Generation and evaluation of a chimeric antibody against coxsackievirus and adenovirus receptor for cancer therapy

• Published in: Cancer science Vol. 110; no. 11; pp. 3595 - 3602
• Main Authors: Sakamoto, Shuichi, Inoue, Hiroyuki, Kaneko, Mika K., Ogasawara, Satoshi, Kajikawa, Masunori, Urano, Sakiko, Ohba, Shun‐ichi, Kato, Yukinari, Kawada, Manabu
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-11-2019; John Wiley and Sons Inc
• Subjects: Adenoviruses; Animal models; Animals; Antibodies, Monoclonal - therapeutic use; Antibody-Dependent Cell Cytotoxicity; Cancer therapies; CAR; Complement System Proteins - immunology; Coxsackie and Adenovirus Receptor-Like Membrane Protein - antagonists & inhibitors; Coxsackie and Adenovirus Receptor-Like Membrane Protein - immunology; Coxsackie and Adenovirus Receptor-Like Membrane Protein - metabolism; Coxsackieviruses; Cytotoxicity; Endocrine Gland Neoplasms - metabolism; Endocrine Gland Neoplasms - therapy; Female; Flow cytometry; Humans; Immunotherapy; Laboratories; Life sciences; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - therapy; Male; Medical research; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Monoclonal antibodies; mouse‐human chimeric antibody; Original; orthotopic transplantation model; Polyclonal antibodies; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - therapy; Proteins; R&D; Research & development; small cell lung cancer; Small cell lung carcinoma; Small Cell Lung Carcinoma - metabolism; Small Cell Lung Carcinoma - therapy; Tight junctions; Tumors; Xenograft Model Antitumor Assays; Xenografts; mouse-human chimeric antibody; prostate cancer; small cell lung cancer; CAR; orthotopic transplantation model
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14196

Coxsackievirus and adenovirus receptor (CAR) is a single‐pass transmembrane protein that is associated with adenoviral infection. CAR is involved in the formation of epithelial tight junctions and promotes tumor growth in some cancers. Previously, we developed mouse monoclonal antibodies against human CAR and found that one, mu6G10A, significantly inhibited tumor growth in xenografts of human cancer cells. Herein, we generated and characterized a mouse‐human chimeric anti‐CAR antibody (ch6G10A) from mu6G10A. ch6G10A had binding activity, inducing antibody‐dependent cellular cytotoxicity and complement‐dependent cytotoxicity, and in vivo anti‐tumor activity against CAR‐expressing prostate cancer DU‐145 cells. In addition, cancer tissue array analysis confirmed that CAR is highly expressed in neuroendocrine lung cancers including small cell lung cancer, and treatment with ch6G10A effectively inhibited in vivo subcutaneous tumor growth of NCI‐H69 small cell lung cancer cells in nude mice. Moreover, treatment with mu6G10A effectively inhibited both in vivo orthotopic tumor growth and distant metastatic formation in mouse xenograft models of a highly metastatic subline of human small cell lung cancer DMS273 cells. These results suggest that targeting therapy to CAR with a therapeutic antibody might be effective against several cancer types including small cell lung cancer.
We describe the generation of a mouse‐human chimeric anti‐CAR antibody and evaluation of anti‐tumor activities of these antibodies. Our results suggest that targeting therapy to CAR with therapeutic antibodies might be effective against several cancers including small cell lung cancer.