A human antibody that inhibits factor IX/IXa function potently inhibits arterial thrombosis without increasing bleeding.
10C12, a human antibody F(ab')2, which specifically binds to the gamma-carboxyglutamic acid domain of factor IX/factor IXa (F.IX/IXa), interferes with all known coagulation processes in which F.IX/IXa is involved. In a rabbit model of carotid artery injury, intravenous administration of 10C12 or heparin decreased thrombosis dose dependently. The dose that resulted in a 90% reduction of thrombus mass (ED90) was a 30-microg/kg bolus of 10C12 or a 100-U/kg bolus plus 1.0 U x kg(-1) x min(-1) infusion of heparin. Heparin, at and below the ED90, significantly prolonged coagulation times and cuticle bleeding times. In contrast, 10C12 had no effect on coagulation or bleeding times at doses up to 4 times the ED90. To further evaluate the effect of 10C12 on bleeding, it was compared with heparin in a novel model of blood loss. At the ED90 of heparin, blood loss induced by a standardized injury to the vasculature of the rabbit tibia increased to more than 2 times that of saline controls. In contrast, the dose of 10C12 required to produce a similar increase in blood loss was more than 30 times the ED90. The antithrombotic potency and relative safety of this fully human antibody suggests that it may have therapeutic value for treatment of thrombotic disorders.
Refino
Canio J
CJ
Department of Physiology, Genentech Inc, South San Francisco, Calif 94080, USA. ken@gene.com
Jeet
Surinder
S
DeGuzman
Leo
L
Bunting
Stuart
S
Kirchhofer
Daniel
D
D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D002341:Carotid Artery Thrombosis / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005164:Factor IX / Q000037:antagonists & inhibitors* / Q000276:immunology; D015949:Factor IXa / Q000037:antagonists & inhibitors* / Q000276:immunology; D006470:Hemorrhage / Q000209:etiology; D006493:Heparin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D007700:Kinetics; D011817:Rabbits; D015203:Reproducibility of Results; D013977:Tibia / Q000098:blood supply
D000925:Anticoagulants; D007140:Immunoglobulin Fab Fragments; D005164:Factor IX; D006493:Heparin; D015949:Factor IXa