Next Generation Antibody–Drug Conjugates: Molecular Design Innovations And Overcoming Resistance – A Comprehensive Review

Abstract

Antibody–drug conjugates (ADCs) represent one of the most transformative advances in targeted cancer therapy, combining the high specificity of monoclonal antibodies with the potent cytotoxic activity of small-molecule drugs. While first- and second-generation ADCs have yielded significant clinical benefit, therapeutic resistance, limited payload delivery, and off-target toxicity remain major barriers. Next-generation ADCs integrate innovations in antibody engineering, linker chemistry, payload diversification, and site-specific conjugation technologies to enhance stability, therapeutic index, and tumour selectivity. Further, the emergence of antibody–drug conjugate combinations, immune-stimulating ADCs, and conditionally activated ADCs is reshaping clinical strategies. This review discusses current advances in molecular design, mechanisms of resistance, and contemporary approaches to overcome therapeutic limitations, highlighting the future direction of ADC-based oncology.