New conjugated monoclonal antibodies: Area of a promising therapy in metastatic breast cancer.

Abstract

Following advances in molecular biology and better understanding of the mechanisms of carcinogenesis, new therapies have been developed with new agents that target tumor cells with minimal effects on normal cells. Monoclonal antibodies represent the model of success of this approach; they are directed against antigens selectively expressed by tumor cells. The conjugation of these monoclonal antibodies with potent cytotoxic drugs makes it possible to improve their efficacy while maintaining a favorable tolerance profile. T-DM1 (Trastuzumab Emtansine) is the first example of advanced development of a conjugated antibody. It works by associating an antitumor activity specific to trastuzumab with the efficient delivery of a potent cytotoxic, delivered selectively and targeted to cancer cells overexpressing HER2. Unlike trastuzumab emtansine, trastuzumab deruxtecan has a released payload that easily crosses the cell membrane, which potentially allows for a potent cytotoxic effect on neighboring tumor cells regardless of target expression. In addition, the released payload has a short half-life, which is designed to minimize systemic exposure. DESTINY breast-01 study has demonstrated the efficacy of trastuzumab deruxtecan in patients with HER2- positive metastatic breast cancer previously treated with trastuzumab emtansine. Trastuzumab deruxtecan is FDA-approved. Sacituzumab govitecan (sacituzumab govitecan-hziy) is a conjugated monoclonal antibody developed by site-specific conjugation of the active metabolite of irinotecan, SN-38 (govitecan). It has demonstrated promising activity in advanced lines for triple-negative breast cancer in a phase I/II study and recently in ASCENT trial phase III. Conjugated monoclonal antibodies have been shown to be effective in different subtypes of metastatic breast cancer.