Anti-HER2 antibody therapy using gene-transduced adipocytes for HER2-positive breast cancer

• Published in: Breast cancer research and treatment Vol. 180; no. 3; pp. 625 - 634
• Main Authors: Masuda, Takahito, Fujimoto, Hiroshi, Teranaka, Ryotaro, Kuroda, Masayuki, Aoyagi, Yasuyuki, Nagashima, Takeshi, Sangai, Takafumi, Takada, Mamoru, Nakagawa, Ayako, Kubota, Yoshitaka, Yokote, Koutaro, Ohtsuka, Masayuki
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.04.2020; Springer; Springer Nature B.V
• Subjects: Adipocytes; Adipocytes - cytology; Adipocytes - metabolism; AKT protein; Analysis; Animals; Antibodies; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - metabolism; Apoptosis; Biopharmaceutics; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer research; Care and treatment; Cell culture; Cell Differentiation; Cell Movement; Cell Proliferation; Enzyme-linked immunosorbent assay; ErbB-2 protein; Female; Gene therapy; Genes; Genetic aspects; Humans; Immunofluorescence; Immunotherapy; Inoculation; Medical care, Cost of; Medical colleges; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Nude; Monoclonal antibodies; Neomycin; Oncology; Phosphorylation; Preclinical Study; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - immunology; Targeted cancer therapy; Trastuzumab; Tumor cell lines; Tumor Cells, Cultured; Viral antibodies; Xenograft Model Antitumor Assays; Xenografts; Breast cancer; Adipocytes; Monoclonal antibody; Molecular target therapy; Gene therapy; Human epidermal growth factor receptor 2
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-020-05581-x

Purpose Although recent advances in molecular target therapy have improved the survival of breast cancer patients, high cost and frequent hospital visits result in both societal and individual burden. To reduce these problems, it has been proposed to produce antibodies in vivo. Here, we constructed gene-transduced human ceiling culture-derived proliferative adipocytes secreting anti-HER2 antibody (HER2-ccdPAs) and evaluated their ability to secrete antibody and mediate an anti-tumor effect. Methods Plasmid lentivirus was used as a recipient for anti-HER2 antibody cDNA and transduced into human proliferative adipocyte. Secretory antibody expression was evaluated by ELISA and western blot. Specific binding of secretory antibody to HER2 was examined by immunofluorescence analysis. Direct and indirect anti-tumor effects of supernatants from HER2-ccdPAs were evaluated using BT474 (HER2+) and MDA-MB-231 (HER2−) breast cancer cell lines. Additionally, whether adipocyte differentiation affects antibody secretion was investigated using supernatant collected from different cell maturation states. Results Anti-HER2 antibody was identified in the supernatant from HER2-ccdPAs and its production increased with the differentiation into mature adipocyte. Antibodies in supernatants from HER2-ccdPAs bound to HER2-positive breast cancer cells similar to trastuzumab. Supernatant from HER2-ccdPAs inhibited the proliferation of BT474 but not MDA-MB-231 cells, and downregulated AKT phosphorylation in BT474 cells compared with controls. Supernatants from HER2-ccdPAs also had an indirect anti-tumor effect on BT474 cells through ADCC. Additionally, Single inoculation of HER2-ccdPAs showed an anti-tumor effect in BT474 xenograft model. Conclusions HER2-ccdPAs might be useful for cell-based gene therapy. This system could be a platform for various antibody therapies.