Antibody-drug conjugate design and mechanisms of action for cancer treatment: state of the art and beyond

Antibody-drug conjugates (ADCs) are a leading area of targeted cancer therapeutics, typically combining a tumour-associated antigen-specific antibody conjugated to a toxic payload that targets key cellular mechanisms, such as mitosis and survival. The global ADC clinical trial landscape has been expanding significantly, with over 430 ADCs reaching early to late clinical studies in the past two decades, up from just 90 between 2004 and 2014. The US Food and Drug Administration (FDA) has so far approved 14 ADCs for use in clinical oncology. This growth is likely driven by significant advances in antibody technology and conjugation methods enabling more effective and precise delivery to cancer cells and more effective payloads that target vital cancer biology. Here, we review the ADCs that have reached clinical approval as well as current and emerging trends in ADC development, and we discuss these from multiple perspectives, including ADC mechanisms of action, emerging antigen targets, linker and conjugation chemistry, payloads, combination of ADC with checkpoint inhibitor immunotherapy and antibody Fc-engineering. We also consider how the field is evolving through the application of artificial intelligence (AI) and pathology-based biomarker discovery. Combined, innovative and emerging ADC design coupled with precision medicine and patient stratification strategies hold great promise to develop diverse and personalised cancer treatments with improved therapeutic indices, and to enhance tolerability compared to traditional chemotherapy and current established ADCs. This review aims to assist researchers in exploring the evolution, characteristics, and development trends in ADC design and to provide new directions for future research.