A highly-specific fully-human antibody and CAR-T cells targeting CD66e/CEACAM5 are cytotoxic for CD66e-expressing cancer cells in vitro and in vivo. (28th January 2022)

• Record Type: Journal Article
• Authors: Baek, Du-San; Kim, Ye-Jin; Vergara, Sandra; Conard, Alex; Adams, Cynthia; Calero, Guillermo; Ishima, Rieko; Mellors, John W.; Dimitrov, Dimiter S.
• Is Part Of: Cancer letters. Volume 525(2022)
• Page Start: 97
• Page End: 107
• Publication Date: 2022-01-28
• Subjects: CEACAM5 -- CEA -- CD66e -- Prostate cancer -- NEPC -- Immunotherapy; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.10.041
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: First report for fully human monoclonal antibody against CEACAM5 without any cross-reactivity to the human membrane proteome. Altered N -linked glycosylation in CEACAM5 affects to the binding of anti -CEACAM5 antibodies. Anti-CEACAM5 antibodies inhibited migration of CEACAM5 positive NEPC cells in vitro. hIgG1 and CAR-T of 1G9 exhibited dose-dependent cytotoxicity to CEACAM5 positive cancer cells without off-target toxicity in vitro and in vivo.