Antibody-drug conjugates in cancer treatment: from molecular design to clinical implementation

Antibody-drug conjugates (ADCs) are a promising innovation in precision oncology, combining tumor-targeting antibodies with potent cytotoxic molecules to improve their therapeutic index and outcomes. This Series paper explores the evolution of ADCs from early development to current EMA-approved therapies, highlighting the key advances in design and mechanisms of action. We expand on the critical components of ADCs (linkers, antibodies and payloads) and how the evolution of the linker technologies, site-specific conjugation and novel payloads are increasingly enhancing their therapeutic index. Pivotal clinical trials in solid and hematologic cancers are summarised, alongside the caveats related to efficacy, safety and accessibility. Challenges such as narrow therapeutic windows driven by dose-limiting toxicities/off-target effects and high production costs are discussed, as well as future directions including combination therapies, overcoming resistance mechanisms, and biomarker-guided patient selection. The need for ongoing innovation and collaboration is key to maximizing the clinical potential of ADCs in Oncology.