Antibody-drug conjugates: Resurgent anticancer agents with multi-targeted therapeutic potential

Antibody-drug conjugates (ADCs) constitute a relatively new group of anticancer agents, whose first appearance took place about two decades ago, but a renewed interest occurred in recent years, following the success of anti-cancer immunotherapy with monoclonal antibodies. Indeed, an ADC combines the selectivity of a monoclonal antibody with the cell killing properties of a chemotherapeutic agent (payload), joined together through an ap-propriate linker. The antibody moiety targets a specific cell surface antigen expressed by tumor cells and/or cells of the tumor microenvironment and acts as a carrier that delivers the cytotoxic payload within the tumor mass. Despite advantages in terms of selectivity and potency, the development of ADCs is not devoid of challenges, due to: i) low tumor selectivity when the target antigens are not exclusively expressed by cancer cells; ii) premature release of the cytotoxic drug into the bloodstream as a consequence of linker instability; iii) development of tumor resistance mechanisms to the payload. All these factors may result in lack of efficacy and/or in no safety improvement compared to unconjugated cytotoxic agents. Nevertheless, the development of antibodies engineered to remain inert until activated in the tumor (e.g., antibodies activated proteolytically after internali-zation or by the acidic conditions of the tumor microenvironment) together with the discovery of innovative tar-gets and cytotoxic or immunomodulatory payloads, have allowed the design of next-generation ADCs that are expected to possess improved therapeutic properties. This review provides an overview of approved ADCs, with related advantages and limitations, and of novel tar-gets exploited by ADCs that are presently under clinical investigation. (c) 2022 Elsevier Inc. All rights reserved.

Automated summary

Antibody-drug conjugates (ADCs) are a new group of anticancer agents that combine the selectivity of monoclonal antibodies with the cell killing properties of chemotherapeutic agents. However, the development of ADCs faces challenges such as low tumor selectivity, premature release of drugs, and tumor resistance mechanisms. The design of inert antibodies and the discovery of innovative targets and drugs have led to the development of next-generation ADCs with improved therapeutic properties.