CN114716548A - 抗-fgfr3抗体及其用途 - Google Patents
抗-fgfr3抗体及其用途 Download PDFInfo
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- CN114716548A CN114716548A CN202111647441.7A CN202111647441A CN114716548A CN 114716548 A CN114716548 A CN 114716548A CN 202111647441 A CN202111647441 A CN 202111647441A CN 114716548 A CN114716548 A CN 114716548A
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Abstract
本发明涉及一种抗‑成纤维细胞生长因子受体3(FGFR3)抗体或其抗原结合片段、编码该抗体或其抗原结合片段的核酸、包含所述核酸的重组表达载体、由所述重组表达载体转染的宿主细胞、所述抗体或其抗原结合片段的制备方法、包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体、包含所述抗体的scFv和由包含一个以上的与免疫细胞活化抗原结合的抗体的scFv的第二结合域组成的scFv的免疫细胞接合双特异性抗体或多特异性抗体、所述抗体或其抗原片段与药物结合的抗体‑药物偶联物(ADC)、包含所述抗‑FGFR3抗体的scFv作为细胞外结构域的抗原结合部位的嵌合抗原受体(CAR)、导入有所述嵌合抗原受体的免疫细胞、包含所述免疫细胞的联合治疗用组合物、包含所述抗体或其抗原结合片段的联合治疗用组合物、用于治疗癌症的组合物、癌症的治疗方法和包含所述抗体或其抗原结合片段的囊泡。
Description
技术领域
本发明涉及一种抗-成纤维细胞生长因子受体3(Fibroblast growth factorreceptor 3,FGFR3)抗体或其抗原结合片段,编码该抗体或其抗原结合片段的核酸,包含所述核酸的重组表达载体,由所述重组表达载体转染的宿主细胞,所述抗体或其抗原结合片段的制备方法,包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体,包含所述抗体的scFv和由包含一个以上的与免疫细胞活化抗原结合的抗体的scFv的第二结合域组成的scFv的免疫细胞接合(immune cell engage)双特异性抗体或多特异性抗体,所述抗体或其抗原片段与药物结合的抗体-药物偶联物(ADC),包含所述抗-FGFR3抗体的scFv作为细胞外结构域的抗原结合部位的嵌合抗原受体(CAR),导入有所述嵌合抗原受体的免疫细胞,包含所述免疫细胞的联合治疗用组合物,包含所述抗体或其抗原结合片段的联合治疗用组合物,用于治疗癌症、炎症或免疫疾病的组合物,癌症、炎症或免疫疾病的治疗方法和包含所述抗体或其抗原结合片段的囊泡(vesicle)。
背景技术
成纤维细胞生长因子(fibroblast growth factor,FGF)及其酪氨酸激酶受体(FGFR)在胚胎形成、各种组织的内稳态、伤口治愈过程和代谢功能中起到重要的作用。在人类中存在具有高度的同源性的FGFR(FGFR1-4)和22个FGF(FGF1-14和FGF16-23)。FGFR包含:包含作为3个免疫域的D1、D2和D3的细胞外区域、单跨膜结构域和分裂细胞质激酶部分。
FGFR1-4引起的信号传导失调与引发各种癌症的病因有关。由于包括基因扩增、染色体易位和激活突变在内的基因组FGFR的变异,促进FGF途径的异常激活诱导和正常细胞的肿瘤转化。特别地,已知FGFR3的扩增与膀胱癌的诱发有关。特别地,在各个种类的癌症中观察到错义FGFR变异,并且由于FGFR3的S249C,可能会增强FGF驱动信号和肿瘤细胞增殖,并且显示对体细胞突变的热点。
以往癌症治疗剂是着重于靶向这种FGF/FGFR途径来进行开发。另外,近年来,在胶质母细胞瘤、肺癌、膀胱癌、口腔癌,头颈部鳞状细胞癌、胆囊癌或宫颈癌等中发现作为致癌变异的通过染色体的重排引起的融合蛋白。这种融合蛋白是由于染色体4的串联重复,通过FGFR3基因和转化酸性含卷曲螺旋蛋白3(transforming acidic coiled-coil containingprotein 3,TACC3)基因的融合形成。由于融合蛋白中FGFR单体足够接近而可以被使其激活的配偶体蛋白质的二聚化结构域(dimerizing domain),FGFR可以被持续激活。FGFR3-TACC3中由于TACC3的卷曲螺旋域(coiled-coil domain),在没有配体结合的情况下使FGFR3自磷酸化和激活。
TACC3属于TACC家族,往往会在多发性骨髓瘤中确认在与包含TACC3和FGFR3的区域对应的染色体4p16中的重排现象,这种重排导致FGFR3或TACC3的表达增加(KN Nelsonet al.,Oncotarget.2018 Sep 28;9(76):34306-34319)。
根据如上所述确认的内容,近年来,正进行对靶向FGFR3或与FGFR3基因的融合基因的抗体的临床试验。
B701(Vofatamab)是对FGFR3的人免疫球蛋白G1单克隆抗体,进行临床,以确认是否显示抗-肿瘤活性以及与多烯紫杉醇的联合可能性。施用抗-FGFR3单克隆抗体B-701时,与FGFR3的野生型和突变均特异性结合并抑制,通过抑制FGFR3的磷酸化,抑制FGFR3的活化和FGFR3介导的信号传导途径。由此,抑制细胞增殖,并且在FGFR3表达肿瘤中诱导细胞死亡。
LY3076226是抗-FGFR3抗体与DM4(微管抑制剂(microtubule inhibitor))接合的抗体-药物偶联物(ADC),进行了是否可以用于晚期或转移癌的临床。进行了临床一期,以确认LY3076226是否对具有FGFR3的过表达或修饰的包括多发性骨髓瘤和淋巴瘤在内的晚期或转移癌、局部晚期、不可切除或转移性尿路癌有效(T Ibrahim et al.,Bladder Cancer,vol.5,no.2,pp.87-102,2019)。
在这种现有的抗-FGFR3抗体中显示出低的亲和力、靶向降解率(degradation)和功效,本发明人为了开发与现有的抗-FGFR3抗体相比亲和力、靶向降解率和功效等得到改善的新型抗-FGFR3抗体而进行很多努力的结果,确认了例如亲和力的抗体的特性、FGFR3结合模式分析、FGFR3降解率确认、癌细胞生长抑制结果和功效试验结果等,特别是通过筛选与公知的抗-FGFR3抗体相比对源自FGFR3-TACC3过表达脑肿瘤患者的细胞具有更敏感的反应性的抗体的策略,筛选具有差异化的特性的抗体,并且确认了所筛选的抗体可以用于期望的癌症治疗,从而完成了本发明。
发明内容
要解决的技术问题
本发明的目的在于提供一种针对成纤维细胞生长因子受体3(FGFR3)的新型抗体或其抗原结合片段。
特别地,本发明的目的在于筛选与公知的抗-FGFR3抗体相比对源自FGFR3-TACC3过表达脑肿瘤患者的细胞具有更敏感的反应性的抗体。
本发明的另一个目的在于提供一种核酸,其编码所述抗体或其抗原结合片段。
本发明的另一个目的在于提供一种宿主细胞,其被包含所述核酸的重组表达载体或所述重组表达载体转染。
本发明的另一个目的在于提供一种与FGFR3特异性结合的抗体或其抗原结合片段的制备方法。
本发明的另一个目的在于提供一种包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体。
本发明的另一个目的在于提供一种包含所述抗体或其抗原结合片段的免疫细胞接合双特异性抗体或多特异性抗体。
本发明的另一个目的在于提供一种所述抗体或其抗原结合片段与药物结合的抗体-药物偶联物(ADC)。
本发明的另一个目的在于提供一种联合治疗用组合物,其包含:嵌合抗原受体(CAR)、导入有所述嵌合抗原受体的免疫细胞、所述免疫细胞,所述嵌合抗原受体包含所述抗-FGFR3抗体的scFv作为细胞外结构域的抗原结合部位。
本发明的另一个目的在于提供一种联合治疗用组合物,其包含所述抗体或其抗原结合片段或者所述免疫细胞接合双特异性抗体或多特异性抗体。
本发明的另一个目的在于提供一种用于治疗癌症的组合物或癌症治疗方法,所述组合物包含:抗体或其抗原结合片段、包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体、包含所述抗体或其抗原结合片段的抗体-药物偶联物、包含所述抗体或其抗原结合片段的嵌合抗原受体、所述嵌合抗原受体。
本发明的又一个目的在于提供一种包含所述抗体或其抗原结合片段的囊泡。
技术方案
为了实现上述目的,本发明提供一种与成纤维细胞生长因子受体3(FGFR3)特异性结合的抗体或其抗原结合片段,其包含:重链CDR1,其包含选自SEQ ID NO.1至SEQ IDNO.18中的一种以上的氨基酸序列;重链CDR2,其包含选自SEQ ID NO.19至SEQ ID NO.41中的一种以上的氨基酸序列;重链CDR3,其包含选自SEQ ID NO.42至SEQ ID NO.66、SEQ IDNO.186至SEQ ID NO.198中的一种以上的氨基酸序列;轻链CDR1,其包含选自SEQ ID NO.67至SEQ ID NO.88中的一种以上的氨基酸序列;轻链CDR2,其包含选自SEQ ID NO.89至SEQID NO.109中的一种以上的氨基酸序列;以及轻链CDR3,其包含选自SEQ ID NO.110至SEQID NO.132、SEQ ID NO.199至SEQ ID NO.202中的一种以上的氨基酸序列。
本发明提供一种编码所述抗体或其抗原结合片段的核酸。
本发明还提供一种包含所述核酸的重组表达载体。
本发明还提供一种宿主细胞,其被所述重组表达载体转染。
本发明还提供一种与FGFR3特异性结合的抗体或其抗原结合片段的制备方法,其包括以下步骤:培养宿主细胞,从而形成抗体;以及分离所形成的抗体并进行提纯。
本发明还提供一种包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体。
本发明还提供一种免疫细胞接合双特异性抗体或多特异性抗体,其包含所述抗体的scFv和由第二结合域组成的scFv,所述第二结合域包含一个以上的与免疫细胞活化抗原结合的抗体的scFv。
本发明还提供一种所述抗体或其抗原结合片段与药物结合的抗体-药物偶联物(ADC)。
本发明还提供一种嵌合抗原受体,其特征在于,所述嵌合抗原受体(CAR)包含:包含抗原结合部位的细胞外结构域、跨膜结构域和细胞内信号传导结构域,所述细胞外结构域的抗原结合部位是所述抗体的scFv。
本发明还提供一种包含所述嵌合抗原受体(CAR)的免疫细胞。
本发明还提供一种联合治疗用组合物,其包含所述免疫细胞和除抗-FGFR3抗体之外的药物。
本发明还提供一种联合治疗用组合物,其包含所述抗体或其抗原结合片段,以及选自(i)免疫细胞;(ii)包含抗原受体(CAR)的免疫细胞,所述抗原受体包含对于除抗-FGFR3抗体之外的抗体的scFv片段作为细胞外结构域;以及(iii)免疫检查点抑制剂(Immune checkpoint inhibitor)中的一种以上。
本发明还提供一种联合治疗用组合物,其包含所述双特异性抗体或多特异性抗体,以及选自(i)免疫细胞;(ii)包含抗原受体(CAR)的免疫细胞,所述抗原受体包含对于除抗-FGFR3抗体之外的抗体的scFv片段作为细胞外结构域;以及(iii)免疫检查点抑制剂中的一种以上。
本发明还提供一种用于治疗癌症的组合物,其包含:所述抗体或其抗原结合片段、包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体、包含所述抗体或其抗原结合片段的抗体-药物偶联物、包含所述抗体或其抗原结合片段的嵌合抗原受体或导入有所述嵌合抗原受体的免疫细胞。
本发明还提供一种用于治疗癌症的组合物,其用于治疗确认为FGFR3和TACC3的融合基因扩增、融合基因存在变异、融合基因过表达或者融合基因一直在表达(组成性激活(constitutive activation))的癌症,并且包含:所述抗体或其抗原结合片段、包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体、包含所述抗体或其抗原结合片段的抗体-药物偶联物、包含所述抗体或其抗原结合片段的嵌合抗原受体或导入有所述嵌合抗原受体的免疫细胞。
本发明还提供一种癌症治疗方法,其包括以下步骤:在源自患者的样品中确认FGFR3和TACC3的融合基因扩增、融合基因存在变异、融合基因过表达或者融合基因一直在表达(组成性激活);在确认FGFR3和TACC3的融合基因扩增、融合基因存在变异、融合基因过表达或融合基因一直在表达(组成性激活)的情况下,施用所述抗体或其抗原结合片段、包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体、包含所述抗体或其抗原结合片段的抗体-药物偶联物、包含所述抗体或其抗原结合片段的嵌合抗原受体或导入所述嵌合抗原受体的免疫细胞。
本发明还提供一种囊泡(vesicle),其为所述抗体或其抗原结合片段表露在所述囊泡的外部或者存在于所述囊泡的内部。
有益效果
与现有的抗-FGFR3抗体相比,本发明的抗-FGFR3抗体或其抗原结合片段显示出对FGFR3的优异的结合力,并且可以有用地用于期望的肿瘤或癌症的预防或治疗。
特别地,通过源自FGFR3-TACC3过表达脑肿瘤患者的细胞的筛选,筛选了与公知的抗-FGFR3抗体相比对FGFR3-TACC3过表达癌细胞具有更优异的功效的抗体。
附图说明
图1示出本发明中使用的基于噬菌体展示(phage display)的生物淘选示意图。图1a示出利用源自FGFR3过表达患者细胞的细胞淘选示意图,图1b是示出利用FGFR3重组蛋白的固相生物淘选的示意图,图1c是利用FGFR3重组蛋白的液相生物淘选的示意图,图1d是利用FGFR3重组蛋白的基于磁性的半自动化淘选示意图。
图2a示出本发明的用于抗体筛选的生物淘选结果。
图2b示出本发明的用于抗体筛选的ELISA筛选(screening)结果。
图2c示出本发明的用于抗体筛选的基于磁珠的淘选(Magnetic beads basedpanning)结果。
图3a示出从scFv到IgG形式的转变示意图。
图3b示出基于Expi293的抗体生产和纯度/物理性能分析结果。
图4a至图4d示出FGFR3抗体(IgG)的亲和(Affinity)ELISA结果。图4a示出针对重组蛋白人(human)FGFR3-IIIc的抗体的特异性结合能力,图4b示出针对重组蛋白人FGFR3-IIIb的抗体的特异性结合能力,图4c示出针对重组蛋白小鼠(mouse)FGFR3d的抗体的特异性结合能力,图4d示出针对重组蛋白食蟹猕猴(cynomolgus monkey)FGFR3的抗体的特异性结合能力。
图5示出通过FGFR3抗体(IgG)的生物大分子相互作用分析系统(Biacore)3000的KD值(value)评价结果。
图6示出源自脑肿瘤患者细胞的FGFR3表达的确认和FGFR3-TACC3融合(fusion)分析结果。图6a示出源自患者细胞的mRNA表达水平(expression level)(RPKM)分析、蛋白质表达量分析(蛋白免疫印迹(Western blotting))、细胞表面表达分析(FACS分析(analysis))结果,图6b示出通过RT-PCR确认FGFR3-TACC3是否融合:融合特异引物(fusionspecific primer)。
图7a示出对源自FGFR3(-TACC3)过表达脑肿瘤患者细胞的FGFR3抗体克隆的细胞表面结合分析结果。图7b示出各浓度的F309抗体对源自FGFR3(-TACC3)过表达脑肿瘤患者细胞的结合模式分析结果。图7c示出F309、FS306抗体对没有FGFR3表达的细胞系的结合力分析结果。
图8示出基于FACS的FGFR3抗体的对源自患者细胞表面FGFR3(-TACC3)降解率(degradation)分析和筛选结果。
图9a示出F309、FS306抗体的FGFR3特异性结合能力分析、配体非竞争性特性确认结果。图9b示出F309、FS306抗体的固有的表位结构域识别:结构域(Domain)I结果。图9c示出用于表位结构域映射的重组结构域设计结果。
图10示出F309、FS306抗体对源自FGFR3-TACC3过表达脑肿瘤患者细胞和FGFR3过表达的细胞系的靶向降解率分析结果。图10a示出F309、FS306抗体的细胞表面FGFR3-TACC3和FGFR3降解率分析:FACS分析结果。图10b示出F309、FS306抗体的总(total)FGFR3-TACC3和FGFR3降解率分析:蛋白免疫印迹结果。
图11示出F309、FS306抗体的细胞内化分析结果。图11a示出源自FGFR3-TACC3过表达脑肿瘤患者细胞中细胞内化分析:ICC分析结果。图11b示出通过溶酶体抑制剂(Lysosomeinhibitor)处理的F309、FS306抗体的溶酶体降解(lysosomal degradation)机制确认结果。
图12示出F309、FS306抗体的FGFR3亚信号传导抑制分析结果
图13a示出配体依赖性细胞生长力抑制分析(FGF1、FGF9)结果。图13b示出非配体依赖性细胞生长力抑制分析(源自FGFR3-TACC3过表达脑肿瘤患者细胞、FGFR3低表达细胞系或源自脑肿瘤患者细胞)结果。
图14a示出F309、FS306的短期(short-term)PK分析结果。图14b示出源自FGFR3-TACC3过表达脑肿瘤患者细胞移植小鼠(PDX)中的抗体功效评价结果。图14c示出F309抗体在PDX模型中的功效评价(源自FGFR3-TACC3过表达脑肿瘤患者细胞)结果。
图15a示出F309抗体的3D、2D结构和战略亲和力提升示意图。图15b示出F309亲和力改良抗体通过亲和力ELISA的亲和力比较结果。图15c示出F309亲和力改良抗体的SPR分析结果。图15d示出F309改良抗体克隆的非配体依赖性细胞生长力抑制分析(源自FGFR3-TACC3过表达脑肿瘤患者细胞)结果。
图16a示出用于确认F309抗体的抗体-药物偶联物(ADC)适用可能性的制备示意图。图16b示出F309-vc MMAE对源自FGFR3-TACC3过表达脑肿瘤患者细胞和FGFR3过表达细胞系的细胞毒性分析结果。图16c示出根据F309-vc MMAE的FGFR3表达量的细胞毒性分析-1结果,图16d示出根据F309-vc MMAE的FGFR3表达量的细胞毒性分析-2结果。
图17示出亲和力成熟抗体的Fv结构和表位结构域映射以及抗原特异性结合分析结果。
图18示出源自FGFR3-TACC3脑肿瘤患者细胞的细胞和细胞系的细胞表面抗原表达程度的分析结果。
图19示出亲和力成熟抗体的细胞内化效率分析结果。
图20示出亲和力成熟抗体的FGFR3(-TACC3)靶向降解率分析结果。
图21示出亲和力成熟抗体的小鼠PK分析结果。
图22示出亲和力成熟抗体的猴PK分析结果。
图23示出包含亲和力成熟抗体的ADC制备示意图(拓扑异构酶I抑制剂(Topoisomerase I inhibitor)接合)。
图24示出包含亲和力成熟抗体的ADC制备示意图(拓扑异构酶I抑制剂接合)。
图25示出包含亲和力成熟抗体的ADC的物理性能和结合能力分析结果。
图26示出包含亲和力成熟抗体的ADC的物理性能分析结果。
图27示出包含亲和力成熟抗体的ADC的体外(in vitro)功效评价结果。
图28示出包含亲和力成熟抗体的ADC的体外功效评价结果。
图29示出包含亲和力成熟抗体的ADC的体内(in vivo)功效评价结果。
图30示出包含亲和力成熟抗体的ADC的体内功效评价结果。
图31示出包含亲和力成熟抗体的ADC的体内功效评价结果。
图32示出包含亲和力成熟抗体的ADC的FGFR3(融合TACC3)脑肿瘤立体定向动物模型中的ADC功效评价结果。
具体实施方式
除非另有定义,否则本说明书中使用的所有技术术语和科学术语具有与本发明所述技术领域的技术人员所通常理解的含义相同的含义。通常,本说明书中使用的命名法是本技术领域中众所周知且通常使用的命名法。
抗-FGFR3抗体
本发明的一个方面涉及一种与成纤维细胞生长因子受体3(FGFR3)特异性结合的抗体或其抗原结合片段,其包含:重链CDR1,其包含选自SEQ ID NO.1至SEQ ID NO.18中的一种以上的氨基酸序列;重链CDR2,其包含选自SEQ ID NO.19至SEQ ID NO.41中的一种以上的氨基酸序列;重链CDR3,其包含选自SEQ ID NO.42至SEQ ID NO.66、SEQ ID NO.186至SEQ ID NO.198中的一种以上的氨基酸序列;轻链CDR1,其包含选自SEQ ID NO.67至SEQ IDNO.88中的一种以上的氨基酸序列;轻链CDR2,其包含选自SEQ ID NO.89至SEQ ID NO.109中的一种以上的氨基酸序列;以及轻链CDR3,其包含选自SEQ ID NO.110至SEQ ID NO.132、SEQ ID NO.199至SEQ ID NO.202中的一种以上的氨基酸序列。
本说明书中使用的术语“抗体(antibody)”是指与FGFR3特异性结合的抗-FGFR3抗体。在本发明的范围中所述抗体不仅包含与FGFR3特异性结合的完整的抗体形式,还包含所述抗体分子的抗原结合片段。根据情况,本发明的抗体可以靶向FGFR3-TACC3。特别地,与公知的抗-FGFR3抗体相比,本发明的抗体被筛选为对FGFR3-TACC3过表达的癌细胞具有更优异的功效的抗体。
完整的抗体是具有两个全长轻链和两个全长重链的结构,并且每个轻链通过二硫键与重链连接。
本说明书中使用术语“重链”均表示包含可变区结构域VH和作为3个恒定区结构域的CH1、CH2和CH3的全长重链及其片段,所述可变区结构域VH包含具有用于向抗原赋予特异性的充分的可变区序列的氨基酸序列。此外,本说明书中使用的术语“轻链”均表示包含可变区结构域VL和恒定区结构域CL的全长轻链及其片段,所述可变区结构域VL包含具有用于向抗原赋予特异性的充分的可变区序列的氨基酸序列。
所述整个抗体包含IgA、IgD、IgE、IgM和IgG的亚型(subtype),特别是IgG包含IgG1、IgG2、IgG3和IgG4。重链恒定区具有γ、μ、α、δ和ε类型,作为亚类具有γ1、γ2、γ3、γ4、α1和α2。轻链的恒定区具有κ和λ类型。
抗体的抗原结合片段或抗体片段是指具有抗原结合功能的片段,并且包含Fab、F(ab′)、F(ab′)2和Fv等。抗体片段中Fab是具有轻链和重链的可变区、轻链的恒定区和重链的第一恒定区(CH1)的结构,其具有一个抗原结合部位。Fab′和Fab的差异在于,所述Fab′具有铰链区(hinge-region),所述铰链区在重链CH1结构域的C-末端包含一种以上的半胱氨酸残基。F(ab′)2是Fab′的铰链区的半胱氨酸残基形成二硫键时形成的。
Fv对应仅具有重链可变区和轻链可变区的最小的抗体片段。双链Fv(two-chainFv)为通过非共价键连接重链可变区和轻链可变区,单链Fv(single-chain Fv,scFv)为一般通过肽接头,重链可变区和轻链可变区以共价键连接或在C-末端直接连接,因此可以像双链Fv一样形成诸如二聚物的结构。这种抗体片段可以通过利用蛋白水解酶(例如,将完整形态的抗体用木瓜蛋白酶限制性切割时可以获得Fab,用胃蛋白酶切割时可以获得F(ab′)2)或基因重组技术来制备。
“Fv”片段是含有完整的抗体识别和结合部位的抗体片段。这种区域是结合一个重链可变域和一个轻链可变域的二聚体。
“Fab”片段包含轻链的可变域和恒定结构域、重链的可变域和第一恒定结构域(CH1)。F(ab′)2抗体片段一般包含由存在于Fab′片段C-末端的铰链区的半胱氨酸共价连接的一双Fab′片段。
“单链Fv(scFv)”抗体片段是由包含抗体的VH和VL结构域的单个多肽链形成的结构体。scFv可以在VH结构域和VL结构域之间进一步包含多肽接头,使得可以形成期望的结构以结合抗原。
一个实施方案中,本发明的抗体包含单克隆抗体、多特异性抗体、人类抗体、人源化抗体、嵌合抗体、scFv、Fab片段、F(ab′)2片段、二硫化物连接的Fvs(sdFv)和抗-独特型(抗-Id)抗体或所述抗体的表位-结合片段等,但并不限定于此。
所述重链恒定区可以选自γ、μ、α、δ或ε中的任一种同种型。例如、恒定区是IgG1、IgG2、IgG3或IgG4。轻链恒定区可以是κ或λ型。
所述单克隆抗体是指实质上从同质性抗体群获得的抗体,即,除了可能以微量存在的可能自然发生的突变之外,占据群的各个抗体是相同的抗体。单克隆抗体具有高度特异性,因此对抗单个抗原位点来诱导。通常,与包含针对不同的决定簇(表位)的不同的抗体的通常的(多克隆)抗体相比,每个单克隆抗体针对抗原上的单个决定簇。
“表位(epitope)”是指抗体可以特异性结合的蛋白质决定簇(determinant)。表位通常由具有化学活性的表面分子群构成,例如由氨基酸或糖侧链构成,一般不仅具有特定的三维结构特征,而且具有特定的电荷特性。立体表位和非立体表位的区别在于,在变性溶剂的存在下,对前者的结合消失,但对后者的结合不消失。
本发明的抗体或其抗原结合片段例如可以与存在于FGFR3的细胞外区域的作为3个免疫域的选自D1、D2和D3中的任一种结合,例如,可以与D1、D2或D3结构域结合。根据情况,本发明的抗体或其抗原结合片段与所述SEQ ID NO.183的FGFR3中的结构域1(SEQ IDNO.184)特异性结合,不与FGF配体进行结合竞争。
所述“人源化”形式的非人(实例:小鼠)抗体是含有源自非人免疫球蛋白的最小序列的嵌合抗体。大部分的情况下,人源化抗体是将来自受体的高变区的残基代替为来自具有期望的特异性、亲和性和能力的非人种(供体抗体)的高变区的残基的人免疫球蛋白,例如,所述非人种为小鼠、大鼠、兔或非人灵长类。
所述“人类抗体”是源自人免疫球蛋白的分子,其表示包含互补决定区、结构区的构成抗体的整个氨基酸序由人的免疫球蛋白构成。
一部分重链和/或轻链与源自特别的物种或属于特别的抗体种类或亚类的抗体中的相应序列相同或同源,另一方面,其余链不仅包含与源自另一物种或属于另一抗体种类或亚类的抗体中的相应序列相同或同源的“嵌合”抗体(免疫球蛋白),而且包含显示出期望的生物学活性的所述抗体的片段。
本发明中使用的抗体的“可变区”是指包含互补决定区(CDR;即,CDR1、CDR2和CDR3)和骨架区(FR)的氨基酸序列的抗体分子的轻链和重链部分。VH是指重链的可变域。VL是指轻链的可变域。
“互补决定区(complement determining region,CDR)”是指抗原结合所需的抗体可变域的氨基酸残基。各可变域通常具有被确认为CDR1、CDR2和CDR3的3个CDR区域。
与公知的抗-FGFR3抗体相比,本发明的抗-FGFR3抗体或其抗原结合片段被筛选为对FGFR3-TACC3过表达的癌细胞具有更优异的功效的抗体,例如,可以包含:
重链可变区,其包含SEQ ID NO.1的重链CDR1、SEQ ID NO.19的重链CDR2和SEQ IDNO.42的重链CDR3,轻链可变区,其包含SEQ ID NO.67的轻链CDR1、SEQ ID NO.89的轻链CDR2和SEQ ID NO.110的轻链CDR3;
重链可变区,其包含SEQ ID NO.2的重链CDR1、SEQ ID NO.20的重链CDR2和SEQ IDNO.43的重链CDR3,轻链可变区,其包含SEQ ID NO.68的轻链CDR1、SEQ ID NO.90的轻链CDR2和SEQ ID NO.111的轻链CDR3;
重链可变区,其包含SEQ ID NO.3的重链CDR1、SEQ ID NO.21的重链CDR2和SEQ IDNO.44的重链CDR3,轻链可变区,其包含SEQ ID NO.69的轻链CDR1、SEQ ID NO.91的轻链CDR2和SEQ ID NO.112的轻链CDR3;
重链可变区,其包含SEQ ID NO.4的重链CDR1、SEQ ID NO.22的重链CDR2和SEQ IDNO.45的重链CDR3,轻链可变区,其包含SEQ ID NO.70的轻链CDR1、SEQ ID NO.92的轻链CDR2和SEQ ID NO.113的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.46的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.114的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.186的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.114的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.187的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.114的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.188的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.114的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.189的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.114的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.190的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.114的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.191的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.114的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.192的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.114的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.193的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.114的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.194的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.114的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.195的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.114的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.196的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.114的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.197的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.114的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.198的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.114的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.46的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.199的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.46的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.200的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.46的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.201的轻链CDR3;
重链可变区,其包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.46的重链CDR3,轻链可变区,其包含SEQ ID NO.71的轻链CDR1、SEQ ID NO.93的轻链CDR2和SEQ ID NO.202的轻链CDR3;
重链可变区,其包含SEQ ID NO.4的重链CDR1、SEQ ID NO.24的重链CDR2和SEQ IDNO.47的重链CDR3,轻链可变区,其包含SEQ ID NO.72的轻链CDR1、SEQ ID NO.94的轻链CDR2和SEQ ID NO.115的轻链CDR3;
重链可变区,其包含SEQ ID NO.6的重链CDR1、SEQ ID NO.25的重链CDR2和SEQ IDNO.48的重链CDR3,轻链可变区,其包含SEQ ID NO.73的轻链CDR1、SEQ ID NO.95的轻链CDR2和SEQ ID NO.112的轻链CDR3;
重链可变区,其包含SEQ ID NO.7的重链CDR1、SEQ ID NO.26的重链CDR2和SEQ IDNO.49的重链CDR3,轻链可变区,其包含SEQ ID NO.74的轻链CDR1、SEQ ID NO.96的轻链CDR2和SEQ ID NO.116的轻链CDR3;
重链可变区,其包含SEQ ID NO.8的重链CDR1、SEQ ID NO.27的重链CDR2和SEQ IDNO.50的重链CDR3,轻链可变区,其包含SEQ ID NO.75的轻链CDR1、SEQ ID NO.97的轻链CDR2和SEQ ID NO.117的轻链CDR3;
重链可变区,其包含SEQ ID NO.9的重链CDR1、SEQ ID NO.28的重链CDR2和SEQ IDNO.51的重链CDR3,轻链可变区,其包含SEQ ID NO.76的轻链CDR1、SEQ ID NO.98的轻链CDR2和SEQ ID NO.118的轻链CDR3;
重链可变区,其包含SEQ ID NO.10的重链CDR1、SEQ ID NO.29的重链CDR2和SEQID NO.52的重链CDR3,轻链可变区,其包含SEQ ID NO.77的轻链CDR1、SEQ ID NO.97的轻链CDR2和SEQ ID NO.119的轻链CDR3;
重链可变区,其包含SEQ ID NO.11的重链CDR1、SEQ ID NO.30的重链CDR2和SEQID NO.53的重链CDR3,轻链可变区,其包含SEQ ID NO.78的轻链CDR1、SEQ ID NO.99的轻链CDR2和SEQ ID NO.120的轻链CDR3;
重链可变区,其包含SEQ ID NO.11的重链CDR1、SEQ ID NO.31的重链CDR2和SEQID NO.54的重链CDR3,轻链可变区,其包含SEQ ID NO.79的轻链CDR1、SEQ ID NO.100的轻链CDR2和SEQ ID NO.121的轻链CDR3;
重链可变区,其包含SEQ ID NO.12的重链CDR1、SEQ ID NO.32的重链CDR2和SEQID NO.55的重链CDR3,轻链可变区,其包含SEQ ID NO.80的轻链CDR1、SEQ ID NO.101的轻链CDR2和SEQ ID NO.122的轻链CDR3;
重链可变区,其包含SEQ ID NO.3的重链CDR1、SEQ ID NO.33的重链CDR2和SEQ IDNO.56的重链CDR3,轻链可变区,其包含SEQ ID NO.81的轻链CDR1、SEQ ID NO.102的轻链CDR2和SEQ ID NO.123的轻链CDR3;
重链可变区,其包含SEQ ID NO.13的重链CDR1、SEQ ID NO.34的重链CDR2和SEQID NO.57的重链CDR3,轻链可变区,其包含SEQ ID NO.82的轻链CDR1、SEQ ID NO.103的轻链CDR2和SEQ ID NO.124的轻链CDR3;
重链可变区,其包含SEQ ID NO.14的重链CDR1、SEQ ID NO.35的重链CDR2和SEQID NO.58的重链CDR3,轻链可变区,其包含SEQ ID NO.83的轻链CDR1、SEQ ID NO.104的轻链CDR2和SEQ ID NO.125的轻链CDR3;
重链可变区,其包含SEQ ID NO.1的重链CDR1、SEQ ID NO.36的重链CDR2和SEQ IDNO.59的重链CDR3,轻链可变区,其包含SEQ ID NO.84的轻链CDR1、SEQ ID NO.105的轻链CDR2和SEQ ID NO.126的轻链CDR3;
重链可变区,其包含SEQ ID NO.6的重链CDR1、SEQ ID NO.23的重链CDR2和SEQ IDNO.60的重链CDR3,轻链可变区,其包含SEQ ID NO.69的轻链CDR1、SEQ ID NO.91的轻链CDR2和SEQ ID NO.127的轻链CDR3;
重链可变区,其包含SEQ ID NO.15的重链CDR1、SEQ ID NO.37的重链CDR2和SEQID NO.61的重链CDR3,轻链可变区,其包含SEQ ID NO.85的轻链CDR1、SEQ ID NO.89的轻链CDR2和SEQ ID NO.128的轻链CDR3;
重链可变区,其包含SEQ ID NO.16的重链CDR1、SEQ ID NO.38的重链CDR2和SEQID NO.62的重链CDR3,轻链可变区,其包含SEQ ID NO.86的轻链CDR1、SEQ ID NO.106的轻链CDR2和SEQ ID NO.129的轻链CDR3;
重链可变区,其包含SEQ ID NO.17的重链CDR1、SEQ ID NO.39的重链CDR2和SEQID NO.63的重链CDR3,轻链可变区,其包含SEQ ID NO.87的轻链CDR1、SEQ ID NO.107的轻链CDR2和SEQ ID NO.130的轻链CDR3;
重链可变区,其包含SEQ ID NO.4的重链CDR1、SEQ ID NO.19的重链CDR2和SEQ IDNO.64的重链CDR3,轻链可变区,其包含SEQ ID NO.88的轻链CDR1、SEQ ID NO.108的轻链CDR2和SEQ ID NO.131的轻链CDR3;
重链可变区,其包含SEQ ID NO.18的重链CDR1,SEQ ID NO.40的重链CDR2和SEQID NO.65的重链CDR3,轻链可变区,其包含SEQ ID NO.85的轻链CDR1、SEQ ID NO.89的轻链CDR2和SEQ ID NO.128的轻链CDR3;或者
重链可变区,其包含SEQ ID NO.16的重链CDR1、SEQ ID NO.41的重链CDR2和SEQID NO.66的重链CDR3,轻链可变区,其包含SEQ ID NO.72的轻链CDR1、SEQ ID NO.109的轻链CDR2和SEQ ID NO.132的轻链CDR3。
“骨架区(FR)”是除了CDR残基之外的可变域残基。各可变域通常具有FR1、FR2、FR3和FR4的4个FR。
抗-FGFR3抗体的对FGFR3的结合亲和性在10-5M至10-12M范围内。例如,抗-FGFR3抗体的对FGFR3的结合亲和性为10-6M至10-12M、10-7M至10-12M、10-8M至10-12M、10-9M至10-12M、10-5M至10-11M、10-6M至10-11M、10-7M至10-11M、10-8M至10-11M、10-9M至10-11M、10-10M至10-11M、10-5M至10-10M、10-6M至10-10M、10-7M至10-10M、10-8M至10-10M、10-9M至10-10M、10-5M至10-9M、10-6M至10-9M、10-7M至10-9M、10-8M至10-9M、10-5M至10-8M、10-6M至10-8M、10-7M至10-8M、10-5M至10-7M、10-6M至10-7M或者10-5M至10-6M。
与所述FGFR3结合的抗体或其抗原结合片段可以包含重链可变区,所述重链可变区包含选自SEQ ID NO.133至SEQ ID NO.157、SEQ ID NO.203至SEQ ID NO.215中的一种以上的氨基酸序列。此外,与所述FGFR3结合的抗体或其抗原结合片段可以包含轻链可变区,所述轻链可变区包含选自SEQ ID NO.158至SEQ ID NO.182、SEQ ID NO.216至SEQ IDNO.219中的一种以上的氨基酸序列。
本发明的具体的实施方案中,可以包含:
SEQ ID NO.133的重链可变区和SEQ ID NO.158的轻链可变区;
SEQ ID NO.134的重链可变区和SEQ ID NO.159的轻链可变区;
SEQ ID NO.135的重链可变区和SEQ ID NO.160的轻链可变区;
SEQ ID NO.136的重链可变区和SEQ ID NO.161的轻链可变区;
SEQ ID NO.137的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.203的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.204的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.205的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.206的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.207的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.208的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.209的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.210的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.211的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.212的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.213的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.214的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.215的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.137的重链可变区和SEQ ID NO.216的轻链可变区;
SEQ ID NO.137的重链可变区和SEQ ID NO.217的轻链可变区;
SEQ ID NO.137的重链可变区和SEQ ID NO.218的轻链可变区;
SEQ ID NO.137的重链可变区和SEQ ID NO.219的轻链可变区;
SEQ ID NO.138的重链可变区和SEQ ID NO.163的轻链可变区;
SEQ ID NO.139的重链可变区和SEQ ID NO.164的轻链可变区;
SEQ ID NO.140的重链可变区和SEQ ID NO.165的轻链可变区;
SEQ ID NO.141的重链可变区和SEQ ID NO.166的轻链可变区;
SEQ ID NO.142的重链可变区和SEQ ID NO.167的轻链可变区;
SEQ ID NO.143的重链可变区和SEQ ID NO.168的轻链可变区;
SEQ ID NO.144的重链可变区和SEQ ID NO.169的轻链可变区;
SEQ ID NO.145的重链可变区和SEQ ID NO.170的轻链可变区;
SEQ ID NO.146的重链可变区和SEQ ID NO.171的轻链可变区;
SEQ ID NO.147的重链可变区和SEQ ID NO.172的轻链可变区;
SEQ ID NO.148的重链可变区和SEQ ID NO.173的轻链可变区;
SEQ ID NO.149的重链可变区和SEQ ID NO.174的轻链可变区;
SEQ ID NO.150的重链可变区和SEQ ID NO.175的轻链可变区;
SEQ ID NO.151的重链可变区和SEQ ID NO.176的轻链可变区;
SEQ ID NO.152的重链可变区和SEQ ID NO.177的轻链可变区;
SEQ ID NO.153的重链可变区和SEQ ID NO.178的轻链可变区;
SEQ ID NO.154的重链可变区和SEQ ID NO.179的轻链可变区;
SEQ ID NO.155的重链可变区和SEQ ID NO.180的轻链可变区;
SEQ ID NO.156的重链可变区和SEQ ID NO.181的轻链可变区;或者
SEQ ID NO.157的重链可变区和SEQ ID NO.182的轻链可变区。
scFv
scFv是由包含抗体的VH和VL结构域的单个多肽链组成的结构,其为抗体片段。scFv可以在VH结构域和VL结构域之间进一步包含多肽接头,使得可以形成期望的结构以抗原结合。
一个实施方案中,包含抗体的VH和VL结构域的单链Fv(scFv)中VH和VL结构域可以通过接头连接。包含选自SEQ ID NO.133至SEQ ID NO.157、SEQ ID NO.203至SEQ IDNO.215中的一种以上的氨基酸序列的重链可变区可以通过接头与包含选自SEQ ID NO.158至SEQ ID NO.182、SEQ ID NO.216至SEQ ID NO.219中的一种以上的氨基酸序列的轻链可变区连接。
本发明的具体的实施方案中,可以包含:
SEQ ID NO.133的重链可变区和SEQ ID NO.158的轻链可变区;
SEQ ID NO.134的重链可变区和SEQ ID NO.159的轻链可变区;
SEQ ID NO.135的重链可变区和SEQ ID NO.160的轻链可变区;
SEQ ID NO.136的重链可变区和SEQ ID NO.161的轻链可变区;
SEQ ID NO.137的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.203的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.204的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.205的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.206的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.207的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.208的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.209的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.210的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.211的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.212的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.213的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.214的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.215的重链可变区和SEQ ID NO.162的轻链可变区;
SEQ ID NO.137的重链可变区和SEQ ID NO.216的轻链可变区;
SEQ ID NO.137的重链可变区和SEQ ID NO.217的轻链可变区;
SEQ ID NO.137的重链可变区和SEQ ID NO.218的轻链可变区;
SEQ ID NO.137的重链可变区和SEQ ID NO.219的轻链可变区;
SEQ ID NO.138的重链可变区和SEQ ID NO.163的轻链可变区;
SEQ ID NO.139的重链可变区和SEQ ID NO.164的轻链可变区;
SEQ ID NO.140的重链可变区和SEQ ID NO.165的轻链可变区;
SEQ ID NO.141的重链可变区和SEQ ID NO.166的轻链可变区;
SEQ ID NO.142的重链可变区和SEQ ID NO.167的轻链可变区;
SEQ ID NO.143的重链可变区和SEQ ID NO.168的轻链可变区;
SEQ ID NO.144的重链可变区和SEQ ID NO.169的轻链可变区;
SEQ ID NO.145的重链可变区和SEQ ID NO.170的轻链可变区;
SEQ ID NO.146的重链可变区和SEQ ID NO.171的轻链可变区;
SEQ ID NO.147的重链可变区和SEQ ID NO.172的轻链可变区;
SEQ ID NO.148的重链可变区和SEQ ID NO.173的轻链可变区;
SEQ ID NO.149的重链可变区和SEQ ID NO.174的轻链可变区;
SEQ ID NO.150的重链可变区和SEQ ID NO.175的轻链可变区;
SEQ ID NO.151的重链可变区和SEQ ID NO.176的轻链可变区;
SEQ ID NO.152的重链可变区和SEQ ID NO.177的轻链可变区;
SEQ ID NO.153的重链可变区和SEQ ID NO.178的轻链可变区;
SEQ ID NO.154的重链可变区和SEQ ID NO.179的轻链可变区;
SEQ ID NO.155的重链可变区和SEQ ID NO.180的轻链可变区;
SEQ ID NO.156的重链可变区和SEQ ID NO.181的轻链可变区;或者
SEQ ID NO.157的重链可变区和SEQ ID NO.182的轻链可变区。
所述接头可以是肽接头,并且可以具有约10-25aa的长度。例如,可以包含诸如甘氨酸和/或丝氨酸的亲水性氨基酸,但并不限定于此。
具体地,所述接头例如可以包含(GS)n、(GGS)n、(GSGGS)n或(GnS)m(n、m分别为1至10),但所述接头例如可以为(GnS)m(n、m分别为1至10)。具体地,所述接头可以包含GGGGS,例如可以为重复三次SEQ ID NO.185的GGGGSGGGGSGGGGS。
“噬菌体展示”是在噬菌体,例如,在纤维状噬菌体颗粒的表面上将变异体多肽展示为作为外壳蛋白的至少一部分的融合蛋白的技术。噬菌体展示的有用性在于,通过针对随机化蛋白质变异体的大型文库,可以迅速且有效地分类以高亲和力与靶抗原结合的序列。在噬菌体上展示肽和蛋白质文库的技术已被用于筛选数百万计的多肽,以找出具有特异性结合特性的多肽。
噬菌体展示技术提供用于形成并筛选与特定配体(实例:抗原)结合的新型蛋白质的强大的工具。通过使用噬菌体展示技术,形成蛋白质变异体的大型文库,并且可以迅速分类以高亲和性与靶抗原结合的序列。将编码变异体多肽的核酸与编码病毒性外壳蛋白的核酸序列融合,例如,所述病毒性外壳蛋白为基因III蛋白质或基因VIII蛋白质。开发了将编码蛋白质或多肽的核酸序列与编码基因III蛋白质的一部分的核酸序列融合的单价噬菌体展示系统。在单价噬菌体展示系统中,基因融合物以低水平表达,并且野生型基因III蛋白质也被表达,从而保持颗粒感染性。
在抗体噬菌体展示文库的开发中,重要的是证明纤维状噬菌体表面上的肽的表达和大肠杆菌(E.coli)的周质中的功能性抗体片段的表达。通过多种方法制备抗体或抗原结合多肽的文库,例如,通过插入随机DNA序列来改变单个基因的方法或者克隆相关基因系的方法。以文库作为对象,可以对伴随期望的特征的抗体或抗原结合蛋白的表达进行筛选。
与用于制备具有期望的特征的抗体的通常的杂种瘤和重组方法相比,噬菌体展示技术具有几种优点。这种技术可以在不使用动物的情况下,在短时间内形成具有各种序列的大型抗体文库。杂种瘤的制备或人源化抗体的制备可能需要数个月的制备周期。此外,完全不需要免疫,因此噬菌体抗体文库还可以对毒性或抗原性低的抗原形成抗体。还可以使用噬菌体抗体文库,从而形成并确认新型治疗抗体。
可以使用从使用噬菌体展示文库而免疫的、非免疫的人、生殖细胞系序列或未致敏的B细胞Ig库(repertory)形成人类抗体的技术。可以使用各种淋巴组织制备未致敏的或非免疫抗原结合文库。
可以从噬菌体展示文库确认并分离高亲和性抗体的技术对于治疗用新型抗体分离很重要。从文库分离高亲和性抗体的技术可能取决于文库的大小、细菌细胞中的生产效率和文库的多样性。由于抗体或抗原结合蛋白的错误折叠和终止密码子的存在引起的无效率的生产,文库的大小会减小。抗体或抗原结合结构域没有正确折叠时,细菌细胞中的表达可能会被抑制。使可变/恒定界面的表面或筛选的CDR残基中的残基交替突变,从而可以改善表达。骨架区的序列是在细菌细胞中形成抗体噬菌体文库时用于提供正确折叠的一个要素。
高亲和性抗体分离中重要的是形成抗体或抗原结合蛋白的多种文库。已发现CDR3区域经常参与抗原结合。重链上的CDR3区域在大小、序列和结构方面的立体形态方面非常多样,因此可以利用其来制备各种文库。
此外,可以通过使用在各位点的所有20个氨基酸,随机化可变重链和轻链的CDR区域,从而可以产生多样性。使用所有20个氨基酸时,形成高度多样化的变异体抗体序列,并且可以增加确认新型抗体的机会。
在可以特异性识别FGFR3的范围内,本发明的抗体或抗体片段不仅包含本说明书中记载的本发明的抗-FGFR3抗体的序列,还可以包含其生物学等效物。例如,为了进一步改善抗体的结合亲和力和/或其它生物学特性,可以进一步改变抗体的氨基酸序列。这种变形例如包括抗体的氨基酸序列残基的缺失、插入和/或取代。这种氨基酸变异是基于氨基酸侧链取代基的相对相似性,例如,疏水性、亲水性、电荷、大小等而形成。根据对氨基酸侧链取代基的大小、形态和种类的分析,可知精氨酸、赖氨酸和组氨酸均是带正电荷的残基;丙氨酸、甘氨酸和丝氨酸具有相似的尺寸;苯基丙氨酸、色氨基酸和酪氨酸具有相似的形态。因此,基于上述考虑,可以认为精氨酸、赖氨酸和组氨酸;丙氨酸、甘氨酸和丝氨酸;以及苯基丙氨酸、色氨基酸和酪氨酸是生物学上的功能等效物。
考虑到具有上述生物学等效活性的变异,本发明的抗体或编码该抗体的核酸分子解释为还包含与SEQ ID NO.中记载的序列显示出实质性的同一性(substantialidentity)的序列。上述实质性的同一性是指将上述本发明的序列和任意的其它序列排比为尽可能对应,并利用本领域中通常利用的算法分析经排比的序列时,显示出最小90%的同源性、最优选为最小95%的同源性、96%以上的同源性、97%以上的同源性、98%以上的同源性、99%以上的同源性的序列。用于序列比较的排比方法是本领域公知的。NCBI局部序列排比检索基本工具((Basic Local Alignment Search Tool,BLAST)可以从NBCI等访问,在网络上可以与诸如blastp、blasm、blastx、tblastn和tblastx的序列分析程序结合使用。BLAST可以从www.ncbi.nlm.nih.gov/BLAST/访问。利用该程序的序列同源性比较方法可以在www.ncbi.nlm.nih.gov/BLAST/blast_help.html中确认。
基于此,与说明书中记载并明示出的序列或整体相比,本发明的抗体或其抗原结合片段可以具有90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或其以上的同源性。这种同源性可以通过根据本领域中公知的方法的序列比较和/或排列来确定。例如,可以利用序列比较算法(即,BLAST或BLAST 2.0)、手动排列、目视检查确定本发明的核酸或蛋白质的百分比序列同源性。
本发明的另一个方面涉及一种编码所述抗体或其抗原结合片段的核酸。分离编码本发明的抗体或其抗原结合片段的核酸,从而可以以重组的方式生产抗体或其抗原结合片段。
“核酸”具有包含全部DNA(gDNA和cDNA)和RNA分子的含义,核酸中作为基本组成单位的核甘酸不仅包含天然的核甘酸,还包含糖或碱基部位被修饰的类似物(analogue)。编码本发明的重链和轻链可变区的核酸的序列可以被修饰。所述修饰包括核甘酸的添加、缺失或非保守性替换或保守性替换。
编码所述抗体的DNA可以通过使用通常的分子生物学方法而容易地分离或合成(例如,通过使用可以与抗体以及编码重链和轻链的DNA特异性结合的寡核苷酸探针),分离核酸,并将该核酸插入到可以复制的载体中以进一步克隆(DNA的扩增)或进一步表达。基于此,本发明的另一个方面涉及一种包含所述核酸的重组表达载体。
本说明书中使用的术语“载体”是用于在宿主细胞中表达目的基因的手段,其包含诸如质粒载体、粘粒载体、噬菌体载体、腺病毒载体、逆转录病毒载体、腺相关病毒载体的病毒载体等。作为载体的成分通常包含以下中的一种以上,但并不受限于此:信号序列、复制起点、一种以上的抗生素抗性标记基因、增强子元件、启动子、转录终止序列。如同启动子和转录终止序列等,编码抗体的核酸可操作地连接。
“可操作地连接”是指核酸表达调节序列(例如:一系列启动子、信号序列或转录调节因子结合位点)和其他核酸序列之间的功能性结合,由此所述调节序列可以调节所述另一核酸序列的转录和/或翻译。
将原核细胞作为宿主时,通常包含可以进行转录的强启动子(例如,tac启动子、lac启动子、lacUV5启动子、lpp启动子、pLλ启动子、pRλ启动子、rac5启动子、amp启动子、recA启动子、SP6启动子、trp启动子和T7启动子等)、用于启动翻译的核糖体结合位点和转录/翻译终止序列。此外,例如,将真核细胞作为宿主时,可以利用源自哺乳动物细胞的基因组的启动子(例如:金属硫蛋白启动子、β-肌动蛋白启动子、人血红蛋白启动子和人肌肉肌酸启动子)或源自哺乳动物病毒的启动子(例如:腺病毒晚期启动子、牛痘病毒7.5K启动子、SV40启动子、巨细胞病毒(CMV)启动子、HSV的tk启动子、小鼠乳腺肿瘤病毒(MMTV)启动子、HIV的LTR启动子、莫洛尼病毒的启动子、EB病毒(Epstein-Barr virus,EBV)的启动子和劳氏肉瘤病毒(RSV)的启动子),作为转录终止序列通常具有聚腺苷酸化序列。
根据情况,载体还可以与另一序列融合,以促进从载体表达的抗体的提纯。融合的序列例如有谷胱甘肽S-转移酶(法玛西亚(Pharmacia)公司,美国)、麦芽糖结合蛋白(NEB,美国)、FLAG(IBI,美国)和6x His(六聚组氨酸(hexahistidine);Quiagen,美国)等。
所述载体包含本领域通常利用的抗生素抗性基因作为选择标记,例如,有对氨苄西林、庆大霉素、羧苄西林、氯霉素、链霉素、卡那霉素、遗传霉素、新霉素和四环素的抗性基因。
本发明的另一个方面涉及一种由所述重组表达载体转染的宿主细胞。用于形成本发明的抗体而使用的宿主细胞可以是原核生物、酵母或高等真核生物细胞,并且不受限于此。
可以利用诸如大肠杆菌(Escherichia coli)、枯草芽孢杆菌(Bacillussubtilis)和苏云金杆菌(Bacillus thuringiensis)芽孢杆菌属菌株;链霉菌属(Streptomyces)、假单胞菌属(Pseudomonas)(例如、恶臭假单胞菌(Pseudomonasputida))、奇异变形杆菌(Proteus mirabilis)和葡萄球菌属(Staphylococcus)(例如,肉葡萄球菌(Staphylococcus carnosus))的原核宿主细胞。
但是,最关注动物细胞,并且有用的宿主细胞系的实例可以是COS-7、BHK、CHO、CHOK1、DXB-11、DG-44、CHO/-DHFR、CV1、COS-7、HEK293、BHK、TM4、VERO、HELA、MDCK、BRL 3A、W138、Hep G2、SK-Hep、MMT、TRI、MRC 5、FS4、3T3、RIN、A549、PC12、K562、PER.C6、SP2/0、NS-0、U20S或HT1080,但并不限定于此。
本发明的另一个方面涉及一种与FGFR3特异性结合的抗体或其抗原结合片段的制备方法,所述方法包括以下步骤:培养所述宿主细胞,从而形成抗体;以及分离所形成的抗体并进行提纯。
所述宿主细胞可以在各种培养基中培养。可以没有限制地使用市售用培养基作为培养基。还可以以适当的浓度包含本领域技术人员公知的其它所有必需补充物。为了表达,例如温度、pH等的培养条件已与筛选的宿主细胞一同使用,这对本领域技术人员而言是显而易见的。
所述抗体或其抗原结合片段的回收例如可以通过离心分离或超滤去除杂质,并将其产物通过利用例如亲和色谱等进行提纯。就附加的其它提纯技术而言,例如,可以使用阴离子或阳离子交换色谱、疏水作用色谱、羟磷灰石色谱等。
双特异性抗体或多特异性抗体
本发明的另一个方面涉及一种包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体。
双特异性抗体是指对一种以上的靶标具有结合能力或拮抗能力的抗体,并且是指对两种彼此不同的靶标具有结合能力或拮抗能力的抗体结合的形态或对一种靶标具有结合能力的抗体和对另一靶标具有拮抗能力的物质结合的抗体。
多特异性抗体是指对至少3种以上的不同的抗原具有结合特异性的抗体。多特异性(multi-specific)抗体可以包含三特异性(Tri-specific)以上的抗体,例如,三特异性抗体、四特异性(Tetra-specific)抗体或靶向四种以上的靶标的抗体。
属于双特异性抗体或多特异性抗体的抗体可以分为基于scFv的抗体、基于Fab的抗体和基于IgG的抗体等。双特异性抗体或多特异性抗体的情况下,可以同时抑制或放大两种以上的信号,因此可以比抑制/放大一种信号的情况更有效,与用各个信号抑制剂处理各个信号的情况相比,可以低剂量给药,并且可以抑制/放大相同的时间和空间下的两种以上的信号。
双特异性抗体或多特异性抗体的制备方法是众所周知的。在传统上,双特异性抗体的重组生产基于两种以上的重链在具有不同的特异性的条件下共表达为两种以上的免疫球蛋白重链/轻链对。
基于scFv的双特异性抗体或多特异性抗体的情况下,可以通过将不同的scFv的VL和VH分别相互组合,以异质二聚体(heterodimeric)的形态制备杂合scFv,从而制备双特异抗体(diabody),可以将不同的scFv相互连接制备串联(tendem)scFv,可以在各个scFv的末端表达Fab的CH1和CL制备异质二聚体的微型抗体(miniantibody),可以通过取代作为Fc的同源二聚体(homodimeric)结构域的CH3结构域的部分氨基酸,从而改变为“knob intohole”形态的异质二聚体的结构,并在不同的各个scFv末端表达这些改变的CH3结构域,制备异质二聚体scFv形态的微抗体(minibody)。
基于Fab的双特异性抗体或多特异性抗体的情况下,可以利用二硫键或介质相互组合对特定抗原的单个Fab′制备为异质二聚体Fab形态,并且可以通过在特定Fab的重链或轻链的末端表达对不同的抗原的scFv,从而使抗原结合价(valency)为2个,或者可以在Fab和scFv之间提供铰链区(hinge region),从而制备为具有4个抗原结合价的同源二聚体形态。此外,通过可以在Fab的轻链末端和重链末端融合对不同的抗原的scFv,获得对抗原的结合价为3个的双靶双抗体(bibody),可以通过在Fab的轻链末端和重链末端分别融合不同的scFv,获得具有对抗原的结合价为3个的三靶双抗体,并且可以通过将3个不同的Fab化学接合来获得。
基于IgG的双特异性抗体或多特异性抗体的情况下,已知以下方法:由TrionPharma公司再杂交小鼠和大鼠杂种瘤,制备杂交的杂交瘤,别名quadromas,从而生产双特异性抗体。此外,可以通过共享轻链部分的同时,对不同的重链改变Fc的CH3同源二聚体结构域的部分氨基酸而制备为异质二聚体的形态,以所谓的‘Holes and Knob’形态制备双特异性抗体。除了异质二聚体形态的双特异性抗体之外,可以将不同的两种scFv分别融合并表达在恒定(constant)域来代替IgG的轻链和重链的可变域,制备为同源二聚体形态的(scFv)4-IgG。此外,据报道,英克隆(ImClone)公司基于作为对人VEGFR-2的嵌合单克隆抗体的IMC-1C11,在该抗体的轻链氨基末端仅融合对小鼠血小板衍生长因子受体-α(Platelet-derived Growth Factor Receptor-α)的单个可变域(single variabledomain),从而制备双特异性抗体。此外,可以通过利用蛋白激酶A(protein kinase A,PKA)R亚基的二聚和对接域(dimerization and docking domain,DDD)和PKA的锚定域(anchoring domain)的所谓的‘对接和锁定(dock and lock,DNL)’方法,制备为对CD20具有多个抗原结合价的抗体。
已开发了各种重组抗体格式,例如,已开发了2价以上、3价以上或4价以上的双特异性抗体或多特异性抗体。例如,还包含国际专利申请公开第WO2001/077342号、第WO2009/080251号、第WO2009/080252号、第WO2009/080253号、第WO2009/080254号、第WO2010/112193号、第WO2010/115589号、第WO2010/136172号、第WO2010/145792号、第WO2010/145793号和第WO2011/117330号中记载的2价以上、3价以上或4价以上的抗体。2价以上、3价以上或4价以上的抗体分别表示在抗体分子中存在2个以上的结合域、3个以上的结合域或4个以上的结合域。
在具体的实施方案中,本发明的双特异性抗体或多特异性抗体可以具体地以IgG完整的抗体或其片段形式包含所述抗-FGFR3抗体或抗原结合片段,例如,可以以单链Fv、VH结构域和/或VL结构域、Fab或(Fab)2的形式包含。
此外,就靶向所述FGFR3的抗体和与其他靶标结合的抗体而言,例如,包含靶向选自PD-1、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、TIGIT、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、运铁蛋白受体(Transferrin receptor)、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1、MARCO中的一种以上的抗体,具体为IgG完整的抗体或其片段形式,例如,单链Fv、Vn结构域和/或VL结构域、Fab或(Fab)2的形式。
通过本发明的双特异性抗体或多特异性抗体,除FGFR3之外,可以确保由其他靶向诱导或介导的附加的结合特异性。
例如,本发明的双特异性抗体可以同时靶向FGFR3和选自PD-1、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、TIGIT、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、运铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1、MARCO中的一种以上。
例如,本发明的多特异性抗体可以同时靶向FGFR3和选自PD-1、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、TIGIT、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、运铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1、MARCO中的两种以上。
免疫细胞接合双特异性抗体或多特异性抗体
本发明的另一个方面涉及一种免疫细胞接合双特异性抗体或多特异性抗体,其包含抗体的scFv和由第二结合域组成的scFv,所述第二结合域包含一个以上的与免疫细胞活化抗原结合的抗体的scFv。
通过所述免疫细胞接合双特异性抗体或多特异性抗体,暂时诱导细胞毒性T细胞和癌症靶细胞之间的溶细胞的突触,从而释放毒性物质。
一个实施方案中,所述免疫细胞可以是选自T细胞、NK细胞、细胞因子诱导的杀伤细胞(Cytokine Induced Killer cell,CIK)、活化的细胞毒性T淋巴细胞(Cytotoxic TLymphocyte,CTL)、巨噬细胞、肿瘤浸润T细胞(肿瘤浸润淋巴细胞(Tumor-InfiltratingLymphocytes),TIL)、树突状细胞中的一种以上。
一个实施方案中,所述免疫细胞活化抗原例如可以选自以下抗原,并且与该抗原结合的抗体可以起到免疫细胞接合作用:
T细胞活化抗原为CD3、TCRα、TCRβ、TCRγ、TCRξ、ICOS、CD28、CD27、HVEM、LIGHT、CD40、4-1BB、OX40、DR3、GITR、CD30、TIM1、SLAM、CD2或CD226;
NK细胞活化抗原为NKp30、NKp40、NKp44、NKp46、NKG2D、DNAM1、DAP10、CD16(例如(e.g.),CD16a、CD16b)、CRTAM、CD27、PSGL1、CD96、CD100(SEMA4D)、NKp80、CD244(SLAMF4或2B4)、SLAMF6、SLAMF7、KIR2DS2、KIR2DS4、KIR3DS1、KIR2DS3、KIR2DS5、KIR2DS1、CD94、NKG2C、NKG2E或CD160;
B细胞活化抗原为OX40、CD40或CD70;
巨噬细胞活化抗原为CD2激动剂、CD40、CD70、toll样受体(Toll-like Receptor,TCR)激动剂、CD47、STING或OX40L;或者
树突状细胞活化抗原为CD2激动剂、OX40、OX40L、41BB激动剂、TCR激动剂、CD47激动剂或STING激动剂。
免疫细胞接合器(immune cell engager)具体记载于美国专利申请公开第2017/0368169号中,可以作为参考导入本发明中。
具体地,所述免疫细胞接合双特异性抗体或多特异性抗体包含串联scFv,并且可以与以下抗原和癌细胞上的表面抗原结合。所述癌细胞上的表面抗原是本发明的抗体靶向的FGFR3:
CD3、TCRα、TCRβ、TCRγ、TCRξ、ICOS、CD28、CD27、HVEM、LIGHT、CD40、4-1BB、OX40、DR3、GITR、CD30、TIM1、SLAM、CD2或CD226;
NKp30、NKp40、NKp44、NKp46、NKG2D、DNAM1、DAP10、CD16(例如,CD16a、CD16b)、CRTAM、CD27、PSGL1、CD96、CD100(SEMA4D)、NKp80、CD244(SLAMF4或2B4)、SLAMF6、SLAMF7、KIR2DS2、KIR2DS4、KIR3DS1、KIR2DS3、KIR2DS5、KIR2DS1、CD94、NKG2C、NKG2E或CD160;
OX40、CD40或CD70;
CD2激动剂、CD40、CD70、TCR(Toll-likeReceptor)激动剂、CD47、STING或OX40L;或者
CD2激动剂、OX40、OX40L、41BB激动剂、TCR激动剂、CD47激动剂或STING激动剂。
所述免疫细胞接合双特异性抗体或多特异性抗体可以包含例如VL(FGFR3)-VH(FGFR3)-VH(CD3或CD16A)-VL(CD3或CD16A)、VH(FGFR3)-VL(FGFR3)-VH(CD3或CD16A)-VL(CD3或CD16A)、VH(CD3或CD16A)-VL(CD3或CD16A)-VH(FGFR3)-VL(FGFR3)或VH(CD3或CD16A)-VL(CD3或CD16A)-VL(FGFR3)-VH(FGFR3)形态的结构。
所述scFv例如包含重链可变区和轻链可变区,所述重链可变区包含选自SEQ IDNO.133至SEQ ID NO.157、SEQ ID NO.203至SEQ ID NO.215中的一种以上的氨基酸序列,所述轻链可变区包含选自SEQ ID NO.158至SEQ ID NO.182、SEQ ID NO.216至SEQ ID NO.219中的一种以上的氨基酸序列,并且所述重链可变区和轻链可变区可以由接头连接。
所述接头可以是肽接头,并且可以具有约10-25aa的长度。例如,可以包含诸如甘氨酸和/或丝氨酸的亲水性氨基酸。
所述接头例如可以包含(GS)n、(GGS)n、(GSGGS)n或(GnS)m(n、m分别为1至10),但所述接头例如可以为(GnS)m(n、m分别为1至10)。具体地,所述接头可以包含GGGGS,例如可以为重复三次SEQ ID NO.185的GGGGSGGGGSGGGGS。
作为所述免疫细胞接合双特异性抗体或多特异性抗体的例示,包含与CD3和CD19结合的博纳吐单抗(blinatumomab)(安进(Amgen));与CD3和EpCAM结合的索利托单抗(solitomab)(安进);与CD3和CEA结合的MEDI 565(MedImmune,安进);以及与CD3和PSMA结合的BAY2010112(拜耳(Bayer),安进)。示例性的DART包含与CD3和CD123结合的MGD006(Macrogenics);以及与CD3和gpA33结合的MGD007(Macrogenics)。示例性的TandAbs可以包含与CD3和CD19结合的AFM11(Affimed Therapeutics);以及与CD30和CD16A结合的AFM13(Affimed Therapeutics)。
抗体-药物偶联物(ADC)
本发明的另一个方面涉及一种所述抗体或其抗原结合片段与药物结合的抗体-药物偶联物(ADC)。
在将抗癌药物递送至靶向癌细胞之前,抗体-药物偶联物的抗癌药物应稳定地结合在抗体。递送到靶标的药物应从抗体游离,从而诱导靶细胞的死亡。为此,药物应稳定地与抗体结合的同时,从靶细胞游离时应具有可以诱导靶细胞的死亡的充分的细胞毒性。
一个实施方案中,所述抗体可以通过接头与药物结合。所述接头是连接抗-FGFR3抗体和药物之间的部位,应具有在细胞内的条件下可切断的形态,即,可以在细胞内环境中使从抗体中释放药物,并且反映抗体的长半衰期而抗体在全身循环中稳定,并且接头和药物的结合应不影响抗体的稳定性和药代动力学。
所述接头例如可以包含可切割接头或不可切割接头。可切割接头的情况下,如同肽接头,可以被细胞内肽酶或蛋白酶切断,例如,可以被溶酶体或内体蛋白酶切断,不可切割接头的情况下,例如,硫醚接头是抗体通过细胞内水解而非选择性地降解后可以释放药物。
一个实施方案中,所述可切割接头可以包含肽接头。所述肽接头具有至少2个以上的氨基酸长度。例如,可以包含Val-Cit、Val-Ala或Val-Cit的二肽或者Phe-Leu或Gly-Phe-Leu-Gly。接头的例示具体记载于国际专利申请公开第WO2004/010957号中,并且可以作为参考导入本发明中。
所述抗体-药物偶联物在靶向癌细胞的抗原结合ADC的抗体区域而形成ADC-抗原复合物后通过内体-溶酶体途径内吞到癌细胞内部。在这种情况下,细胞毒性药物的细胞内释放是根据受内体/溶酶体的内部环境被调节。
一个实施方案中,所述可切割接头为pH敏感性,可以在特定pH值下对水解敏感。通常,pH敏感性接头表示可以在酸性条件下被水解。例如,可以为在溶酶体中水解的酸不稳定接头(acid-labile linker),例如可以为腙、缩氨脲、氨硫脲、顺式-乌头酰胺(cis-aconitic amide)、原酸酯、乙缩醛、缩酮等。
另一个实施方案中,所述接头可以在还原条件下被切断,例如二硫化物接头可以属于此。可以通过使用N-琥珀酰亚胺-S-乙酰硫代乙酸酯(N-succinimidyl-S-acetylthioacetate,SATA)、N-琥珀酰亚胺-3-(2-吡啶基二硫代)丙酸酯(N-succinimidyl-3-(2-pyridyldithio)propionate,SPDP)、N-琥珀酰亚胺-3-(2-吡啶基二硫代)丁酸酯(N-succinimidyl-3-(2-pyridyldithio)butyrate,SPDB)和N-琥珀酰亚胺-氧羰基-α-甲基-α-(2-吡啶基-二硫基)甲苯(N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio)toluene,SMPT)形成各种二硫键。这种二硫化物接头可以通过细胞内谷胱甘肽的硫醇和二硫化物交换而降解。
所述药物和/或药物-接头可以通过抗体的赖氨酸随机接合,或者可以通过还原二硫键链时暴露的半胱氨酸接合。根据情况,可以通过基因工程制备的标记接合,例如,可以通过肽或蛋白质中存在的半胱氨酸来结合接头-药物。所述通过基因工程制备的标记,例如,肽或蛋白质可以包含例如可以通过类异戊二烯转移酶识别的氨基酸基序。所述肽或蛋白质在肽或蛋白质的羧基末端具有缺失(deletion),或者在肽或蛋白质的羧基(C)末端具有通过间隔区单元的共价键的添加。
所述肽或蛋白质可以与氨基酸基序直接共价结合或者与间隔区单元共价结合而与氨基酸基序连接。所述氨基酸间隔区单元由1-20个氨基酸组成,其中,优选为甘氨酸(Glycine)单元。
所述类异戊二烯转移酶例如可以为法呢基蛋白转移酶(farnesyl proteintransferase,FTase)或香叶烯基转移酶(geranylgeranyl transferase,GGTase),FTase和GGTaseI可以识别CAAX基序,GGTase II可以识别XXCC、XCXC或CXX基序(其中,C为半胱氨酸,A为脂肪族氨基酸,X为决定类异戊二烯转移酶的底物特异性的氨基酸)。
另一个实施方案中,所述接头可以包含β-葡糖苷酸(beta-glucuronide)接头,所述β-葡糖苷酸接头大多存在于溶酶体中,或者被几种肿瘤细胞中过表达的β-葡萄糖醛酸酶(β-glucuronidase)识别而水解。与肽接头不同,由于具有高亲水性(hydrophilicity),因此具有与高疏水性的药物结合时可以增加抗体-药物复合物的溶解度的优点。
对此,可以使用国际专利申请公开第WO2015/182984号中公开的β-葡糖苷酸接头,例如,包含自我牺牲型基团(self-immolative group)的β-葡糖苷酸接头,并且可以作为参考导入上述文件。
根据情况,所述接头例如可以是非可切割接头,在细胞内仅通过抗体水解步骤释放药物,例如,生产氨基酸-接头-药物复合物。这种类型的接头可以是硫醚基或马来酰亚胺己酰基(maleimidocaproyl),并且可以保持血液内稳定性。
根据本发明的一个实施方案,可以通过还原抗体的二硫键链时暴露的半胱氨酸,接头-药物随机结合或者导入具有序列GGGGGGGCVIM的抗体末端结合肽,从而结合接头-药物。
所述药物(包含化学式(1)的D)可以以显示药理效应的制剂与抗体结合,具体可以为化学治疗剂、毒素、微RNA(miRNA)、小干扰核糖核酸(siRNA)、短发夹RNA(shRNA)或放射性同位素。所述化学治疗剂例如可以为细胞毒性制剂或免疫抑制剂。具体可以包含微管蛋白抑制剂、有丝分裂抑制剂、拓扑异构酶抑制剂或可以发挥DNA嵌入剂的功能的化学治疗剂。此外,可以包含用于治疗癌症、炎症或免疫疾病的药物。例如,可以包含免疫调节化合物、抗癌剂、抗病毒剂、抗菌剂、抗真菌剂、驱虫剂或它们的组合。
所述抗癌剂例如可以是选自美登素类化合物、澳瑞他汀(包含MMAE、MMAF)、氨喋呤、放线菌素、博来霉素、他利霉素、喜树碱、N8-乙酰基亚精胺、1-(2氯乙基)-1,2-二甲基磺酰肼、埃斯波霉素、依托泊苷、6-巯嘌呤、尾海兔素、单端孢霉烯、卡奇霉素、泰素(taxol)、紫杉烷、紫杉醇(paclitaxel)、多烯紫杉醇(docetaxel)、甲氨蝶呤、长春新碱、长春花碱、阿霉素、美法仑、丝裂霉素A、丝裂霉素C、苯丁酸氮芥、倍癌霉素、L-天门冬酰胺酶(L-asparaginase)、巯嘌呤(mercaptopurine)、硫鸟嘌呤(thioguanine)、羟基脲(hydroxyurea)、阿糖胞苷(cytarabine)、环磷酰胺(cyclophosphamide)、异环磷酰胺(ifosfamide)、亚硝基脲(nitrosourea)、顺铂(cisplatin)、卡铂(carboplatin)、丝裂霉素(mitomycin)、达卡巴嗪(dacarbazine)、甲基苄肼(procarbazine)、托泊替康(topotecan)、氮芥(nitrogen mustard)、环磷酰胺(cytoxan)、依托泊苷(etoposide)、5-氟尿嘧啶(5-fluorouracil)、双氯乙基亚硝基脲(bischloroethylnitrosourea,CNU)、伊立替康(irinotecan)、喜树碱(camptothecin)、博来霉素(bleomycin)、伊达比星(idarubicin)、道诺霉素(daunorubicin)、更生霉素(dactinomycin)、普卡霉素(plicamycin)、米托蒽醌(mitoxantrone)、天门冬酰胺酶(asparaginase)、长春瑞滨(vinorelbine)、苯丁酸氮芥(chlorambucil)、美法仑(melphalan)、卡莫司汀(carmustine)、洛莫司汀(lomustine)、白消安(busuLfan)、曲奥舒凡(treosulfan)、氮烯咪胺(decarbazine)、依托泊苷(etoposide)、替尼泊苷(teniposide)、托泊替康(topotecan)、9-氨基喜树碱(9-aminocamptothecin)、克立那托(crisnatol)、丝裂霉素C(mitomycin C)、三甲曲沙(trimetrexate)、霉酚酸(mycophenolic acid)、噻唑呋啉(tiazofurin)、利巴韦林(ribavirin)、5-乙炔基-1-β-D-呋喃核糖基咪唑-4-羧酰胺(5-ethynyl-1-beta-Dribofuranosylimidazole-4-carboxamide,EICAR)、硫酸羟脲(hydroxyurea)、去铁胺(deferoxamine)、氟尿苷(floxuridine)、去氧氟尿苷(doxifluridine)、雷替曲塞(raltitrexed)、阿糖胞苷(cytarabine(ara C))、胞嘧啶阿拉伯糖苷(cytosinearabinoside)、氟达拉滨(fludarabine)、他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)、甲地孕酮(megestrol)、戈舍瑞林(goserelin)、醋酸亮丙瑞林(leuprolide acetate)、氟他胺(flutamide)、比卡鲁胺(bicalutamide)、EB1089、CB1093、KH1060、维替泊芬(verteporfin)、酞菁(phthalocyanine)、光敏剂Pe4(photosensitizer Pe4)、去甲氧基-竹红菌素A(demethoxy-hypocrellinA)、干扰素-α(Interferon-α)、干扰素-γ(Interferon-γ)、肿瘤坏死因子(tumor necrosis factor)、吉西他滨(Gemcitabine)、万珂(velcade)、瑞米德(revamid)、泰拉米德(thalamid)、洛伐他汀(lovastatin)、1-甲基-4-苯基吡啶鎓离子(1-methyl-4-phenylpyridiniumion)、星形孢菌素(staurosporine)、放线菌素D(actinomycin D)、更生霉素(dactinomycin)、博来霉素A2(bleomycin A2)、博来霉素B2(bleomycinB2)、培洛霉素(peplomycin)、表阿霉素(epirubicin)、吡柔比星(pirarubicin)、佐柔比星(zorubicin)、米托蒽醌(mitoxantrone)、维拉帕米(verapamil)以及毒胡萝卜素(thapsigargin)、核酸酶和源自细菌或动植物的毒素中的一种以上,但并不限定于此。
所述抗炎药可以包含通过与糖皮质激素受体结合来减轻炎症或肿胀的类固醇制剂、通过对应合成引起炎症的前列腺素的环氧化酶(COX)来缓解疼痛的非甾体抗炎药(NSAIDs)或改变炎症细胞的活化和转运的免疫特异性抗炎药(ImSAIDs)等,但并不限定于此。
作为所述免疫疾病治疗剂可以包含咪唑硫嘌呤、苯丁酸氮芥、环磷酰胺、环孢素、麦考酚酯、咪唑硫嘌呤(azathioprine)或甲氨蝶呤(methotrexate),但并不限定于此。
具体地,作为免疫抑制剂可以为作为钙调磷酸酶抑制剂的他克莫司(tacrolimus)、作为基因合成抑制剂的麦考酚酸酯(mycopheno late mofetil)或作为抗炎类固醇的泼尼松(predni sone)等,但并不限定于此。
根据情况,为了与接头和接头试剂上的亲电子基团形成共价键,所述药物可以包含可反应的选自胺、硫醇、羟基、酰肼、肟、肼、氨硫脲、肼羧酸酯和芳酰肼基中的一种以上的亲核基团。
本发明的具体的实施方案中通过MC-vc-PAB接头制备了将本发明的抗体或其抗原结合片段与药物连接的ADC,例如,与澳瑞他汀(MMAE)连接的ADC。确认了这种ADC显示出期望的细胞毒性。
嵌合抗原受体(CAR)
本发明的另一个方面涉及一种嵌合抗原受体,其特征在于,所述嵌合抗原受体(CAR)包含:包含抗原结合部位的细胞外结构域、跨膜结构域和细胞内信号传导结构域,所述细胞外结构域的抗原结合部位是所述抗体的scFv。
嵌合抗原受体(CAR)是被设计为可以对靶抗原和表达该抗原的细胞诱导免疫反应的合成结构。CAR包含细胞外结构域、跨膜结构域和细胞内信号传导结构域。可以将编码识别在癌细胞的表面特异性表达的癌细胞表面抗原的受体的基因导入免疫细胞中以使癌细胞死亡。通过包含与癌细胞中特异性表达的抗原结合的受体的免疫细胞,可以仅靶向癌细胞并引起免疫反应。所述CAR包含本发明的抗-FGFR3抗体的scFv作为细胞外结构域的抗原识别部位。
第一代CAR中包含:包含癌细胞中特异性表达的抗原识别部位的细胞外结构域、跨膜结构域和细胞内信号传导结构域,作为信号传导结构域仅利用CD3ζ,但对癌症的治疗效果甚微,并且存在持续时间短的问题。这种第一代CAR具体记载于美国授权专利第6319494号中,并且作为参考导入本发明中。
为了提高对免疫细胞的反应性,制备了结合共刺激结构域(CD28或CD137/4-1BB)和CD3ζ的第二代CAR,与第一代CAR相比,残留在体内的包含CAR的免疫细胞的数量显著增加。第二代CAR利用一种共刺激结构域,而第三代CAR中利用了两种以上的共刺激结构域。为了实现活体内包含CAR的免疫细胞的扩增和持续性,可以将共刺激结构域与4-1BB、CD28或OX40等结合。第二代CAR具体记载于美国授权专利第7741465号、第7446190号或第9212229号中,第三代CAR具体记载于美国授权专利第8822647号中,并且作为参考导入本发明中。
第四代CAR中包含编码诸如IL-12或IL-15的细胞因子的附加基因,使得细胞因子的基于CAR的免疫蛋白质可以进一步被表达,第五代CAR为了增强免疫细胞而进一步包含白介素受体链,例如,IL-2Rβ。第四代CAR具体记载于美国授权专利第10316102号中,第五代CAR具体记载于美国授权专利第10336810号中,并且作为参考导入本发明中。
一个实施方案中,所述细胞外结构域的抗原结合部位是抗体的scFv。包含抗体的VH和VL结构域的scFv中VH和VL结构域可以通过接头连接。重链可变区可以通过接头与轻链可变区连接,所述重链可变区包含选自SEQ ID NO.133至SEQ ID NO.157、SEQ ID NO.203至SEQ ID NO.215中的一种以上的氨基酸序列,所述轻链可变区包含选自SEQ ID NO.158至SEQ ID NO.182、SEQ ID NO.216至SEQ ID NO.219中的一种以上的氨基酸序列。
所述接头可以是肽接头,并且可以具有约10-25aa的长度。例如,可以包含诸如甘氨酸和/或丝氨酸的亲水性氨基酸。
所述接头例如可以包含(GS)n、(GGS)n、(GSGGS)n或(GnS)m(n、m分别为1至10),但所述接头例如可以为(GnS)m(n、m分别为1至10)。具体地,所述接头可以包含GGGGS,例如可以为重复三次SEQ ID NO.185的GGGGSGGGGSGGGGS。
所述跨膜结构域可以源自天然或合成供应源。供应源为天然的情况下,结构域可以源自任意的膜结合蛋白或跨膜蛋白。所述跨膜结构域可以包含T-细胞受体、CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154、ICOS的α、β或ζ链。合成所述跨膜结构域时可以包含诸如亮氨酸和缬氨酸的疏水性残基,或者可以在各末端包含包含苯基丙氨酸、色氨基酸和缬氨酸的肽。2-10个氨基酸长度的短的低聚核苷酸-或多肽接头可以在跨膜结构域和CAR的细胞质信号传导结构域之间形成结合。可以将甘氨酸-丝氨酸肽用作接头。
所述信号传导结构域可以诱导对CAR所在的免疫细胞的正常效应物功能的活化。例如,可以通过细胞因子的分泌来诱导细胞溶解活化或辅助活化。所述信号传导结构域转导效应物功能信号,因此可以包含充分的细胞内信号传导结构域的切段的片段。
作为所述信号传导结构域可以包含介入抗原受体后用于启动信号传导而协同作用的T细胞受体(TCR)和共同受体的细胞质。
并且已知通过单独TCR形成的信号不足以完全活化T细胞而需要共刺激信号。因此,通过TCR启动抗原依赖性初级活化的情况以及以抗原依赖性方式作用以提供次级或共刺激信号的情况可能会涉及T细胞活化。初级细胞质信号传导序列以刺激方式或以抑制方式调节TCR复合物的初级活化。以刺激方式作用的初级细胞质信号传导序列可以含有基于免疫受体的酪氨酸的活化基序或公知为ITAM的信号传导基序。含有初级细胞质信号传导序列的ITAM的实例可以包含TCRζ、FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD5、CD22、CD79a、CD79b和CD66d。
根据情况,CAR的细胞质结构域可以包含CD3ζ链部分和共刺激信号传导区域。共刺激信号传导区域是指包含共刺激分子的细胞内结构域的CAR的一个部分。例如,可以包含与CD27、CD28、4-1BB(CD137)、OX40、CD30、CD40、PD-1、ICOS、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3和CD83特异性结合的配体等。CAR的细胞质信号传导部分中的细胞质信号传导序列可以通过2-10个氨基酸连接,例如,通过包含甘氨酸-丝氨酸的肽接头连接。
本发明的另一个方面涉及一种导入所述嵌合抗原受体(CAR)的免疫细胞。
所述免疫细胞可以通过诱导免疫而引发期望的癌症治疗效果,例如,可以选自T细胞、NK细胞、细胞因子诱导的杀伤细胞(CIK)、活化的细胞毒性T淋巴细胞(CTL)、巨噬细胞、肿瘤浸润T细胞(肿瘤浸润淋巴细胞,TIL)、树突状细胞,但并不限定于此。
根据情况,可以进一步导入有嵌合抗原受体(CAR),所述嵌合抗原受体包含对于所述除抗-FGFR3抗体之外的抗体的scFv作为细胞外结构域的抗原结合部位。
所述除抗-FGFR3抗体之外的抗体可以为靶向例如选自PD-1、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、TIGIT、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、运铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1、MARCO中的一种以上的抗体或其抗原结合片段。
囊泡(vesicle)和外泌体
本发明的另一个方面涉及一种囊泡,其中,所述囊泡为抗体或其抗原结合片段表露在所述囊泡的外部或者存在于所述囊泡的内部。
所述囊泡是可以通过细胞膜将靶蛋白直接引入到细胞内的囊泡,并且包含细胞膜和本发明的抗体或其抗原结合片段。
本发明的囊泡可以是包含细胞膜和待递送的靶制剂的形态。这种囊泡的例示具体记载于美国专利公开第2018/0177725号中,并且可以作为参考导入本发明中。
所述囊泡例如可以具有40-500nm、具体为100-300nm、80-200nm或100nm的平均直径。所述囊泡例如可以为约100nm、200nm、300nm、400nm或500nm。
所述囊泡除了包含细胞膜和本发明的抗体或其抗原结合片段之外,可以不包含线粒体、溶酶体或高尔基体等其它细胞内小器官。
所述囊泡可以包含膜以分为内部和外部,并且所述抗体或其抗原结合片段可以存在于膜而向外部表露,或者向内部表露,或者从膜分离而存在于囊泡内部。
所述囊泡的膜可以根据所要应用的抗体或其抗原结合片段的靶标而不同,为了递送至与本发明的抗体或其抗原结合片段结合的FGFR3表达的癌细胞,例如,可以为癌细胞膜,但并不限定于此。
所述癌细胞例如可以包含诱发霍奇金淋巴瘤、非霍奇金淋巴瘤(例如,B细胞淋巴瘤、弥漫大B细胞淋巴瘤、滤泡型淋巴瘤、慢性淋巴细胞白血病、套细胞淋巴瘤、边区B细胞淋巴瘤、伯基特淋巴瘤、淋巴浆细胞淋巴瘤、毛细胞白血病)、急性髓性白血病、慢性髓性白血病、骨髓增生异常综合征、多发性骨髓瘤或急性淋巴细胞白血病的癌细胞。
此外,可以包含诱发实体肿瘤的癌细胞,例如诱发卵巢癌、直肠癌、胃癌、睾丸癌、肛门周围癌、子宫癌、结肠癌、直肠癌、肾细胞癌、肝癌、非小细胞肺癌、小肠癌、食道癌、黑素瘤、卡波西肉瘤、内分泌系统癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内恶性黑素瘤、子宫癌、脑干胶质瘤、垂体腺癌、表皮样癌、宫颈鳞状细胞癌、输卵管癌、子宫内膜癌、阴道癌、软组织肉瘤、尿道癌、外阴癌、阴茎癌、膀胱癌、肾癌或输尿管癌、肾盂癌、脊髓肿瘤、中枢神经系统(CNS)的新生物、原发性CNS淋巴瘤、肿瘤血管新生以及所述癌症的转移病变癌细胞。
进一步地,例如,可以包含诱发胶质母细胞瘤、肺癌、膀胱癌、口腔癌、头颈部鳞状细胞癌、胆囊癌或宫颈癌的癌细胞。
所述囊泡例如可以为外泌体。所述外泌体是指用于细胞间信号传导而具有蛋白质、DNA、RNA等并向细胞外分泌的大小为50-200nm的膜结构的小囊泡。
外泌体中包含有细胞内的各种蛋白质、DNA、RNA等。包含在这种外泌体中并向细胞外分泌的物质通过与细胞膜的融合(fusion)或内吞作用(endocytosis)再次引入到其他细胞内,从而还起到细胞间的通讯者的作用。此外,可以分析包含在这种外泌体中并向细胞外分泌的物质来用于特定疾病的诊断。
根据本发明,所述抗体或其抗原结合片段向外泌体外部表露或存在于其内部。所述外泌体具有膜结构,可以分为内部和外部,并且所述抗体或其抗原结合片段存在于外泌体膜,因此可以向外部表露或者向内部表露或者从膜分离并存在于外泌体内部。
所述外泌体可以为在源自具有各种靶向特性的免疫细胞/干细胞的人工外泌体上装载特定药物靶向并递送至人体内的所期望的病变组织,从而显著减少对其它组织产生的副作用,并且以少量的药物也可以极大化治疗功效的形态,例如,具体记载于国际公开专利第WO2011/002239号中,并且作为参考导入本发明中。
所述抗体或其抗原结合片段存在于外泌体膜并向外部表露或向内部表露时,可以将所述抗体或其抗原结合片段与外泌体特异性标记融合的形式进行表达,从而在外泌体内部捕获所述抗体或其抗原结合片段。所述外泌体膜与表达FGFR3的细胞的细胞膜融合时,所述抗体或其抗原结合片段可以递送至细胞。
可以在所述外泌体表面展示所述抗体或其抗原结合片段。例如,可以在外泌体表面表达前列腺素F2受体负调节剂(Prostaglandin F2 Receptor Negative Regulator,PTGFRN)蛋白,并在PTGFRN蛋白融合其他靶蛋白。这种外泌体具体记载于国际公开专利第WO2014/076137号、第WO2018/09119号等中,并且作为参考导入本发明中。
在内部包含所述抗体或其抗原结合片段的外泌体的情况下,可以通过使用光特异性结合蛋白,将所述抗体或其抗原结合片段与所述标记蛋白暂时结合来制备。在所述外泌体内部可以以不与膜结合的状态捕获靶蛋白。所述外泌体通过内化递送至细胞内时,外泌体被降解,从而所述抗体或其抗原结合片段可以递送至细胞。
使所述抗体或其抗原结合片段存在于内部的过程具体记载于国际公开专利第WO2016/178532号和第WO2018/062973号等中,并且作为参考导入本发明中。
例如,可以利用作为光特异性结合蛋白的CIBN和CRY2,具体地,可以将编码这些融合蛋白的基因导入外泌体生成细胞中,使所述CIBN以与作为所述标记蛋白的一种的CD9融合的形态表达并且使所述CRY2以与所述抗体或其抗原结合片段融合的形式表达。所述外泌体生成细胞中表达的CIBN-CD9融合蛋白由于CD9而包含在外泌体中,此时,向所述细胞照射蓝光LED灯时,所述外泌体生成细胞中表达的靶蛋白-CRY2融合蛋白的CRY2结构域结合在与CD9融合的CIBN结构域中,因此形成靶蛋白-CRY2-CIBN-CD9形式的可逆诱导的融合蛋白,并且由于CD9,如上所述的融合蛋白可以包含在外泌体内部。如此生产在内部包含靶蛋白的外泌体后,不再照射所述蓝光LED灯时,CIBN-CRY2结合被释放,从而靶蛋白可以以不与外泌体的细胞膜结合的状态包含在外泌体内部。
治疗用组合物
本发明的另一个方面涉及一种用于治疗癌症、炎症或免疫疾病的组合物,其包含:所述抗体或其抗原结合片段、包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体、包含所述抗体或其抗原结合片段的抗体-药物偶联物、包含所述抗体或其抗原结合片段的嵌合抗原受体或包含所述嵌合抗原受体的免疫细胞。
本发明例如可以为用于预防或治疗癌症的药物组合物,其包含:(a)本发明的对FGFR3的抗体或其抗原结合片段、包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体、包含所述抗体或其抗原结合片段的抗体-药物偶联物、包含所述抗体或其抗原结合片段的嵌合抗原受体或包含所述嵌合抗原受体的免疫细胞的药物有效量;以及(b)药学上可接受的载体。本发明还可以是癌症的预防或治疗方法,所述方法包括将本发明的对FGFR3的抗体或其抗原结合片段、包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体、包含所述抗体或其抗原结合片段的抗体-药物偶联物、包含所述抗体或其抗原结合片段的嵌合抗原受体或包含所述嵌合抗原受体的免疫细胞施用于癌症患者。
“预防”是指通过施用本发明的组合物来抑制癌症的生长或延迟进展的所有行为,“治疗”是指癌症发展的抑制、肿瘤的缓解或癌症的消除。
所述癌症例如包含霍奇金淋巴瘤、非霍奇金淋巴瘤(例如,B细胞淋巴瘤、弥漫大B细胞淋巴瘤、滤泡型淋巴瘤、慢性淋巴细胞白血病、套细胞淋巴瘤、边区B细胞淋巴瘤、伯基特淋巴瘤、淋巴浆细胞淋巴瘤、毛细胞白血病)、急性髓性白血病、慢性髓性白血病、骨髓增生异常综合征、多发性骨髓瘤或急性淋巴细胞白血病。
所述癌症例如包含卵巢癌、直肠癌、胃癌、睾丸癌、肛门周围癌、子宫癌、结肠癌、直肠癌、肾细胞癌、肝癌、非小细胞肺癌、小肠癌、食道癌、黑素瘤、卡波西肉瘤、内分泌系统癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内恶性黑素瘤、子宫癌、脑干胶质瘤、垂体腺癌、表皮样癌、宫颈鳞状细胞癌、输卵管癌、子宫内膜癌、阴道癌、软组织肉瘤、尿道癌、外阴癌、阴茎癌、膀胱癌、肾癌或输尿管癌、肾盂癌、脊髓肿瘤、中枢神经系统(CNS)的新生物、原发性CNS淋巴瘤、肿瘤血管新生、所述癌症的转移病变或所述癌症的组合。
所述癌症例如可以为胶质母细胞瘤、肺癌、膀胱癌、口腔癌、头颈部鳞状细胞癌、胆囊癌或宫颈癌。特别地,胶质母细胞瘤的情况下,所述抗体或其抗原结合片段需要通过血脑屏障(blood-brain barrier),所述血脑屏障是存在于脑和脊柱以及其周围循环系统之间的脑的毛细血管内皮细胞膜内通过紧密连接(junction)而形成的屏障。为了通过BBB,可以与转运体连接使用。为了通过BBB递送药物,例如有使用缓激肽或诸如高强度聚焦超声(High-intensity focused ultrasound,HIFU)的方法来破坏BBB的渗透压的方法。此外,可以包括诸如细胞中内在的葡萄糖和氨基酸转运体、胰岛素或转铁蛋白的受体介导的转胞吞作用的递送系统的使用或阻断糖蛋白的活性流出递送(外排转运体(effluxtransporter))的方法。
所述炎症例如可以为慢性阻塞性肺病、乳糜泄、结膜炎、耳炎、过敏性鼻炎、齿龈炎、口腔溃疡、支气管炎、胃食管反流病(GERD)、食道炎、胃炎、肠炎、消化性溃疡、炎症性肠病(IBD)、克罗恩病、肠易激综合症(IBS)、肠炎或过敏反应、尿道炎、膀胱炎、阴道炎、直肠肛门炎、嗜酸性粒细胞性胃肠炎或类风湿性关节炎,但并不限定于此。
所述免疫疾病例如可以为获得性免疫缺陷病、自身免疫性疾病、全身性红斑狼疮、硬皮症、干燥综合征、多发性肌炎和皮肌炎、类风湿性多肌痛、颞动脉炎、结节性多动脉炎或贝赫切特综合征等。
本发明的组合物中包含的药学上可接受的载体是制剂化时通常利用的载体,所述载体包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯树胶、磷酸钙、藻朊酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、水、糖浆、甲基纤维素、羟苯甲酸甲酯、羟苯丙酯、滑石、硬脂酸镁和矿物油等,但并不限定于此。本发明的组合物除了所述成分之外可以进一步包含润滑剂、润湿剂、甜味剂、调味剂、乳化剂、混悬剂、防腐剂等。
本发明的药物组合物可以口服或非口服给药,非口服给药的情况下,可以通过静脉注射、皮下注射、肌肉注射、腹腔注射、内皮给药、局部给药、鼻腔给药、肺部给药和直肠内给药等方式给药。
口服施用时,蛋白质或肽会被消化,因此口服用组合物应包覆活性药剂或者防止在胃中的降解的方式进行制剂化。此外,药物组合物可以通过任意的装置给药以使活性物质可以移动至靶细胞。
本发明的组合物的合适的剂量是根据诸如制剂化方法、施用方式、患者的年龄、体重、性别、病态、饮食、施用时间、施用途径、排泄速度和反应感应性的因素而不同,通常熟练的医生可以容易确定对所期望的治疗或预防有效的剂量并开处方。例如,本发明的药物组合物的一天的剂量为0.0001-100mg/kg。本说明书中术语“药物有效量”是指对预防或治疗癌症或自身免疫病所充分的量。
本发明的药物组合物可以根据本发明所属技术领域的技术人员容易实施的方法,利用药学上可接受的载体和/或赋形剂来进行制剂化,制备为单位剂量形式或者通过引入到多剂量容器中来制备。此时,剂型可以是油性或水性介质中的溶液、悬浮液或乳状液形式或者还可以为提取物、散剂、栓剂、粉剂、颗粒剂、片剂或胶囊剂形式,并且可以进一步包含分散剂或稳定剂。
联合治疗
本发明涉及一种包含免疫细胞和除抗-FGFR3抗体之外的药物的联合治疗用组成。
一个实施方案中,所述除抗-FGFR3抗体之外的药物可以包含化学治疗剂或除抗-FGFR3抗体之外的抗体。
所述药物可以为选自美登素类化合物、澳瑞他汀(包含MMAE、MMAF)、氨喋呤、放线菌素、博来霉素、他利霉素、喜树碱、N8-乙酰基亚精胺、1-(2氯乙基)-1,2-二甲基磺酰肼、埃斯波霉素、依托泊苷、6-巯嘌呤、尾海兔素、单端孢霉烯、卡奇霉素、泰素、紫杉烷、紫杉醇、多烯紫杉醇、甲氨蝶呤、长春新碱、长春花碱、阿霉素、美法仑、丝裂霉素A、丝裂霉素C、苯丁酸氮芥、倍癌霉素、L-天门冬酰胺酶、巯嘌呤、硫鸟嘌呤、羟基脲、阿糖胞苷、环磷酰胺、异环磷酰胺、亚硝基脲、顺铂、卡铂、丝裂霉素、达卡巴嗪、甲基苄肼、托泊替康、氮芥、环磷酰胺、依托泊苷、5-氟尿嘧啶、双氯乙基亚硝基脲(CNU)、伊立替康、喜树碱、博来霉素、伊达比星、道诺霉素、更生霉素、普卡霉素、米托蒽醌、天门冬酰胺酶、长春瑞滨、苯丁酸氮芥、美法仑、卡莫司汀、洛莫司汀、白消安、曲奥舒凡、氮烯咪胺、依托泊苷、替尼泊苷、托泊替康、9-氨基喜树碱、克立那托、丝裂霉素C、三甲曲沙、霉酚酸、噻唑呋啉、利巴韦林、5-乙炔基-1-β-D-呋喃核糖基咪唑-4-羧酰胺(EICAR)、硫酸羟脲、去铁胺、氟尿苷、去氧氟尿苷、雷替曲塞、阿糖胞苷(ara C)、胞嘧啶阿拉伯糖苷、氟达拉滨、他莫昔芬、雷洛昔芬、甲地孕酮、戈舍瑞林、醋酸亮丙瑞林、氟他胺、比卡鲁胺、EB1089、CB1093、KH1060、维替泊芬、酞菁、光敏剂Pe4、去甲氧基-竹红菌素A、干扰素-α、干扰素-γ、肿瘤坏死因子、吉西他滨、万珂、瑞米德、泰拉米德、洛伐他汀、1-甲基-4-苯基吡啶鎓离子、星形孢菌素、放线菌素D、更生霉素、博来霉素A2、博来霉素B2、培洛霉素、表阿霉素、吡柔比星、佐柔比星、米托蒽醌、维拉帕米以及毒胡萝卜素、核酸酶和源自细菌或动植物的毒素中的一种以上。
一个实施方案中,所述除抗-FGFR3抗体之外的抗体例如可以为靶向选自PD-1、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、TIGIT、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、运铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1、MARCO中的一种以上的抗体或其抗原结合片段。
本发明涉及一种联合治疗用组合物,其包含抗体或其抗原结合片段,以及选自(i)免疫细胞;(ii)包含抗原受体(CAR)的免疫细胞,所述抗原受体包含对于除抗-FGFR3抗体之外的抗体的scFv作为细胞外结构域;以及(iii)免疫检查点抑制剂中的一种以上。
此外,本发明涉及一种联合治疗用组合物,其包含所述免疫细胞接合双特异性抗体或多特异性抗体,以及选自(i)免疫细胞;(ii)包含抗原受体(CAR)的免疫细胞,所述抗原受体包含对于除抗-FGFR3抗体之外的抗体的scFv片段作为细胞外结构域;以及(iii)免疫检查点抑制剂中的一种以上。
所述免疫细胞诱导免疫治疗,例如可以诱导免疫而诱发期望的癌症治疗效果,所述免疫细胞例如,可以选自T细胞、NK细胞、细胞因子诱导的杀伤细胞(CIK)、活化的细胞毒性T淋巴细胞(CTL)、巨噬细胞、肿瘤浸润T细胞(肿瘤浸润淋巴细胞,TIL)、树突状细胞,但并不限定于此。
所述除抗-FGFR3抗体之外的抗体是靶向除FGFR3之外的靶标的抗体,例如可以是与LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、TIGIT、CD134(0X40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、运铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1或MARCO结合的抗体或其抗原结合片段,但并不限定于此。
本发明涉及一种联合治疗用组合物,其包含抗体或其抗原结合片段,以及选自(i)免疫细胞;(ii)包含抗原受体(CAR)的免疫细胞,所述抗原受体包含对于除抗-FGFR3抗体之外的抗体的scFv作为细胞外结构域;以及(iii)免疫检查点抑制剂中的一种以上。
此外,本发明涉及一种联合治疗用组合物,其包含所述免疫细胞接合双特异性抗体或多特异性抗体,以及选自(i)免疫细胞;(ii)包含抗原受体(CAR)的免疫细胞,所述抗原受体包含对于除抗-FGFR3抗体之外的抗体的scFv片段作为细胞外结构域;和(iii)免疫检查点抑制剂中的一种以上。
所述免疫细胞诱导免疫治疗,例如可以诱导免疫而诱发期望的癌症治疗效果,所述免疫细胞例如,可以选自T细胞、NK细胞、细胞因子诱导的杀伤细胞(CIK)、活化的细胞毒性T淋巴细胞(CTL)、巨噬细胞,肿瘤浸润T细胞(肿瘤浸润淋巴细胞,TIL)、树突状细胞,但并不限定于此。
所述除抗-FGFR3抗体之外的抗体是靶向除FGFR3之外的靶标的抗体,例如可以为与LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、TIGIT、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、运铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1或MARCO结合的抗体或其抗原结合片段,但并不限定于此。
所述免疫检查点抑制剂是指在抗原递呈细胞(antigen presenting cell,APC)和免疫细胞(例如T细胞)相遇的位点,是指可以阻断T细胞抑制信号来诱导T细胞活化的制剂。所述免疫检查点抑制剂例如可以为靶向PD-1、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、CD258(LIGHT)、TIGIT、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200或CD200R的药物,但并不限定于此。
作为联合给药对象的第一成分和第二成分分别可以同时施用。此外,作为所述联合给药对象的第一成分和第二成分分别还可以以一定时间间隔单独施用。所述联合给药对象中可以在施用第一成分前或后,单独施用第二成分。
伴随诊断(Companion diagnostics,CDx)
伴随诊断是用于预测患者对特定药物治疗的反应性的分子诊断技术的一种,在药物的应用中,提出应用对象患者的筛选标准并考虑符合该标准的诊断、预后和预测生物标志物的特异性和敏感性,从而可以提出可以用合适的药物治疗患者的标准。
抗癌剂的情况下,对显示反应的患者非常有效,但显示反应的患者的比率低,因此筛选出显示效果的患者是非常重要的,可以通过伴随诊断筛选对抗癌剂显示反应的患者,并提升患者的治疗效率。
本发明的另一个方面涉及一种用于治疗癌症的组合物,其用于治疗确认为FGFR3和TACC3的融合基因扩增、融合基因存在变异、融合基因过表达或者融合基因一直在表达(组成性激活)的癌症,并且包含:所述抗体或其抗原结合片段、包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体、抗体-药物偶联物、嵌合抗原受体或包含所述嵌合抗原受体的免疫细胞。
本发明还涉及一种癌症治疗方法,其包括:在源自患者的样品中确认FGFR3和TACC3的融合基因扩增、融合基因存在变异、融合基因过表达或者融合基因一直在表达(组成性激活)的情况下,施用所述抗体或其抗原结合片段、包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体、抗体-药物偶联物、嵌合抗原受体或包含所述嵌合抗原受体的免疫细胞。
所述样品是指从患者的组织或体液获得的生物学对象。组织样品的供应源可以为:诸如源自冷冻的和/或保存的器官、组织样品、活组织检查或抽出物的固型组织;血液或任意的血液组成成分(例如,血清、血浆);骨髓或任意的骨髓组成成分;诸如尿液、脑脊液、全血、血浆和血清的体液。样品可以包含非细胞分离(例如,尿液、血浆、血清或其它非细胞体液)。样品可以包含体液,例如,血液(例如,全血)。具体地,所述样品可以为从患者获得的全血样品、全骨髓样品、全外周血样品或全肿瘤样品。所述“全”样品是指实际上没有从该样品去除或分离的成分(例如,细胞)的样品。所述样品,例如,血样可以在使用前被稀释(例如,通过生理相容性缓冲液或培养基)。另一个具体实施方案中,“全”样品,例如全组织样品或全肿瘤样品实质上保持源自起源组织的微环境,例如实质上可以保持肿瘤或免疫微环境的结构。具体地,样品,例如肿瘤样品可以被加工(例,研磨、切碎、混合、粉碎等)为更小的块,并且可以被稀释(例如,通过生理相容性缓冲液或培养基)。
所述基因的表达确认是确认该基因是否存在和表达程度的过程,可以通过聚合酶链反应(PCR)进行,根据情况可以使用逆转录聚合酶链式反应(RT-PCR)、竞争性逆转录聚合酶链式反应(Competitive RT-PCR)、实时逆转录聚合酶链式反应(Real-time RT-PCR)、RNA酶保护分析法(RNase protection assay,RPA)、RNA印迹法(Northern blotting)、DNA芯片来进行。
聚合酶链式反应(PCR)可以通过利用引物的基因扩增反应来进行。可以进行多重PCR、实时(real-time)PCR、差示聚合酶链反应(differential display PCR,DD-PCR)、cDNA末端快速扩增(rapid amplification of cDNA ends,RACE)、反向聚合酶链式反应(inverse polymerase chain reaction,IPCR)、小载体(vectorette)PCR和交错式热不对称PCR(thermal asymmetric interlaced PCR,TAIL-PCR)等进行。
还可以通过基因编码检测蛋白质是否表达。这是确认从所述基因表达的蛋白质是否存在和表达程度的过程。可以利用对所述蛋白质特异性结合的抗体、寡肽、配体、肽核酸(Peptide nucleic acid,PNA)或适体(aptamer)等确认蛋白质的量。
为此的分析方法可以包括利用蛋白免疫印迹、酶联免疫吸附测定(enzyme linkedimmunosorbent assay,ELISA)、放射免疫分析(Radioimmunoassay,RIA)、放射免疫扩散法(radioimmunodiffusion)、奥克特洛尼(Ouchterlony)免疫扩散法、火箭(rocket)免疫电泳、组织免疫染色、免疫沉淀分析法(Immunoprecipitation Assay)、补体结合分析法(Complement Fixation Assay)、流式细胞术(荧光激活细胞分选仪(FluorescenceActivated Cell Sorter,FACS))、蛋白质芯片(protein chip)的方法等。
实施例
以下,通过实施例对本发明进行更详细的说明。这些实施例仅用于例示本发明,并不解释为本发明的范围受限于这些实施例,这对于本领域技术人员而言是显而易见的。
实施例1:对FGFR3具有特异性的噬菌体抗体筛选,细胞淘选(噬菌体展示技术)
本研究组使用合成scFv噬菌体文库(synthetic scFv phage library){(1)Bai,Xuelian&Kim,Jihye&Kang,Seungmin&Kim,Wankyu&Shim,Hyunbo.(2015).A Novel HumanscFv Library with Non-Combinatorial Synthetic CDR Diversity.PloSone.10.e0141045.10.1371/journal.pone.0141045.,(2)Yang,Hye&Kang,Kyung&TCW,Julia&Shim,Hyunbo.(2009).Construction of a large synthetic human scFv librarywith six diversified CDRs and high functional diversity.Molecules andcells.27.225-35.10.1007/s10059-009-0028-9.},进行用于筛选具有细胞内化功能的抗体的细胞淘选(cell panning)方法。通过RPKM分析值和通过蛋白免疫印迹确认蛋白质表达的方法来验证FGFR3过表达细胞(682T)、FGFR3低表达细胞(626T),并选定相应细胞。用预先回收的噬菌体文库原液(phage library stock)处理FGFR3低表达细胞,在4度下反应1小时,然后通过离心分离机仅回收上清液并处理预先准备的FGFR3过表达细胞,并在4度下反应1小时。之后,通过培养基去除非特异性噬菌体(phage),并在37度下培养30分钟,从而回收细胞内化的抗体。就回收方法而言,通过低pH缓冲液(low pH buffer)清洗并去除非特异性细胞表面结合噬菌体,然后通过裂解缓冲液(lysis buffer)溶解细胞,从而回收存在于细胞内部的通过FGFR3特异性结合而具有细胞内化功能的抗体,并感染大肠杆菌(E.coli)。将被感染的大肠杆菌再次扩增,进一步进行相同的细胞淘选方法2次,从而总共进行3次细胞淘选后进行ELISA筛选,从而筛选FGFR3特异性抗体。相应实验示意图如[图1a]所示。
实施例2:对FGFR3具有特异性的噬菌体抗体筛选,抗原固定淘选(噬菌体展示技术)
使用相同的噬菌体文库,进行通常被广泛使用的固定抗原淘选(immobilizedantigen panning)。将FGFR3-IIIc/Fc抗原和阴性(negative)/Fc抗原分别以3ug/ml包被在免疫管(immune-tube)上(过夜(overnight),4度),并先将预先回收的噬菌体文库原液在常温下在预先封闭的阴性/Fc(pre-blocked negative/Fc)抗原中反应1小时。之后,回收上清液,在常温下在预先封闭的FGFR3-IIIc/Fc管(tube)中反应1小时。之后,通过PBST清洗去除非特异性噬菌体后通过低pH缓冲液回收对FGFR3-IIIc/Fc抗原具有特异性的噬菌体。用该噬菌体感染大肠杆菌后经过扩增过程,进一步进行相同的淘选(panning)方法3次,总共进行4次生物淘选(bio-panning)后进行ELISA筛选,从而筛选FGFR3特异性抗体。相应实验示意图如[图1b]所示。
实施例3:对FGFR3具有特异性的噬菌体抗体筛选,磁珠淘选;半自动化淘选(噬菌体展示技术)
使用相同的噬菌体文库,进行半自动化生物淘选(semi-automation bio-panning)。该方法是基于磁珠的淘选(magnetic beads based panning),是以现有的通常使用的操作指南(manual)方法在生物素化(biotinylation)的靶抗原中处理噬菌体并经过结合(binding)过程后利用色谱柱或磁室(magnetic chamber)等进行清洗并回收抗原特异性噬菌体的方式[图1c]。本发明人将这一系列的过程导入半自动化系统来进行。在Kingfisher Flex(赛默科技(Thermo scientific))设备中,将噬菌体文库原液、生物素化的(biotinylated)FGFR3-IIIc/Fc抗原、链霉亲和素-M280免疫磁珠(streptavidin-M280dynabeads)、0.1%的PBST清洗缓冲液(wash buffer)、洗脱缓冲液(elution buffer)等试剂(reagent)分配在Kingfisher Flex的24个深孔(deep well)中,通过预制的软件协议(software protocol)(BindItTM软件(Software))进行生物淘选[图1d]。将生物淘选重复3-4次,从而扩增与FGFR3抗原特异性结合的噬菌体并回收。使用该噬菌体,进行ELISA筛选,从而筛选FGFR3特异性抗体。
实施例4:基于亲和力ELISA的抗体筛选
各生物淘选方法的产物是大肠杆菌宿主细胞(TG1)状态,将这些E.coli宿主细胞以单克隆涂抹在琼脂LB/氨苄西林(Agar LB/Ampicillin)培养基上来确保,并任意地接种到SB/氨苄西林培养基进行培养(3小时,37度)。之后,为了诱导scFv-pIII蛋白,以最终浓度1mM的IPTG处理各孔(well),并在30度下培养过夜。第二天,使用离心分离机去除培养的96孔板(well plate)的上清液,仅回收大肠杆菌,用1x TES溶液(20%w/v蔗糖、50mM的Tris、1mM的EDTA、pH 8.0)进行处理,在4度下悬浮1小时以上,然后进一步用0.2x TES溶液进行处理并悬浮2小时以上,从而提取存在于大肠杆菌细胞周质部位的scFv-pIII蛋白。前一天预先将FGFR3重组蛋白和阴性重组蛋白以1ug/ml在96孔板中过夜并在4度的条件下包被板(plate),用提取的scFv-pIII处理各板,并在常温下反应1小时。反应后通过PBST进行清洗,用结合有HRP的抗-HA抗体处理1小时,并再次经过清洗过程诱导显色反应(TMB底物(substrate)),从而测量O.D值(450nm)。计算FGFR3重组蛋白/阴性重组蛋白的O.D比例(ratio),从而筛选FGFR3特异性scFv-pIII克隆。就筛选标准而言,换算成(阳性(positive)/阴性)相对的比例,对其值为2以上的克隆进行抗体序列分析。
利用源自患者的细胞的生物淘选的情况下,对于完成的输出(output)噬菌体,取564个单克隆进行ELISA筛选,其中鉴定出10个阳性克隆[图2a]。抗原固定生物淘选的情况下,通过进行两次独立实验,分别对658个单克隆进行ELISA筛选(总共1316个),其中鉴定出328个阳性克隆[图2b]。在完成基于磁性的半自动生物淘选后,对376个克隆进行ELISA筛选,并鉴定出26个阳性克隆[图2c]。
实施例5:抗体序列分析
亲和力ELISA筛选分析结果,对O.D比例(FGFR3抗原/阴性抗原)为2以上的克隆进行抗体序列的分析。在LB/氨苄西林培养基中培养在14ml的圆管(round tube)中筛选的克隆的具有噬菌粒载体(phagemid vector)的大肠杆菌,然后进行DNA制备(prep)(小量制备(mini-prep)),从而提取质粒(plasmid)DNA。提取的DNA通过使用与具有噬菌粒载体的scFv序列的部分匹配的引物(primer)进行分析。
根据各方法的序列分析结果,细胞淘选时分析两种抗体固有序列,抗原固定淘选时分析26种抗体独特序列,半自动淘选时分析8种抗体独特序列。在此基础上,对每个相应的克隆进行scFv形式的重复ELISA的结果,最终鉴定出25种显示FGFR3特异性结合能力的克隆,并且分析了重链、轻链的序列。
[表1]
[表2]
[表3]
[表4]
实施例6:scFv抗体片段向IgG的转换以及抗体生产
基于序列分析确认的FGFR3抗体序列为基准,在本研究组拥有的重链生产载体和轻链生产载体进行克隆,从而构建IgG生产载体。基于构建的生产载体,使用哺乳动物蛋白表达系统(mammalian protein expression system)(Expi293F)生产FGFR3抗体,并且基于AKTA prime plus设备的作为亲和层析的MabSelect SuReTM回收高纯度抗体并提纯。基于SDS-PAGE、尺寸排阻层析HPLC(size-exclusion chromatography HPLC,SEC-HPLC)分析,对完成的样品分析高纯度样品特性(图3a、图3b)。
实施例7:FGFR3抗体的抗原结合能力评价;ELISA
为了确认生产的抗体(IgG)对FGFR3抗原的结合能力,进行亲和力ELISA。以1-2ug/ml将FGFR3抗原包被到96孔板上(4度,过夜),然后用3%的脱脂牛奶(skim milk)(PBS)进行封闭(blocking)(常温,1小时)。之后,用预先系列稀释的抗体样品进行一式两份(duplicate)和一式三份(triplicate)处理,并在常温下反应1小时。之后,进行PBST清洗2-3次,然后将结合HRP的抗人(anti-human)Fab抗体稀释在脱脂牛奶中并进行处理(常温,1小时),再次用PBST清洗并进行显色反应(TMB底物)。之后,确认以450nm的O.D测量的值。
通过相同的方法在人FGFR3 IIIb(1264-FR-050,R&D)、IIIc(766-FR-050,R&D)、小鼠(mouse)FGFR3(9089-FR,R&D)、猴(monkey)FGFR3(90313-C02H,义翘神州(sinobiological))抗原中进行确认。
确认在各浓度下各抗体的结合能力(图4a至图4d),O.D值转换成相对值并图表化。基于EC50计算KD值(value)(表5a至表5d)。
[表5a][rhFGFR3-IIIc特异性结合能力:通过直接结合ELISA测定的EC50(EC50determined by direct-binding ELISA)]
[表5b][rhFGFR3-IIIb特异性结合能力:通过直接结合ELISA测定的EC50]
[表5c][rmFGFR3-IIIc特异性结合能力:通过直接结合ELISA测定的EC50]
[表5d][rcynoFGFR3-IIIc特异性结合能力:通过直接结合ELISA测定的EC50]
实施例8:FGFR3抗体的抗原结合能力评价;SPR
为了评价生产的抗体(IgG)对FGFR3亚型(subtype)和亚家族(subfamily)的结合能力,进行SPR分析。对FGFR3抗原的FGFR3抗体候选组的基于SRP的亲和力测量使用Biacore-T200设备。通过胺偶联,将与ELISA结合能力中所记载的抗原相同的抗原直接固定在CM5生物传感器芯片上,并且达到约300RU。以30ug/分钟的流速,在180秒的结合时间期间以约20nM浓度依次连续注入2倍的稀释液(25度),然后以相同的流速进行分离步骤180秒。在各个注入之间注入10mM的甘氨酸-HCl作为缓冲剂,从而再生CM5生物传感器芯片。使用一对一朗缪尔结合模型计算结合速度和解离速度。平衡解离常数(KD)以Koff/Kon的比例来计算(图5,表6)。
[表6]
N.D:未定义(not defined)
N.B:未结合(non-binding)
实施例9:FGFR3蛋白表达量的确认;蛋白免疫印迹,FACS分析
为了对本发明中发掘的FGFR3抗体进行细胞表面结合(cell surface binding)和其它分析(assay)以选定FGFR3过表达细胞,进行蛋白免疫印迹和FACS分析。将源自患者的细胞和癌症细胞系选定为mRNA表达水平(RPKM),并对各个细胞通过传代培养确保一定细胞数量,然后在蛋白免疫印迹的情况下,制备溶解产物(1ysate)来验证,在FACS分析的情况下,直接确认细胞表面FGFR3表达。首先,在蛋白免疫印迹的情况下,用cOmpleteTM溶解-M(cOmpleteTM Lysis-M)(罗氏(Roche))溶解各个细胞后进行布拉德福(bradford)蛋白质定量分析,对20ug的溶解产物进行蛋白免疫印迹。确认总FGFR3(sc-13121,santa-cruz)和β-肌动蛋白(beta-actin),从而比较细胞系之间的FGFR3蛋白的相对表达量。FACS的情况下,以3.0-5.0E+05细胞(cells)/管(tube)分配传代培养的各个细胞,在4度下将FGFR3-PE直接抗体(direct antibody)(FAB766P,R&D)反应1小时后清洗2-3次,然后用BD FACSAriaTM III(BD Biosciences)进行分析。
蛋白免疫印迹(Western blot)结果,682T、526T的源自患者的细胞被鉴定为是FGFR3过表达细胞。另一方面,626T、559T被鉴定为几乎没有FGFR3表达。在FACS结果中也验证了相同的情况。特别地,认为682T细胞在细胞表面具有非常高的FGFR3表达水平(图6a)。
实施例10:FGFR3-TACC3融合的验证;RT-PCR
FGFR3在各种癌中以过表达、扩增、变异、融合形式出现。其中,据报道,带有FGFR3-TACC3融合的患者的膀胱癌和脑肿瘤的预后不好。因此,对此的治疗剂具有可以克服未满足的医疗需求的可能性。因此,本发明中基于对源自患者的细胞的FGFR3-TACC3融合分析进行分组,对其使用RT-PCR技术来进行确认。通过传代培养将源自患者的细胞GBM15-682T、GBM14-526T、BT16-1154T、GBM14-606T、NS10-783T进行增殖后回收一定量,并使用RNeasy小型试剂盒(Mini Kit)(Qiagen)提取RNA。提取的RNA不稳定,因此进行RT-PCR(SuperscriptIV逆转录酶(Reverse transcriptase))而合成为cDNA。为了分析FGFR3-TACC3的融合位点(fusion site),使用UCSC基因组浏览器(genome browser)确认研究的融合位点,并制备引物以可以识别FGFR3-TACC3特异性区域(FW:5’-TGATCATGCGGGAGTGCTG-3’,RV:5’-CTCCTCACACCTGCTCCTC-3’)。使用所制备的引物对cDNA进行PCR实验,确认FGFR3-TACC3融合特异性区域是否扩增。与此同时,也一同确认作为对照组的GAPDH。其结果,GBM15-682T、GBM14-526T、BT16-1154T被鉴定为是FGFR3-TACC3融合(PCR预计大小,400-500bp)。其中,GBM15-682T、GBM14-526T预计为是相同的融合,BT16-1154T预计为是不同的融合[图6b]。基于源自FGFR3-TACC3融合脑肿瘤患者的细胞,分析进一步的FGFR3抗体克隆的特性和抗癌效果。
实施例11:FGFR3抗体的细胞结合能力评价;FACS分析
为了确认本发明中所确认的源自FGFR3-TACC3过表达患者细胞的发掘抗体的结合能力,进行FACS分析。以3.0-5.0E+05细胞/管分配各细胞,在进行清洗(PBS)步骤后,在4度下用100-200nM的发掘抗体处理。之后,通过相同的清洗方法去除未附着的抗体样品后用抗人alexa-488偶联物(anti-human alexa-488 conjugate)(目录(Catalog)#A-11013,Invitrogen)抗体处理,通过BD FACSAriaTM III(BD Biosciences)检测附着在细胞表面的抗体,从而确认细胞表面结合能力。发掘抗体分别显示出不同亲和力的细胞结合能力(图7a)。在相同的条件下对F309克隆分析根据浓度的细胞表面结合能力,并且确认了具有与浓度成比例的细胞表面结合能力,从而验证了具有FGFR3特异性结合能力(图7b)。对于未表达FGFR3的细胞系,对其的未结合也进行了进一步地分析(图7c)。
实施例12:FGFR3抗体的靶向降解率评价;FACS
通过FACS筛选对本发明中发掘的候选抗体的FGFR3靶向降解率。代表性地,将作为FGFR3过表达细胞的GBM15-682T的源自患者的细胞传代培养,以3.0E+05细胞/管进行分配,并分别用40ug/ml的候选抗体进行处理(2小时,37度)。之后,清洗2-3次后,处理FGFR3-PE(FAB766P,R&D)并在4度下反应1小时。通过相同的方法清洗2-3次,然后用BD FACSAriaTMIII(BD Biosciences)进行分析。其可以比较抗体处理后的细胞表面的总FGFR3表达水平。与IgG对照(control)进行比较,基于几何平均(Geomean)值进行比较分析。通过相同的方法,按时间(4小时、2小时、1小时、30分钟、15分钟)处理抗体,从而确认根据时间的发掘抗体的细胞表面FGFR3降解率。KMS11细胞系中进行了相同的操作。
对于优先发掘的抗体,以相同的条件,在一个浓度下进行相对比较,在此基础上,确认F309、FS306抗体有效减少细胞表面的FGFR3(图8)。此外,F309、FS306克隆的情况下,细胞表面的总FGFR3表达随时间减少,由此进一步确认这些克隆具有FGFR3降解率。此外,认为与作为其它抗体的B701、LY3076226(D11)抗体相比,F309、FS306抗体具有显著的降解率。(图10a)
实施例13:FGFR3表位结构域映射
FGFR3由三个结构域组成,因此为了分析发掘抗体的FGFR3结合域,在各个结构域(FGFR3 Ig结构域I、结构域II、结构域III)附加Fc标记(tag),通过哺乳动物细胞蛋白质表达系统生产并提纯(图9c)。对提纯的结构域的抗体的结合能力分析通过与上述ELISA相同的方式进行,以1ug/ml包被后处理抗体,并诱导TMB显色反应以进行测量。确认了F309、FS306克隆与FGFR3结构域1号特异性结合(图9b)。如文献中所报道,确认了作为比较组抗体的B701(Vofatamab,Rainier Therapeutics)和D11(LY3076226,礼来(Eli Lilly)公司)在结构域2号和结构域3号之间结合。但是,本发明中进行的结构域2号中包含比较组抗体的表位。此外,据报道,FGFR3和FGF1、FGF9等配体与FGFR3的Ig结构域II、结构域III结合。基于此进行竞争ELISA分析(Competition ELIS assay)。其结果,如预期,B701、D11抗体显示出与FGF配体竞争性地与FGFR3结合的情况,但观察到F309抗体与FGF配体无关地与FGFR3结合。这可以判断为是与上述FGFR3 Ig结构域I结合的支持依据。(图9a)
实施例14:FGFR3抗体的靶向降解率评价;蛋白免疫印迹
通过蛋白免疫印迹验证对本发明中发掘的候选抗体的FGFR3靶向降解率,与FACS方法相似地,作为代表性的细胞使用GBM15-682T的源自患者的细胞。将细胞以2.0E+06细胞/孔分配到6孔板中,以30ug/ml的浓度处理各抗体,并在37度下反应3小时。之后,制备溶解产物,通过布拉德福定量法计算20ug的各样品,并进行蛋白免疫印迹。用sc-13121抗体观察总FGFR3。KMS11细胞系也以相同的浓度和反应条件进行实验。与FACS结果相同地,确认了F309、FS306克隆的总FGFR3降解率优异。(图10b)
实施例15:抗体细胞内化(Antibody cellular internalization);免疫细胞化学(Immunocytochemistry,ICC))
通过ICC方法进一步验证抗体的细胞内化机制。作为FGFR3过表达细胞使用GBM15-682T,作为低表达细胞使用U87MG。在GBM15-682T的源自患者的细胞的情况下,由于不附着在ICC载玻片,因此预先包被PLO试剂并在其上面培养细胞,在U87MG的情况下,作为粘附细胞,没有进行PLO处理。首先,作为细胞内化条件,用30ug/ml的各个抗体处理附着在ICC载玻片的细胞,并在37度下反应2小时。细胞内化非活化条件是在相同的浓度和4度下反应2小时。之后,进行清洗并用2%的PFA固定(10分钟,4度)。相同的清洗方法再进行一次,并在常温下使0.1%的Triton-X反应3分钟,从而穿透细胞,并再次进行清洗。然后,在常温下用1%的BSA封闭30分钟,并在4度条件下用第一抗体处理过夜。第一抗体使用作为溶酶体标志物的LAMP-1抗体和抗人IgG。第二天进行清洗并用第二抗体在4度和遮光的条件下反应1小时。第二抗体使用探测第一抗体的具有荧光显色的抗体(Alexa 488;抗人LAMP1,Alexa 594;抗人IgG)。清洗后进行DAPI染色,然后通过共聚焦(confocal)显微镜分析各样品。分析结果,确认了F309、FS306克隆在4度条件下处理时附着在作为FGFR3过表达细胞的GBM15-682T表面,并确认在37度条件下进行细胞内化,因此观察到抗体与溶酶体位置(LAMP-1)相同。在此基础上,预测克隆与细胞表面FGFR3结合后被细胞内化而从在溶酶体中降解。(图11a)
实施例16:FGFR3抗体的靶向降解机制;通过溶酶体抑制的抗体机制分析
在本发明中,为了阐明上述发掘抗体的FGFR3靶向降解机制,进行了通过溶酶体抑制剂的验证。据报道有如下机制,抗体与细胞表面特异性抗原结合时,进行受体(抗原)介导的细胞内化(Receptor mediated endocytosis)并且在溶酶体中受体和抗体一同降解。因此,验证在FGFR3抗体中已确认FGFR3降解率的抗体在溶酶体中的降解,并且通过蛋白免疫印迹确认对用溶酶体抑制剂处理的样品和未用溶酶体抑制剂处理的样品的总FGFR3水平。以1.5E+06细胞/孔将GBM15-682T分配到6孔板中,并在37度条件下用浓度为100nM的已知为溶酶体抑制剂的刀豆霉素(Concanamycin)处理2小时。作为对照组,用DMSO处理。2小时后以30ug/ml和37度的条件下用各个抗体3小时处理。之后,以与上述蛋白免疫印迹方法相同的方法进行,从而确认总FGFR3水平。即使在作为溶酶体抑制剂的刀豆霉素处理条件下用F309、FS306克隆处理,总FGFR3也没有减少,并且在未处理作为溶酶体抑制剂的刀豆霉素的条件下总FGFR3显著减少,由此认为F309、FS306克隆附着在细胞表面FGFR3后细胞内化,从而在溶酶体中与FGFR3一同降解。(图11b)
实施例17:信号通路抑制试验(Signaling pathway inhibition assay);蛋白免疫印迹
FGFR3亚信号传导抑制分析通过蛋白免疫印迹进行。以与上述蛋白免疫印迹方法相同的方法进行,将GBM15-682T的源自患者的细胞分配在6孔板中,并用30ug/ml的各个抗体处理(37度,3小时)。之后,为了激活FGFR3相关亚信号传导,用50ng/ml的FGF1、FGF9代表性配体处理(一同用50ug/ml的硫酸肝素(heparin sulfate)处理),并在37度下反应30分钟。之后,制备溶解产物,并对20ug的各个样品进行蛋白免疫印迹。FGFR3亚信号传导途径的磷酸化和激活是使用以下抗体来验证;p-FGFR3(ab155960,Abcam)、p-ERK(4370s,CST)、p-AKT(9271s,CST)。确认了F309、FS306克隆抑制作为FGFR3亚信号传导的p-FGFR3、p-ERK、p-AKT。(图12)
实施例18:癌细胞生长抑制能力分析;配体依赖性环境
为了确认对于本发明中发掘的抗体的配体依赖性环境中的癌细胞生长抑制能力,在无血清(serum free)条件下,以10000细胞/孔将GBM15-682T分配在96孔黑色平底(96well black-flat bottom plate)板中,在饥饿(starvation)一天后,第二天用作为配体的FGF1(232-FA,R&D)、FGF9(273-F9,R&D)处理以使最终浓度为50ng/ml,并且对抗体进行系列稀释并以各浓度处理。之后,在37度的CO2培养箱中培养7天。细胞生长是通过发光细胞活性分析(Luminescent Cell Viability Assay)进行测量,并且比较了相对于对照组的抗体处理组的细胞生长。用配体处理该细胞时,可以确认配体加快1.5-2倍左右的癌症生长,因此,确认用各浓度的克隆处理时,与IgG对照(对照组)相比,细胞生长被抑制20-30%。(图13a)
实施例19:癌细胞生长抑制能力分析;非配体依赖性环境
基于本发明中记载的细胞生长测量法,在非配体依赖性环境中评价抗体的癌细胞生长抑制能力。以10000细胞/孔将GBM15-682T的源自患者的细胞分配在96孔黑色平底板中,并且对抗体进行系列稀释并以各浓度处理。之后,在37度的CO2培养箱中培养7天。细胞生长是通过发光细胞活性分析进行测量,并且比较了相对于对照组的抗体处理组的细胞生长。在没有配体的环境中用抗体处理时,确认与IgG对照(对照组)相比,F309、FS306克隆抑制细胞生长30-40%。在作为FGFR3低表达细胞系的U87MG和源自患者的细胞(626T)中,没有观察到癌细胞生长抑制能力。认为这是根据FGFR3表达的生长抑制特征。(图13b)
实施例20:体内(In vivo)短期PK分析和异种移植模型中的功效评价
为了确认在活体内施用发掘抗体时是否初始清除(clearance)而进行短期PK。将10mg/kg的抗体施用于Balb/c小鼠,以施用后立即、1小时、2小时、4小时、1天、2天的间隔确保各个个体的血样。为了去除血液的血细胞,通过离心分离机确保血浆,并且基于ELISA定量血浆中的抗体滴度(titer)。其结果,确认与对照抗体相似地,F309、FS306抗体均存在正常的抗体的初始PK,而没有在初期被清除的情况。(图14a)
为了进行发掘抗体的体内功效评价,本研究组制备了异种移植模型。通过皮下注射,将GBM15-682T注入(1.0E+06细胞)到Bab/c裸(nude)小鼠的侧腹以形成肿瘤,并且平均形成100-150mm3肿瘤时,将小鼠再次分组,并指定5只为一组。对各组以每周三次或每周两次并以各浓度腹腔内注射抗体和溶剂(vehicle)。使用卡尺(calipers)并用V=0.5a×b2(a:肿瘤长轴的长度,b:肿瘤短轴的长度)公式计算肿瘤体积。在测量肿瘤的同一天还测量小鼠的体重。确认分别施用10mg/kg(每周三次)F309、FS306克隆时分别抑制癌症生长约50%和约40%(图14a)。认为F309的情况下,以各浓度每周施用两次时(30mpk、10mpk、3mpk),以优异的抗癌效果抑制癌症生长(图14b)。
实施例21:F309抗体亲和力成熟工程
为了进一步改善F309的显著的FGFR3降解率和癌症生长抑制能力,进行亲和力成熟。制备在M13噬菌体表面展示F309 scFv片段(重链可变部位;VH,轻链可变部位;VL)的噬菌粒载体,并将其用作文库模型。为了亲和力成熟,基于抗体的Kabat编号,选定CDR H1、H2、H3和CDR L1、L2、L3,对各个CDR,使用包含NNK简并密码子(degeneration codon)的引物,从而制备F309突变体(mutant)文库(图15a)。对各个文库进行上述生物淘选(抗原固定淘选)3-4次,在此基础上,相对于F309亲本抗体亲和力更加提高的抗体是通过基于ELISA的亲和力筛选来确保克隆。确保的克隆通过进行再现实验来进行再验证,最终通过抗体序列分析获得F309的亲和力成熟突变体。与亲本抗体相比,判断确保的F309突变体对FGFR3重组蛋白的特异性结合能力显著提高(图15b)。进一步地,通过SSM001-SSM010突变体的氨基酸残基组合,设计并制备了进一步的突变体SSM023、SSM024、SSM026、SSM034、SSM036、SSM234、SSM236。为了验证对其的抗体的FGFR3抗原特异性结合能力分析而进行ELISA,其结果确认更加提高的FGFR3抗原亲和力[图15b、图15c]。在GBM15-682T进行对突变体抗体的生物学活性的分析,其结果可以确认相对于F309亲本抗体增加的癌症生长抑制(图15d)。
[表7]
[表8]
[表9]
[表10]
[表11][rhFGFR3-IIIb特异性结合能力:通过直接结合ELISA测量的EC50]
[第-次筛选]
[第二次筛选]
[表12]
·N.D:未定义
·N.B:未结合
[表13]
实施例22:F309抗体的ADC适用可能性验证
抗体-药物偶联物的情况下,具有以下机制:抗体与细胞表面的抗原特异性结合,通过受体介导的细胞内化引入到细胞内部,并且被细胞内部的溶酶体和蛋白酶降解,从而通过接合的毒性物质杀死细胞。该抗体-药物偶联物作为可以极大化治疗效果的平台,被广泛地用作新一代抗体治疗剂平台。在本发明中,想要确认对于对FGFR3、FGFR3-TACC3融合细胞的内化和靶向降解率优异的克隆作为抗体-药物偶联物的适用可能性。如本发明中所记载,F309、FS306克隆的FGFR3靶向降解率和细胞内化已得到验证,因此判断F309、FS306克隆可以用作抗体-药物偶联物平台,从而对其进行实施。其中,对F309克隆的抗体-药物偶联物的制备使用PerKitTM抗体MMAE偶联试剂盒(PerKitTM Antibody MMAE Conjugation Kit)(CellMosaic),该平台是第一代抗体-药物偶联物技术(西雅图遗传学公司开发的一种方法(a method developed by Seattle Genetics):Sun e tal.2005,Bioconjugate Chem.16,1282-1290),是任意地将-vc MMAE接合在抗体的链间二硫化物(interchain disulfide)的方式(图16a)。将各种源自患者的细胞和癌细胞系选定为FACS的表达基准,相对地分组为高(High)、中(Mild)、低(Low),并且对此进行F309的细胞毒性实验。评价方法如本发明中所记载,通过发光细胞活性分析进行测量。其结果,确认了与FGFR3细胞表面表达量成比例地显示出显著的F309-vc MMAE的细胞毒性(图16b至图16c),为了确保进一步的竞争力,用相同的试剂盒(Kit)应用作为FGFR3-ADC的临床开发中的LY3076226亲本抗体,从而比较效果。F309-vc MMAE在作为FGFR3-TACC3融合的GBM15-682T中显示出比LY3076266-vc MMAE更优异的细胞毒性。用IC50和最大抑制(MAX inhibition)分析根据各FGFR3表达量的对ADC的细胞的生长抑制效果,并标记在(图16d)的表格(table)中。
实施例23:亲和力成熟抗体的表位结构域映射和抗原亲和力分析
对亲和力成熟抗体F309#SSM236(以下,AMB302#1.2)也进行前面所进行的表位结构域映射。确认了亲本抗体的情况下,与结构域D1结合,并且确认了使用相同的各结构域(结构域I、结构域II、结构域III)进行分析时,亲和力成熟抗体也与结构域D1特异性结合。再次确认了该抗体的情况下,对人/食蟹猕猴(cyno)FGFR3具有特异性结合能力(图17)。各抗原的KD值如下表14所示。
表14.利用生物大分子相互作用分析系统(Biacore)(SPR分析)的对亲和力成熟变异抗体的结合力分析(KD常数)
实施例24:亲和力成熟抗体的细胞内化和靶向降解率评价
对于亲和力相当成熟的F309变异体,进行有效降解细胞表面的FGFR3靶标的验证。通过在前发明中进行的相同的方法,首先,通过FACS验证FGFR3细胞表面表达量的确认以及细胞内化评价,并且通过蛋白免疫印迹进行靶向降解率。确认了亲和力成熟变异体的情况下,具有相当大的细胞内化功效和靶向降解率(图18至图20)。
实施例25:亲和力成熟抗体的小鼠/猴PK分析
为了验证亲和力成熟抗体(AMB302#1.2,SSM236)的活体PK谱,对小鼠/猴个体进行分析。将10mg/kg、1mg/kg、0.1mg/kg的单克隆抗体施用于小鼠BALB/c小鼠(mice)(8周,~20g,n=3,雌性(female)),施用后立即、10分钟、1小时、3小时、5小时、8小时、24小时、2天、3天、7天、10天、14天、17天、21天、28天为间隔交叉三个存活的个体,根据各时间眼眶取血。为了去除血液的血细胞,通过离心分离机确保血浆,并且基于定量(quantification)ELISA对血浆内的抗体滴度进行定量。其结果,确认AMB302#1.2抗体的情况下,在小鼠活体内具有10天以上的稳定的半衰期(t1/2)特性和CL。此外,在所有施用浓度下没有观察到生物学特异性临床副作用和体重变化(图21)。
在一只猴子个体(2-3年,~3kg,雌性,天然)中施用25mg/kg后进行50mg/kg的单次施用,并且根据各时间采集血样(10分钟、1小时和6小时、1天、2天、3天、7天、10天、14天、21天和28天)。为了去除获得的血液中的血细胞,通过离心分离机确保血浆,并且通过定量ELISA对血浆内的抗体进行定量。其结果,确认了与小鼠中的结果相似的稳定的半衰期(10天以上)和CL倾向。此外,在所有施用浓度下没有观察到生物学特异性临床副作用和体重变化(图22)。
实施例26:亲和力成熟抗体的ADC制备
对本发明中通过亲和力成熟工程获得的变异体进行ADC制备(图23)。在提纯的抗体样品中用当量比为8.0以上的三(2-羧乙基)膦盐酸盐(TCEP)进行处理,在37度下完全还原2小时。还原后用pH7.4的PBS交换缓冲液,并对该样品,在37度下,与在DMA中溶解接头-有效载荷(拓扑异构酶I抑制剂(Topoisomerase I inhibitor,当量比为10.0)而一同还原的抗体接合2小时。接合后通过离心色谱柱(Amicon Ultra-15离心过滤器装置(CentrifugalFilter Units))交换缓冲液。
通过相同的方法部分还原抗体,从而制备接合接头-有效载荷(倍癌霉素衍生物(Duocarmycin derivatives),接头(linker)-AMB401)的ADC(图24)。
实施例27:亲和力成熟抗体ADC分析(TOPOI)
对于完成合成的ADC样品(TOPOI接合ADC),通过ELISA确认抗原亲和力,通过与本发明中进行的亲和力ELISA相同的方法进行,并确认了与亲本抗体具有相同的抗原结合能力。此外,通过SEC-HPLC分析确认了制备的ADC的高纯度物理性能特征。
DAR分析是通过LC-MS进行,并且对制备的ADC分别进行附着在重链、轻链的接头-有效载荷的质谱分析,并且将其进行换算时,可以确认DAR大约为6以上(图25)。
实施例28:亲和力成熟抗体ADC分析(倍癌霉素,接头-AMB401)
对于完成合成的ADC样品(倍癌霉素,接头-AMB401;ADC),该物质的分析是通过SEC-HPLC来分析纯度,并且通过HIC-HPLC和PLRP分析来分析DAR。该物质的情况下,确认了具有98%以上的纯度和DAR为约4左右的均匀的物理性能特征(图26:20mM的pH为6.0的组氨酸-醋酸盐(Histidine-acetate))。
实施例29:源自患者的类器官体外(Ex vivo)模型中的亲和力成熟变异体ADC功效评价(ADC-TOPOI)
使用制备的ADC,对源自FGFR3(TACC3融合)过表达患者的类器官的功效进行评价。从源自脑肿瘤患者癌症组织分离癌细胞制作单个球状体类器官(single spheroidorganoid)模型。使用两种具有FGFR3-TACC3融合的源自患者的细胞(AMB-BT-0050T、AMB-BT-0112T)和没有FGFR3-TACC3融合的源自患者的细胞(AMB-BT-0013T)过夜培养(overnight incubation)以形成单个球状体(single spheroid),然后用ADC进行处理,培养一周后确认其结果。据分析,在阴性对照(Negative control)中,没有ADC和对照ADC之间的敏感性(sensitivity)差异,并且与对照ADC相比,在两种具有FGFR3-TACC3融合的源自患者的细胞中,与FGFR3表达量成比例地特异性地显著抑制球状体生长(spheroid growth)并诱导细胞死亡。特别是亲和力成熟的变异抗体-ADC的情况下,确认了与亲本抗体-ADC相比,在FGFR3(TACC3融合)过表达细胞中诱导显著提高的细胞毒性和死亡。对于FGFR3(TACC3融合)过表达细胞,显示出0.3nM以下的IC50,对于阴性细胞,显示出90nM以上的IC50(图27)。
实施例30:源自患者的类器官体外模型中的亲和力成熟变异体ADC功效评价(ADC-倍癌霉素,接头-AMB401)
通过与实施例27相同的方法,进行AMB302#1.2-倍癌霉素ADC的体外功效评价。对于源自FGFR3(TACC3)过表达脑肿瘤患者的细胞显示出约0.3nM的低IC50,对于阴性细胞显示出100nM以上的高IC50。这表示该ADC诱导与FGFR3表达显著成比例的细胞死亡(图28)。
实施例31:FGFR3(TACC3融合)脑肿瘤立体定向动物模型中的ADC功效评价(ADC-TOPOI)
评价通过ADC治疗的脑肿瘤立体定向动物模型(脑肿瘤,GBM)中的存活率增加(图29)。培养作为FGFR3过表达细胞的AMB-BT-0050T(682T)的源自患者的细胞,将2×10^5的细胞与5ul的培养基混合以进行准备。在免疫缺陷小鼠的前囟的左1.7mm且上0.5mm的位置处以3.2mm的深度注入准备的细胞系来制作脑肿瘤小鼠模型。总共分为对照、对照-TOPOI、AMB302#1.2-TOPOI(单次施用、多次施用)等4个组,每组用7只小鼠进行评价。候选药物在制作模型后的第七天通过静脉注射单次施用。在第15天,为了生物标志物(Biomarker)分析等,每组取2只来进行中间取样。每周测量2次小鼠的体重,存在20%以上的体重减少时进行安乐死以提取小鼠的脑。确认AMB302#1.2-TOPOI的情况下仅通过单次施用小鼠生存期间也增加70%以上。
在相同的模型中将AMB302#1.1-TOPO1施用2次(间隔一周,10mg/kg)时,小鼠生存期间也显著增加100%以上。此外,通过中间取样比较小鼠的脑的肿瘤尺寸时,与对照组相比,ADC处理个体的情况下,没有发现肿瘤。此外,确认了与基于亲本抗体的ADC相比,亲和力成熟ADC诱导明确提高的肿瘤抑制和存活率的增加(图30)。
实施例32:FGFR3(TACC3融合)皮下移植模型中的ADC功效评价(ADC-TOPOI)
通过皮下注射(subcutaneous,s.c),将RT112细胞注入(1.0E+06细胞)Bab/c裸小鼠的侧腹以形成肿瘤,并且肿瘤平均形成100-150mm3时,将小鼠再次分组,并指定5只为一组。对各组静脉注射ADC和溶剂(vehicle)两次(间隔一周,5mp/kg)。使用卡尺并用V=0.5a×b2(a:肿瘤长轴的长度,b:肿瘤短轴的长度)公式计算肿瘤体积。在测量肿瘤的同一天,还测量小鼠的体重。施用ADC-TOPOI时,确认了分别完全抑制癌症生长,从而确认了具有优异的抗癌效果(图31)。
实施例33:FGFR3(TACC3融合)脑肿瘤立体定向动物模型中的ADC功效评价(ADC-倍癌霉素,接头-AMB401)
在前面进行的相同的模型中单次施用(10mg/kg)或者多次施用(10mg/kg,Q4D)AMB302#1.1-AMB401,从而进行功效评价。在相应ADC施用组中确认存活率显著增加,特别是在进行多次施用的组中确认存活率增加30%以上(图32)。
以上,对本发明内容的特定部分进行了详细描述,对于本领域技术人员而言,显然这种具体的技术仅仅是优选的实施方案,本发明的范围并不受限于此。因此,本发明的实质性的范围将由权利要求及其等同物来定义。
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<220>
<223> VH CDR3
<400> 60
Gly Pro Asn Ser His Ile Tyr Pro Tyr Phe Tyr Tyr
1 5 10
<210> 61
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 61
Gly Ile Leu Phe Met Thr Ile Thr Leu Pro Tyr Ser Ser Asp Gly Met
1 5 10 15
Asp Val
<210> 62
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 62
His Pro Leu Leu Ser Ile Phe Ser Leu Pro Tyr Tyr Ser Asp Ala Met
1 5 10 15
Asp Val
<210> 63
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 63
Lys Trp Pro Thr Phe Asp Tyr
1 5
<210> 64
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 64
Asp Trp Glu Gln Phe Asp Tyr
1 5
<210> 65
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 65
His Thr Val Ile Glu Ala Leu Glu Ala Ala Tyr Tyr Asp Asp Gly Met
1 5 10 15
Asp Val
<210> 66
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 66
His Gly Gly Asp Glu Thr Asn Tyr Phe Gln Ser Tyr Tyr Asp Gly Met
1 5 10 15
Asp Val
<210> 67
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 67
Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Asp Val Thr
1 5 10
<210> 68
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 68
Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn Tyr Val Ser
1 5 10
<210> 69
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 69
Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Asp Val Ser
1 5 10
<210> 70
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 70
Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn Ala Val Ser
1 5 10
<210> 71
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 71
Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Tyr Val Ser
1 5 10
<210> 72
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 72
Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Asp Val Tyr
1 5 10
<210> 73
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 73
Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn Thr Val Ser
1 5 10
<210> 74
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 74
Arg Ala Ser Gln Ser Ile Ser Thr Phe Leu Asn
1 5 10
<210> 75
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 75
Arg Ala Ser Gln Ser Ile Thr Asp Tyr Leu Ala
1 5 10
<210> 76
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 76
Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn
1 5 10
<210> 77
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 77
Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 78
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 78
Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Asn
1 5 10
<210> 79
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 79
Thr Ala Ala Ala Ser Asp Ile Ala Ser Asn Tyr Val Gln
1 5 10
<210> 80
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 80
Ser Asp Asn Ile Gly Ser Lys Ser Val His
1 5 10
<210> 81
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 81
Gly Gly Asn Asn Ile Gly Ser Lys Ser Val His
1 5 10
<210> 82
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 82
Gly Gly Asp Asn Ile Gly Thr Lys Ser Val His
1 5 10
<210> 83
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 83
Ser Arg Asn Asn Ile Gly Ser Lys Ser Met His
1 5 10
<210> 84
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 84
Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Asp Val Asn
1 5 10
<210> 85
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 85
Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Ala Val Thr
1 5 10
<210> 86
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 86
Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn Asp Val Ser
1 5 10
<210> 87
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 87
Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Tyr
1 5 10
<210> 88
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 88
Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Phe Asn
1 5 10
<210> 89
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 89
Asp Asp Asn His Arg Pro Ser
1 5
<210> 90
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 90
Tyr Asn Ser His Arg Pro Ser
1 5
<210> 91
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 91
Ser Asn Ser His Arg Pro Ser
1 5
<210> 92
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 92
Asp Asp Ser Lys Arg Pro Ser
1 5
<210> 93
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 93
Ala Asp Ser Lys Arg Pro Ser
1 5
<210> 94
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 94
Ala Asp Asn His Arg Pro Ser
1 5
<210> 95
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 95
Tyr Asp Ser His Arg Pro Ser
1 5
<210> 96
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 96
Asp Ala Thr Asn Arg Ala Thr
1 5
<210> 97
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 97
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 98
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 98
Asp Ala Ser Asn Arg Ala Ala
1 5
<210> 99
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 99
Asp Thr Ser Asn Lys His Ser
1 5
<210> 100
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 100
Glu Asp Thr Lys Arg Pro Ser
1 5
<210> 101
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 101
Ser Asn Asn Gln Arg Pro Ser
1 5
<210> 102
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 102
Gln Asp Thr Lys Arg Pro Ser
1 5
<210> 103
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 103
Gly Asn Ser Asn Arg Pro Ser
1 5
<210> 104
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 104
Asp Asn Asn Lys Arg Pro Ser
1 5
<210> 105
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 105
Tyr Asp Ser Asn Arg Pro Ser
1 5
<210> 106
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 106
Ser Asp Asn His Arg Pro Ser
1 5
<210> 107
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 107
Ala Asn Asn Gln Arg Pro Ser
1 5
<210> 108
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 108
Ser Asn Ser Gln Arg Pro Ser
1 5
<210> 109
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2
<400> 109
Ser Asp Ser Asn Arg Pro Ser
1 5
<210> 110
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 110
Gly Thr Trp Asp Ala Ser Leu Ser Ala Tyr Val
1 5 10
<210> 111
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 111
Ala Thr Trp Asp Asp Ser Leu Ser Gly Tyr Val
1 5 10
<210> 112
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 112
Gly Thr Trp Asp Asp Ser Leu Asn Gly Tyr Val
1 5 10
<210> 113
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 113
Gly Ala Trp Asp Tyr Ser Leu Ser Ala Tyr Val
1 5 10
<210> 114
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 114
Ala Ser Trp Asp Tyr Ser Leu Ser Gly Tyr Val
1 5 10
<210> 115
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 115
Gly Ala Trp Asp Ala Ser Leu Asn Gly Tyr Val
1 5 10
<210> 116
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 116
Gln Gln Ala Asn Ser Phe Pro Leu Thr
1 5
<210> 117
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 117
Gln Gln Ser Tyr Ser Thr Pro Phe Thr
1 5
<210> 118
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 118
Cys Gln Gln Tyr Ser Ser Phe Pro Leu Thr
1 5 10
<210> 119
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 119
Gln Gln Ser Tyr Ser Thr Pro Ile Thr
1 5
<210> 120
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 120
Ala Ala Trp Asp Asn Ser Leu Asn Gly Gln Leu
1 5 10
<210> 121
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 121
Ala Thr Trp Asp Asp Ser Leu Arg Gly Trp Val
1 5 10
<210> 122
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 122
Gln Ser Tyr Asp Ser Ser Thr Val Val
1 5
<210> 123
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 123
Gln Ser Tyr Asp Ser Arg Gln Leu Val
1 5
<210> 124
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 124
Gln Ser Tyr Asp Ser Ser Leu Ser Gly Tyr Val
1 5 10
<210> 125
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 125
Ser Ser Tyr Thr Ser Ser Ser Thr Leu Val
1 5 10
<210> 126
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 126
Ala Ala Trp Asp Ser Ser Leu Ser Gly Tyr Val
1 5 10
<210> 127
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 127
Gly Thr Trp Asp Tyr Ser Leu Ser Gly Tyr Val
1 5 10
<210> 128
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 128
Gly Ala Trp Asp Asp Ser Leu Ser Ala Tyr Val
1 5 10
<210> 129
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 129
Gly Ala Trp Asp Ser Ser Leu Asn Ala Tyr Val
1 5 10
<210> 130
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 130
Gly Thr Trp Asp Asp Ser Leu Ser Gly Tyr Val
1 5 10
<210> 131
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 131
Gly Ala Trp Asp Ser Ser Leu Ser Ala Tyr Val
1 5 10
<210> 132
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 132
Gly Thr Trp Asp Tyr Ser Leu Asn Gly Tyr Val
1 5 10
<210> 133
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 133
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Pro Gly Ser Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Trp Ser Lys Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 134
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 134
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Leu Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Tyr His Gly Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ser Arg Leu Cys Gln Thr Ser Gly Cys Tyr Ser Asp Asp
100 105 110
Ala Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 135
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 135
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser His Gly Gly Ser Ser Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Arg Leu Glu Ser Pro Phe Leu Ala Gln Ser Tyr Ala Tyr
100 105 110
Ala Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 136
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 136
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Pro Gly Ser Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Trp Thr Arg Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 137
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 137
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Gly Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Ala Pro Thr Asn Glu Met Ser Arg Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 138
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 138
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Tyr Gly Ser Gly Asn Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 139
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 139
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys His Leu Pro Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 140
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 140
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Ala Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ile Pro Ile Ser Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Gly Gly Tyr Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 141
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 141
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ile Ile His Pro Gly Gly Ser Asp Ser Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Ala Trp Phe Asp Ser Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 142
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 142
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Ser Asp Ile
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Tyr Ser Ser Asp Ser Thr Tyr Tyr Asn Pro Ser Leu Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Gly Val Gly Tyr Thr Thr Ser Ser Arg Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 143
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 143
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Gln Gly Ala Ser Trp Met Asp Met Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 144
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 144
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ile Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Tyr Thr Gly Asp Thr Tyr Ser Asn Pro Ser Leu Lys
50 55 60
Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Tyr Ala Thr Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 145
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 145
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ile Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Tyr Ser Gly Asp Thr Tyr Tyr Asn Pro Ser Leu Glu
50 55 60
Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Ile Gly Ser Ser Trp Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 146
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 146
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Trp Ile Asn Thr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Thr Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Arg Gly Met Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 147
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 147
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asn Trp Arg Gly Ala Thr Thr Ala Tyr Ala Asp Ser Leu
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Asp Tyr Gly Leu Phe Asp Ile Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 148
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 148
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Val Ser Gly Ser Gly Thr Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu His
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Thr Gln Arg Trp Gly Ala Phe Asp Pro Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 149
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 149
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Val Ser Tyr Ser Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Leu
50 55 60
Gln Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Arg Asn Ala Ile Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 150
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 150
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Pro Asp Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Pro Leu Ile Tyr Glu Leu Pro Ile Gly Tyr Ser Ser Tyr
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 151
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 151
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Gly Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Pro Asn Ser His Ile Tyr Pro Tyr Phe Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 152
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 152
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Ser Pro Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ile Leu Phe Met Thr Ile Thr Leu Pro Tyr Ser Ser Asp
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 153
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 153
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Phe His Asp Ser Gly Asn Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys His Pro Leu Leu Ser Ile Phe Ser Leu Pro Tyr Tyr Ser Asp
100 105 110
Ala Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 154
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 154
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Ser Gly Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Lys Trp Pro Thr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 155
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 155
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Pro Gly Ser Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Trp Glu Gln Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 156
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 156
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Ser Asp Asn Ser Ser Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys His Thr Val Ile Glu Ala Leu Glu Ala Ala Tyr Tyr Asp Asp
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 157
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 157
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr His Asn Gly Ser Ser Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys His Gly Gly Asp Glu Thr Asn Tyr Phe Gln Ser Tyr Tyr Asp
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 158
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 158
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Asp Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ala Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 159
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 159
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asn Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 160
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 160
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asn Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 161
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 161
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Ala Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Asp Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp Tyr Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 162
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 162
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 163
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 163
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Asp Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp Ala Ser Leu
85 90 95
Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 164
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 164
Gln Ser Val Leu Thr Gln Leu Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Thr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu
85 90 95
Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 165
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 165
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Thr Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Thr Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 166
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 166
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Thr Asp Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 167
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 167
Glu Ile Val Leu Thr Gln Gly Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Val
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Ala Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ser Phe Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 168
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 168
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 169
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 169
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Thr Ser Asn Lys His Ser Gly Asp Arg Phe Ser Gly Ser
50 55 60
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asn Ser Leu Asn Gly
85 90 95
Gln Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 170
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 170
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Ala Ala Ala Ser Asp Ile Ala Ser Asn
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Glu Asp Thr Lys Arg Pro Ser Gly Val Pro Tyr Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp Ser Leu
85 90 95
Arg Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 171
<211> 105
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 171
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Asp Asn Ile Gly Ser Lys Ser Val His
20 25 30
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Ser
35 40 45
Asn Asn Gln Arg Pro Ser Gly Val Ser Asp Arg Phe Ser Gly Ser Lys
50 55 60
Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu Asp
65 70 75 80
Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Thr Val Val Phe
85 90 95
Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 172
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 172
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val
20 25 30
His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Gln Asp Thr Lys Arg Pro Ser Gly Val Pro Asn Arg Phe Ser Gly Ser
50 55 60
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Arg Gln Leu Val
85 90 95
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 173
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 173
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Gly Gly Asp Asn Ile Gly Thr Lys Ser Val
20 25 30
His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asn Arg Phe Ser Gly Ser
50 55 60
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly
85 90 95
Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 174
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 174
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Ala Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Arg Asn Asn Ile Gly Ser Lys Ser Met
20 25 30
His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Asp Asn Asn Lys Arg Pro Ser Gly Val Ser Asp Arg Phe Ser Gly Ser
50 55 60
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser Ser Thr Leu
85 90 95
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 175
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 175
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Asp Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asp Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ser Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 176
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 176
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Asp Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asn Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 177
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 177
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ala Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp Asp Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 178
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 178
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Asp Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp Ser Ser Leu
85 90 95
Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 179
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 179
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Thr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 180
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 180
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Thr Phe Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asn Ser Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp Ser Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 181
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 181
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ala Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp Asp Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 182
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 182
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Asp Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Ser Leu
85 90 95
Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 183
<211> 806
<212> PRT
<213> 人工序列
<220>
<223> FGFR3
<400> 183
Met Gly Ala Pro Ala Cys Ala Leu Ala Leu Cys Val Ala Val Ala Ile
1 5 10 15
Val Ala Gly Ala Ser Ser Glu Ser Leu Gly Thr Glu Gln Arg Val Val
20 25 30
Gly Arg Ala Ala Glu Val Pro Gly Pro Glu Pro Gly Gln Gln Glu Gln
35 40 45
Leu Val Phe Gly Ser Gly Asp Ala Val Glu Leu Ser Cys Pro Pro Pro
50 55 60
Gly Gly Gly Pro Met Gly Pro Thr Val Trp Val Lys Asp Gly Thr Gly
65 70 75 80
Leu Val Pro Ser Glu Arg Val Leu Val Gly Pro Gln Arg Leu Gln Val
85 90 95
Leu Asn Ala Ser His Glu Asp Ser Gly Ala Tyr Ser Cys Arg Gln Arg
100 105 110
Leu Thr Gln Arg Val Leu Cys His Phe Ser Val Arg Val Thr Asp Ala
115 120 125
Pro Ser Ser Gly Asp Asp Glu Asp Gly Glu Asp Glu Ala Glu Asp Thr
130 135 140
Gly Val Asp Thr Gly Ala Pro Tyr Trp Thr Arg Pro Glu Arg Met Asp
145 150 155 160
Lys Lys Leu Leu Ala Val Pro Ala Ala Asn Thr Val Arg Phe Arg Cys
165 170 175
Pro Ala Ala Gly Asn Pro Thr Pro Ser Ile Ser Trp Leu Lys Asn Gly
180 185 190
Arg Glu Phe Arg Gly Glu His Arg Ile Gly Gly Ile Lys Leu Arg His
195 200 205
Gln Gln Trp Ser Leu Val Met Glu Ser Val Val Pro Ser Asp Arg Gly
210 215 220
Asn Tyr Thr Cys Val Val Glu Asn Lys Phe Gly Ser Ile Arg Gln Thr
225 230 235 240
Tyr Thr Leu Asp Val Leu Glu Arg Ser Pro His Arg Pro Ile Leu Gln
245 250 255
Ala Gly Leu Pro Ala Asn Gln Thr Ala Val Leu Gly Ser Asp Val Glu
260 265 270
Phe His Cys Lys Val Tyr Ser Asp Ala Gln Pro His Ile Gln Trp Leu
275 280 285
Lys His Val Glu Val Asn Gly Ser Lys Val Gly Pro Asp Gly Thr Pro
290 295 300
Tyr Val Thr Val Leu Lys Thr Ala Gly Ala Asn Thr Thr Asp Lys Glu
305 310 315 320
Leu Glu Val Leu Ser Leu His Asn Val Thr Phe Glu Asp Ala Gly Glu
325 330 335
Tyr Thr Cys Leu Ala Gly Asn Ser Ile Gly Phe Ser His His Ser Ala
340 345 350
Trp Leu Val Val Leu Pro Ala Glu Glu Glu Leu Val Glu Ala Asp Glu
355 360 365
Ala Gly Ser Val Tyr Ala Gly Ile Leu Ser Tyr Gly Val Gly Phe Phe
370 375 380
Leu Phe Ile Leu Val Val Ala Ala Val Thr Leu Cys Arg Leu Arg Ser
385 390 395 400
Pro Pro Lys Lys Gly Leu Gly Ser Pro Thr Val His Lys Ile Ser Arg
405 410 415
Phe Pro Leu Lys Arg Gln Val Ser Leu Glu Ser Asn Ala Ser Met Ser
420 425 430
Ser Asn Thr Pro Leu Val Arg Ile Ala Arg Leu Ser Ser Gly Glu Gly
435 440 445
Pro Thr Leu Ala Asn Val Ser Glu Leu Glu Leu Pro Ala Asp Pro Lys
450 455 460
Trp Glu Leu Ser Arg Ala Arg Leu Thr Leu Gly Lys Pro Leu Gly Glu
465 470 475 480
Gly Cys Phe Gly Gln Val Val Met Ala Glu Ala Ile Gly Ile Asp Lys
485 490 495
Asp Arg Ala Ala Lys Pro Val Thr Val Ala Val Lys Met Leu Lys Asp
500 505 510
Asp Ala Thr Asp Lys Asp Leu Ser Asp Leu Val Ser Glu Met Glu Met
515 520 525
Met Lys Met Ile Gly Lys His Lys Asn Ile Ile Asn Leu Leu Gly Ala
530 535 540
Cys Thr Gln Gly Gly Pro Leu Tyr Val Leu Val Glu Tyr Ala Ala Lys
545 550 555 560
Gly Asn Leu Arg Glu Phe Leu Arg Ala Arg Arg Pro Pro Gly Leu Asp
565 570 575
Tyr Ser Phe Asp Thr Cys Lys Pro Pro Glu Glu Gln Leu Thr Phe Lys
580 585 590
Asp Leu Val Ser Cys Ala Tyr Gln Val Ala Arg Gly Met Glu Tyr Leu
595 600 605
Ala Ser Gln Lys Cys Ile His Arg Asp Leu Ala Ala Arg Asn Val Leu
610 615 620
Val Thr Glu Asp Asn Val Met Lys Ile Ala Asp Phe Gly Leu Ala Arg
625 630 635 640
Asp Val His Asn Leu Asp Tyr Tyr Lys Lys Thr Thr Asn Gly Arg Leu
645 650 655
Pro Val Lys Trp Met Ala Pro Glu Ala Leu Phe Asp Arg Val Tyr Thr
660 665 670
His Gln Ser Asp Val Trp Ser Phe Gly Val Leu Leu Trp Glu Ile Phe
675 680 685
Thr Leu Gly Gly Ser Pro Tyr Pro Gly Ile Pro Val Glu Glu Leu Phe
690 695 700
Lys Leu Leu Lys Glu Gly His Arg Met Asp Lys Pro Ala Asn Cys Thr
705 710 715 720
His Asp Leu Tyr Met Ile Met Arg Glu Cys Trp His Ala Ala Pro Ser
725 730 735
Gln Arg Pro Thr Phe Lys Gln Leu Val Glu Asp Leu Asp Arg Val Leu
740 745 750
Thr Val Thr Ser Thr Asp Glu Tyr Leu Asp Leu Ser Ala Pro Phe Glu
755 760 765
Gln Tyr Ser Pro Gly Gly Gln Asp Thr Pro Ser Ser Ser Ser Ser Gly
770 775 780
Asp Asp Ser Val Phe Ala His Asp Leu Leu Pro Pro Ala Pro Pro Ser
785 790 795 800
Ser Gly Gly Ser Arg Thr
805
<210> 184
<211> 138
<212> PRT
<213> 人工序列
<220>
<223> FGFR3 D1
<400> 184
Met Gly Ala Pro Ala Cys Ala Leu Ala Leu Cys Val Ala Val Ala Ile
1 5 10 15
Val Ala Gly Ala Ser Ser Glu Ser Leu Gly Thr Glu Gln Arg Val Val
20 25 30
Gly Arg Ala Ala Glu Val Pro Gly Pro Glu Pro Gly Gln Gln Glu Gln
35 40 45
Leu Val Phe Gly Ser Gly Asp Ala Val Glu Leu Ser Cys Pro Pro Pro
50 55 60
Gly Gly Gly Pro Met Gly Pro Thr Val Trp Val Lys Asp Gly Thr Gly
65 70 75 80
Leu Val Pro Ser Glu Arg Val Leu Val Gly Pro Gln Arg Leu Gln Val
85 90 95
Leu Asn Ala Ser His Glu Asp Ser Gly Ala Tyr Ser Cys Arg Gln Arg
100 105 110
Leu Thr Gln Arg Val Leu Cys His Phe Ser Val Arg Val Thr Asp Ala
115 120 125
Pro Ser Ser Gly Asp Asp Glu Asp Gly Glu
130 135
<210> 185
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 接头
<400> 185
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 186
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 186
Asp Tyr Pro Thr Asn Glu Met Ser Arg Phe Asp Tyr
1 5 10
<210> 187
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 187
Asp Gly Pro Thr Asn Glu Met Ser Arg Phe Asp Tyr
1 5 10
<210> 188
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 188
Asp Ala Pro Met Asn Glu Met Ser Arg Phe Asp Tyr
1 5 10
<210> 189
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 189
Asp Ala Pro Thr Asn Glu Ile Ser Arg Phe Asp Tyr
1 5 10
<210> 190
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 190
Asp Ala Pro Thr Asn Glu Pro Ser Arg Phe Asp Tyr
1 5 10
<210> 191
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 191
Asp Ala Pro Thr Asn Glu Glu Ser Arg Phe Asp Tyr
1 5 10
<210> 192
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 192
Asp Gly Pro Met Asn Glu Met Ser Arg Phe Asp Tyr
1 5 10
<210> 193
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 193
Asp Gly Pro Thr Asn Glu Ile Ser Arg Phe Asp Tyr
1 5 10
<210> 194
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 194
Asp Gly Pro Thr Asn Glu Glu Ser Arg Phe Asp Tyr
1 5 10
<210> 195
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 195
Asp Ala Pro Met Asn Glu Ile Ser Arg Phe Asp Tyr
1 5 10
<210> 196
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 196
Asp Ala Pro Met Asn Glu Glu Ser Arg Phe Asp Tyr
1 5 10
<210> 197
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 197
Asp Gly Pro Met Asn Glu Ile Ser Arg Phe Asp Tyr
1 5 10
<210> 198
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 198
Asp Gly Pro Met Asn Glu Glu Ser Arg Phe Asp Tyr
1 5 10
<210> 199
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 199
Ala Val Trp Asp Tyr Ser Leu Ser Gly Tyr Val
1 5 10
<210> 200
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 200
Ala Ser Trp Asp Tyr Ser Leu Thr Gly Tyr Val
1 5 10
<210> 201
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 201
Ala Ser Trp Asp Tyr Ser Leu Asp Gly Tyr Val
1 5 10
<210> 202
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3
<400> 202
Ala Ser Trp Asp Tyr Ser Leu Glu Gly Tyr Val
1 5 10
<210> 203
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 203
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Gly Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Tyr Pro Thr Asn Glu Met Ser Arg Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 204
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 204
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Gly Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Gly Pro Thr Asn Glu Met Ser Arg Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 205
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 205
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Gly Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Ala Pro Met Asn Glu Met Ser Arg Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 206
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 206
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Gly Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Ala Pro Thr Asn Glu Ile Ser Arg Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 207
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 207
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Gly Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Ala Pro Thr Asn Glu Pro Ser Arg Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 208
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 208
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Gly Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Ala Pro Thr Asn Glu Glu Ser Arg Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 209
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 209
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Gly Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Gly Pro Met Asn Glu Met Ser Arg Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 210
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 210
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Gly Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Gly Pro Thr Asn Glu Ile Ser Arg Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 211
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 211
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Gly Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Gly Pro Thr Asn Glu Glu Ser Arg Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 212
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 212
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Gly Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Ala Pro Met Asn Glu Ile Ser Arg Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 213
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 213
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Gly Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Ala Pro Met Asn Glu Glu Ser Arg Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 214
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 214
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Gly Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Gly Pro Met Asn Glu Ile Ser Arg Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 215
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 215
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Gly Asp Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Gly Pro Met Asn Glu Glu Ser Arg Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 216
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 216
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Val Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 217
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 217
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Tyr Ser Leu
85 90 95
Thr Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 218
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 218
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Tyr Ser Leu
85 90 95
Asp Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 219
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 219
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Tyr Ser Leu
85 90 95
Glu Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
Claims (45)
1.一种与成纤维细胞生长因子受体3(FGFR3)特异性结合的抗体或其抗原结合片段,其包含:
重链CDR1,其包含选自SEQ ID NO.1至SEQ ID NO.18中的一种以上的氨基酸序列;
重链CDR2,其包含选自SEQ ID NO.19至SEQ ID NO.41中的一种以上的氨基酸序列;
重链CDR3,其包含选自SEQ ID NO.42至SEQ ID NO.66、SEQ ID NO.186至SEQ IDNO.198中的一种以上的氨基酸序列;
轻链CDR1,其包含选自SEQ ID NO.67至SEQ ID NO.88中的一种以上的氨基酸序列;
轻链CDR2,其包含选自SEQ ID NO.89至SEQ ID NO.109中的一种以上的氨基酸序列;以及
轻链CDR3,其包含选自SEQ ID NO.110至SEQ ID NO.132、SEQ ID NO.199至SEQ IDNO.202中的一种以上的氨基酸序列。
2.根据权利要求1所述的抗体或其抗原结合片段,其包含重链可变区,所述重链可变区包含选自SEQ ID NO.133至SEQ ID NO.157、SEQ ID NO.203至SEQ ID NO.215中的一种以上的氨基酸序列。
3.根据权利要求1所述的抗体或其抗原结合片段,其包含轻链可变区,所述轻链可变区包含选自SEQ ID NO.158至SEQ ID NO.182、SEQ ID NO.216至SEQ ID NO.219中的一种以上的氨基酸序列。
4.根据权利要求1所述的抗体或其抗原结合片段,其中,所述抗体包含重链可变区和轻链可变区,所述重链可变区包含SEQ ID NO.5的重链CDR1、SEQ ID NO.23的重链CDR2和选自SEQ ID NO.203至SEQ ID NO.215中的任一种的重链CDR3,所述轻链可变区包含SEQ IDNO.71的轻链CDRl、SEQ ID NO.93的轻链CDR2和选自SEQ ID NO.216至SEQ ID NO.219中的任一种的轻链CDR3。
5.根据权利要求1所述的抗体或其抗原结合片段,其包含单链Fvs(scFv)、单链抗体、Fab、F(ab′)、二硫化物连接的Fvs(sdFv)。
6.根据权利要求5所述的抗体或其抗原结合片段,其特征在于,所述scFv是通过接头连接重链可变区和轻链可变区而形成,所述重链可变区包含选自SEQ ID NO.133至SEQ IDNO.157中的一种以上的氨基酸序列,所述轻链可变区包含选自SEQ ID NO.158至SEQ IDNO.182中的一种以上的氨基酸序列。
7.根据权利要求6所述的抗体或其抗原结合片段,其中,所述接头包含(GnS)m(n、m分别为1至10)。
8.一种核酸,其编码权利要求1至7中任一项所述的抗体或其抗原结合片段。
9.一种重组表达载体,其包含权利要求8所述的核酸。
10.一种宿主细胞,其由权利要求9所述的重组表达载体转染。
11.根据权利要求10所述的宿主细胞,其中,所述宿主细胞是COS-7、BHK、CHO、CHOK1、DXB-11、DG-44、CHO/-DHFR、CV1、COS-7、HEK293、BHK、TM4、VERO、HELA、MDCK、BRL 3A、W138、Hep G2、SK-Hep、MMT、TRI、MRC 5、FS4、3T3、RIN、A549、PC12、K562、PER.C6、SP2/0、NS-0、U20S或HT1080。
12.一种与FGFR3特异性结合的抗体或其抗原结合片段的制备方法,其包括以下步骤:
培养权利要求10所述的宿主细胞,从而形成抗体;以及
分离所形成的抗体并进行提纯。
13.一种双特异性抗体或多特异性抗体,其包含权利要求1至7中任一项所述的抗体或其抗原结合片段。
14.根据权利要求13所述的双特异性抗体或多特异性抗体,其中,所述双特异性抗体或多特异性抗体包含选自PD-1、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、TIGIT、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、运铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1、MARCO中的一种以上作为配偶体。
15.一种免疫细胞接合双特异性抗体或多特异性抗体,其包含权利要求1至7中任一项所述的抗体的scFv和由第二结合域组成的scFv,所述第二结合域包含个种以上的与免疫细胞活化抗原结合的抗体的scFv。
16.根据权利要求15所述的双特异性抗体或多特异性抗体,其特征在于,所述scFv通过接头连接重链可变区和轻链可变区而形成,所述重链可变区包含选自SEQ ID NO.133至SEQID NO.157、SEQ ID NO.203至SEQ ID NO.215中的一种以上的氨基酸序列,所述轻链可变区包含选自SEQ ID NO.158至SEQ ID NO.182、SEQ ID NO.216至SEQ ID NO.219中的一种以上的氨基酸序列。
17.根据权利要求16所述的双特异性抗体或多特异性抗体,其中,所述接头包含(GnS)m(n、m分别为1至10)。
18.一种抗体-药物偶联物(ADC),其由权利要求1至7中任一项所述的抗体或其抗原结合片段与药物结合而成。
19.根据权利要求18所述的抗体-药物偶联物,其特征在于,所述药物是:
(1)抗癌剂,其选自美登素类化合物、澳瑞他汀(包含MMAE、MMAF)、氨喋呤、放线菌素、博来霉素、他利霉素、喜树碱、N8-乙酰基亚精胺、1-(2氯乙基)-1,2-二甲基磺酰肼、埃斯波霉素、依托泊苷、6-巯嘌呤、尾海兔素、单端孢霉烯、卡奇霉素、泰素、紫杉烷、紫杉醇、多烯紫杉醇、甲氨蝶呤、长春新碱、长春花碱、阿霉素、美法仑、丝裂霉素A、丝裂霉素C、苯丁酸氮芥、倍癌霉素、L-天门冬酰胺酶、巯嘌呤、硫鸟嘌呤、羟基脲、阿糖胞苷、环磷酰胺、异环磷酰胺、亚硝基脲、顺铂、卡铂、丝裂霉素、达卡巴嗪、甲基苄肼、托泊替康、氮芥、环磷酰胺、依托泊苷、5-氟尿嘧啶、双氯乙基亚硝基脲(CNU)、伊立替康、喜树碱、博来霉素、伊达比星、道诺霉素、更生霉素、普卡霉素、米托蒽醌、天门冬酰胺酶、长春瑞滨、苯丁酸氮芥、美法仑、卡莫司汀、洛莫司汀、白消安、曲奥舒凡、氮烯咪胺、依托泊苷、替尼泊苷、托泊替康、9-氨基喜树碱、克立那托、丝裂霉素C、三甲曲沙、霉酚酸、噻唑呋啉、利巴韦林、5-乙炔基-1-β-D-呋喃核糖基咪唑-4-羧酰胺(EICAR)、硫酸羟脲、去铁胺、氟尿苷、去氧氟尿苷、雷替曲塞、阿糖胞苷(araC)、胞嘧啶阿拉伯糖苷、氟达拉滨、他莫昔芬、雷洛昔芬、甲地孕酮、戈舍瑞林、醋酸亮丙瑞林、氟他胺、比卡鲁胺、EB1089、CB1093、KH1060、维替泊芬、酞菁、光敏剂Pe4、去甲氧基-竹红菌素A、干扰素-α、干扰素-γ、肿瘤坏死因子、吉西他滨、万珂、瑞米德、泰拉米德、洛伐他汀、1-甲基-4-苯基吡啶鎓离子、星形孢菌素、放线菌素D、更生霉素、博来霉素A2、博来霉素B2、培洛霉素、表阿霉素、吡柔比星、佐柔比星、米托蒽醌、维拉帕米以及毒胡萝卜素、核酸酶和源自细菌或动植物的毒素中的一种以上;
(2)抗炎药,其包含类固醇制剂、非甾体抗炎药(NSAIDs)或免疫特异性抗炎药(ImSAIDs);或者
(3)免疫疾病治疗剂,其包含咪唑硫嘌呤、苯丁酸氮芥、环磷酰胺、环孢素、麦考酚酯、咪唑硫嘌呤或甲氨蝶呤。
20.根据权利要求18所述的抗体-药物偶联物,其特征在于,所述抗体或其抗原结合片段通过接头与药物结合。
21.根据权利要求20所述的抗体-药物偶联物,其特征在于,所述接头是可切割接头或不可切割接头。
22.根据权利要求21所述的抗体-药物偶联物,其特征在于,所述可切割接头是酸不稳定接头、二硫化物接头、肽接头或β-葡糖苷酸接头,或者所述不可切割接头包含硫醚基或马来酰亚胺己酰基。
23.根据权利要求20所述的抗体-药物偶联物,其特征在于,所述接头结合在抗体的二硫键还原时暴露的半胱氨酸残基或者结合在与抗体结合的标签上存在的半胱氨酸残基。
24.一种嵌合抗原受体,其特征在于,所述嵌合抗原受体(CAR)包含:包含抗原结合部位的细胞外结构域、跨膜结构域和细胞内信号传导结构域,所述细胞外结构域的抗原结合部位是权利要求1至7中任一项所述的抗体的scFv。
25.根据权利要求24所述的组合物,其特征在于,所述scFv是通过接头连接重链可变区和轻链可变区而形成的,所述重链可变区包含选自SEQ ID NO.133至SEQ ID NO.157中的一种以上的氨基酸序列,所述轻链可变区包含选自SEQ ID NO.158至SEQ ID NO.182中的一种以上的氨基酸序列。
26.根据权利要求25所述的组合物,其中,所述接头包含(GnS)m(n、m分别为1至10)。
27.一种免疫细胞,其中,所述免疫细胞中导入有权利要求24所述的嵌合抗原受体(CAR)。
28.根据权利要求27所述的免疫细胞,其中,所述免疫细胞是选自T细胞、NK细胞、细胞因子诱导的杀伤细胞(CIK)、活化的细胞毒性T淋巴细胞(CTL)、巨噬细胞、肿瘤浸润T细胞(肿瘤浸润淋巴细胞,TIL)、树突状细胞中的一种以上。
29.根据权利要求27所述的免疫细胞,其中,所述免疫细胞中进一步导入有嵌合抗原受体(CAR),所述嵌合抗原受体包含对于除所述抗-FGFR3抗体之外的抗体的scFv作为细胞外结构域的抗原结合部位。
30.根据权利要求29所述的免疫细胞,其中,所述除抗-FGFR3抗体之外的抗体靶向选自PD-1、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、TIGIT、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、运铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1、MARCO中的一种以上。
31.一种联合治疗用组合物,其包含权利要求27所述的免疫细胞和除抗-FGFR3抗体之外的药物。
32.根据权利要求31所述的组合物,其中,所述除抗-FGFR3抗体之外的药物靶向选自PD-1、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、TIGIT、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、运铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1、MARCO中的一种以上。
33.一种联合治疗用组合物,其包含权利要求1至7中任一项所述的抗体或其抗原结合片段,以及选自(i)免疫细胞;(ii)包含抗原受体(CAR)的免疫细胞,所述抗原受体包含对于除抗-FGFR3抗体之外的抗体的scFv作为细胞外结构域;以及(iii)免疫检查点抑制剂中的一种以上。
34.根据权利要求33所述的组合物,其中,所述免疫细胞是选自T细胞、NK细胞、细胞因子诱导的杀伤细胞(CIK)、活化的细胞毒性T淋巴细胞(CTL)、巨噬细胞、肿瘤浸润T细胞(肿瘤浸润淋巴细胞,TIL),树突状细胞中的一种以上。
35.根据权利要求33所述的组合物,其中,所述除抗-FGFR3抗体之外的抗体靶向选自PD-1、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、TIGIT、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、运铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1、MARCO中的一种以上。
36.根据权利要求33所述的组合物,其中,所述免疫检查点抑制剂是靶向选自PD-1、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、TIGIT、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、运铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1、MARCO中的一种以上的药物。
37.一种联合治疗用组合物,其包含权利要求13所述的双特异性抗体或多特异性抗体,以及选自(i)免疫细胞;(ii)包含抗原受体(CAR)的免疫细胞,所述抗原受体包含对于除抗-FGFR3抗体之外的抗体的scFv片段作为细胞外结构域;以及(iii)免疫检查点抑制剂中的一种以上。
38.根据权利要求37所述的组合物,其中,所述除抗-FGFR3抗体之外的抗体靶向选自PD-1、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、TIGIT、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、运铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1、MARCO中的一种以上。
39.根据权利要求37所述的组合物,其中,所述免疫检查点抑制剂是靶向选自PD-1、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、TIGIT、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、运铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1、MARCO中的一种以上的药物。
40.一种用于治疗癌症、炎症或免疫疾病的组合物,其包含:权利要求1至7中任一项所述的抗体或其抗原结合片段、包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体、包含所述抗体或其抗原结合片段的抗体-药物偶联物、包含所述抗体或其抗原结合片段的嵌合抗原受体或包含所述嵌合抗原受体的免疫细胞。
41.一种用于治疗癌症、炎症或免疫疾病的组合物,其包含:权利要求1至7中任一项所述的抗体或其抗原结合片段、包含所述抗体或其抗原结合片段的抗体-药物偶联物。
42.一种用于治疗癌症、炎症或免疫疾病的组合物,其用于治疗确认为FGFR3和TACC3的融合基因扩增、融合基因存在变异、融合基因过表达或者融合基因一直在表达(组成性激活)的癌症,并且所述组合物包含:权利要求1至7中任一项所述的抗体或其抗原结合片段、包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体、抗体-药物偶联物、嵌合抗原受体或者包含所述嵌合抗原受体的免疫细胞。
43.一种癌症、炎症或免疫疾病的治疗方法,其包括以下步骤:
在源自患者的样品中确认FGFR3和TACC3的融合基因扩增、融合基因存在变异、融合基因过表达或者融合基因一直在表达(组成性激活);
在确认FGFR3和TACC3的融合基因扩增、融合基因存在变异、融合基因过表达或融合基因一直在表达(组成性激活)的情况下,施用权利要求1至7中任一项所述的抗体或其抗原结合片段、包含所述抗体或其抗原结合片段的双特异性抗体或多特异性抗体、抗体-药物偶联物、嵌合抗原受体或包含所述嵌合抗原受体的免疫细胞。
44.一种囊泡,其中,权利要求1至7中任一项所述的抗体或其抗原结合片段表露在所述囊泡的外部或者存在于所述囊泡的内部。
45.根据权利要求44所述的囊泡,其中,所述囊泡为外泌体。
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AU2022205325A1 (en) | 2023-08-24 |
US20240101684A1 (en) | 2024-03-28 |
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CA3204209A1 (en) | 2022-07-14 |
WO2022149837A1 (ko) | 2022-07-14 |
EP4276112A1 (en) | 2023-11-15 |
CN116981693A (zh) | 2023-10-31 |
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