title: PEGylated Biopharmaceuticals: Current Experience and Considerations for Nonclinical Development.
abstract: PEGylation (the covalent binding of one or more polyethylene glycol molecules to another molecule) is a technology frequently used to improve the half-life and other pharmaceutical or pharmacological properties of proteins, peptides, and aptamers. To date, 11 PEGylated biopharmaceuticals have been approved and there is indication that many more are in nonclinical or clinical development. Adverse effects seen with those in toxicology studies are mostly related to the active part of the drug molecule and not to polyethylene glycol (PEG). In 5 of the 11 approved and 10 of the 17 PEGylated biopharmaceuticals in a 2013 industry survey presented here, cellular vacuolation is histologically observed in toxicology studies in certain organs and tissues. No other effects attributed to PEG alone have been reported. Importantly, vacuolation, which occurs mainly in phagocytes, has not been linked with changes in organ function in these toxicology studies. This article was authored through collaborative efforts of industry toxicologists/nonclinical scientists to address the nonclinical safety of large PEG molecules (>10 kilo Dalton) in PEGylated biopharmaceuticals. The impact of the PEG molecule on overall nonclinical safety assessments of PEGylated biopharmaceuticals is discussed, and toxicological information from a 2013 industry survey on PEGylated biopharmaceuticals under development is summarized. Results will contribute to the database of toxicological information publicly available for PEG and PEGylated biopharmaceuticals.
authors.affiliation: Bayer HealthCare, San Francisco, California, USA inge.ivens@bayer.com.
authors.forename: Inge A
authors.initials: IA
authors.lastname: Ivens
authors.affiliation: Bristol-Myers Squibb Co., New Brunswick, New Jersey, USA.
authors.forename: William
authors.initials: W
authors.lastname: Achanzar
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Baumann
authors.affiliation: Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Brändli-Baiocco
authors.affiliation: Access BIO, Boyce, Virginia, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Cavagnaro
authors.affiliation: GlaxoSmithKline, LLC, King of Prussia, Pennsylvania, USA.
authors.forename: Maggie
authors.initials: M
authors.lastname: Dempster
authors.affiliation: UCB BioPharma, Braine L'Alleud, Belgium.
authors.forename: B Olympe
authors.initials: BO
authors.lastname: Depelchin
authors.affiliation: Lilly Research Laboratories, Indianapolis, Indiana, USA.
authors.forename: Armando R Irizarry
authors.initials: AR
authors.lastname: Rovira
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Dill-Morton
authors.affiliation: Biogen, Inc., Cambridge, Massachusetts, USA.
authors.forename: Joan H
authors.initials: JH
authors.lastname: Lane
authors.affiliation: Baxalta Innovations GmbH, Vienna, Austria.
authors.forename: Birgit M
authors.initials: BM
authors.lastname: Reipert
authors.affiliation: Janssen R&D, LLC, Spring House, Pennsylvania, USA.
authors.forename: Theodora
authors.initials: T
authors.lastname: Salcedo
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, California, USA.
authors.forename: Becky
authors.initials: B
authors.lastname: Schweighardt
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, California, USA.
authors.forename: Laurie S
authors.initials: LS
authors.lastname: Tsuruda
authors.affiliation: Baxalta Innovations GmbH, Vienna, Austria.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Turecek
authors.affiliation: Integrated Biologix GmbH, Basel, Switzerland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sims
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology*; D006801:Humans; D011092:Polyethylene Glycols / Q000737:chemistry / Q000633:toxicity*
chemical_list: D011092:Polyethylene Glycols
keywords: PEG; PEGylation; biopharmaceutical; nonclinical; polyethylene glycol; toxicology; vacuolation