Next-generation antibody-drug conjugates for breast cancer: Moving beyond HER2 and TROP2

Antibody-drug conjugates (ADCs) have reshaped the treatment of several malignancies, including breast cancer. Two ADCs are currently approved for the treatment of each breast cancer subtype, including the HER2 targeted ADCs trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), and the TROP2-targeted ADC sacituzumab govitecan. Each of the ADC components (antibody, linker, and payload) plays a key role in determining the efficacy and toxicity profile of an individual ADC, and their modification can lead to major changes in the clinical profile of these agents. Leveraging the knowledge from three decades of development in the field, several novel ADCs are currently being investigated. Some approaches include targeting different antigens beyond the established HER2/TROP2, or evaluating innovative constructs, such as bispecific ADCs, ADCs with dual payload, immune-modulating ADCs, radionuclide drug conjugates, and masked ADCs, among others. In this review article we discuss the evolving landscape of novel ADCs, highlighting opportunities and challenges emerging in the field.