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

• Published in: Blood Vol. 99; no. 9; pp. 3235 - 3240
• Main Authors: Singh, Inderjit, Smith, Alberto, Vanzieleghem, Beatrijs, Collen, Désiré, Burnand, Kevin, Saint-Remy, Jean-Marie, Jacquemin, Marc
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.05.2002; The Americain Society of Hematology
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - therapeutic use; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Disease Models, Animal; Drug Evaluation, Preclinical; Factor VIII - administration & dosage; Factor VIII - immunology; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - adverse effects; Fibrinolytic Agents - pharmacokinetics; Hemorrhage - chemically induced; Humans; Male; Medical sciences; Mice; Mice, Knockout; Pharmacology. Drug treatments; Venae Cavae; Venous Thrombosis - drug therapy; Animal model; Treatment efficiency; Rodentia; Factor VIII; Cardiovascular disease; Monoclonal antibody; Thrombosis; Vascular disease; Vertebrata; Chemotherapy; Mammalia; Treatment; Partial; Mouse; Animal; Immunotherapy; Antithrombotic agent; Inhibitor; Vena cava
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V99.9.3235

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.