Inhibition of factor VIII with a partially inhibitory human recombinant monoclonal antibody prevents thrombotic events in a transgenic model of type II HBS antithrombin deficiency in mice.
Venous thromboembolic disease is a major cause of morbidity and mortality, necessitating antithrombotic therapy. A human monoclonal anti-factor (F)VIII antibody, LCL-mAb-LE2E9, produced by a lymphoblastoid cell line derived from a hemophilia A patient with inhibitor to wild-type but not mutant self FVIII, was previously reported to achieve efficient inhibition of thrombosis in an experimental vena cava thrombosis model in mice. Here, the antithrombotic efficacy of a recombinant DNA-derived version of this anti-FVIII antibody (rec-mAb-LE2E9) was tested in mice which carry a type II heparin binding site antithrombin deficiency mutation and display spontaneous chronic thrombosis in several sites including the penile vein of sexually active males. The recombinant anti-FVIII antibody (100 microg, repeated after 3 days) prevented thrombotic priapism in all treated males, whereas all control animals treated with saline (group of four animals) developed priapism within 6 days after mating (P < 0.05 for treated vs. saline). The rec-mAb-LE2E9 and the original LCL-mAb-LE2E9 were equally effective (five and seven males/group, respectively). These results confirm that FVIII inhibition represents a potent antithrombotic strategy, and show that both LCL-mAb-LE2E9 and rec-mAb-LE2E9 efficiently prevent thrombosis in a physiological model representative of thrombosis in patients with a severe prothrombotic risk.
Dewerchin
M
M
Center for Transgene Technology and Gene Therapy, VIB, KULeuven Campus Gasthuisberg, Leuven, Belgium. mieke.dewerchin@med.kuleuven.ac.be
Van der Elst
L
L
Singh
I
I
Grailly
S
S
Saint-Remy
J-M
JM
Collen
D
D
Jacquemin
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology*; D000990:Antithrombin III / Q000235:genetics; D020152:Antithrombin III Deficiency / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D005169:Factor VIII / Q000037:antagonists & inhibitors* / Q000276:immunology; D005260:Female; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011317:Priapism / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D013927:Thrombosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D000990:Antithrombin III; D005169:Factor VIII