title: Mechanically-induced aggregation of the monoclonal antibody cetuximab.
abstract: This study focuses on the mechanically-induced aggregation of the anticancer monoclonal antibody cetuximab and its mechanism by comparing two commercially-available formulations (old formulation [OF]: 2mg/ml in phosphate buffer; new formulation [NF]: 5mg/ml in citrate buffer with polysorbate 80 and glycine). Cetuximab aggregation under stirring was followed during a 24h period and several methods were used to describe the aggregation kinetics (turbidimetry, size-exclusion high performance liquid chromatography, cation-exchange chromatography, dynamic light scattering and peptide mapping). Depending on the formulation, the aggregation process followed different kinetics: biexponential for the OF and mono-exponential for the NF. The percentage of aggregation after 24h stirring-period was about 25% for the OF but was only 2% for the NF corresponding to a ten-fold improvement, demonstrating a strong protecting effect of polysorbate and glycine. The aggregates are mainly due to an increased exposure of antibody molecules to air/liquid interface and are formed without chemical alteration of the antibody structure. This improvement of cetuximab stability by a new formulation seems linked to the stabilisation of cetuximab under dimeric form by a higher protein concentration and the presence of stabilizing excipients.
authors.affiliation: Department of Pharmacy, CHU Henri-Mondor, AP-HP, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94000 Créteil, France.
authors.forename: A
authors.initials: A
authors.lastname: Lahlou
authors.forename: B
authors.initials: B
authors.lastname: Blanchet
authors.forename: M
authors.initials: M
authors.lastname: Carvalho
authors.forename: M
authors.initials: M
authors.lastname: Paul
authors.forename: A
authors.initials: A
authors.lastname: Astier
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000737:chemistry*; D000068818:Cetuximab; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004339:Drug Compounding; D004355:Drug Stability; D005079:Excipients; D008027:Light; D009391:Nephelometry and Turbidimetry; D010316:Particle Size; D010449:Peptide Mapping; D012542:Scattering, Radiation; D013056:Spectrophotometry, Ultraviolet; D013314:Stress, Mechanical
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D005079:Excipients; D000068818:Cetuximab