title: Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs.
abstract: Despite proven benefits, prophylactic treatment for hemophilia A is hampered by the short half-life of factor VIII. A recombinant factor VIII-Fc fusion protein (rFVIIIFc) was constructed to determine the potential for reduced frequency of dosing. rFVIIIFc has an ∼ 2-fold longer half-life than rFVIII in hemophilia A (HemA) mice and dogs. The extension of rFVIIIFc half-life requires interaction of Fc with the neonatal Fc receptor (FcRn). In FcRn knockout mice, the extension of rFVIIIFc half-life is abrogated, and is restored in human FcRn transgenic mice. The Fc fusion has no impact on FVIII-specific activity. rFVIIIFc has comparable acute efficacy as rFVIII in treating tail clip injury in HemA mice, and fully corrects whole blood clotting time (WBCT) in HemA dogs immediately after dosing. Furthermore, consistent with prolonged half-life, rFVIIIFc shows 2-fold longer prophylactic efficacy in protecting HemA mice from tail vein transection bleeding induced 24-48 hours after dosing. In HemA dogs, rFVIIIFc also sustains partial correction of WBCT 1.5- to 2-fold longer than rFVIII. rFVIIIFc was well tolerated in both species. Thus, the rescue of FVIII by Fc fusion to provide prolonged protection presents a novel pathway for FVIII catabolism, and warrants further investigation.
authors.affiliation: Research and Development, Biogen Idec Hemophilia, Waltham, MA 02451, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Dumont
authors.forename: Tongyao
authors.initials: T
authors.lastname: Liu
authors.forename: Susan C
authors.initials: SC
authors.lastname: Low
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: George
authors.initials: G
authors.lastname: Kamphaus
authors.forename: Paul
authors.initials: P
authors.lastname: Sakorafas
authors.forename: Cara
authors.initials: C
authors.lastname: Fraley
authors.forename: Douglas
authors.initials: D
authors.lastname: Drager
authors.forename: Thomas
authors.initials: T
authors.lastname: Reidy
authors.forename: Justin
authors.initials: J
authors.lastname: McCue
authors.forename: Helen W G
authors.initials: HW
authors.lastname: Franck
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Merricks
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Nichols
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Bitonti
authors.forename: Glenn F
authors.initials: GF
authors.lastname: Pierce
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D003029:Coagulants / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000188:drug therapy / Q000378:metabolism; D004285:Dogs; D005169:Factor VIII / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics* / Q000627:therapeutic use; D057809:HEK293 Cells; D006207:Half-Life; D006467:Hemophilia A / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011961:Receptors, Fc / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014914:Whole Blood Coagulation Time
chemical_list: D003029:Coagulants; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D005169:Factor VIII; C100688:Fc receptor, neonatal