Antibody-drug conjugates (ADCs) have advanced cancer therapy by combining antibody specificity with cytotoxic potency. However, clinical experience has revealed challenges limiting their efficacy and safety. This review addresses key questions in ADC development and corresponding optimization strategies. It discusses the relationship between target antigen expression and clinical response and the role of antibodies beyond targeting. Enhancing ADC distribution via bispecific targeting and probody masking is summarized. Traditional assumptions in linker design, such as favoring maximum stability, are re-evaluated to improve clinical outcomes. Innovations in linker chemistry encompass tumor microenvironment-responsive release mechanisms and bioorthogonal reactions. Emerging payload strategies like immune-stimulating ADCs (ISACs) and degrader-antibody conjugates (DACs) expand therapeutic possibilities but introduce new safety challenges. Ultimately, merely increasing ADC structural complexity is insufficient. Understanding tumor delivery barriers and bridging preclinical-clinical gaps will be vital to fully realize the potential of ADCs in precision oncology.
Keywords: ADC; ISAC; antibody-drug conjugate; immune-stimulating antibody conjugate; linker stability; solid tumor; targeted cancer therapy.
Copyright © 2025. Published by Elsevier Inc.