Antithrombotic effects of controlled inhibition of factor VIII with a partially inhibitory human monoclonal antibody in a murine vena cava thrombosis model

Abstract

AbstractThe 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.