Half-life extension of therapeutics: Applications and mechanisms

The clinical effectiveness of peptide and protein therapeutics is often limited by their short circulating half-life, necessitating frequent injections. Therefore, half-life extension strategies have emerged as centerpieces in biopharmaceutical development to enhance therapeutic efficacy, reduce dosing frequency, and improve patient outcomes. A variety of approaches have been being investigated and used to prolong systemic exposure of protein drugs. Increasing hydrodynamic volume and enabling neonatal Fc receptor recycling are 2 mechanisms that are being applied to extend the half-life of many therapeutic proteins. In this review, we discuss elimination mechanisms of protein therapeutics, underlying mechanisms and strategies for their half-life extension, impact of half-life extension on primary pharmacokinetic parameters, and critical factors to be considered to choose effective half-life extension strategy. Despite these advances, challenges remain in balancing half-life extension with biological activity, stability, and manufacturability. Ongoing research aims to optimize these technologies to meet the growing demand for long-acting biologics in chronic disease management. As half-life extension continues to evolve, it holds promise not only in improving therapeutic performance but also in expanding the applicability of protein drugs across a broader range of clinical indications. SIGNIFICANCE STATEMENT: The clinical utility of many protein and peptide therapeutics is limited by insufficient circulation time. Half-life extension strategies such as PEGylation, albumin fusion, and Fc fusion have demonstrated benefits clinically and permit extended dosing windows.