Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs.
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.
Russell
Karen E
KE
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.
Olsen
Eva H N
EH
Raymer
Robin A
RA
Merricks
Elizabeth P
EP
Bellinger
Dwight A
DA
Read
Marjorie S
MS
Rup
Bonita J
BJ
Keith
James C
JC
McCarthy
Kyle P
KP
Schaub
Robert G
RG
Nichols
Timothy C
TC
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
D000910:Antibodies, Heterophile; D011994:Recombinant Proteins; D005164:Factor IX