Covalent attachment of polyethylene glycol (PEG) to active proteins (PEGylation technology) successfully generated several FDA-approved compounds, including four blockbusters, which are considered non immunogenic. However, PEG antibodies and intolerance to the infusion were reported in some patients with gout treated with pegloticase, a PEG-uricase recently approved by the FDA (Food and Drug Administration, USA). Therefore, we reviewed the literature concerning immunogenicity of PEG alone or covalently attached to proteins. We consulted databases (Scirus, Pub Med, Cochrane Library, and Science Direct) and the references of selected articles and main journals publishing articles on the subject. Animal studies clearly showed that PEG-uricases and some other PEGylated proteins might elicit antibody formation against PEG. This anti-PEG response can accelerate the clearance of PEGylated proteins. Of major importance is the recent finding of a 22%-25% occurrence of PEG antibodies in healthy blood donors. PEG antibodies may limit therapeutic efficacy and/or reduce tolerance of PEG-asparaginase (PEG-ASNase) in patients with acute lymphoblastic leukemia and of pegloticase in patients with chronic gout, but apparently do not impair hyposensitization of allergic patients with mPEG-modified ragweed extract and honey bee venom or the response to PEGinterferon in patients with hepatitis C. In conclusion, pre-existing or newly developed PEG antibodies may limit therapeutic efficacy and/or reduce tolerance of PEGylated proteins in some patients. The immunogenicity of PEGylated therapeutic agents in clinical use or development deserves to be re-examined by investigating PEG antibodies.
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