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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:517.)
© 2002 American Heart Association, Inc.

Thrombosis

A Human Antibody That Inhibits Factor IX/IXa Function Potently Inhibits Arterial Thrombosis Without Increasing Bleeding

Canio J. Refino; Surinder Jeet; Leo DeGuzman; Stuart Bunting; Daniel Kirchhofer

From the Department of Physiology, Genentech Inc, South San Francisco, Calif.

Correspondence to Canio J. Refino, Genentech Inc, Physiology Dept, MS #42, 1 DNA Way, South San Francisco, CA 94080. E-mail ken{at}gene.com

10C12, a human antibody F(ab')₂, which specifically binds to the -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-µg/kg bolus of 10C12 or a 100-U/kg bolus plus 1.0 U · kg^-1 · 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.

Key Words: thrombosis • factor IX • anticoagulants • antibody

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