A review on the immunogenicity towards marketed PEGylated enzyme therapeutics in pre-clinical and clinical settings

Abstract

Polyethylene glycol (PEG) is considered as the “gold standard” for modification of biologics and other molecules used in pharmaceuticals, cosmetics, and healthcare products due to its ability to enhance the efficacy and safety of the products. In the pharmaceutical sector, PEGylation of protein therapeutics has improved their biodistribution, leading to extended circulation half-life, reduced immune recognition, and improved serum stability compared to their non-PEGylated counterparts. However, growing clinical and preclinical evidence reveals that PEGylated drugs can elicit anti-drug antibodies (ADAs), directed against the PEG moiety (anti-PEG), the therapeutic protein (anti-protein), or other conjugated components (e.g. anti-linkers). These ADAs have been associated with reduced therapeutic efficacy through accelerated blood clearance (ABC) and increased incidence of immunogenic reactions, particularly hypersensitivity reactions (HSRs). In recent decades, widespread exposure to PEG-containing products has increased the likelihood of pre-existing ADAs, mainly anti-PEG, in the general population. Simultaneously, advances in assay sensitivity have improved ADA detection, revealing a broader prevalence of immunogenic responses to marketed PEGylated drugs. This review summarizes the mechanisms underlying immune responses to PEGylated proteins and presents a comprehensive evaluation of the immunogenicity profiles of all PEGylated enzyme therapeutics approved for clinical use to date. Special attention is given to the impact of clinical study design, therapeutic indication, and PEG structural characteristics on immunogenic outcomes. ADAs, ABC phenomenon, and/or immunogenic reactions were reported upon application of all these products. Furthermore, it was determined that the patient population characteristics, particularly prior PEG exposure and immune status, along with study inclusion criteria, had a greater influence on immunogenicity than PEG structure alone. Accordingly, future clinical evaluations should incorporate more diverse and representative populations, systematically assess pre-existing ADAs, and employ standardized, highly specific immunogenicity assays. Such strategies are essential to accurately evaluate the safety and efficacy of both existing and next-generation PEGylated therapeutics.