Antibody response to recombinant human coagulation factor VIII in a new rat model of severe hemophilia A

• Published in: Journal of thrombosis and haemostasis 2016-04, Vol.14 (4), p.747-756
• Main Authors: Lövgren, K. M., Søndergaard, H., Skov, S., Weldingh, K. N., Tranholm, M., Wiinberg, B.
• Format: Article
• Language: English
• Subjects: animal model; Animals; Antibodies, Neutralizing - immunology; Antibody Formation; Blood Coagulation - drug effects; Disease Models, Animal; factor VIII; Factor VIII - therapeutic use; Female; Hemophilia; hemophilia A; Hemophilia A - blood; Hemophilia A - genetics; Hemophilia A - immunology; Heterozygote; Homozygote; Humans; Immunoglobulin G - immunology; Immunoglobulin M - immunology; Immunoglobulins; Male; neutralizing antibodies; Partial Thromboplastin Time; Protein Binding; Rats; rattus; Recombinant Proteins - therapeutic use; Rodents; Studies; Thrombin - metabolism
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.13259

Essentials Validation of a hemophilia A rat as a translational and predictive model for immunogenicity assessment. Study of the antibody response toward clinically relevant doses of recombinant coagulation factor VIII. A reproducible antibody response was demonstrated when following a human prophylaxis regimen. Antibodies developed after 4–6 intravenous doses and inhibitory titers resembled levels in human patients. Summary 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. Objectives 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.