title: Recombinant canine B-domain-deleted FVIII exhibits high specific activity and is safe in the canine hemophilia A model.
abstract: Production of recombinant B-domain-deleted canine factor VIII (cFVIII-BDD) unexpectedly revealed superior protein yields with 3-fold increased specific activity relative to human FVIII-BDD (hFVIII-BDD). We also determined that activated cFVIII-BDD is more stable than activated hFVIII-BDD. Furthermore, cFVIII-BDD is efficient at inducing hemostasis in human plasma containing FVIII inhibitors. Infusion of cFVIII-BDD in hemophilia A dogs resulted in correction of the disease phenotype with a pharmacokinetic profile similar to clinical experience with hFVIII-BDD. Notably, immune tolerance challenges with cFVIII-BDD in young and adult hemophilia A dogs did not induce the formation of neutralizing or nonneutralizing antibodies to cFVIII. These data establish the framework to quantitatively investigate the efficacy and safety in preclinical studies of novel therapies for hemophilia A.
authors.affiliation: Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Denise E
authors.initials: DE
authors.lastname: Sabatino
authors.forename: Christian Furlan
authors.initials: CF
authors.lastname: Freguia
authors.forename: Raffaella
authors.initials: R
authors.lastname: Toso
authors.forename: Andrey
authors.initials: A
authors.lastname: Santos
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Merricks
authors.forename: Haig H
authors.initials: HH
authors.lastname: Kazazian
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Nichols
authors.forename: Rodney M
authors.initials: RM
authors.lastname: Camire
authors.forename: Valder R
authors.initials: VR
authors.lastname: Arruda
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D005169:Factor VIII / Q000276:immunology / Q000378:metabolism* / Q000627:therapeutic use; D006467:Hemophilia A / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D011994:Recombinant Proteins; D005169:Factor VIII