Half-life extension and immunogenicity in therapeutic proteins: mechanisms, trade-offs, and a decision framework

Therapeutic proteins are central to modern pharmacotherapy, yet their clinical utility is often constrained by short plasma half-life and immunogenicity. Six major half-life extension platforms-PEGylation, hydrophilic polypeptide (XTEN/PAS) fusion, glycoengineering, Fc domain-based strategies, human serum albumin (HSA)-centered approaches, and lipidation-have yielded numerous clinically approved therapeutics, yet are typically reviewed in isolation. This review presents a systematic, mechanism-driven comparison of these platforms, evaluating their effects on pharmacokinetics, tissue distribution, immunogenicity, conformational stability, and manufacturability. We highlight key molecular principles, representative clinical candidates, and emerging hybrid designs. Based on this synthesis, we propose a decision framework that aligns platform selection with therapeutic indication, modality, and development constraints. Finally, we discuss unresolved challenges-including accurate immunogenicity prediction and regulatory harmonization-that must be addressed to fully realize safer, longer-acting biologics. This review equips pharmacologists and biotherapeutic developers with an evidence-based, cross-platform toolkit to rationally design and select next-generation long-acting protein therapeutics.