title: Recombinant activated factor VII (rFVIIa): characterization, manufacturing, and clinical development.
abstract: Recombinant activated coagulation factor VII (rFVIIa) (NovoSeven) was developed for treatment of bleeding in hemophilia patients with inhibitors (antibodies) against factors VIII or IX. rFVIIa initiates the coagulation cascade by binding to tissue factor at the site of injury and causes the formation of sufficient amounts of thrombin to trigger coagulation. Patients with a variety of other coagulation deficiencies than hemophilia characterized by an impaired thrombin generation and life-threatening bleeding have been reported as successfully treated with rFVIIa. Data are now entered into clinical registries established to further monitor this experimental treatment with NovoSeven. rFVIIa is produced free of any added human protein. The amino acid sequence of rFVIIa is identical to plasma-derived FVIIa (pdFVIIa). Posttranslational modifications (i.e., gamma-carboxylations, N- and O-glycosylations) are qualitatively identical in pdFVIIa and rFVIIa although some quantitative differences exist. The activities of rFVIIa and pdFVIIa are indistinguishable. Manufacturing of rFVIIa involves expression in baby hamster kidney (BHK) cells followed by purification, including three ion-exchange and one immunoaffinity chromatography steps. The last anion-exchange chromatography step ensures completion of the autoactivation of recombinant factor VII (rFVII) to rFVIIa. This review describes the mechanism of action, characterization, manufacturing, and preclinical and current clinical evidence for the efficacy and safety of rFVIIa.
authors.affiliation: IO Biopharm, Novo Nordisk A/S, Novo Allé, DK-2880 Bagsvaerd, Lyngby, Denmark. bju@novonordisk.com
authors.forename: B
authors.initials: B
authors.lastname: Jurlander
authors.forename: L
authors.initials: L
authors.lastname: Thim
authors.forename: N K
authors.initials: NK
authors.lastname: Klausen
authors.forename: E
authors.initials: E
authors.lastname: Persson
authors.forename: M
authors.initials: M
authors.lastname: Kjalke
authors.forename: P
authors.initials: P
authors.lastname: Rexen
authors.forename: T B
authors.initials: TB
authors.lastname: Jørgensen
authors.forename: P B
authors.initials: PB
authors.lastname: Østergaard
authors.forename: E
authors.initials: E
authors.lastname: Erhardtsen
authors.forename: S E
authors.initials: SE
authors.lastname: Bjørn
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D003001:Cloning, Molecular; D005167:Factor VII / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D015942:Factor VIIa; D006801:Humans; D007218:Industrial Microbiology / Q000379:methods*; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D014170:Transformation, Genetic
chemical_list: D011994:Recombinant Proteins; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa