Antibody-Drug Conjugates in Modern Prodrug Design: Linker Chemistry and Payload Strategies

Antibody–drug conjugates (ADCs) represent one of the most advanced manifestations of modern prodrug design, combining the target specificity of monoclonal antibodies with the potency of cytotoxic small-molecule payloads. By selectively delivering potent drugs to antigen-expressing cells, ADCs improve efficacy while reducing systemic toxicity relative to conventional chemotherapy. Clinical performance depends on the coordinated function of three components: the antibody, which directs recognition and internalization; the linker, which governs stability and payload release; and the payload, which determines the mechanism and magnitude of cytotoxicity. This review examines ADCs through the lens of prodrug pharmacology, tracing their evolution from Ehrlich's "magic bullet" concept to contemporary approved agents, with emphasis on the causal relationship between target biology, linker chemistry, and payload selection. Current linker technologies, payload classes, conjugation strategies, and FDA-approved ADCs are discussed alongside major challenges (linker instability, off-target toxicity, resistance, and manufacturing complexity) and emerging platforms including bispecific ADCs, ISACs, DACs, and AI-assisted design. Collectively, ADCs achieve classical prodrug goals through a multi-layered targeting strategy, establishing them as a leading paradigm in precision drug delivery.