前列腺癌
癌症研究
抗体依赖性细胞介导的细胞毒性
细胞毒性T细胞
癌细胞
单克隆抗体
抗原
抗体
体外
体内
癌症
生物
化学
免疫学
生物化学
生物技术
遗传学
作者
Du-San Baek,Ye‐Jin Kim,Sandra Vergara,Alex Conard,Cynthia Adams,Guillermo Calero,Rieko Ishima,John W. Mellors,Dimiter S. Dimitrov
标识
DOI:10.1016/j.canlet.2021.10.041
摘要
Neuro-endocrine prostate cancer (NEPC) accounts for about 20% of lethal metastatic castration-resistant prostate cancer (CRPC). NEPC has the most aggressive biologic behavior of all prostate cancers and is associated with poor patient outcome. Effective treatment for NEPC is not available because NEPC exhibit distinct cell-surface expression profiles compared to other types of prostate cancer. Recently, the carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) (known as CEA or CD66e) was suggested to be a specific surface protein marker for NEPC. Therefore, we identified a new, fully-human anti-CEACAM5 monoclonal antibody, 1G9, which bound to the most proximal membrane domains, A3 and B3, of CEACAM5 with high affinity and specificity. It shows no off-target binding to other CEACAM family members, membrane distal domains of CEACAM5, or 5800 human membrane proteins. IgG1 1G9 exhibited CEACAM5-specific ADCC activity toward CEACAM5-positive prostate cancer cells in vitro and in vivo. Chimeric antigen receptor T cells (CAR-T) based on scFv 1G9 induced specific and strong antitumor activity in a mouse model of prostate cancer. Our results suggest that IgG1 and CAR-T cells based on 1G9 are promising candidate therapeutics for CEACAM5-positive NEPC and other cancers.
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