Antithrombotic effects of controlled inhibition of factor VIII with a partially inhibitory human monoclonal antibody in a murine vena cava thrombosis model.
The human monoclonal antibody mAb-LE2E9 partially inactivates human factor VIII (FVIII), leaving approximately 10% residual activity. The antithrombotic efficacy of the antibody was evaluated in mouse models of inferior vena cava thrombosis. Thrombi were induced in wild-type mice given either the antibody or saline. No thrombi occurred in any of 8 mice treated with mAb-LE2E9, whereas 6 of 8 control mice developed thrombi (P =.007). Treatment with mAb-LE2E9 did not result in a severe bleeding phenotype: a tail-cutting experiment that resulted in death of C57BL/6 FVIII-deficient (FVIII(-/-)) mice did not cause hemorrhagic death in mice treated with mAb-LE2E9. To evaluate the antithrombotic effect of mAb-LE2E9 in presence of human FVIII, thrombus formation was induced in FVIII(-/-) mice reconstituted intravenously with recombinant human FVIII (rhFVIII) or rhFVIII preincubated with mAb-LE2E9. Only 1 of 9 mice produced a thrombus in the rhFVIII/antibody complex-treated group, compared with 7 of 9 in the control group (P =.015). FVIII(-/-) mice were also reconstituted with rhFVIII and then injected with either mAb-LE2E9 or saline. One of 14 mice in the group treated with the antibody developed a thrombus, compared with 10 of 14 in the control group (P =.001). The thrombi occurring in antibody-treated animals were smaller than in controls (P <.01). All animals survived, and there were no bleeding complications. Thus, the mAb-LE2E9 antibody inhibits thrombosis without causing an overt bleeding tendency.
Singh
Inderjit
I
Center for Molecular and Vascular Biology, University of Leuven, Belgium.
Smith
Alberto
A
Vanzieleghem
Beatrijs
B
Collen
Désiré
D
Burnand
Kevin
K
Saint-Remy
Jean-Marie
JM
Jacquemin
Marc
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005169:Factor VIII / Q000008:administration & dosage / Q000276:immunology*; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014684:Venae Cavae; D020246:Venous Thrombosis / Q000188:drug therapy*
D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D005169:Factor VIII