Antibody-targeted drugs and drug resistance--challenges and solutions

Antibody-based therapy of various human malignancies has shown efficacy in the past 30 years and is now one of the most successful and leading strategies for targeted treatment of patients harboring hematological malignancies and solid tumors. Antibody-drug conjugates (ADCs) aim to take advantage of the affinity and specificity of monoclonal antibodies (mAbs) to selectively deliver potent cytotoxic drugs to antigen-expressing tumor cells. Key parameters for ADC include choosing the optimal components of the ADC (the antibody, the linker and the cytotoxic drug) and selecting the suitable cell-surface target antigen. Building on the success of recent FDA approval of brentuximab vedotin (Adcetris) and ado-trastuzumab emtansine (Kadcyla), ADCs are currently a class of drugs with a robust pipeline with clinical applications that are rapidly expanding. The more ADCs are being evaluated in preclinical models and clinical trials, the clearer are becoming the parameters and the challenges required for their therapeutic success. This rapidly growing knowledge and clinical experience are revealing novel modalities and mechanisms of resistance to ADCs, hence offering plausible solutions to such challenges. Here, we review the key parameters for designing a powerful ADC, focusing on how ADCs are addressing the challenge of multiple drug resistance (MDR) and its rational overcoming.