title: Non-Arrhenius protein aggregation.
abstract: Protein aggregation presents one of the key challenges in the development of protein biotherapeutics. It affects not only product quality but also potentially impacts safety, as protein aggregates have been shown to be linked with cytotoxicity and patient immunogenicity. Therefore, investigations of protein aggregation remain a major focus in pharmaceutical companies and academic institutions. Due to the complexity of the aggregation process and temperature-dependent conformational stability, temperature-induced protein aggregation is often non-Arrhenius over even relatively small temperature windows relevant for product development, and this makes low-temperature extrapolation difficult based simply on accelerated stability studies at high temperatures. This review discusses the non-Arrhenius nature of the temperature dependence of protein aggregation, explores possible causes, and considers inherent hurdles for accurately extrapolating aggregation rates from conventional industrial approaches for selecting accelerated conditions and from conventional or more advanced methods of analyzing the resulting rate data.
authors.affiliation: Pfizer Inc., BioTherapeutics Pharmaceutical Sciences, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. wei.2.wang@pfizer.com
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Roberts
mesh_terms: D000818:Animals; D006801:Humans; D011487:Protein Conformation; D055550:Protein Stability; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D013696:Temperature
chemical_list: D011506:Proteins