Recombinant Factor IX Fc Fusion Protein Maintains Full Procoagulant Properties and Exhibits Prolonged Efficacy in Hemophilia B Mice.

Abstract

INTRODUCTION:

Hemophilia B is an inherited X chromosome-linked disorder characterized by impaired blood clotting owing to the absence of functional coagulation factor IX. Due to the relatively short half-life of factor IX, patients with hemophilia B require frequent factor IX infusions to maintain prophylaxis. We have developed a recombinant factor IX (rFIX) fused to the Fc region of IgG (rFIXFc) with an extended half-life in animals and humans.

MATERIALS AND METHODS:

Procoagulant properties of rFIXFc and rFIX (BENEFIX®) were compared to determine the effect of the Fc region on rFIXFc hemostatic function. Specifically, we assessed rFIXFc activation, intermolecular interactions within the Xase complex, inactivation by antithrombin III (AT) and thrombin generation potential compared with rFIX. We also assessed the acute and prophylactic efficacy profiles of rFIXFc and rFIX in vivo in hemophilia B mouse bleeding models.

RESULTS AND CONCLUSIONS:

The activation by factor XIa or factor VIIa/tissue factor, inhibition by AT, interaction profiles with phospholipids, affinities for factor VIIIa within the context of the Xase complex, and thrombin generation profiles were similar for rFIXFc and rFIX. Xase complexes formed with either molecule exhibited similar kinetic profiles for factor Xa generation. In acute efficacy models, mice infused with rFIXFc or rFIX were equally protected from bleeding. However, in prophylactic efficacy models, protection from bleeding was maintained approximately three times longer in rFIXFc-dosed mice than in those given rFIX; this prolonged efficacy correlates with the previously observed half-life extension. We conclude that rFIXFc retains critical FIX procoagulant attributes and that the extension in rFIXFc half-life translates into prolonged efficacy in hemophilia B mice.

• Authors: Garabet G Toby, Tongyao Liu, Yang Buyue, Xin Zhang, Alan J Bitonti, Glenn F Pierce, Jurg M Sommer, Haiyan Jiang, Robert T Peters
• Journal: PloS one (PLoS One) Vol. 11 Issue 2 Pg. e0148255 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 26840952 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Coagulants
• Immunoglobulin Fc Fragments
• Recombinant Fusion Proteins
• factor IX Fc fusion protein
• Antithrombin III
• Factor IX
• Factor VIIa
• Factor XIa
• Thrombin

Topics

• Animals
• Antithrombin III (pharmacology)
• Blood Coagulation (drug effects)
• Blood Coagulation Tests
• Coagulants (pharmacology)
• Disease Models, Animal
• Enzyme Activation (physiology)
• Factor IX (genetics, pharmacology)
• Factor VIIa (pharmacology)
• Factor XIa (pharmacology)
• Half-Life
• Hemophilia B (drug therapy)
• Hemorrhage (drug therapy)
• Immunoglobulin Fc Fragments (genetics, pharmacology)
• Mice
• Mice, Inbred C57BL
• Recombinant Fusion Proteins (genetics, pharmacology)
• Thrombin (biosynthesis)