Antibody-drug conjugates as multimodal therapies against hard-to-treat cancers

Antibody-drug conjugates (ADCs) are rapidly emerging as an effective multimodal approach for the targeted delivery of cytotoxic small molecules to tumours with aberrantly overexpressed markers. Recent advances in antibody engineering and the emergence of highly potent cytotoxic drugs have created unprecedented scope for precision-based design of novel ADCs against chemotherapy-resistant tumours. However, their clinical translation faces the challenge of balancing efficacy and toxicity. Innovations in conjugation chemistries and antibody engineering are addressing these challenges, yet a more comprehensive in vitro − in vivo correlation is critical to accelerating their clinical translation. This review examines the latest advancements in ADC-based therapies for hard-to-treat cancers, focusing on design considerations that define their efficacy in breast cancer and glioblastoma multiforme. Additionally, we highlight current challenges in reconciling ADC quality attributes influencing their in vivo performance, which impedes their clinical translation. By integrating cutting-edge advancements in antibody engineering with industrial insights, this review casts a spotlight on the pivotal role of ADCs as a powerful biomolecular toolbox for delivering next-generation therapies to address unmet clinical need.