title: Post hoc assessment of the immunogenicity of bioengineered factor VIIa demonstrates the use of preclinical tools.
abstract: Immunogenicity is an important consideration in the licensure of a therapeutic protein because the development of neutralizing anti-drug antibodies (ADAs) can affect both safety and efficacy. Neoantigens introduced by bioengineering of a protein drug are a particular cause for concern. The development of a bioengineered recombinant factor VIIa (rFVIIa) analog was discontinued after phase 3 trials because of the development of ADAs. The unmodified parent molecule (rFVIIa), on the other hand, has been successfully used as a drug for more than two decades with no reports of immunogenicity in congenital hemophilia patients with inhibitors. We used computational and experimental methods to demonstrate that the observed ADAs could have been elicited by neoepitopes in the engineered protein. The human leukocyte antigen type of the patients who developed ADAs is consistent with this hypothesis of a neoepitope-driven immune response, a finding that might have implications for the preclinical screening of therapeutic protein analogs.
authors.affiliation: Global Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. zuben.sauna@fda.hhs.gov kplm@novonordisk.com.
authors.forename: Kasper
authors.initials: K
authors.lastname: Lamberth
authors.affiliation: Global Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Stine Louise
authors.initials: SL
authors.lastname: Reedtz-Runge
authors.affiliation: Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapeutics, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Simon
authors.affiliation: Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapeutics, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Ksenia
authors.initials: K
authors.lastname: Klementyeva
authors.affiliation: Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapeutics, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Gouri Shankar
authors.initials: GS
authors.lastname: Pandey
authors.affiliation: Global Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Søren Berg
authors.initials: SB
authors.lastname: Padkjær
authors.affiliation: Global Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Véronique
authors.initials: V
authors.lastname: Pascal
authors.affiliation: Global Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Ileana R
authors.initials: IR
authors.lastname: León
authors.affiliation: Global Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Charlotte Nini
authors.initials: CN
authors.lastname: Gudme
authors.affiliation: Laboratory of Experimental Immunology, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Buus
authors.affiliation: Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapeutics, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA. zuben.sauna@fda.hhs.gov kplm@novonordisk.com.
authors.forename: Zuben E
authors.initials: ZE
authors.lastname: Sauna
mesh_terms: D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000276:immunology; D049109:Cell Proliferation; D002648:Child; D018592:Cross-Over Studies; D003627:Data Interpretation, Statistical; D004311:Double-Blind Method; D000939:Epitopes / Q000276:immunology; D005169:Factor VIII / Q000276:immunology*; D015942:Factor VIIa / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology; D006467:Hemophilia A / Q000097:blood* / Q000628:therapy*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D008297:Male; D009154:Mutation; D015202:Protein Engineering / Q000379:methods*; D011994:Recombinant Proteins / Q000276:immunology; D012984:Software; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D006680:HLA Antigens; D000949:Histocompatibility Antigens Class II; D011994:Recombinant Proteins; C000596433:vatreptacog alfa; C078147:F8 protein, human; D005169:Factor VIII; D015942:Factor VIIa