TY - JOUR
T1 - Antibody response to recombinant human coagulation factor VIII in a new rat model of severe hemophilia A
AU - Löfgren, Karin Maria
AU - Sondergaard, H.
AU - Skov, Søren
AU - Weldingh, K. N.
AU - Tranholm, M.
AU - Wiinberg, B.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - Background: Neutralizing antibodies towardFVIII replacement therapy (inhibitors) are the most seri-ous treatment-related complication in hemophilia A(HA). A rat model of severe HA (F8/) has recentlybeen developed, but an immunological characterization isneeded to determine the value of using the model forresearch into inhibitor development. Objectives: Charac-terize the antibody response towards recombinant humancoagulation factor VIII (rhFVIII) in the HA rat, follow-ing a human prophylactic dosing regimen. Methods: Twoidentical studies were performed, which included a totalof 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 at50 IU kg1twice weekly for 4 weeks. Predosing bloodsamples were analyzed for binding and neutralizing anti-rhFVIII antibodies at weeks 1–7. Results: In both studies,antibodies developed after 4–6 administrations ofrhFVIII, and neutralizing antibodies reached levels simi-lar to human patients (range 1–111 BU, median 6.0 BU)at the end of the study. There was no significant differ-ence between the two studies or between genotypes intime to response or levels reached for binding and neu-tralizing antibodies. Interestingly, early spontaneousbleeds were associated with a faster antibody response.Conclusions: Following intravenous administration ofhuman FVIII, according to a clinical prophylaxis regi-men, a robust and reproducible antibody response is seenin this HA rat model, suggesting that the model is usefulfor intervention studies with the aim of suppressing,delaying, or preventing the inhibitor response. Also,bleeds seem to have an adjuvant effect on the immuneresponse.
AB - Background: Neutralizing antibodies towardFVIII replacement therapy (inhibitors) are the most seri-ous treatment-related complication in hemophilia A(HA). A rat model of severe HA (F8/) has recentlybeen developed, but an immunological characterization isneeded to determine the value of using the model forresearch into inhibitor development. Objectives: Charac-terize the antibody response towards recombinant humancoagulation factor VIII (rhFVIII) in the HA rat, follow-ing a human prophylactic dosing regimen. Methods: Twoidentical studies were performed, which included a totalof 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 at50 IU kg1twice weekly for 4 weeks. Predosing bloodsamples were analyzed for binding and neutralizing anti-rhFVIII antibodies at weeks 1–7. Results: In both studies,antibodies developed after 4–6 administrations ofrhFVIII, and neutralizing antibodies reached levels simi-lar to human patients (range 1–111 BU, median 6.0 BU)at the end of the study. There was no significant differ-ence between the two studies or between genotypes intime to response or levels reached for binding and neu-tralizing antibodies. Interestingly, early spontaneousbleeds were associated with a faster antibody response.Conclusions: Following intravenous administration ofhuman FVIII, according to a clinical prophylaxis regi-men, a robust and reproducible antibody response is seenin this HA rat model, suggesting that the model is usefulfor intervention studies with the aim of suppressing,delaying, or preventing the inhibitor response. Also,bleeds seem to have an adjuvant effect on the immuneresponse.
KW - animal model
KW - factor VIII
KW - hemophilia A
KW - neutralizing antibodies
KW - rattus
U2 - 10.1111/jth.13259
DO - 10.1111/jth.13259
M3 - Journal article
C2 - 26784374
SN - 1538-7933
VL - 14
SP - 747
EP - 756
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
IS - 4
ER -