Pharmacological properties and clinical trial results of datopotamab deruxtecan (Dato-DXd, Datroway^®)

Abstract

Antibody-drug conjugate (ADC) is a next-generation antibody therapeutics designed to deliver drugs selectively and efficiently to cancer cells, offering high efficacy and reduced side effects. Daiichi Sankyo has established a novel DXd-ADC technology using DXd, a derivative of the topoisomerase I inhibitor exatecan, as its payload. With this technology, we developed trastuzumab deruxtecan, the first DXd-ADC directed toward HER2. To generate a novel DXd-ADC covering unmet medical needs, we have developed a novel trophoblast cell surface antigen 2 (TROP2)-directed DXd-ADC, datopotamab deruxtecan (Dato-DXd). In the preclinical studies, we confirmed that Dato-DXd binds to TROP2 on cancer cell surface and, following internalization and lysosomal trafficking, releases DXd. The released DXd induces DNA damage and apoptosis in cancer cells. Additionally, Dato-DXd showed TROP2-dependent antitumor activity in multiple human cancer cell line-derived and patient-derived xenograft mouse models. Clinically, the global phase III trial targeting hormone receptor-positive, HER2-negative, unresectable or recurrent breast cancer led to its first approval in Japan in December 2024, followed by the approvals in the US and Europe later.