Enhancing Therapeutic Protein and Peptide Efficacy through Albumin- and Polymer-Mediated Strategies Jae Hun, Lee College of Engineering Gwangju Institute of Science and Technology

Abstract

Therapeutic proteins and peptides represent a rapidly growing class of biologics due to their specificity, efficacy, and versatility in treating various diseases, including cancer and metabolic disorders. Despite their clinical potential, these biologics often face critical limitations such as rapid clearance, proteolytic instability, immunogenicity, and poor tissue penetration, which restrict their therapeutic effectiveness and patient compliance. This dissertation investigates two advanced molecular engineering strategies—polymer- mediated and albumin-mediated approaches—to overcome these pharmacological challenges. The polymer-mediated strategy employs zwitterionic bottlebrush polymers (ZBPs), designed for site-specific conjugation to therapeutic proteins, providing superior hydration, steric shielding, and immunological protection compared to conventional PEGylation. Using urate oxidase (UOX) as a model protein, the study demonstrates that ZBP conjugation preserves enzymatic activity, significantly enhances proteolytic stability, and effectively reduces antibody recognition. The albumin-mediated strategy leverages the naturally prolonged circulation and FcRn recycling properties of human serum albumin (HSA). By genetically fusing therapeutic proteins with albumin-binding domains (ABDs), this approach extends systemic half-life and improves biodistribution. This strategy is applied to two therapeutic systems: single-chain variable fragment-based antibody-drug conjugates (scFv-based ADCs) for cancer therapy and multi-agonist peptides with tunable albumin- binding affinity for obesity control. These two applications were employed to evaluate in vivo pharmacokinetics and therapeutic potential in relevant disease models. Collectively, these results validate the effectiveness of polymer- and albumin-mediated engineering strategies in overcoming critical pharmacological barriers, providing a robust foundation for the development of next-generation therapeutic proteins and peptides with enhanced clinical efficacy.