title: A Multidimensional Analytical Comparison of Remicade and the Biosimilar Remsima.
abstract: In April 2016, the Food and Drug Administration approved the first biosimilar monoclonal antibody (mAb), Inflectra/Remsima (Celltrion), based off the original product Remicade (infliximab, Janssen). Biosimilars promise significant cost savings for patients, but the unavoidable differences between innovator and copycat biologics raise questions regarding product interchangeability. In this study, Remicade and Remsima were examined by native mass spectrometry, ion mobility, and quantitative peptide mapping. The levels of oxidation, deamidation, and mutation of individual amino acids were remarkably similar. We found different levels of C-terminal truncation, soluble protein aggregates, and glycation that all likely have a limited clinical impact. Importantly, we identified more than 25 glycoforms for each product and observed glycoform population differences, with afucosylated glycans accounting for 19.7% of Remicade and 13.2% of Remsima glycoforms, which translated into a 2-fold reduction in the level of FcγIIIa receptor binding for Remsima. While this difference was acknowledged in Remsima regulatory filings, our glycoform analysis and receptor binding results appear to be somewhat different from the published values, likely because of methodological differences between laboratories and improved glycoform identification by our laboratory using a peptide map-based method. Our mass spectrometry-based analysis provides rapid and robust analytical information vital for biosimilar development. We have demonstrated the utility of our multiple-attribute monitoring workflow using the model mAbs Remicade and Remsima and have provided a template for analysis of future mAb biosimilars.
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan , 428 Church Street, Ann Arbor, Michigan 48109, United States.|Biointerfaces Institute, University of Michigan , 2800 Plymouth Road, Ann Arbor, Michigan 48109, United States.
authors.forename: Karthik
authors.initials: K
authors.lastname: Pisupati
authors.affiliation: Department of Chemistry, University of Michigan , 930 North University Street, Ann Arbor, Michigan 48109, United States.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas , 2010 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: Solomon
authors.initials: S
authors.lastname: Okbazghi
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan , 428 Church Street, Ann Arbor, Michigan 48109, United States.|Biointerfaces Institute, University of Michigan , 2800 Plymouth Road, Ann Arbor, Michigan 48109, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Benet
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan , 428 Church Street, Ann Arbor, Michigan 48109, United States.|Biointerfaces Institute, University of Michigan , 2800 Plymouth Road, Ann Arbor, Michigan 48109, United States.
authors.forename: Rose
authors.initials: R
authors.lastname: Ackermann
authors.affiliation: MS Bioworks , 3950 Varsity Drive, Ann Arbor, Michigan 48108, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Ford
authors.affiliation: Promega Corporation , 2800 Woods Hollow Road, Fitchburg, Wisconsin 53711, United States.
authors.forename: Sergei
authors.initials: S
authors.lastname: Saveliev
authors.affiliation: Promega Corporation , 2800 Woods Hollow Road, Fitchburg, Wisconsin 53711, United States.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hosfield
authors.affiliation: Promega Corporation , 2800 Woods Hollow Road, Fitchburg, Wisconsin 53711, United States.
authors.forename: Marjeta
authors.initials: M
authors.lastname: Urh
authors.affiliation: Protein Metrics Inc. , 1622 San Carlos Avenue, San Carlos, California 94070, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Carlson
authors.affiliation: Protein Metrics Inc. , 1622 San Carlos Avenue, San Carlos, California 94070, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Becker
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas , 2010 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Tolbert
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan , 428 Church Street, Ann Arbor, Michigan 48109, United States.|Biointerfaces Institute, University of Michigan , 2800 Plymouth Road, Ann Arbor, Michigan 48109, United States.|Department of Biomedical Engineering, University of Michigan , 2200 Bonisteel Boulevard, Ann Arbor, Michigan 48109, United States.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Schwendeman
authors.affiliation: Department of Chemistry, University of Michigan , 930 North University Street, Ann Arbor, Michigan 48109, United States.
authors.forename: Brandon T
authors.identifier: 0000-0002-6084-2328
authors.initials: BT
authors.lastname: Ruotolo
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan , 428 Church Street, Ann Arbor, Michigan 48109, United States.|Biointerfaces Institute, University of Michigan , 2800 Plymouth Road, Ann Arbor, Michigan 48109, United States.
authors.forename: Anna
authors.identifier: 0000-0002-8023-8080
authors.initials: A
authors.lastname: Schwendeman
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry*; D059451:Biosimilar Pharmaceuticals / Q000737:chemistry*; D002850:Chromatography, Gel; D006031:Glycosylation; D000069285:Infliximab / Q000737:chemistry*; D007368:Interferometry; D013058:Mass Spectrometry / Q000379:methods; D010449:Peptide Mapping
chemical_list: D000911:Antibodies, Monoclonal; D059451:Biosimilar Pharmaceuticals; C000591237:CT-P13; D000069285:Infliximab