Formulation Matters: The Overlooked Engine of Stability and Success in Antibody–Drug Conjugates

Backgrounds: Antibody–drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the cytotoxic potency of drugs, representing a significant class of targeted cancer therapeutics. Despite their clinical success, formulation-related instability, rather than biological inefficacy, is a major contributing factor to setbacks in ADC development. This review examines the biochemical, physicochemical, and formulation factors that contribute to ADC stability, with a focus on excipient selection, conjugation site heterogeneity, and linker–payload reactivity. Methods: This comprehensive review was based on a selection of peer-reviewed mechanistic, analytical, and manufacturability studies on ADC stability. Our goal was to highlight formulation strategies, degradation pathways, and solid-state stabilization principles that affect the pharmacokinetics and therapeutic efficacy of ADC. Results: Results demonstrate how formulation variability including buffer composition, excipient choice, ionic strength, and lyophilization can directly affect payload release, linker cleavage, kinetics, and antibody conformation. It has been demonstrated that techniques, such as lyophilization with glass-forming matrices and the addition of surfactants, enhance stability against hydrolysis, oxidation, and aggregation. Developments in analytical characterization, such as real-time kinetic modeling and multi-attribute techniques based on mass spectrometry, have made quantification of degradation and bioactivity losses more predictable in ADC formulations. The connection between chemical stability and formulation outcomes is being redefined by new techniques, such as model-informed optimization and AI-driven design. Conclusions: ADC formulation is now a key component of molecular stability, clinical reliability, and regulatory compliance rather than a secondary consideration. By guaranteeing long-term stability, better pharmacokinetics, and improved therapeutic indices across next-generation designs, these approaches have the potential to revolutionize ADC development.