Unlocking the potential of antibody–drug conjugates for cancer therapy

Abstract

Nine different antibody–drug conjugates (ADCs) are currently approved as cancer treatments, with dozens more in preclinical and clinical development. The primary goal of ADCs is to improve the therapeutic index of antineoplastic agents by restricting their systemic delivery to cells that express the target antigen of interest. Advances in synthetic biochemistry have ushered in a new generation of ADCs, which promise to improve upon the tissue specificity and cytotoxicity of their predecessors. Many of these drugs have impressive activity against treatment-refractory cancers, although hurdles impeding their broader use remain, including systemic toxicity, inadequate biomarkers for patient selection, acquired resistance and unknown benefit in combination with other cancer therapies. Emerging evidence indicates that the efficacy of a given ADC depends on the intricacies of how the antibody, linker and payload components interact with the tumour and its microenvironment, all of which have important clinical implications. In this Review, we discuss the current state of knowledge regarding the design, mechanism of action and clinical efficacy of ADCs as well as the apparent limitations of this treatment class. We then propose a path forward by highlighting several hypotheses and novel strategies to maximize the potential benefit that ADCs can provide to patients with cancer. Antibody–drug conjugates (ADCs) constitute a unique class of anticancer agents with demonstrated clinical efficacy against several different cancer types. Herein, the authors discuss the design and mechanisms of action of ADCs and how these properties are reflected in the clinical activity and toxicity profiles of such agents. Potential strategies to overcome the limitations of ADCs and thereby maximize their therapeutic benefit for patients with cancer are also proposed. Antibody–drug conjugates (ADCs) comprise three main components: an antibody, a linker and a payload. The clinical properties of ADCs depend on the characteristics of all three of these components. The mechanism of action of ADCs is complex, often requiring drug internalization followed by intracellular processing and payload release. Unlike many standard therapies used in oncology, ADCs must be acted upon by cancer cells for optimal effectiveness. The pharmacodynamic properties of ADCs make them uniquely suited for activity in treatment-refractory cancers, which is reflected in the current clinical indications for ADCs in oncology. ADCs exhibit both on-target and off-target toxicities; while most toxicities seem to be related to the nature of the payload, notable examples of target-dependent toxicities exist. Important and potentially practice-changing innovations in ADC design, biomarker development and combination therapies are ongoing in preclinical and clinical studies. An improved understanding of the interactions between ADCs and tumours is essential for clinicians and scientists to realize the true potential of this drug class for the treatment of cancer. Antibody–drug conjugates (ADCs) comprise three main components: an antibody, a linker and a payload. The clinical properties of ADCs depend on the characteristics of all three of these components. The mechanism of action of ADCs is complex, often requiring drug internalization followed by intracellular processing and payload release. Unlike many standard therapies used in oncology, ADCs must be acted upon by cancer cells for optimal effectiveness. The pharmacodynamic properties of ADCs make them uniquely suited for activity in treatment-refractory cancers, which is reflected in the current clinical indications for ADCs in oncology. ADCs exhibit both on-target and off-target toxicities; while most toxicities seem to be related to the nature of the payload, notable examples of target-dependent toxicities exist. Important and potentially practice-changing innovations in ADC design, biomarker development and combination therapies are ongoing in preclinical and clinical studies. An improved understanding of the interactions between ADCs and tumours is essential for clinicians and scientists to realize the true potential of this drug class for the treatment of cancer.