Antibody drug conjugate: the "biological missile" for targeted cancer therapy

Abstract

Antibody-drug conjugate (ADC) is typically composed of a monoclonal antibody (mAbs) covalently attached to a cytotoxic drug via a chemical linker. It combines both the advantages of highly specific targeting ability and highly potent killing effect to achieve accurate and efficient elimination of cancer cells, which has become one of the hotspots for the research and development of anticancer drugs. Since the first ADC, Mylotarg^® (gemtuzumab ozogamicin), was approved in 2000 by the US Food and Drug Administration (FDA), there have been 14 ADCs received market approval so far worldwide. Moreover, over 100 ADC candidates have been investigated in clinical stages at present. This kind of new anti-cancer drugs, known as "biological missiles", is leading a new era of targeted cancer therapy. Herein, we conducted a review of the history and general mechanism of action of ADCs, and then briefly discussed the molecular aspects of key components of ADCs and the mechanisms by which these key factors influence the activities of ADCs. Moreover, we also reviewed the approved ADCs and other promising candidates in phase-3 clinical trials and discuss the current challenges and future perspectives for the development of next generations, which provide insights for the research and development of novel cancer therapeutics using ADCs.

Fig. 1. Timeline depicting important events in the development and approval of ADC drugs over the past century since the “magic bullet” was proposed by Paul Enrlich 1910.

ADC, antibody-drug conjugate; CEA, Carcinoembryonic antigen; ALL, acute lymphoid leukemia; BR96, an antibody binding to Lewis Y; DOX, doxorubicin; FDA, the U.S. Food and Drug Administration

Fig. 2. The structure and characteristic of an ADC drug.

The core components including target antigen, antibody, linker, cytotoxic drug along with their key functions are demonstrated.

Fig. 3. The important target antigens from tumor cells (overexpressed and driver genes) and tumor microenvironment (vasculature and stroma) are used for the development of ADC.

Created with BioRender.com

Fig. 4. The overview of the mechanisms of ADC for killing cancer cells via different approaches.

Upper-Right: The main core mechanism of action of ADCs; Lower-Left: The antibody component of ADCs engages with immune effector cells to elicit antitumor immunity including CDC, ADCC, and ADCP effects; Lower-Right: The antibody component of ADCs retains its activity profile and can therefore interfere with target function, dampen downstream signaling to inhibit tumor growth. Created with BioRender.com