The Dawn of the Antibody-Drug Conjugates Era: How T-DM1 Reinvented the Future of Chemotherapy for Solid Tumors

Abstract

Delivering targeted chemotherapy through antibody-drug conjugates (ADC) has emerged as an extremely effective therapeutic strategy for multiple types of cancer. The first agent of this class to be established for treating a solid tumor was trastuzumab emtansine (T-DM1), approved in 2013 for the treatment of HER2-positive metastatic breast cancer. Much of the knowledge that led to this approval came from the landmark Cancer Research publication by Lewis Phillips and colleagues in 2008, where they described the in vitro and in vivo efficacy, pharmacokinetics, and toxicity of T-DM1, demonstrating its relevant preclinical activity against HER2-positive breast cancer models. In this article, the authors also explored the use of different linkers to conjugate the cytotoxic payload to the trastuzumab vehicle, demonstrating improved stability, efficacy, and tolerability of the compound when adopting a specific thioether linker. The findings from this work not only set the stage for the clinical development of T-DM1, but also highlighted the modularity of ADCs, with small changes in their components able to dramatically impact their activity and toxicity. This finding would prove key for the development of novel ADCs, several of which are now reshaping the way we treat breast cancer and other cancer types. In this commentary, we discuss the key implications of the work by Phillips and colleagues, putting it in context of the current and anticipated expansion in the use of ADCs to treat cancer. See related article by Phillips et al., Cancer Res 2008;68:9280-90.