HC可变区
<400> 42
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Val Ser Ser Asn
20 25 30
Tyr Arg Trp His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Asn Ile Ala Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Pro Ser Ile Thr Arg Ala Met Asp Ala Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 43
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> hCl3a LC可变区
<400> 43
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Asn Ile Phe Lys Asn
20 25 30
Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Asn Asn Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Tyr Gln Tyr Asn Ser Gly Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 44
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> hCl3b LC可变区
<400> 44
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 Ser Ser Gln Asn Ile Phe Lys Asn
20 25 30
Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Asn Asn Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Tyr Gln Tyr Asn Ser Gly Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 45
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> hCl3c LC可变区
<400> 45
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Asn Ile Phe Lys Asn
20 25 30
Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Asn Asn 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 Tyr Gln Tyr Asn Ser Gly Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 46
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> hCl1a HC全长
<400> 46
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 Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ala Gln Lys Phe
50 55 60
Gln 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 Val Phe Tyr Gly Tyr Thr Met Asp Ala 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 Asn 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 Asp Glu Leu 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
<210> 47
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> hCl1b, hCl1c和hCl1d HC全长
<400> 47
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 Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ser Gln Lys Phe
50 55 60
Gln 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 Val Phe Tyr Gly Tyr Thr Met Asp Ala 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 Asn 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 Asp Glu Leu 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
<210> 48
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> hCl1e HC全长
<400> 48
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 Asp Tyr
20 25 30
Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ala Gln Lys Phe
50 55 60
Gln 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 Val Phe Tyr Gly Tyr Thr Met Asp Ala 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 Asn 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 Asp Glu Leu 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
<210> 49
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> hCl1f和hCl1g HC全长
<400> 49
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 Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Ala Tyr Thr Gly Lys Pro Thr Tyr Ala Gln Lys Phe
50 55 60
Gln 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 Val Phe Tyr Gly Tyr Thr Met Asp Ala 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 Asn 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 Asp Glu Leu 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
<210> 50
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> hCl1h, hCl1i和hCl1j HC全长
<400> 50
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 Asp Tyr
20 25 30
Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Ala Tyr Thr Gly Lys Pro Thr Tyr Ala Gln Lys Phe
50 55 60
Gln 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 Val Tyr Tyr Gly Tyr Thr Met Asp Ala 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 Asn 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 Asp Glu Leu 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
<210> 51
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> hCl1a, hCl1b, hCl1e和hCl1i LC全长
<400> 51
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Phe Ser Val Lys Arg Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Asn Phe Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 52
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> hCl1c和hCl1j LC全长
<400> 52
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 Thr Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Phe Ala Ile Lys Arg Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 53
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> hCl1d和hCl1g LC全长
<400> 53
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 Thr Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Phe Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Val Asn Arg Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Lys Phe Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 54
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> hCl1f和hCl1h LC全长
<400> 54
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asp Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Val Lys Arg Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Gly Ser Asn Phe Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 55
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> IMAB362 HC全长
<400> 55
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Ser Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu 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 Asn 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 Asp Glu Leu 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
<210> 56
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> IMAB362 LC全长
<400> 56
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ser Tyr Pro Phe Thr Phe Gly Ser 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> 57
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CLDN18.2的N端胞外,与糖基化无关
<400> 57
Asp Gln Trp Ser Thr Gln Asp Leu Tyr Asn
1 5 10
<210> 58
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CLDN18.2的N端胞外,大体上未糖基化
<400> 58
Asn Asn Pro Val Thr Ala Val Phe Asn Tyr Gln
1 5 10
<210> 59
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CLDN18.2的N端胞外域,未糖基化
<400> 59
Ser Thr Gln Asp Leu Tyr Asn Asn Pro Val Thr Ala Val Phe
1 5 10
<210> 60
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CLDN18.1和CLDN18.2亚型共有的C端胞外域中的泛CLDN18肽
<400> 60
Thr Asn Phe Trp Met Ser Thr Ala Asn Met Tyr Thr Gly
1 5 10
<210> 61
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 如WO2005/113587所公开的CLDN18.2的特定表位
<400> 61
Ala Leu Met Ile Val Gly Ile Val Leu Gly Ala Ile Gly Leu Leu Val
1 5 10 15
<210> 62
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 如WO2005/113587所公开的CLDN18.2的特定表位
<400> 62
Arg Ile Gly Ser Met Glu Asp Ser Ala Lys Ala Asn Met Thr Leu Thr
1 5 10 15
Ser Gly Ile Met Phe Ile Val Ser
20
<210> 63
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> CLDN18.2的第一胞外域,具有N端和C端延伸
<400> 63
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ala Ala Gln Pro Ala Arg Arg Ala Arg Arg Thr
20 25 30
Lys Leu Gly Thr Glu Leu Gly Ser Thr Pro Val Trp Trp Asn Ser Ala
35 40 45
Asp Gly Arg Met Asp Gln Trp Ser Thr Gln Asp Leu Tyr Asn Asn Pro
50 55 60
Val Thr Ala Val Phe Asn Tyr Gln Gly Leu Trp Arg Ser Cys Val Arg
65 70 75 80
Glu Ser Ser Gly Phe Thr Glu Cys Arg Gly Tyr Phe Thr Leu Leu Gly
85 90 95
Leu Pro Ala Met Leu Gln Ala Val Arg Ala Ala Ile Gln His Ser Gly
100 105 110
Gly Arg Ser Arg Arg Ala Arg Thr Lys Thr His Leu Arg Arg Gly Ser
115 120 125
Glu
<210> 64
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 如WO2008/145338所公开的在第一胞外域内的重叠肽
<400> 64
Met Asp Gln Trp Ser Thr Gln Asp Leu Tyr Asn Asn Pro Val Thr
1 5 10 15
<210> 65
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 如WO2008/145338所公开的在第一胞外域内的重叠肽
<400> 65
Leu Tyr Asn Asn Pro Val Thr Ala Val Phe Asn Tyr Gln Gly Leu
1 5 10 15
<210> 66
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 如WO2008/145338所公开的在第一胞外域内的重叠肽
<400> 66
Val Phe Asn Tyr Gln Gly Leu Trp Arg Ser Cys Val Arg Glu Ser
1 5 10 15
<210> 67
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 如WO2008/145338所公开的在第一胞外域内的重叠肽
<400> 67
Gln Gly Leu Trp Arg Ser Cys Val Arg Glu Ser Ser Gly Phe Thr
1 5 10 15
<210> 68
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 如WO2008/145338所公开的在第一胞外域内的重叠肽
<400> 68
Arg Ser Cys Val Arg Glu Ser Ser Gly Phe Thr Glu Cys Arg Gly
1 5 10 15
<210> 69
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 如WO2013/167259所公开的CLDN18.2的C端表位
<400> 69
Thr Glu Asp Glu Val Gln Ser Tyr Pro Ser Lys His Asp Tyr Val
1 5 10 15
<210> 70
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 如WO2013/167259所公开的CLDN18.2的C端表位
<400> 70
Glu Val Gln Ser Tyr Pro Ser Lys His Asp Tyr Val
1 5 10
<210> 71
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> cCl1-1, cCl1-2, hCl1a HCDR1
<400> 71
gactacgcga tgcac 15
<210> 72
<211> 51
<212> DNA
<213> 人工序列
<220>
<223> cCl1-1 HCDR2
<400> 72
tggatcaaca cgtacacggg gaagccgaca tacgcggacg acttcaaggg g 51
<210> 73
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> cCl1-1, cCl1-3 HCDR3
<400> 73
gccgtcttct acggatatac gatggacgcg 30
<210> 74
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> cCl1-1 VH
<400> 74
cagatccagc tcgtccagag cgggccggag ctgaagaagc cgggggagag cgtgaagatc 60
tcgtgcaagg cgagcggata tacgttcacg gactacgcga tgcactgggt caagcaagcg 120
ccggggaaag ggctgaagtg gatggggtgg atcaacacgt acacggggaa gccgacatac 180
gcggacgact tcaaggggcg attcgtgttc tcgctggagg cgagcgcgag cacggcgaac 240
ctgcaaatct cgaacctgaa gaacgaggac acggcgacgt acttctgcgc gcgggccgtc 300
ttctacggat atacgatgga cgcgtggggg cagggtacca gcgtgacggt ctcgagc 357
<210> 75
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> cCl1-1 LCDR1
<400> 75
cgggcgagcg aggacatcta ctcgaacctg gcg 33
<210> 76
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> cCl1-1 LCDR2
<400> 76
tccgtcaagc ggctgcaaga c 21
<210> 77
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> cCl1-1 LCDR3
<400> 77
ctgcaaggga gcaacttccc gctgacg 27
<210> 78
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> cCl1-1 VL
<400> 78
gacatccaga tgacgcagag cccggcgtcg ctgagcgcga gcctggggga gacgatctcg 60
atcgcgtgcc gggcgagcga ggacatctac tcgaacctgg cgtggtatca acagaagagc 120
gggaagagcc cgcagctgct gatcttctcc gtcaagcggc tgcaagacgg cgtcccgagc 180
cgattctcgg ggagcgggag cgggacgcag tactcgctga agatctcggg gatgcagccg 240
gaggacgagg gggactactt ctgcctgcaa gggagcaact tcccgctgac gttcgggtcg 300
ggtaccaaac tcgagatcaa a 321
<210> 79
<211> 51
<212> DNA
<213> 人工序列
<220>
<223> cCl1-2 HCDR2
<400> 79
tggatcaacg cgtacacggg gaagccgacc tacgcggacg acttcaaggg g 51
<210> 80
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> cCl1-2 HCDR3
<400> 80
gccgtctact acggatatac gatggac 27
<210> 81
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> cCl1-2 VH
<400> 81
cagatccagc tcgtccagag cgggccggag ctgaagaagc cgggggagag cgtgaagatc 60
tcgtgcaaga cgagcggata tacgttcacg gactacgcga tgcactgggt caagcagggg 120
ccagggaaag ggatgaagtg gatggggtgg atcaacgcgt acacggggaa gccgacctac 180
gcggacgact tcaaggggcg attcgtgctg agcctggagg cgagcgcctc gacggcgaac 240
ctgcaaatct cgaacctgaa gaacgaggac acggcgacgt acttctgcgc gcgggccgtc 300
tactacggat atacgatgga cgcgtggggg cagggtacca gcgtgatcgt ctcgagc 357
<210> 82
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> cCl1-2 LCDR1
<400> 82
cggacgagcg aggacatcta ctcgaacttc gcg 33
<210> 83
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> cCl1-2 LCDR2
<400> 83
tcagtcaacc ggctgcaaga c 21
<210> 84
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> cCl1-2, cCl1-3, hCl1d, hCl1g LCDR3
<400> 84
ctgcaaggga gcaagttccc gctgacg 27
<210> 85
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> cCl1-1 VL
<400> 85
gacatccaga tgacgcagag cccggcgagc ctgagcgcga gcctggggga gacgatctcg 60
atcgagtgcc ggacgagcga ggacatctac tcgaacttcg cgtggttcca gcagaagagc 120
gggaagagcc cgcagctgct gatctactca gtcaaccggc tgcaagacgg cgtcccgagc 180
cgattctcgg ggagcgggag cgggacgcag tactcgctga agatctcggg gatgcagccg 240
gaggacgagg gggactactt ctgcctgcaa gggagcaagt tcccgctgac gttcgggagc 300
ggtaccaaac tcgagatcaa a 321
<210> 86
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> cCl1-3 HCDR1
<400> 86
gactacgcga tgtac 15
<210> 87
<211> 51
<212> DNA
<213> 人工序列
<220>
<223> cCl1-3 HCDR2
<400> 87
tggatcaaca cgtacacggg gaagccgacc tacgcggacg acttcaaggg g 51
<210> 88
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> cCl1-3 VH
<400> 88
cagatccagc tcgtccagag cgggccggag ctgaagaagc cgggggagag cgtgaagatc 60
tcgtgcaagg cgagcggata tacgttcacg gactacgcga tgtactgggt caagcaagtg 120
ccggggaaag ggctgcgatg gatggggtgg atcaacacgt acacggggaa gccgacctac 180
gcggacgact tcaaggggcg attcgtgttc tcgctggagg cgagcgcgag cacggcgaac 240
ctgcaaatct cgaacctgaa gaacgaggac acggcgacgt acttctgcgc gcgggccgtc 300
ttctacggat atacgatgga cgcgtggggg cagggtacca gcgtgacggt ctcgagc 357
<210> 89
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> cCl1-3 LCDR1
<400> 89
cggacgagcg aggacatcta ctcgaacctg gcg 33
<210> 90
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> cCl1-3 LCDR2
<400> 90
gcgatcaagc ggctgcaaga c 21
<210> 91
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> cCl1-3 VL
<400> 91
gacatccaga tgacgcagag cccggcgagc ctgagcgcga gcctggggga gacgatctcg 60
atcgcgtgcc ggacgagcga ggacatctac tcgaacctgg cgtggtatca acagaagagc 120
gggaagagcc cgcagctgct gatcttcgcg atcaagcggc tgcaagacgg cgtcccgagc 180
cgattctcgg ggagcgggag cgggacgcag tactcgctga agatctcggg gatgcagccg 240
gaggacgagg gggactactt ctgcctgcaa gggagcaagt tcccgctgac gttcgggtcg 300
ggtaccaaac tcgagatcaa a 321
<210> 92
<211> 51
<212> DNA
<213> 人工序列
<220>
<223> hCl1a HCDR2
<400> 92
tggatcaata catacacggg gaagccgact tatgcgcaaa aattccaagg a 51
<210> 93
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> hCl1a HCDR3
<400> 93
gcggtcttct acggatatac gatggatgcc 30
<210> 94
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> cCl1a VH
<400> 94
caggtccaac tagtccaaag cggggcggaa gtcaagaagc ccggagcatc cgtcaaagtc 60
agctgcaagg cgagcggata tacatttacg gactacgcga tgcactgggt caggcaagcc 120
cctgggcaaa ggctcgaatg gatgggatgg atcaatacat acacggggaa gccgacttat 180
gcgcaaaaat tccaaggaag agtcacaatt acgcgggata catccgcatc taccgcctac 240
atggagctaa gctcgctgcg gagcgaggat acggcggtct actattgcgc ccgagcggtc 300
ttctacggat atacgatgga tgcctggggg cagggtaccc tggtcacggt ctcgagc 357
<210> 95
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> hCl1a, hCl1b, hCl1e, hCl1i LCDR1
<400> 95
agggcctccg aagacatcta ctccaacctg gca 33
<210> 96
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> hCl1a, hCl1b, hCl1e, hCl1i LCDR2
<400> 96
agcgtcaaaa gactacaaga t 21
<210> 97
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> hCl1a, hCl1b, hCl1e, hCl1i LCDR3
<400> 97
ttgcaaggaa gcaatttccc cttgact 27
<210> 98
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> cCl1a, hCl1b, hCl1e, hCl1i VL
<400> 98
gacattcaaa tgacgcaaag cccatcatcg ctgagcgcat cggtcgggga tagagtcacc 60
ataacatgca gggcctccga agacatctac tccaacctgg catggtatca acaaaaaccg 120
gggaaggctc cgaagctgct gatatttagc gtcaaaagac tacaagatgg agtaccgagc 180
cgattttcgg gaagcgggag cgggacggat ttcacgctga ccatatcaag tttgcaaccg 240
gaggattttg cgacatacta ttgcttgcaa ggaagcaatt tccccttgac tttcgggcaa 300
ggtaccaagg tcgagatcaa a 321
<210> 99
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> hCl1b, hCl1c, hCl1d HCDR1
<400> 99
gattatgcaa tgcac 15
<210> 100
<211> 51
<212> DNA
<213> 人工序列
<220>
<223> hCl1b, hCl1c, hCl1d HCDR2
<400> 100
tggattaaca cctacacggg caagcccaca tactcccaaa aattccaagg a 51
<210> 101
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> hCl1b, hCl1c, hCl1d HCDR3
<400> 101
gctgtattct atggatatac aatggatgcc 30
<210> 102
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> hCl1b, hCl1c, hCl1d VH
<400> 102
caggtccaat tagtccaaag cggggcggaa gtcaagaagc cgggggcgag cgtcaaagtc 60
tcatgcaaag cgagcggata cacatttacg gattatgcaa tgcactgggt caggcaagca 120
cccggacaaa ggctggaatg gatgggatgg attaacacct acacgggcaa gcccacatac 180
tcccaaaaat tccaaggaag ggtcacgata acgagagaca cgagcgcgag caccggaatg 240
gatgggatgg attaacacct acacgggcaa gcccacatac tcccaaaaat tccaaggaag 300
ggtcacgata acgagagaca cgagcgcgag caccgtaccc tggtcaccgt ctcgagc 357
<210> 103
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> hCl1c, hCl1j LCDR1
<400> 103
cgaacgagcg aggacatata ctcaaacctt gca 33
<210> 104
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> hCl1c, hCl1j LCDR2
<400> 104
gcgataaaga ggctgcaaga c 21
<210> 105
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> hCl1c, hCl1j LCDR3
<400> 105
ttgcaaggct ccaaatttcc cctgaca 27
<210> 106
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> hCl1c, hCl1j VL
<400> 106
gacatccaaa tgactcaaag cccatcatcg ctatcggcat cggtcgggga tagagtcacg 60
ataacatgcc gaacgagcga ggacatatac tcaaaccttg catggtatca acaaaagccg 120
gggaaggccc cgaagctact gatattcgcg ataaagaggc tgcaagacgg agttccatca 180
cgattttcgg gatctggctc ggggaccgat tttacgctga ctatatcatc gctgcaaccg 240
gaagattttg caacatacta ctgcttgcaa ggctccaaat ttcccctgac attcggacaa 300
ggtaccaagg tcgagatcaa a 321
<210> 107
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> hCl1d, hCl1g LCDR1
<400> 107
cggacgagcg aggatattta ttcgaacttt gca 33
<210> 108
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> hCl1d, hCl1g LCDR2
<400> 108
cagtcaatcg gctacaagat 20
<210> 109
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> hCl1d, hCl1g VL
<400> 109
gacatccaaa tgacgcaatc accgagctcg ctgagcgcat ctgtcgggga ccgtgtcaca 60
atcacatgcc ggacgagcga ggatatttat tcgaactttg catggtatca acaaaaaccg 120
ggcaaggctc cgaaactttt gatttattca gtcaatcggc tacaagatgg cgtcccgagc 180
cgatttagcg ggagcggatc gggaaccgac tttacgctga cgatatcatc gctacaaccg 240
gaggacttcg cgacttatta ctgcctacaa gggagcaaat tcccgctgac attcggacaa 300
ggtaccaagg tcgagatcaa a 321
<210> 110
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> hCl1e HCDR1
<400> 110
gattacgcaa tgtac 15
<210> 111
<211> 51
<212> DNA
<213> 人工序列
<220>
<223> hCl1e HCDR2
<400> 111
tggataaata cctatacggg aaagccaaca tacgcccaaa aattccaagg c 51
<210> 112
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> hCl1e HCDR3
<400> 112
gccgtctttt atggatatac gatggacgca 30
<210> 113
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> hCl1e VH
<400> 113
caggtccaac tggtccaatc gggggctgaa gtcaaaaagc cgggggcgag cgtcaaagtc 60
agctgcaaag catcgggata cacatttacg gattacgcaa tgtactgggt caggcaagca 120
cccggccaac gactggaatg gatgggctgg ataaatacct atacgggaaa gccaacatac 180
gcccaaaaat tccaaggccg cgtcacaata acgcgggaca cgagcgcatc gacggcttat 240
atggaactat catcgctgcg atcggaagac acggcggtct attattgcgc acgcgccgtc 300
ttttatggat atacgatgga cgcatggggg cagggtaccc tggtcacggt ctcgagc 357
<210> 114
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> hCl1f, hCl1g HCDR1
<400> 114
gactacgcaa tgcac 15
<210> 115
<211> 51
<212> DNA
<213> 人工序列
<220>
<223> hCl1f, hCl1g HCDR2
<400> 115
tggattaatg cctacacggg gaagccgacc tacgcacaaa aattccaagg a 51
<210> 116
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> hCl1f, hCl1g HCDR3
<400> 116
gccgtcttct atggatatac gatggatgct 30
<210> 117
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> hCl1f, hCl1g VH
<400> 117
caggtccaat tggtccaaag cggggcggag gtcaagaagc cgggggcgag cgtcaaagtc 60
tcatgcaagg caagcggata tacatttacg gactacgcaa tgcactgggt ccggcaagcc 120
cctgggcaac ggctggaatg gatgggatgg attaatgcct acacggggaa gccgacctac 180
gcacaaaaat tccaaggacg agtcacgatt acgcgggata ctagcgcgag caccgcatat 240
atggagctaa gctcgctgcg atctgaggat accgctgtat actactgcgc gagagccgtc 300
ttctatggat atacgatgga tgcttggggg cagggtaccc tggtcacggt ctcgagc 357
<210> 118
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> hCl1f, hCl1h LCDR1
<400> 118
cgagcttcgg aggacatcta tagcaacttg gct 33
<210> 119
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> hCl1f, hCl1h LCDR2
<400> 119
agcgtcaaaa ggctccaaga c 21
<210> 120
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> hCl1f, hCl1h LCDR3
<400> 120
ctacaaggct ctaacttccc attgaca 27
<210> 121
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> hCl1f, hCl1h VL
<400> 121
gatatccaaa tgacgcaatc accatctagc ctatcggcct ctgtggggga ccgagtcacc 60
atcacatgcc gagcttcgga ggacatctat agcaacttgg cttggtatca acaaaagccg 120
gggaaagcac caaagctgct gatatatagc gtcaaaaggc tccaagacgg agtcccaagc 180
cgattctcgg gctccggctc cgggacggat tttacgctga caatttcgag cctgcaaccg 240
gaggactttg caacctacta ttgcctacaa ggctctaact tcccattgac atttgggcaa 300
ggtaccaagg tcgagatcaa a 321
<210> 122
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> hCl1h, hCl1i, hCl1j HCDR1
<400> 122
gactacgcta tgtat 15
<210> 123
<211> 51
<212> DNA
<213> 人工序列
<220>
<223> hCl1h, hCl1i, hCl1j HCDR2
<400> 123
tggattaatg cctacaccgg gaagccgact tatgcgcaaa aatttcaagg a 51
<210> 124
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> hCl1h, hCl1i, hCl1j HCDR3
<400> 124
gcggtctact atggatatac gatggacgca 30
<210> 125
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> hCl1h, hCl1i, hCl1j VH
<400> 125
caggtccaac tggttcaatc tggagcggaa gtcaagaagc ccggagcatc cgtcaaagtc 60
tcgtgcaagg catctggata cacattcacc gactacgcta tgtattgggt ccggcaagcc 120
cccggacaac ggctggaatg gatgggatgg attaatgcct acaccgggaa gccgacttat 180
gcgcaaaaat ttcaaggaag ggtcacgatt acgcgggaca cgagcgcctc aaccgcatac 240
atggagctat cgagcctgcg aagcgaggac accgcggtct actactgcgc gcgggcggtc 300
tactatggat atacgatgga cgcatggggg cagggtaccc tggtcacggt ctcgagc 357
<210> 126
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> HC CDR2仅用于hCl1x,而不是嵌合克隆cCl1-1,2,3
<220>
<221> 杂项特征
<222> (4)..(4)
<223> T或A
<220>
<221> 杂项特征
<222> (12)..(12)
<223> A或S
<400> 126
Trp Ile Asn Xaa Tyr Thr Gly Lys Pro Thr Tyr Xaa Gln Lys Phe Gln
1 5 10 15
Gly
<210> 127
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 恒定轻链-CL结构域
<400> 127
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> 128
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 恒定重链-CH1+Fc结构域
<400> 128
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 129
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 恒定重链中的L234A/L235A突变-CH1+Fc结构域
<400> 129
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 Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 130
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 恒定重链中的L236A/L236A/P329G突变-CH1+Fc结构域
<400> 130
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 Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 131
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 分选酶标签
<400> 131
Arg Leu Pro Gln Thr Gly Gly
1 5
<210> 132
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 分选酶标签
<400> 132
Gly Gly Gly Gly Ser Leu Pro Gln Thr Gly Gly
1 5 10
<210> 133
<211> 261
<212> PRT
<213> 智人
<400> 133
Met Ala Val Thr Ala Cys Gln Gly Leu Gly Phe Val Val Ser Leu Ile
1 5 10 15
Gly Ile Ala Gly Ile Ile Ala Ala Thr Cys Met Asp Gln Trp Ser Thr
20 25 30
Gln Asp Leu Tyr Asn Asn Pro Val Thr Ala Val Phe Asn Tyr Gln Gly
35 40 45
Leu Trp Arg Ser Cys Val Arg Glu Ser Ser Gly Phe Thr Glu Cys Arg
50 55 60
Gly Tyr Phe Thr Leu Leu Gly Leu Pro Ala Met Leu Gln Ala Val Arg
65 70 75 80
Ala Leu Met Ile Val Gly Ile Val Leu Gly Ala Ile Gly Leu Leu Val
85 90 95
Ser Ile Phe Ala Leu Lys Cys Ile Arg Ile Gly Ser Met Glu Asp Ser
100 105 110
Ala Lys Ala Asn Met Thr Leu Thr Ser Gly Ile Met Phe Ile Val Ser
115 120 125
Gly Leu Cys Ala Ile Ala Gly Val Ser Val Phe Ala Asn Met Leu Val
130 135 140
Thr Asn Phe Trp Met Ser Thr Ala Asn Met Tyr Thr Gly Met Gly Gly
145 150 155 160
Met Val Gln Thr Val Gln Thr Arg Tyr Thr Phe Gly Ala Ala Leu Phe
165 170 175
Val Gly Trp Val Ala Gly Gly Leu Thr Leu Ile Gly Gly Val Met Met
180 185 190
Cys Ile Ala Cys Arg Gly Leu Ala Pro Glu Glu Thr Asn Tyr Lys Ala
195 200 205
Val Ser Tyr His Ala Ser Gly His Ser Val Ala Tyr Lys Pro Gly Gly
210 215 220
Phe Lys Ala Ser Thr Gly Phe Gly Ser Asn Thr Lys Asn Lys Lys Ile
225 230 235 240
Tyr Asp Gly Gly Ala Arg Thr Glu Asp Glu Val Gln Ser Tyr Pro Ser
245 250 255
Lys His Asp Tyr Val
260
Claims (15)
1.结合CLDN18.2的抗体或其片段,其中所述抗体或其片段展现出与表达CLDN18.2的健康组织相比对表达CLDN18.2的肿瘤组织的结合增加。
2.结合CLDN18.2的抗体或其片段,其包含分别为SEQ ID NO:21、SEQ ID NO:22和SEQID NO:23的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:24、SEQ ID NO:25和SEQ IDNO:26的LCDR1、LCDR2和LCDR3序列。
3.权利要求1或2的抗体或其片段,其包含:
a.分别为SEQ ID NO:1、SEQ ID NO:15和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;
b.分别为SEQ ID NO:1、SEQ ID NO:16和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;
c.分别为SEQ ID NO:1、SEQ ID NO:16和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:17、SEQ ID NO:14和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列;
d.分别为SEQ ID NO:1、SEQ ID NO:16和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列;
e.分别为SEQ ID NO:12、SEQ ID NO:15和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;
f.分别为SEQ ID NO:1、SEQ ID NO:20和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;
g.分别为SEQ ID NO:1、SEQ ID NO:20和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列;
h.分别为SEQ ID NO:12、SEQ ID NO:20和SEQ ID NO:8的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;或
i.分别为SEQ ID NO:12、SEQ ID NO:20和SEQ ID NO:8的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:17、SEQ ID NO:14和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列。
4.权利要求1或2的抗体或其片段,其包含:
a.分别为SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的LCDR1、LCDR2和LCDR3序列;
b.分别为SEQ ID NO:1、SEQ ID NO:7和SEQ ID NO:8的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:9、SEQ ID NO:10和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列;或
c.分别为SEQ ID NO:12、SEQ ID NO:2和SEQ ID NO:3的HCDR1、HCDR2和HCDR3序列,以及分别为SEQ ID NO:13、SEQ ID NO:14和SEQ ID NO:11的LCDR1、LCDR2和LCDR3序列,
优选地包含:
d.SEQ ID NO:27的VH序列和SEQ ID NO:28的VL序列;
e.SEQ ID NO:29的VH序列和SEQ ID NO:30的VL序列;或
f.SEQ ID NO:31的VH序列和SEQ ID NO:32的VL序列。
5.权利要求1-3中任一项的抗体或其片段,其包含:
a.与SEQ ID NO:33的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VH序列;
b.与SEQ ID NO:34的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VH序列;
c.与SEQ ID NO:35的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VH序列;
d.与SEQ ID NO:36的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VH序列;或
e.与SEQ ID NO:37的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VH序列;
和
f.与SEQ ID NO:38的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VL序列;
g.与SEQ ID NO:39的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VL序列;
h.与SEQ ID NO:40的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VL序列;或
i.与SEQ ID NO:41的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的VL序列,
优选地包含:
a.SEQ ID NO:33的VH序列;
b.SEQ ID NO:34的VH序列;
c.SEQ ID NO:35的VH序列;
d.SEQ ID NO:36的VH序列;或
e.SEQ ID NO:37的VH序列;
和
f.SEQ ID NO:38的VL序列;
g.SEQ ID NO:39的VL序列;
h.SEQ ID NO:40的VL序列;或
i.SEQ ID NO:41的VL序列。
6.权利要求1或2的抗体或其片段,其包含:
a.SEQ ID NO:33的VH序列和SEQ ID NO:38的VL序列;
b.SEQ ID NO:34的VH序列和SEQ ID NO:38的VL序列;
c.SEQ ID NO:34的VH序列和SEQ ID NO:39的VL序列;
d.SEQ ID NO:34的VH序列和SEQ ID NO:40的VL序列;
e.SEQ ID NO:35的VH序列和SEQ ID NO:38的VL序列;
f.SEQ ID NO:36的VH序列和SEQ ID NO:41的VL序列;
g.SEQ ID NO:36的VH序列和SEQ ID NO:40的VL序列;
h.SEQ ID NO:37的VH序列和SEQ ID NO:41的VL序列;
i.SEQ ID NO:37的VH序列和SEQ ID NO:38的VL序列;或
j.SEQ ID NO:37的VH序列和SEQ ID NO:39的VL序列。
7.权利要求1-3中任一项的抗体,其包含:
a.与SEQ ID NO:46的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:51的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
b.与SEQ ID NO:47的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:51的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
c.与SEQ ID NO:47的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:52的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
d.与SEQ ID NO:47的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:53的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
e.与SEQ ID NO:48的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:51的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
f.与SEQ ID NO:47的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:54的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
g.与SEQ ID NO:49的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:53的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
h.与SEQ ID NO:50的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:54的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
i.与SEQ ID NO:50的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:51的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列;
j.与SEQ ID NO:50的重链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的重链序列,以及与SEQ ID NO:52的轻链序列的氨基酸序列具有至少80%、至少85%、至少90%、至少95%或至少98%的序列同一性的轻链序列,
优选地包含:
k.SEQ ID NO:46的重链序列和SEQ ID NO:51的轻链序列;
l.SEQ ID NO:47的重链序列和SEQ ID NO:51的轻链序列;
m.SEQ ID NO:47的重链序列和SEQ ID NO:52的轻链序列;
n.SEQ ID NO:47的重链序列和SEQ ID NO:53的轻链序列;
o.SEQ ID NO:48的重链序列和SEQ ID NO:51的轻链序列;
p.SEQ ID NO:47的重链序列和SEQ ID NO:54的轻链序列;
q.SEQ ID NO:49的重链序列和SEQ ID NO:53的轻链序列;
r.SEQ ID NO:50的重链序列和SEQ ID NO:54的轻链序列;
s.SEQ ID NO:50的重链序列和SEQ ID NO:51的轻链序列;
t.SEQ ID NO:50的重链序列和SEQ ID NO:52的轻链序列,
或其具有工程化Fc结构域的版本。
8.结合CLDN18.2的抗体或其片段,其中所述抗体或其片段
(i)与包含SEQ ID NO:46的重链序列和SEQ ID NO:51的轻链序列的抗体结合相同的表位;
(ii)与包含SEQ ID NO:46的重链序列和SEQ ID NO:51的轻链序列的抗体竞争结合;和/或
(iii)竞争性抑制包含SEQ ID NO:46的重链序列和SEQ ID NO:51的轻链序列的抗体与CLDN18.2的结合。
9.权利要求1至8中任一项的抗体或其片段,其中所述抗体或其片段
a.是IgA1、IgA2、IgD、IgE、IgG1、IgG2、IgG3、IgG4、合成IgG、IgM、F(ab)2、Fv、scFv、IgGACH2、F(ab’)2、scFvCH3、Fab、VL、VH、scFv4、scFv3、scFv2、dsFv、Fv、scFv-Fc、(scFv)2、非消耗性IgG、双抗体、二价抗体或其Fc工程化版本;
b.是人源化的;
c.不结合CLDN18.1;
d.是分离的;和/或
e.与IMAB362相比对翻译后脱酰胺化的易感性更低。
10.权利要求1至9中任一项的抗体或其片段,其中与表达CLDN18.2的健康组织相比对表达CLDN18.2的肿瘤组织的结合增加通过流式细胞术或通过免疫组织化学测量。
11.权利要求1至9中任一项的抗体或其片段,其中所述抗体或其片段以比IMAB362结合在HEK293T细胞或PA-TU-8988-High细胞中表达的CLDN18.2的EC50值高至少1.1倍、高至少1.2倍、高至少1.5倍、高至少2倍或高至少2.5倍但高不超过3倍的EC50值结合在HEK293T细胞或PA-TU-8988-High细胞中表达的CLDN18.2,任选地其中通过流式细胞术(FC)滴定测量结合。
12.核酸,其编码权利要求1至11中任一项的抗体或其片段。
13.载体,其包含权利要求12的核酸。
14.宿主细胞,其包含权利要求12的核酸或权利要求13的载体。
15.权利要求1至11中任一项的抗体或其片段、权利要求12的核酸、权利要求13的载体或权利要求14的宿主细胞,其用于治疗以下受试者:
a.患有赘生性疾病,
b.具有形成赘生性疾病的风险,和/或
c.被诊断为赘生性疾病;
任选地其中所述赘生性疾病选自胰腺癌、胃癌、食道癌、卵巢癌和肺癌。
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JP2024528917A (ja) | 2021-08-13 | 2024-08-01 | サイチューン ファーマ | 癌を治療するための抗体-薬物コンジュゲートとのIL-2/IL-15Rβγアゴニストの組み合わせ |
CN117897403A (zh) * | 2021-09-24 | 2024-04-16 | 盛禾(中国)生物制药有限公司 | 一种抗Claudin18.2抗体及其应用 |
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DE102004024617A1 (de) | 2004-05-18 | 2005-12-29 | Ganymed Pharmaceuticals Ag | Differentiell in Tumoren exprimierte Genprodukte und deren Verwendung |
EP1997832A1 (en) | 2007-05-29 | 2008-12-03 | Ganymed Pharmaceuticals AG | Monoclonal antibodies against Claudin-18 for treatment of cancer |
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WO2021130291A1 (en) | 2021-07-01 |
ZA202205738B (en) | 2023-01-25 |
MX2022007849A (es) | 2022-07-19 |
BR112022012327A2 (pt) | 2022-10-18 |
CL2022001727A1 (es) | 2023-01-27 |
KR20220119117A (ko) | 2022-08-26 |
AU2020410998A1 (en) | 2022-06-16 |
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