Recombinant Activated Factor VII (rFVIIa): Characterization, Manufacturing, and Clinical Development

Birgit Jurlander; Lars Thim; Niels K. Klausen; Egon Persson; Marianne Kjalke; Per Rexen; Tom B. Jørgensen; Per B. Østergaard; Elisabeth Erhardtsen; Søren E. Bjørn

doi:10.1055/s-2001-16890

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2001; 27(4): 373-384
DOI: 10.1055/s-2001-16890

Recombinant Activated Factor VII (rFVIIa): Characterization, Manufacturing, and Clinical Development

Birgit Jurlander¹ , Lars Thim² , Niels K. Klausen³ , Egon Persson⁴ , Marianne Kjalke⁴ , Per Rexen⁵ , Tom B. Jørgensen⁵ , Per B. Østergaard⁶ , Elisabeth Erhardtsen⁷ , Søren E. Bjørn²

¹IO Biopharm, Novo Nordisk A/S, Lyngby, Denmark
²Protein Chemistry, Novo Nordisk A/S, Lyngby, Denmark
³Protein Drug Delivery, Novo Nordisk A/S, Lyngby, Denmark
⁴Vascular Biochemistry, Novo Nordisk A/S, Lyngby, Denmark
⁵Factor VIIa Bulk Production, Novo Nordisk A/S, Lyngby, Denmark
⁶Regulatory Affairs, Novo Nordisk A/S, Lyngby, Denmark
⁷Clinical Development, Novo Nordisk A/S, Lyngby, Denmark

Abstract

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., γ-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.

KEYWORD

Factor VIIa - rFVIIa - recombinant expression - in vitro activation - biological activity

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