title: Antibody response to recombinant human coagulation factor VIII in a new rat model of severe hemophilia A.
abstract: BACKGROUND
  Neutralizing antibodies toward FVIII replacement therapy (inhibitors) are the most serious treatment-related complication in hemophilia A (HA). A rat model of severe HA (F8(-/-) ) has recently been developed, but an immunological characterization is needed to determine the value of using the model for research into inhibitor development.
  
  
  OBJECTIVE
  Characterize the antibody response towards recombinant human coagulation factor VIII (rhFVIII) in the HA rat, following a human prophylactic dosing regimen.
  
  
  METHODS
  Two identical studies were performed, which included a total of 17 homozygous HA rats (F8(-/-) , 0% FVIII activity), 12 heterozygous rats (F8(+/-) ), and 12 wild-type (F8(+/+) ) rats. All rats received intravenous injections of rhFVIII at 50 IU kg(-1) twice weekly for 4 weeks. Predosing blood samples were analyzed for binding and neutralizing anti-rhFVIII antibodies at weeks 1-7.
  
  
  RESULTS
  In both studies, antibodies developed after 4-6 administrations of rhFVIII, and neutralizing antibodies reached levels similar to human patients (range 1-111 BU, median 6.0 BU) at the end of the study. There was no significant difference between the two studies or between genotypes in time to response or levels reached for binding and neutralizing antibodies. Interestingly, early spontaneous bleeds were associated with a faster antibody response.
  
  
  CONCLUSIONS
  Following intravenous administration of human FVIII, according to a clinical prophylaxis regimen, a robust and reproducible antibody response is seen in this HA rat model, suggesting that the model is useful for intervention studies with the aim of suppressing, delaying, or preventing the inhibitor response. Also, bleeds seem to have an adjuvant effect on the immune response.
authors.affiliation: Translational Hemophilia Pharmacology, Global Research, Novo Nordisk A/S, Maaloev, Denmark.|Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: K M
authors.initials: KM
authors.lastname: Lövgren
authors.affiliation: Diabetes Complications Pharmacology, Global Research, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: H
authors.initials: H
authors.lastname: Søndergaard
authors.affiliation: Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Skov
authors.affiliation: Immunogenicity Assessment, Global Research, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: K N
authors.initials: KN
authors.lastname: Weldingh
authors.affiliation: Hemophilia Pharmacology, Global Research, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Tranholm
authors.affiliation: Translational Hemophilia Pharmacology, Global Research, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Wiinberg
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000917:Antibody Formation; D001777:Blood Coagulation / Q000187:drug effects*; D004195:Disease Models, Animal; D005169:Factor VIII / Q000627:therapeutic use*; D005260:Female; D006467:Hemophilia A / Q000097:blood* / Q000235:genetics / Q000276:immunology*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D008297:Male; D010314:Partial Thromboplastin Time; D011485:Protein Binding; D051381:Rats; D011994:Recombinant Proteins / Q000627:therapeutic use; D013917:Thrombin / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011994:Recombinant Proteins; C078147:F8 protein, human; D005169:Factor VIII; D013917:Thrombin
keywords: animal model; factor VIII; hemophilia A; neutralizing antibodies; rattus