The prevention of the occurrence and reoccurrence of myocardial infarction, stroke, PAOD and pulmonary embolism remain a pressing clinical priority. Well over 12.5 million people in the US suffer from one or more of these conditions, resulting in approximately 1 million deaths each year and a health care expenditure of over $US100 billion each year. While thrombolytics offer opportunities for the acute treatment of thrombotic diseases (we have recently overviewed one such molecule SY161-P5), the prevention of the occurrence and reoccurrence of these diseases is based upon the use of anticoagulants as a first line therapeutic strategy. This market is currently approaching $US6 billion per year worldwide. Unfortunately many anticoagulants in current use suffer a number of limitations including a high incidence of serious or dose limiting hemorrhage, and in the case of heparin, heparin-induced-thrombocytopenia and thrombosis syndrome. The development of anti-coagulants with a lower risk of hemorrhage is thus required. Neutralizing antibodies targeting coagulation factors represent an increasingly attractive approach to thrombotic disease with neutralizing anti-factor VIII antibodies representing one particularly promising therapeutic candidate (click here for DiscoveryDossier). More recently Genentech have developed 10C12, a human antibody F(ab')2, which specifically binds to the gamma-carboxyglutamic acid domain of factor IX/factor IXa. 10C12 decreased thrombosis in a rabbit model of carotid artery injury with an ED90 value of 30-microg/kg. Moreover, 10C12 had no effect on coagulation or bleeding times at doses up to 4 times the ED90 directly contrasting with heparin which affected both parameters at it's ED90. 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.

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