Mechanisms contributing to ado-trastuzumab emtansine-induced toxicities: a gateway to better understanding of ADC-associated toxicities. (16th March 2021)

• Record Type: Journal Article
• Authors: Endo, Yukinori; Mohan, Nishant; Dokmanovic, Milos; Wu, Wen Jin
• Is Part Of: Antibody therapeutics. Volume 4:Number 1(2021)
• Page Start: 55
• Page End: 59
• Publication Date: 2021-03-16
• Subjects: antibody-drug conjugate -- HER2-positive metastatic breast cancer -- payload -- ado-trastuzumabemtansine/T-DM1 -- off-target toxicity; Immunoglobulins -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Therapeutic use -- Periodicals; Immunotechnology -- Periodicals; 616.0798
• DOI: 10.1093/abt/tbab005
• Languages: English
• ISSNs: 2516-4236

Abstract

ABSTRACT: In order to improve the safety of novel therapeutic drugs, better understanding of the mechanisms of action is important. Ado-trastuzumab emtansine (also known as T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2-positive breast cancer. While the treatment with T-DM1 results in significant efficacy in the selected patient population, nonetheless, there are concerns with side effects such as thrombocytopenia and hepatotoxicity. While current understanding of the mechanism of T-DM1-mediated side effects is still incomplete, there have been several reports of HER2-dependent and/or -independent mechanisms that could be associated with the T-DM1-induced adverse events. This review highlights the importance of HER2-independent mechanism of T-DM1 to induce hepatotoxicity, which offers a new insight into a role for CKAP5 in the overall maytansinoid-based ADC (DM1 and DM4)-mediated cytotoxicity. This discovery provides a molecular basis for T-DM1-induced off-target toxicity and opens a new avenue for developing the next generation of ADCs.