Extracellular payload release from non-internalizing antibody–drug conjugates: mechanisms and linker technologies

Antibody‒drug conjugates (ADCs) have taken on a significant role in precision oncology. These molecules, referred to as 'biological missiles', can deliver cytotoxic drugs directly to cancer cells. Traditional ADCs rely on endocytosis and intracellular release of payloads, but this approach becomes complicated due to issues like antigen loss, tumor heterogeneity, and impaired endocytosis, leading to therapeutic resistance. To address these challenges, noninternalizing ADCs have been developed, utilizing extracellular payload release methods. These structures employ advanced linker technologies to ensure stability in vivo and selective activation in the tumor microenvironment, achieving effective cytotoxic diffusion among tumor cells through the 'bystander effect'. This review discusses the evolution from early linker designs to complex methods based on tumor-specific conditions or external triggers. It also examines the categories of noninternalizing ADC linkers and the latest developments in clinical research, exploring prospects for enhancing the efficacy and safety of ADCs in oncology applications.