title: Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs.
abstract: Intravenous administration of recombinant human factor IX (rhFIX) acutely corrects the coagulopathy in hemophilia B dogs. To date, 20 of 20 dogs developed inhibitory antibodies to the xenoprotein, making it impossible to determine if new human FIX products, formulations, or methods of chronic administration can reduce bleeding frequency. Our goal was to determine whether hemophilia B dogs rendered tolerant to rhFIX would have reduced bleeding episodes while on sustained prophylactic rhFIX administered subcutaneously. Reproducible methods were developed for inducing tolerance to rhFIX in this strain of hemophilia B dogs, resulting in a significant reduction in the development of inhibitors relative to historical controls (5 of 12 versus 20 or 20, P <.001). The 7 of 12 tolerized hemophilia B dogs exhibited shortened whole blood clotting times (WBCTs), sustained detectable FIX antigen, undetectable Bethesda inhibitors, transient or no detectable antihuman FIX antibody titers by enzyme-linked immunosorbent assay (ELISA), and normal clearance of infused rhFIX. Tolerized hemophilia B dogs had 69% reduction in bleeding frequency in year 1 compared with nontolerized hemophilia B dogs (P =.0007). If proven safe in human clinical trials, subcutaneous rhFIX may provide an alternate approach to prophylactic therapy in selected patients with hemophilia B.
authors.affiliation: Francis Owen Blood Research Laboratory, Department of Pathology and Laboratory Medicine, UNC School of Medicine, CB# 3114, 350 S Old Fayetteville Rd, Chapel Hill, NC 27516.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Russell
authors.forename: Eva H N
authors.initials: EH
authors.lastname: Olsen
authors.forename: Robin A
authors.initials: RA
authors.lastname: Raymer
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Merricks
authors.forename: Dwight A
authors.initials: DA
authors.lastname: Bellinger
authors.forename: Marjorie S
authors.initials: MS
authors.lastname: Read
authors.forename: Bonita J
authors.initials: BJ
authors.lastname: Rup
authors.forename: James C
authors.initials: JC
authors.lastname: Keith
authors.forename: Kyle P
authors.initials: KP
authors.lastname: McCarthy
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schaub
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Nichols
mesh_terms: D000818:Animals; D017849:Animals, Inbred Strains; D000831:Animals, Newborn; D000910:Antibodies, Heterophile / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D004285:Dogs; D005164:Factor IX / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D002836:Hemophilia B / Q000150:complications / Q000188:drug therapy*; D006470:Hemorrhage / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D007108:Immune Tolerance; D007279:Injections, Subcutaneous; D008297:Male; D010865:Pilot Projects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D015203:Reproducibility of Results
chemical_list: D000910:Antibodies, Heterophile; D011994:Recombinant Proteins; D005164:Factor IX