title: Potential induction of anti-PEG antibodies and complement activation toward PEGylated therapeutics.
abstract: Conjugation of polyethylene glycol (PEG) to therapeutics has proven to be an effective approach to increase the serum half-life. However, the increased use of PEGylated therapeutics has resulted in unexpected immune-mediated side-effects. There are claims that these are caused by anti-PEG antibodies inducing rapid clearance. These claims are however hampered by the lack of standardized and well-validated antibody assays. PEGylation has also been associated with the activation of the complement system causing severe hypersensitivity reactions. Here, we critically review the clinical and analytical tools used. In addition, we propose an explanation of the immune-mediated side-effects of PEGylated products based on the haptogenic properties of PEG, responsible for complement activation and the induction of anti-PEG antibodies.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands. Electronic address: j.j.f.verhoef@uu.nl.
authors.forename: Johan J F
authors.initials: JJ
authors.lastname: Verhoef
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Carpenter
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Anchordoquy
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.
authors.forename: Huub
authors.initials: H
authors.lastname: Schellekens
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001215:Asparaginase / Q000276:immunology* / Q000627:therapeutic use; D003167:Complement Activation; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000627:therapeutic use; D010455:Peptides / Q000276:immunology* / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000627:therapeutic use; D014503:Urate Oxidase / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D000906:Antibodies; D016898:Interferon-alpha; D010455:Peptides; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; C042705:pegaspargase; D004317:Doxorubicin; D014503:Urate Oxidase; D001215:Asparaginase; C556270:peginesatide; C031545:Pegloticase