Induction of Anti-PEG Immune Responses by PEGylation of Proteins

Modification of proteins with polyethylene glycol (PEG) (PEGylation) is a gold standard technique that improves the solubility, pharmacokinetics, and immunogenicity of modified proteins. To date more than 10 PEGylated protein formulations have been approved, and more than 20 PEGylated drugs are entering clinical trials. PEG has been considered non-immunogenic and non-toxic, but several studies have shown that PEG acquires immunogenicity following attachment to nanoparticles. The administration of PEGylated liposomes, micelles and proteins induces the production of antibodies against PEG (anti-PEG antibodies) in animals and human subjects. Indeed, approximately 20% of healthy human subjects possess pre-existing anti-PEG antibodies prior to treatment with PEGylated therapeutics. The induced and pre-existing anti-PEG antibodies cause not only the elimination of PEGylated proteins from blood circulation, but also allergic responses via the release of anaphylatoxins. Consequently, therapeutic outcomes for PEGylated proteins are impaired. The utility of PEGylated proteins could be improved by attenuating the PEG-related immune response. On the other hand, anti-PEG immune responses might be exploited for vaccine applications. Our recent studies demonstrated that anti-PEG antibodies mediate the delivery of antigens encapsulated in PEGylated liposomes, and enhance antigen-specific immune responses. In this review, we summarize anti-PEG antibody induction by PEGylated proteins and alterations in anti-PEG IgM-mediated pharmacokinetics and pharmacodynamics. These findings extend our knowledge of PEG-related immune responses.