Immunological responses to PEGylated proteins: Anti-PEG antibodies

Abstract

PEGylation, the covalent coupling of polyethylene glycol (PEG) chains to therapeutic proteins, is a commonly used technique for mitigating some pharmacokinetic limitations of protein therapeutics by improving their circulation half-lives. Nevertheless, in contrast to the generally accepted belief that PEG is nonimmunogenic, a growing body of literature provides evidence that PEG may, in some circumstances, indeed be immunogenic and result in the formation of anti-PEG antibodies. The existence of such antibodies has been implicated in the observation of accelerated blood clearance of PEGylated proteins and particles, which may impair therapeutic efficacy and cause adverse reactions during the clinical application of PEGylated proteins. Therefore, it is important to understand nature of, and the underlying causes for, anti-PEG immune responses against PEGylated proteins. In this chapter, we discuss the prevalence of preexisting and treatment-induced anti-PEG antibodies and their clinical impact on the therapeutic efficacy and/or safety of PEGylated proteins, the mechanisms behind anti-PEG immune reactions, and the factors contributing to both PEG immunogenicity and antigenicity. In addition, several alternative approaches, besides PEGylation, to improve the pharmacokinetics of therapeutic proteins are suggested.