Anti-PEG Antibodies and Their Biological Impact on PEGylated Drugs: Challenges and Strategies for Optimization

Polyethylene glycol (PEG) has been widely utilized in optimizing therapeutics due to its excellent biocompatibility and chemical stability. However, multiple dosing of PEGylated drugs may result in toxicity due to PEG accumulation in tissues, leading to the formation of anti-PEG antibodies (APAs), which can accelerate drug clearance, reduce efficacy, and alongside enhanced side effects, such as allergic reactions. Notably, pre-existing APAs have also been detected in individuals with no prior exposure to PEGylated drugs, raising additional clinical concerns. This review summarizes the mechanisms of APA generation, the factors influencing PEG immunogenicity, and the biological consequences of APAs on drug pharmacokinetics, efficacy, and safety. We also discuss current challenges in APA detection and highlight strategies to minimize immunogenic responses, including PEG modification, immunomodulation, and alternative polymers. This review aims to provide a comprehensive reference for the rational design, evaluation, and clinical management of PEGylated drugs.