Challenges of Antibody Drug Conjugates in Cancer Therapy: Current Understanding of Mechanisms and Future Strategies

Abstract

Antibody drug conjugates (ADCs) are a class of powerful anti-cancer therapeutics composed of a potent cytotoxic drug, a cancer cell-targeting monoclonal antibody (mAb), and a linker connecting the drug to the antibody. Despite often being referred to as magic bullet, ADCs are still far from perfect and further improvements are required to enhance the therapeutic potential of ADCs. The goal of ADCs is to improve the therapeutic index of cytotoxic drugs. Nevertheless, many of the current ADCs still have relatively narrow therapeutic index and limited clinical success. This manuscript is a comprehensive review of the up-to-date knowledge on mechanism of action of ADCs, key factors that affect the safety and efficacy of ADCs, and the challenges and new strategies associated with rational design of ADCs. The major challenges of developing an effective ADC include selection of the appropriate target antigens, the chemically stable linkers, and the highly potent cytotoxic drugs. Each component of an ADC must be optimized to fully realize the goal of improvement of efficacy and tolerability of the ADC. Understanding of these key determining factors can provide guidance for the development of these complex molecules.