Potential induction of anti-PEG antibodies and complement activation toward PEGylated therapeutics

• Published in: Drug discovery today Vol. 19; no. 12; pp. 1945 - 1952
• Main Authors: Verhoef, Johan J.F., Carpenter, John F., Anchordoquy, Thomas J., Schellekens, Huub
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2014
• Subjects: Animals; Antibodies - immunology; Asparaginase - immunology; Asparaginase - therapeutic use; Complement Activation; Doxorubicin - analogs & derivatives; Doxorubicin - immunology; Doxorubicin - therapeutic use; Humans; Interferon-alpha - immunology; Interferon-alpha - therapeutic use; Peptides - immunology; Peptides - therapeutic use; Polyethylene Glycols - therapeutic use; Urate Oxidase - immunology; Urate Oxidase - therapeutic use
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2014.08.015

•PEGylated nanocarriers are linked to the accelerated blood clearance (ABC) phenomenon.•The ABC is induced by anti-PEG antibodies and/or complement activation.•PEGylated proteins can induce complement activation and anti-PEG antibodies.•Anti-PEG antibody data are difficult to interpret because no validated assay exists. 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.