CN111944048A - 抗cldn抗体及其药物组合物和检测方法 - Google Patents
抗cldn抗体及其药物组合物和检测方法 Download PDFInfo
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Abstract
本发明提供一种抗CLDN抗体及其药物组合物和检测方法,其中,所述抗体的重链包含一种或一种以上的CDR,重链的CDR与SEQ ID No.1至SEQ ID No.7中或者SEQ ID No.15至SEQ ID No.30中的任意一条的CDR序列相比,相差不多于三个氨基酸,所述抗体的轻链包含一种或一种以上的CDR,轻链的CDR与SEQ ID No.8至SEQ ID No.14中或者SEQ ID No.31至SEQ ID No.46中的任意一条的CDR序列相比,相差不多于三个氨基酸。本发明的抗CLDN抗体,与细胞系及肿瘤组织细胞结合的能力较IMAB362强,并且抗肿瘤效果较IMAB362强。
Description
技术领域
本发明涉及一种抗CLDN抗体,本发明还涉及一种包含抗CLDN抗体的药物组合物,本发 明还涉及检测生物样品中是否存在CLDN的方法。
背景技术
紧密连接(tight junction,TJ)在细胞间物质流转中起到关键作用,还通过阻断膜蛋白和膜脂 径向扩散维持细胞极性,此外还参与招募调控细胞增殖、分化和运动的信号分子。紧密连接由 紧密连接蛋白(Claudin,CLDN)形成,而紧密连接蛋白家族由超过20种蛋白分子组成,其成员 均含有一个四次跨膜的结构域和相似的氨基酸序列,但组织分布具有一定特异性。人类CLDN 基因以成对形式分布在不同染色体上,这暗示了某些CLDN基因来源于基因复制。
CLDN蛋白分子量大多处于20-34kDa范围内,最大区别是胞内C-端的序列和大小,该段序 列包含1个PDZ结构域结合基序,该基序使得CLDN蛋白能够直接和胞质内的紧密连接相关蛋 白,如ZO-1、ZO-2、ZO-3以及MUPP1相互作用。此外,这段序列种含有磷酸化位点等转录后 修饰位点,能够影响蛋白分子的定位和功能。MAPK(mitogen-activated proteinkinase)或者PKC (protein kinase C)能够磷酸化CLDN1,cAMP(cyclic AMP)诱导CLDN5磷酸化,都能促进 CLDN蛋白的屏障功能,而PKA介导的CLDN16磷酸化则能增强镁离子运输。
CLDN在调控细胞旁路的选择性渗透中起到关键作用,CLDN2和CLDN15参与形成阳离子 通道和阳离子孔隙,CLDN4/7/10则参与构成阴离子通道和孔隙。在某些细胞系中claudin蛋白 高表达,从而影响跨膜电阻和渗透性。在培养的表皮来源细胞中,CLDN1/4/5/7能够提高跨膜电 阻,而CLDN2和CLDN10反之。
CLDN基因突变被认为与多种疾病有关。CLDN1突变可能会导致硬化性胆管炎(sclerosing cholangitis)和鱼鳞癣(ichthyosis),CLDN16和CLDN19突变则被认为与低镁症(hypomagnesemia) 和高钙尿症(hypercalcinuria)有关。
CLDN蛋白的差异性表达被认为与多种癌症相关联。CLDN1和CLDN7在侵入性乳腺癌、 前列腺癌和食管癌中发生下调,而在宫颈癌、结肠癌、食管癌、胃癌等多种癌症中发现CLDN3/4 发生不同程度上调。Sahin等发现在正常组织中,CLDN18的isoform 2亚型(CLDN18.2)只在 胃黏膜的分化后表皮细胞中表达,在胃干细胞区域则未见表达,但在原发性胃癌及其转移灶中 均发现异常高表达。在胰腺癌、食管癌和肺癌中也有CLDN18.2高表达的报道。由于CLDN18.2 定位于细胞膜表面,其生物学功能和特征决定了它是一种理想的治疗靶点,而近年来针对该靶 点也有单抗面世,其中发展最快的是Ganymed公司的IMAB362(Claudiximab)。IMAB362在 肿瘤细胞表面结合CLDN18.2,诱导抗体依赖的细胞毒性作用(antibody-dependent cytotoxicity, ADCC)和补体依赖的细胞毒性作用(complementdependent cytotoxicity,CDC)从而杀伤肿瘤 细胞。而与化疗结合使用时,IMAB362还能增强T细胞浸润及上调促炎症因子。
发明内容
本发明的目的在于提供一种抗CLDN抗体及其药物组合物和检测方法。
本发明采用了如下技术方案:
一种抗CLDN抗体,其特征在于,包括重链和轻链:
其中,抗体的重链包含一种或一种以上的CDR,重链的CDR与SEQ ID No.1至SEQ IDNo.7 中或者SEQ IDNo.15至SEQ ID No.30中的任意一条的CDR序列相比,相差不多于三个氨基酸,
抗体的轻链包含一种或一种以上的CDR,轻链的CDR与SEQ ID No.8至SEQ IDNo.14中 或者SEQ ID No.31至SEQ ID No.46中的任意一条的CDR序列相比,相差不多于三个氨基酸。
进一步,本发明的抗CLDN抗体,还具有这样的特征:抗体的重链选自SEQ ID No.1至No.7 中的任意一条。
进一步,本发明的抗CLDN抗体,还具有这样的特征:抗体的轻链选自如SEQ IDNo.8至SEQ ID No.14中或者SEQ ID No.31至SEQ ID No.46中的任意一条。
进一步,本发明的抗CLDN抗体,还具有这样的特征:抗体的重链选自SEQ ID No.15至 SEQ ID No.30中的任意一条。
进一步,本发明的抗CLDN抗体,还具有这样的特征:抗体的轻链选自SEQ ID No.31至 SEQ ID No.46中的任意一条。
进一步,本发明的抗CLDN抗体,还具有这样的特征:其中,抗体的重链和轻链的组合有:
SEQ ID No.1和SEQ ID N0.8,SEQ ID No.2和SEQ ID N0.9,SEQ ID No.3和SEQ IDNo.10,
SEQ ID No.4和SEQ ID No.11,SEQ ID No.5和SEQ ID No.12,SEQ ID No.6和SEQID No.13,
SEQ ID No.7和SEQ ID No.14,SEQ ID No.15和SEQ ID No.31,SEQ ID No.16和SEQ ID No.32,
SEQ ID No.17和SEQ ID No.33,SEQ ID No.18和SEQ ID No.34,SEQ ID No.19和SEQ ID No.35,
SEQ ID No.20和SEQ ID No.36,SEQ ID No.21和SEQ ID No.37,SEQ ID No.22和SEQ ID No.38,
SEQ ID No.23和SEQ ID No.39,SEQ ID No.24和SEQ ID No.40,SEQ ID No.25和SEQ ID No.41,
SEQ ID No.26和SEQ ID No.42,SEQ ID No.27和SEQ ID No.43,SEQ ID No.28和SEQ ID No.44,
SEQ ID No.29和SEQ ID No.45,SEQ ID No.30和SEQ ID No.46。
本发明还提供一种编码如上所述的抗体的多核苷酸。
本发明还提供一种包含上述任意一项所述的抗体的药物组合物。
本发明还提供上述任意一项所述的抗体,在制备抗肿瘤药物中的应用。
本发明还提供一种检测生物样品中是否存在CLDN的方法,其特征在于,包括:给予生物 样品如上述任意一项所述的抗体的步骤,其中所述抗体具有可检测标志物,以及检测是否存在 所述可检测标志物,或者检测所述可检测标志物含量的步骤。
发明的有益效果
本发明的抗CLDN抗体,与细胞结合的能力较IMAB362强。并且本发明的抗体比IMAB362 在体内动物药效中表现出更好的抑制肿瘤生长的效果。
附图说明
图1a是对照抗体QP024025对CHOS细胞的结合能力
图1b是杂交瘤筛选出的抗体QP188189对CHOS细胞的结合能力
图1c是杂交瘤筛选出的抗体QP190191对CHOS细胞的结合能力
图1d是杂交瘤筛选出的抗体QP192193对CHOS细胞的结合能力
图1e是杂交瘤筛选出的抗体QP196198对CHOS细胞的结合能力
图1f是杂交瘤筛选出的抗体QP199200对CHOS细胞的结合能力
图1g是杂交瘤筛选出的抗体QP201202对CHOS细胞的结合能力
图1h是杂交瘤筛选出的抗体QP207208对CHOS细胞的结合能力
图2a是噬菌体筛选出的抗体QP10731074对CHOS细胞的结合能力。
图2b是噬菌体筛选出的抗体QP10791080对CHOS细胞的结合能力。
图2c是噬菌体筛选出的抗体QP10851086对CHOS细胞的结合能力。
图2d是噬菌体筛选出的抗体QP10911092对CHOS细胞的结合能力。
图2e是噬菌体筛选出的抗体QP10971098对CHOS细胞的结合能力。
图2f是噬菌体筛选出的抗体QP10991100对CHOS细胞的结合能力。
图3a是噬菌体筛选出的抗体QP11051106对CHOS细胞的结合能力。
图3b是噬菌体筛选出的抗体QP11071108对CHOS细胞的结合能力。
图3c是噬菌体筛选出的抗体QP11091110对CHOS细胞的结合能力。
图3d是噬菌体筛选出的抗体QP11111112对CHOS细胞的结合能力。
图3e是噬菌体筛选出的抗体QP11131114对CHOS细胞的结合能力。
图3f是噬菌体筛选出的抗体QP11151116对CHOS细胞的结合能力。
图4a是噬菌体筛选出的抗体QP11171118对CHOS细胞的结合能力。
图4b是噬菌体筛选出的抗体QP11031104对CHOS细胞的结合能力。
图4c是噬菌体筛选出的抗体QP10451046对CHOS细胞的结合能力。
图4d是噬菌体筛选出的抗体QP10471048对CHOS细胞的结合能力。
图5a是对照抗体QP024025对不同293T瞬转细胞株的结合能力。
图5b是杂交瘤筛选出的抗体QP188189对不同293T瞬转细胞株的结合能力
图5c是杂交瘤筛选出的抗体QP190191对不同293T瞬转细胞株的结合能力
图5d是杂交瘤筛选出的抗体QP192193对不同293T瞬转细胞株的结合能力。
图5e是杂交瘤筛选出的抗体QP196198对不同293T瞬转细胞株的结合能力。
图5f是杂交瘤筛选出的抗体QP199200对不同293T瞬转细胞株的结合能力。
图5g是杂交瘤筛选出的抗体QP201202对不同293T瞬转细胞株的结合能力。
图5h是杂交瘤筛选出的抗体QP207208对不同293T瞬转细胞株的结合能力。
图6a是噬菌体筛选出的抗体QP10451046对不同293T瞬转细胞株的结合能力。
图6b是噬菌体筛选出的抗体QP10711072对不同293T瞬转细胞株的结合能力。
图6c是噬菌体筛选出的抗体QP10731074对不同293T瞬转细胞株的结合能力。
图6d是噬菌体筛选出的抗体QP10851086对不同293T瞬转细胞株的结合能力。
图6e是噬菌体筛选出的抗体QP10911092对不同293T瞬转细胞株的结合能力。
图6f是噬菌体筛选出的抗体QP10991100对不同293T瞬转细胞株的结合能力。
图6g是噬菌体筛选出的抗体QP11031104对不同293T瞬转细胞株的结合能力。
图6h是噬菌体筛选出的抗体QP11051106对不同293T瞬转细胞株的结合能力。
图7a是噬菌体筛选出的抗体QP11071108对不同293T瞬转细胞株的结合能力。
图7b是噬菌体筛选出的抗体QP11091110对不同293T瞬转细胞株的结合能力。
图7c是噬菌体筛选出的抗体QP11111112对不同293T瞬转细胞株的结合能力。
图7d是噬菌体筛选出的抗体QP11131114对不同293T瞬转细胞株的结合能力。
图7e是噬菌体筛选出的抗体QP11151116对不同293T瞬转细胞株的结合能力。
图7f是噬菌体筛选出的抗体QP11171118对不同293T瞬转细胞株的结合能力。
图8a是对照抗体与胃癌PDX模型GA0006肿瘤细胞结合能力实验中,对照组IMAB362的曲线。
图8b是抗体与胃癌PDX模型GA0006肿瘤细胞结合能力实验中QP190191的曲线。
图8c是抗体与胃癌PDX模型GA0006肿瘤细胞结合能力实验中QP192193的曲线。
图8d是抗体与胃癌PDX模型GA0006肿瘤细胞结合能力实验中QP201202的曲线。
图8e是抗体与胃癌PDX模型GA0006肿瘤细胞结合能力实验中QP207208的曲线。
图8f是抗体与胃癌PDX模型GA0006肿瘤细胞结合能力实验中QP11091110的曲线。
图8g是抗体与胃癌PDX模型GA0006肿瘤细胞结合能力实验中QP11131114的曲线。
图8h是抗体与胃癌PDX模型GA0006肿瘤细胞结合能力实验中QP11151116的曲线。
图9是抗体对胃癌PDX模型GA0006的药效试验。
图10A是PBS组(阴性对照)处理在分组后的肿瘤生长曲线。
图10B是QP192193组处理在分组后的肿瘤生长曲线。
图10C是QP207208组处理在分组后的肿瘤生长曲线。
图10D是QP11151116组处理在分组后的肿瘤生长曲线。
图10E是对照抗体IMAB362组处理在分组后的肿瘤生长曲线。
图11是加入本发明各抗体及对照抗体各组小鼠肿瘤D31重量。
图12是各实验组的肿瘤体积实拍图。
图13是各组小鼠的体重曲线。
图14是各组小鼠的体重变化率曲线。
具体实施方式
以下结合附图来说明本发明的具体实施方式。
本发明的抗体,包括但不限于人源抗体。本发明中所提供的各种抗体的筛选方法,通常优 先采用较为便利的杂交瘤筛选抗体,然而这个靶点的抗原(claudin18.2)较难获得,因此也同 时采用了噬菌体库筛选抗体。本实施方式中筛选得到的抗claudin18.2的抗体序列如下所示:
杂交瘤筛选的抗体,重链可变区(VH)CDR如序列中带下划线的部分所示
>QP189
QVQLQQSGAELVKPGASVKLSCKASGYTFTSYGINWVRQRPEQGLEWIGWLFPGDGTIKYNENFKGKATLTTDRSSSAAYMQLSRLTSEDSAVYFCARGGYYGNAMDYWGQGTSVTVSS
>QP191
EVKLVESGGGLVKPGGSLKLSCAASGFTFSNYAMSWVRQTPEKRLEWVASIISGGRTYYLDSEKGRFTISRDNARNNLYLQMSSLRSEDTAMYYCTRIYYGNSFDYWGQGTTLTVSS
>QD193
QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIYPGNGDTTYNGKFKGQATLTADKSSSTVYMQLSSLTSEDSAVYFCARFVKGNAMDYWGQGTSVTVSS
>QD198
QVQLKESGPGLVAPSQSLSITCTVSGFSLTIYGVHWVRQPPGRGLEWLGVIWAGGSTNYNSALMSRLSISKDNSKSQVFLKVNSLQTDDTAMYYCARDYYYGSGFDYWGQGTTLTVSS
>QD200
DVQLVESGGGLVQPGGSRKLSCAASGFTFSSFGMHWVRQAPEKGLEWVAYISSGSNSIYYVDTVKGRFTISRDNPKNTLFLQMTSLKSEDTAMYYCARNAYYGNSFDYWGQGTTLTVSS
>QD202
EVQLQQSGPELVKPGASVKMSCKASGYTFTNYFVHWVKQKPGQGLEWIGYINPYNDDTKYNEKFKGKATLTSDKSSSTAYMDLSSLTSEDSAVYYCLSLRFFAYWGQGTLVTVSA
>QD208
EVQLQQSGPELVKPGASVKMSCKASGYTFTSYIMHWVKQKPGQGLEWIGYINPYNDGTKYNEKFKGKATLTSDKSSSTVYMELSSLTSEDSAVYCCARLGFTTRNAMDYWGQGTSVTVSS
轻链序列:
其中,轻链可变区(VL)CDR如序列中带下划线的部分所示。
>QD188
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKSYLTWYQQKPGQPPKLLIYWASTRESG VPDRFTGSGSGTDFTLTISSVQAEDLAVYFCQNDYFYPYTFGGGTKLEIK
>QD190
DIVMTQSPSSQTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESG VPDRFTGSGSGTDFTLTISNMQAEDLAVYYCQNDYSYPFTFGSGTKLEIK
>QD192
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQNPGQPPKMLIYWASTRES GVPDRFTGSGSGIDFSLTISSVQAEDLALYYCQNAYSYPFTFGSGTKLEIK
>QD196
DIVMTQSPSSLSVSAGEKVTMSCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYGASTRESG VPDRFTGSGSGTDFTLTISSVRAEDLAVYYCQNDHYYPFTFGSGTKLEIK
>QD199
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESG VPDRFTGSGSGTVFTLTISSVQAEDLAVYFCQNNYYYPLTFGAGTKLELK
>QD201
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQAPKLLIYWASTRESG VPDRFIGSGSGTDFTLTISHVQAEDLAVYFCQNDYSYPLTFGAGTNLELK
>QD207
DIVMTQSPSSLSVSAGEKVTMNCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYGASTRESG VPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDHSYPFTFGSGTKLEIK
噬菌体库筛选的抗体,重链可变区(VH)CDR如序列中带下划线的部分所示
>QD1045
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDYAFTGFDYWGQGTLVTVSS
>QD1047
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSSAYGTYSMDYWGQGTLVTVSS
>QD1073
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTGVYYCARGSGSWFGPYFDYWGQGTTVTVSS
>QD1079
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARTDGATPFDYWGQGTTVTVSS
>QD1085
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARRSYYGTGAFDYWGQGTTVTVSS
>QD1091
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSLGYFSGLAFDYWGQGTTVTVSS
>QD1097
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGYNWSFGMDYWGQGTTVTVSS
>QD1099
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARAGYFPRSLDYWGQGTTVTVSS
>QD1103
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGYSWYWLFGFDYWGQGTTVTVSS
>QD1105
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGGDWGGYMDYWGQGTTVTVSS
>QD1107
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDYYYYFWFDYWGQGTLVTVSS
>QD1109
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDYYYYYWFDYWGQGTLVTVSS
>QD1111
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGYYYYFWFDYWGQGTLVTVSS
>QD1113
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSAAYYYFWFDYWGQGTLVTVSS
>QD1115
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSYYYYFWYDYWGQGTLVTVSS
>QD1117
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKAIDYYTFDYWGQGTLVTVSS
轻链序列:
其中,轻链可变区(VL)CDR如序列中带下划线的部分所示。
>QD1046
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVP DRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALMTPTFGQGTKVEIK
>QD1048
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVP DRFSGSGSGTDFTLKISRVEAEDVGVYYCMQDLWPRTFGQGTKVEIK
>QD1074
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVP DRFSGSGSGTDFTLKISRVEAEDVGVYYCMQAAQSPTFGQGTKVEIK
>QD1080
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVP DRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALNTPPTFGQGTKVEIK
>QD1086
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVT DRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALMTPTFGQGTKVEIK
>QD1092
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVP DRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGRQFPTFGQGTKVEIK
>QD1098
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVP DRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGLNTFTFGQGTKVEIK
>QD1100
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVP DRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQWDTFGQGTKVEIK
>QD1104
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVP DRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTGTFGQGTKVEIK
>QD1106
DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESG VPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYTTPFTFGQGTKVEIK
>QD1108
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGS GSGTEFTLTISSLQPDDFATYYCQQYNSYSTFGQGTKVEIK
>QD1110
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGS GSGTEFTLTISSLQPDDFATYYCQQYSSYSPTFGQGTKVEIK
>QD1112
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGS GSGTKFTLTISSLQPDDFATYYCQQYSTYPLTFGQGTKVEIK
>QD1114
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGS GSGTEFTLTISSLQPDDFATYYCQQYLSYPPTFGQGTKVEIK
>QD1116
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGS GSGTEFTLTISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK
>QD1118
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGS GSGTEFTLTISSLQPDDFATYYCQQYSTYPLTFGQGTKVEVK
抗体结合能力实验:
实验一:FACS检测抗体对肿瘤细胞系结合能力
a)1.96孔板铺细胞,每孔2×105个细胞,1000×rpm离心5分钟,1×PBS细胞清洗一次, 吸去上清多余液体;
b)加入3%BSA-PBS溶液封闭细胞,4℃封闭60分钟;
c)封闭液稀释待测抗体至5ug/ml,加入到孔中,4℃孵育60分钟;
d)吸去抗体,每孔220ul 1×PBS细胞清洗三次;
e)每孔加入50ul PE-anti-human FC(1:200稀释)二抗,4℃避光孵育40分钟;
f)吸去抗体,每孔1×PBS细胞清洗四次;
g)上机检测。
实验二:FACS检测抗体对PDX组织肿瘤细胞结合能力
a)每个瘤子准备一个gentleMACSTM C Tube和3ml消化液,消化液按照TumorDissociation Kit(miltenyibiotech,130-096-730)说明书配制,现配现用;
b)处死小鼠,用洁净工具取瘤,1×PBS清洗后去除附着在肿瘤表面的血管、脂肪、筋膜等 组织。每根消化管可消化不大于0.8g的肿瘤组织,以保证肿瘤组织被消化液完全消化;
c)将肿瘤组织置于6孔板的孔中,加入消化液,用洁净镊子和解剖刀将肿瘤组织切割为约 1mm3小块;
d)将组织块放入gentleMACSTM C Tube,使用残留消化液清洗孔板并一起转移至消化管中, 放置于冰面上;
e)将消化管倒置放入gentleMACS全自动组织处理器,选择程序37_c_m_TDK_1进行消化。 程序结束后,取下消化管,300×g瞬时离心收集细胞和剩余组织;
f)弃上清,用1×PBS重悬细胞和组织,将细胞悬液加至细胞过滤网上,置于50ml离心管 中,用10ml PBS使悬液过筛网成为单细胞悬液;
g)300×g离心5分钟,去上清,5ml PBS重悬,细胞计数并调整细胞浓度至每份样品1×106个细胞;
h)每份样品加入100ul浓度为1μg/ml Mouse BD Fc Block(CAT#553141)PBS溶液重悬细 胞,加入20ul human FcR Blocking Reagent,混匀,室温避光孵育10分钟;
i)加入5ug/ml一抗,4℃避光孵育60分钟;
j)加入2ml FACS wash buffer,轻柔重悬细胞,300×g离心5分钟,去上清,重复2次;
k)加入100ul含PE标记的human IgG Fc二抗和染料的FACS wash buffer避光孵育细胞60 分钟;
l)加入2ml FACS wash buffer,轻柔重悬细胞,300×g离心5分钟,去上清,重复2次;
m)200ul FACS wash buffer重悬细胞,上机检测。
实验附图中hybridoma clone in CHOS system和phage clone in CHOS system即分别指杂交瘤 和噬菌体筛选出的抗体对CHOS细胞的结合能力。图中的CHO18.2:CHOS-CLDN18.2稳转细 胞,CHO18.1:CHOS-CLDN18.1稳转细胞,CHOS:CHOS转染空载体。
CHOS是仓鼠卵巢细胞永生化得到的细胞系,使用FACS(流式细胞荧光分选技术)来检测 抗体对细胞系结合能力。
图1a到图1h显示了杂交瘤筛选出的抗体对CHOS细胞的结合能力。
图2a到图2f,图3a到图3f以及图4a到图4d显示了噬菌体筛选出的抗体对CHOS细胞的 结合能力。
实验目的:在CHOS细胞系中验证抗体与claudin18.1(非特异性结合)和claudin18.2的结 合能力。
在CHOS细胞系的附图中,每一个panel由一种待测抗体对3种CHOS细胞系的FACS检测结果组合而成,其中:
1.红色曲线③,表明待测抗体对转染空载体的CHOS细胞系(CHOS)的结合能力,即阴性对 照;
2.蓝色曲线②,表明待测抗体对转染claudin18.1的CHOS细胞系(CHO18.1)的结合能力, 即检测非特异性结合;
3.黄色曲线①,表明待测抗体对转染claudin18.2的CHOS细胞系(CHO18.2)的结合能力, 即检测目的蛋白结合能力。
图5a到图5h,显示了杂交瘤筛选出的抗体对293T细胞的结合能力。
图6a到图6h以及图7a到图7f显示了噬菌体筛选出的抗体对CHOS细胞的结合能力。
图中,293T-QD012:293T-CLDN18.1瞬转细胞
293T-QD010:293T-CLDN18.2瞬转细胞
实验目的:在293-T细胞系中验证抗体与claudin18.1(非特异性结合)和claudin18.2的结 合能力。
293T-QD210:293T-CLDN18.2-18.1ECD1瞬转细胞;CLDN18.2的第1个胞外结构域更换为 18.1的第1个胞外结构域
293T-QD211:293T-CLDN18.1-18.2ECD1瞬转细胞;CLDN18.1的第1个胞外结构域更换为 18.2的第1个胞外结构域
实验目的:在293-T细胞系中验证抗体结合区域是claudin18.2的exon-1编码的结构域。
hybridom clone in 293T及phage clone in 293T同理分别指杂交瘤和噬菌体筛选出的抗体对不 同293T瞬转细胞株的结合能力。
在293T中实验目的与在CHO细胞系中相同,各个曲线及其代表的涵义解释如下。
1.红色曲线⑤,表明待测抗体对瞬转空载体的293T细胞系的结合能力,即阴性对照;
2.蓝色曲线④,表明待测抗体对瞬转claudin18.2的293T细胞系(293T-QD010)的结合,检测 目的蛋白结合能力;
3.橙色曲线③,表明待测抗体对瞬转claudin18.1的293T细胞系(293T-QD012)的结合,检测 非特异性结合;
4.深绿曲线②,表明待测抗体对瞬转claudin18.1-18.2ECD1(CLDN18.1的第1个胞外结构域 更换为18.2的第1个胞外结构域,后者是设计抗体结合位点所在区域)的293T细胞系 (293T-QD211)的结合,验证抗体结合位点所在结构域;
5.浅绿曲线①,表明待测抗体对瞬转claudin18.2-18.1ECD1(CLDN18.2的第1个胞外结构域 更换为18.1的第1个胞外结构域,前者是设计抗体结合位点所在区域)的293T细胞系 (293T-QD210)的结合,验证该结构域对抗体结合的必要性。
图8a到图8h显示了抗体与胃癌PDX模型GA0006肿瘤细胞结合能力实验。
表1:抗体与胃癌PDX模型GA0006肿瘤细胞结合比例
以上实验结果表明,本发明所提供的抗体,与蛋白的结合能力更好,并且非特异性结合的 情况较低。
在其它的实施方式中,本发明还提供一种编码如上所述的抗体的多核苷酸,这些编码本发 明所提供的抗体的多核苷酸,当是以DNA的形式提供时,其可以包含在后续的转录和编辑过程 中会被去除的非编码序列,也可以只包含编码与本发明实施例中所提供的抗体相对应的序列以 及在进行蛋白表达时所必须的序列。
本发明还提供一种包含上述任意一项所述的抗体的药物组合物,本发明所提供的药物组合 物,可以仅包含实施方式中所提供抗体中的任意一种或者至少两种的组合物。
本领域的技术人员应当清楚的是,对于药物组合物,还包含药物上可接受的赋形剂,利用 制成粉剂或者片剂等其它剂型所需要的常规赋形剂均应当作为制药过程中所应当添加的成分。
本发明还提供一种检测生物样品中是否存在CLDN的方法,其特征在于,包括:
给予生物样品如上述任意一项所述的抗体的步骤,其中所述抗体具有可检测标志物,以及 检测是否存在所述可检测标志物,或者检测所述可检测标志物含量的步骤。
动物药效试验
a)从胃癌异种移植模型GA0006荷瘤小鼠收取肿瘤组织,切成直径为2-3mm的瘤块接种 于Balb/c裸小鼠右前肩胛处皮下;
b)当Balb/c裸小鼠平均肿瘤体积到达约100mm3时,将小鼠随机分组,每组6只。称量 所有动物的体重,并用游标卡尺测量肿瘤体积。根据肿瘤体积,采用随机分组方法进 行分组,保证不同组别间的肿瘤体积相似。各组内的肿瘤体积的变异系数(CV)用公式 CV=SD/MTV×100%计算,应小于40%。随机分组使用StudyDirectorTM完成。分组 当天为D0,并于当天开始给药。详细的给药方法、给药剂量和给药途径见下表。
表2:动物药效试验的给药参数
组别 | 动物数 | 给药组 | 剂量(mg/kg) | 给药方式 | 给药周期 |
1 | 6 | Vehicle control | -- | i.p. | BIW×4周 |
2 | 6 | QP192193 | 10 | i.p. | BIW×4周 |
3 | 6 | QP207208 | 10 | i.p. | BIW×4周 |
4 | 6 | QP11151116 | 10 | i.p. | BIW×4周 |
5 | 6 | IMAB362 | 10 | i.p. | BIW×4周 |
给药体积为10μL/g.
表1和表2中的抗体编号的含义,例如QP190191,表示一条重链和一条轻链的组合。
c)开始给药后,每周测量两次小鼠体重和肿瘤体积。肿瘤体积计算公式:肿瘤体积(mm3) =1/2×(a×b2)(其中a表示长径,b表示短径)。当最后一次给药后一星期终止实 验,处死小鼠,取瘤称重、拍照。选用以下分析方法进行数据分析:
相对肿瘤增殖率,T/C(%),即在某一时间点,治疗组和对照组相对肿瘤体积或瘤重的百分比值。计算公式为:T/C%=TRTV/CRTV×100%(TRTV:治疗组平均 RTV;CRTV:对照组平均RTV;RTV=Vt/V0,V0为分组时该动物的瘤体积,Vt为 治疗后该动物的瘤体积);
相对肿瘤抑制率,TGI(%),计算公式为:TGI%=(1-T/C)×100%(T和C分别 为治疗组和对照组在某一特定时间点的相对肿瘤体积(RTV))。
PBS对照组小鼠在给药后第31天平均肿瘤体积为911.16±177.81mm3。抗体分子QP192193(10mg/kg)、QP207208(10mg/kg)、和QP11151116(10mg/kg)组在给药 后第31天平均肿瘤体积分别为580.97±67.97mm3、680.28±193.50mm3、和722.38± 118.07mm3,TGI分别为36.34%、25.34%、和20.72%,对照分子IMAB362(10mg/kg) 在给药后第31天平均肿瘤体积为661.28±104.49mm3,TGI为27.42%(见下表)。三 个筛选出的分子均在一定程度上抑制了肿瘤的生长,虽然没有统计学显著性差异,但 QP192193表现优于对照分子IMAB362的趋势,QP207208和QP11151116也表现出与 IMAB362相同水平的抑制肿瘤生长能力。而且小鼠体重在给药过程中没有发生明显下 降,说明抗体分子对小鼠没有明显毒副作用。
肿瘤重量的分析结果与肿瘤体积的结果相似。PBS对照组小鼠在给药后第31天平均肿瘤重量为722.57±176.32mg,抗体分子QP192193、QP207208、和QP11151116治 疗组在结束给药后第31天平均肿瘤重量分别为455.5±46.42mg、391.93±111.15mg和 432.03±66.25mg,TGI分别为36.96%、45.76%和40.21%;对照分子IMAB362治疗组 在给药后第31天平均肿瘤重量为435.78±91mg,TGI为39.69%。(见下表)
因此通过PDX动物药效试验,我们发现筛选出的抗体分子抗体分子具有比对照分子IMAB362 更优或相同水平的体内抑制肿瘤能力。
实验结果如图9至图14所示,其中,抗体对胃癌PDX模型GA0006的药效试验的结果如图9所 示。图10A是PBS组(阴性对照)处理在分组后的肿瘤生长曲线。图10B是QP192193组处理在 分组后的肿瘤生长曲线。图10C是QP207208组处理在分组后的肿瘤生长曲线。图10D是 QP11151116组处理在分组后的肿瘤生长曲线。图10E是对照抗体IMAB362组处理在分组后的肿 瘤生长曲线。图11是加入本发明各抗体及对照抗体各组小鼠肿瘤D31重量。图12是各实验组 的肿瘤体积实拍图。图13是各组小鼠的体重曲线。图14是各组小鼠的体重变化率曲线。从实 验结果中可见,发明的抗体比IMAB362在体内动物药效中表现出更好的抑制肿瘤生长的效果。
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65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Gly Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ser Gly Ser Trp Phe Gly Pro Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 18
<211> 118
<212> PRT
<213> artificial
<400> 18
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Asp Gly Ala Thr Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 19
<211> 120
<212> PRT
<213> artificial
<400> 19
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ser Tyr Tyr Gly Thr Gly Ala Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 20
<211> 121
<212> PRT
<213> artificial
<400> 20
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Gly Tyr Phe Ser Gly Leu Ala Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 21
<211> 119
<212> PRT
<213> artificial
<400> 21
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Asn Trp Ser Phe Gly Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 22
<211> 119
<212> PRT
<213> artificial
<400> 22
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Gly Tyr Phe Pro Arg Ser Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 23
<211> 121
<212> PRT
<213> artificial
<400> 23
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Ser Trp Tyr Trp Leu Phe Gly Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 24
<211> 119
<212> PRT
<213> artificial
<400> 24
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Asp Trp Gly Gly Tyr Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 25
<211> 119
<212> PRT
<213> artificial
<400> 25
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Tyr Tyr Tyr Tyr Phe Trp Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 26
<211> 119
<212> PRT
<213> artificial
<400> 26
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 Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Tyr Tyr Tyr Tyr Tyr Trp Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 27
<211> 119
<212> PRT
<213> artificial
<400> 27
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 Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Tyr Tyr Tyr Tyr Phe Trp Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 28
<211> 120
<212> PRT
<213> artificial
<400> 28
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 Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ser Ala Ala Tyr Tyr Tyr Phe Trp Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 29
<211> 120
<212> PRT
<213> artificial
<400> 29
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 Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ser Tyr Tyr Tyr Tyr Phe Trp Tyr Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 30
<211> 118
<212> PRT
<213> artificial
<400> 30
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 Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Ile Asp Tyr Tyr Thr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 31
<211> 111
<212> PRT
<213> artificial
<400> 31
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Met Thr Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 32
<211> 111
<212> PRT
<213> artificial
<400> 32
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Asp
85 90 95
Leu Trp Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 33
<211> 111
<212> PRT
<213> artificial
<400> 33
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Ala Gln Ser Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 34
<211> 112
<212> PRT
<213> artificial
<400> 34
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Asn Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 35
<211> 111
<212> PRT
<213> artificial
<400> 35
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Thr
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Met Thr Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 36
<211> 111
<212> PRT
<213> artificial
<400> 36
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Arg Gln Phe Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 37
<211> 111
<212> PRT
<213> artificial
<400> 37
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Leu Asn Thr Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 38
<211> 111
<212> PRT
<213> artificial
<400> 38
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Trp Asp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 39
<211> 111
<212> PRT
<213> artificial
<400> 39
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Gly Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 40
<211> 113
<212> PRT
<213> artificial
<400> 40
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Thr Thr Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 41
<211> 106
<212> PRT
<213> artificial
<400> 41
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 42
<211> 107
<212> PRT
<213> artificial
<400> 42
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Ser Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 43
<211> 107
<212> PRT
<213> artificial
<400> 43
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Lys Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 44
<211> 107
<212> PRT
<213> aritficial
<400> 44
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Ser Tyr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 45
<211> 107
<212> PRT
<213> artificial
<400> 45
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 46
<211> 107
<212> PRT
<213> artificial
<400> 46
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Val Lys
100 105
Claims (10)
1.一种抗CLDN抗体,其特征在于,包括重链和轻链:
其中,所述抗体的重链包含一种或一种以上的CDR,重链的CDR与SEQ ID No.1至SEQ IDNo.7中或者SEQ ID No.15至SEQ ID No.30中的任意一条的CDR序列相比,相差不多于三个氨基酸,
所述抗体的轻链包含一种或一种以上的CDR,轻链的CDR与SEQ ID No.8至SEQ IDNo.14中或者SEQ ID No.31至SEQ ID No.46中的任意一条的CDR序列相比,相差不多于三个氨基酸。
2.如权利要求1所述的抗CLDN抗体,其特征在于:
抗体的重链选自SEQ ID No.1至No.7中的任意一条。
3.如权利要求2所述的抗CLDN抗体,其特征在于:
抗体的轻链选自如SEQ ID No.8至SEQ ID No.14中或者SEQ ID No.31至SEQ ID No.46中的任意一条。
4.如权利要求1所述的抗CLDN抗体,其特征在于:
抗体的重链选自SEQ ID No.15至SEQ ID No.30中的任意一条。
5.如权利要求4所述的抗CLDN抗体,其特征在于:
抗体的轻链选自SEQ ID No.31至SEQ ID No.46中的任意一条。
6.如权利要求1所述的抗CLDN抗体,其特征在于:
其中,抗体的重链和轻链的组合有:
SEQ ID No.1和SEQ ID N0.8,
SEQ ID No.2和SEQ ID N0.9,
SEQ ID No.3和SEQ ID No.10,
SEQ ID No.4和SEQ ID No.11,
SEQ ID No.5和SEQ ID No.12,
SEQ ID No.6和SEQ ID No.13,
SEQ ID No.7和SEQ ID No.14,
SEQ ID No.15和SEQ ID No.31,
SEQ ID No.16和SEQ ID No.32,
SEQ ID No.17和SEQ ID No.33,
SEQ ID No.18和SEQ ID No.34,
SEQ ID No.19和SEQ ID No.35,
SEQ ID No.20和SEQ ID No.36,
SEQ ID No.21和SEQ ID No.37,
SEQ ID No.22和SEQ ID No.38,
SEQ ID No.23和SEQ ID No.39,
SEQ ID No.24和SEQ ID No.40,
SEQ ID No.25和SEQ ID No.41,
SEQ ID No.26和SEQ ID No.42,
SEQ ID No.27和SEQ ID No.43,
SEQ ID No.28和SEQ ID No.44,
SEQ ID No.29和SEQ ID No.45,
SEQ ID No.30和SEQ ID No.46。
7.一种编码如权利要求1-6中任意一项所述的抗体的多核苷酸。
8.一种包含如权利要求1-6中任意一项所述的抗体的药物组合物。
9.如权利要求权利要求1-6中任意一项所述的抗体,在制备抗肿瘤药物中的应用。
10.一种检测生物样品中是否存在CLDN的方法,其特征在于,包括:
给予生物样品如权利要求1-6中任意一项所述的抗体的步骤,其中所述抗体具有可检测标志物,
以及检测是否存在所述可检测标志物,或者检测所述可检测标志物含量的步骤。
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311263551.2A CN117264059A (zh) | 2019-05-16 | 2019-05-16 | 抗cldn抗体及其药物组合物和检测方法 |
CN202311263549.5A CN117659190A (zh) | 2019-05-16 | 2019-05-16 | 抗cldn抗体及其药物组合物和检测方法 |
CN201910410255.8A CN111944048B (zh) | 2019-05-16 | 2019-05-16 | 抗cldn抗体及其药物组合物和检测方法 |
PCT/CN2020/083570 WO2020228447A1 (zh) | 2019-05-16 | 2020-04-07 | 抗cldn抗体及其药物组合物和检测方法 |
JP2021568696A JP7249696B2 (ja) | 2019-05-16 | 2020-04-07 | 抗cldn抗体並びにその医薬組成物および検出方法 |
BR112021022757A BR112021022757A2 (pt) | 2019-05-16 | 2020-04-07 | Anticorpo anti-cldn e composição farmacêutica do mesmo e método de detecção para o mesmo |
EP20804959.3A EP3971207A4 (en) | 2019-05-16 | 2020-04-07 | ANTI-CLDN ANTIBODY, ASSOCIATED PHARMACEUTICAL COMPOSITION AND CORRESPONDING DETECTION METHOD |
US17/611,370 US20220235128A1 (en) | 2019-05-16 | 2020-04-07 | Anti-cldn antibody and pharmaceutical composition thereof and detection method therefor |
KR1020217041245A KR20220010002A (ko) | 2019-05-16 | 2020-04-07 | 항-cldn 항체 및 이의 약학적 조성물과 검출 방법 |
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Cited By (6)
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CN112940124A (zh) * | 2021-04-14 | 2021-06-11 | 南京凯地医疗技术有限公司 | 靶向Claudin18.2的人源化单克隆抗体及其制备方法和应用 |
WO2021218874A1 (zh) * | 2020-04-27 | 2021-11-04 | 启愈生物技术(上海)有限公司 | 一种靶向人claudin和人PDL1蛋白的双特异抗体及其应用 |
CN114181311A (zh) * | 2021-12-20 | 2022-03-15 | 华东师范大学 | 一种全人源抗DLL3 scFv及其在CART细胞治疗中的应用 |
WO2022111616A1 (zh) * | 2020-11-30 | 2022-06-02 | 石药集团巨石生物制药有限公司 | 抗cldn18.2抗体、药物偶联物及其制备方法和用途 |
CN114634566A (zh) * | 2020-12-16 | 2022-06-17 | 广州百暨基因科技有限公司 | 一种抗Claudin18_2的抗原结合片段、抗体及其应用 |
WO2022143794A1 (zh) * | 2020-12-30 | 2022-07-07 | 百奥泰生物制药股份有限公司 | 抗cldn18.2抗体及其制备方法和应用 |
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WO2020160560A2 (en) | 2019-02-01 | 2020-08-06 | Novarock Biotherapeutics, Ltd. | Anti-claudin 18 antibodies and methods of use thereof |
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WO2021218874A1 (zh) * | 2020-04-27 | 2021-11-04 | 启愈生物技术(上海)有限公司 | 一种靶向人claudin和人PDL1蛋白的双特异抗体及其应用 |
WO2022111616A1 (zh) * | 2020-11-30 | 2022-06-02 | 石药集团巨石生物制药有限公司 | 抗cldn18.2抗体、药物偶联物及其制备方法和用途 |
CN114634566A (zh) * | 2020-12-16 | 2022-06-17 | 广州百暨基因科技有限公司 | 一种抗Claudin18_2的抗原结合片段、抗体及其应用 |
WO2022126687A1 (zh) * | 2020-12-16 | 2022-06-23 | 广州百暨基因科技有限公司 | 一种抗Claudin18.2的抗原结合片段、抗体及其应用 |
CN114634566B (zh) * | 2020-12-16 | 2023-09-19 | 广州百暨基因科技有限公司 | 一种抗Claudin18_2的抗原结合片段、抗体及其应用 |
WO2022143794A1 (zh) * | 2020-12-30 | 2022-07-07 | 百奥泰生物制药股份有限公司 | 抗cldn18.2抗体及其制备方法和应用 |
CN112940124A (zh) * | 2021-04-14 | 2021-06-11 | 南京凯地医疗技术有限公司 | 靶向Claudin18.2的人源化单克隆抗体及其制备方法和应用 |
CN112940124B (zh) * | 2021-04-14 | 2022-04-05 | 南京凯地医疗技术有限公司 | 靶向Claudin18.2的人源化单克隆抗体及其制备方法和应用 |
CN114181311A (zh) * | 2021-12-20 | 2022-03-15 | 华东师范大学 | 一种全人源抗DLL3 scFv及其在CART细胞治疗中的应用 |
CN114181311B (zh) * | 2021-12-20 | 2023-06-20 | 华东师范大学 | 一种全人源抗DLL3 scFv及其在CART细胞治疗中的应用 |
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EP3971207A1 (en) | 2022-03-23 |
CN117264059A (zh) | 2023-12-22 |
US20220235128A1 (en) | 2022-07-28 |
JP2022532784A (ja) | 2022-07-19 |
CN111944048B (zh) | 2023-10-03 |
KR20220010002A (ko) | 2022-01-25 |
JP7249696B2 (ja) | 2023-03-31 |
CN117659190A (zh) | 2024-03-08 |
WO2020228447A1 (zh) | 2020-11-19 |
EP3971207A4 (en) | 2023-09-06 |
BR112021022757A2 (pt) | 2022-02-15 |
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