title: Recombinant factor VIII Fc (rFVIIIFc) fusion protein reduces immunogenicity and induces tolerance in hemophilia A mice.
abstract: Anti-factor VIII (FVIII) antibodies is a major complication of FVIII replacement therapy for hemophilia A. We investigated the immune response to recombinant human factor VIII Fc (rFVIIIFc) in comparison to BDD-rFVIII and full-length rFVIII (FL-rFVIII) in hemophilia A mice. Repeated administration of therapeutically relevant doses of rFVIIIFc in these mice resulted in significantly lower antibody responses to rFVIII compared to BDD-rFVIII and FL-rFVIII and reduced antibody production upon subsequent challenge with high doses of rFVIIIFc. The induction of a tolerogenic response by rFVIIIFc was associated with higher percentage of regulatory T-cells, a lower percentage of pro-inflammatory splenic T-cells, and up-regulation of tolerogenic cytokines and markers. Disruption of Fc interactions with either FcRn or Fcγ receptors diminished tolerance induction, suggesting the involvement of these pathways. These results indicate that rFVIIIFc reduces immunogenicity and imparts tolerance to rFVIII demonstrating that recombinant therapeutic proteins may be modified to influence immunogenicity and facilitate tolerance.
authors.affiliation: Hematology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States. Electronic address: sriram.krishnamoorthy@biogen.com.
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnamoorthy
authors.affiliation: Hematology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States.
authors.forename: Tongyao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Hematology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States.
authors.forename: Douglas
authors.initials: D
authors.lastname: Drager
authors.affiliation: Hematology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States.
authors.forename: Susannah
authors.initials: S
authors.lastname: Patarroyo-White
authors.affiliation: Hematology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States.
authors.forename: Ekta Seth
authors.initials: ES
authors.lastname: Chhabra
authors.affiliation: Hematology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Peters
authors.affiliation: Division of Hematology, University of Washington School of Medicine, Puget Sound Blood Center, Seattle, WA 98104, United States.
authors.forename: Neil
authors.initials: N
authors.lastname: Josephson
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Lillicrap
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.affiliation: Hematology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States.
authors.forename: Glenn F
authors.initials: GF
authors.lastname: Pierce
authors.affiliation: Hematology Research, Biogen, 115 Broadway, Cambridge, MA 02142, United States. Electronic address: haiyan.jiang.b@gmail.com.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005169:Factor VIII / Q000276:immunology* / Q000494:pharmacology; D005434:Flow Cytometry; D006467:Hemophilia A / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007141:Immunoglobulin Fc Fragments / Q000276:immunology* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000276:immunology* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D005169:Factor VIII
keywords: Factor VIII; Fc fusion protein; FcRn; Hemophilia A; Immune tolerance; Immunogenicity; Regulatory T cells