Hagiyama Man, Mimae Takahiro, Wada Akihiro, Takeuchi Fuka, Yoneshige Azusa, Inoue Takao, Kotoku Naoyuki, Hamada Hironobu, Sekido Yoshitaka, Okada Morihito, Ito Akihiko
Department of Pathology, Kindai University Faculty of Medicine, Osaka, Japan.
Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan.
Front Cell Dev Biol. 2022 Jul 12;10:945007. doi: 10.3389/fcell.2022.945007. eCollection 2022.
Malignant pleural mesothelioma (MPM) is a highly aggressive malignant tumor, and the effective therapeutic drugs are limited. Thus, the establishment of novel therapeutic method is desired. Considerable proportion of MPMs are shown to express cell adhesion molecule 1 (CADM1), and to use CADM1 to bind to and proliferate on the pleural mesothelial surface, suggesting that CADM1 is a possible therapeutic target. Here, anti-CADM1 ectodomain chicken monoclonal antibodies, 3E1 and 9D2, were examined for their possible therapeutic utility. The full-length form of CADM1 was expressed in eight out of twelve human MPM cell lines. MPM cell lines were cultured on a confluent monolayer of mesothelial MeT-5A cells in the presence of 9D2, the neutralizing antibody. 9D2 suppressed the cell growth of CADM1-positive MPM cells with the loss and aggregation of CADM1 molecules on the MPM cell membrane, but not of CADM1-negative MPM cells. Co-addition of 3E1, lacking the neutralizing action, enhanced the growth-suppressive effect of 9D2. The two antibodies were tested as drug delivery vectors. 3E1 was converted into a humanized antibody (h3E1) and conjugated with monomethyl auristatin E (MMAE), a tubulin polymerization inhibitor. When the resulting h3E1-MMAE antibody-drug conjugate (ADC) was added to the standard cultures of CADM1-positive MPM cells, it suppressed the cell growth in a dose-dependent manner. Co-addition of 9D2 enhanced the growth-suppressive effect of h3E1-MMAE ADC. Anti-CADM1 ectodomain antibodies were suggested to serve as both antibody drugs and drug vectors in the treatment of MPM.
恶性胸膜间皮瘤（MPM）是一种侵袭性很强的恶性肿瘤，有效的治疗药物有限。因此，需要建立新的治疗方法。相当一部分MPM显示表达细胞粘附分子1（CADM1），并利用CADM1在胸膜间皮表面结合并增殖，这表明CADM1是一个可能的治疗靶点。在此，研究了抗CADM1胞外域鸡单克隆抗体3E1和9D2的潜在治疗效用。CADM1的全长形式在12个人类MPM细胞系中的8个中表达。在存在中和抗体9D2的情况下，将MPM细胞系培养在间皮MeT-5A细胞的汇合单层上。9D2抑制了CADM1阳性MPM细胞的生长，导致MPM细胞膜上CADM1分子丢失和聚集，但对CADM1阴性MPM细胞没有影响。缺乏中和作用的3E1的共同添加增强了9D2的生长抑制作用。这两种抗体被测试作为药物递送载体。3E1被转化为人源化抗体（h3E1）并与微管蛋白聚合抑制剂单甲基奥瑞他汀E（MMAE）偶联。当将所得的h3E1-MMAE抗体药物偶联物（ADC）添加到CADM1阳性MPM细胞的标准培养物中时，它以剂量依赖性方式抑制细胞生长。9D2的共同添加增强了h3E1-MMAE ADC的生长抑制作用。抗CADM1胞外域抗体被认为在MPM治疗中既可以作为抗体药物，也可以作为药物载体。
