Antibody-drug conjugates as immune modulators: current landscape, challenges, and opportunities

Antibody-drug conjugates (ADCs), originally developed for oncology applications, have emerged as a promising targeted therapeutic platform that combines the antigen specificity of monoclonal antibodies with the potency of small-molecule payloads. The clinical success of ADCs in cancer therapy has stimulated a growing interest in its application for immunomodulation, including autoimmune diseases, chronic inflammatory disorders, and transplantation. In the context of immune modulation, ADCs offer the advantage for selective depletion or functional regulation of pathogenic immune cells while maintaining overall immune homeostasis. However, ADC designing for immunological diseases presents unique challenges, including lower antigen expression, distinct immune microenvironments, the need for higher target selectivity prolonged. Furthermore, linker-payload strategies must be carefully tuned to promote immune modulation in pathogenic sites while minimizing off-target effect. This review provides the overall landscape of ADCs for immunomodulatory applications with critical analysis of recent preclinical and clinical advances, highlighting the rationale for target selection and linker-payload design considerations. In addition, we discuss current challenges, lessons learned from oncology ADCs, and future opportunities. We hope this review will be helpful for optimum design of ADC to progress from broad immunosuppression toward a selective immunomodulation in autoimmune diseases, inflammatory disorders, and transplantation.