Use of anti-factor xi antibodies for prevention of thrombus formation

Abstract

The present invention relates to binding molecules such as antibodies that specifically bind plasma coagulation factor XI and that inhibit factor XI activation and/or activity. The factor XI-binding molecules of the invention may used in methods for preventing or treating diseases, disorders and/or conditions that are mediated by factor XI activation and/or wherein inhibition of factor XI has a beneficial effect.

1 . A binding molecule that specifically binds factor XI and inhibits factor XI activity, for use in preventing or treating a disease, disorder and/or condition that is mediated by factor XI activation and/or wherein inhibition of factor XI has a beneficial effect. 
     
     
         2 . A binding molecule according to  claim 1 , wherein the binding molecule inhibits at least one of:
 (a) binding at or near the peptidyl bond Arg 369 -Ile 370  in factor XI, thereby preventing cleavage of the bond;   (b) binding at or near the active site located in the factor XI light chain region of the molecule;   (c) binding at or near sites in factor XI sites that are involved in interactions with factor IX   (d) binding to the factor XI A1 domain, thereby preventing the interaction of factor XI with high molecular weight kininogen and/or thrombin; and   (e) binding to the facctor XI A2 or A3 domain, thereby preventing the interaction of factor XI with factor IX, heparin and/or platelets.   
     
     
         3 . A binding molecule according to  claim 1 , wherein the binding molecule preferentially binds to the activated form of factor XI. 
     
     
         4 . A binding molecule according to  claim 3 , wherein the binding molecule inhibits functional activity of the activated form of factor XI by one or more of:
 (a) binding at or near to the active site located in the factor XI light chain region;   (b) binding at or near sites factor XI sites that are involved in interactions with factor IX;   (c) binding to the factor XI A1 domain, thereby preventing the interaction of factor XI with high molecular weight kininogen and/or thrombin; and   (d) binding to the factor XI A2 or A3 domain, thereby preventing the interaction of factor XI with factor IX, heparin and/or platelets.   
     
     
         5 . A binding molecule according to  claim 1 , wherein the binding molecule is an antibody or a factor XI-binding antibody fragment. 
     
     
         6 . A binding molecule according to  claim 1 , wherein the binding molecule is administered at a dosage equivalent to a dosage of 0.5-20 mg of IgG per kg body weight. 
     
     
         7 . A binding molecule according to  claim 1 , wherein the binding molecule is administered at a dosage that yields a molar ratio in serum that is equal to or less than 4 moles of factor XI binding sites to 1 mole of factor XI, wherein the factor XI binding sites of the binding molecule have a Kd that is equal to or less than 1 nM. 
     
     
         8 . A binding molecule according to  claim 1 , for use in preventing or treating a pathological thrombosis or in preventing thrombosis in a subject who is at increased risk of developing thrombosis resulting from a medical procedure. 
     
     
         9 . A binding molecule according to  claim 8 , for use in preventing or treating at least one of the following disorders, diseases or conditions: myocardial infarction, ischemic stroke, cardio-embolism due to atrial fibrillation, vascular access thrombosis, deep venous thrombosis, arterial thrombosis, coronary artery thrombosis, atherosclerosis, arthritis, vasculitis, respiratory distress syndrome, ischemic heart disease, ischemic cerebral disease, pulmonary embolism, venous thrombo-embolism resulting from surgery or immobilization, thrombosis and occlusion of a synthetic graft, stent or AV-fistula, prosthetic heart valve, diffuse intravascular coagulation, hemodialysis, atrial fibrillation, sepsis, septic shock, organ failure, kidney failure, toxicity induced by the in vivo administration of a therapeutic protein, multiple trauma, ischemia-reperfusion injury, local undesired fibrin deposition or fibrin deposition in lung alveoli during adult respiratory distress. 
     
     
         10 . A binding molecule according to  claim 1 , wherein the binding molecule is administered intravenously, intramuscularly or subcutaneously. 
     
     
         11 . A binding molecule according to  claim 10 , wherein the binding molecule is administered intravenously as a bolus infusion or as a continuous infusion over an interval of up to 24 hours. 
     
     
         12 . A binding molecule according to  claim 9 , for use in preventing, reducing or treating thrombosis and occlusion of a synthetic graft, stent or AV-fistula in a kidney undergoing regular renal dialysis, wherein the binding molecule is administered to the patient in dialyzed body fluid that is returned to the patient. 
     
     
         13 . A binding molecule according to  claim 9 , for use in preventing or treating thrombosis in a patient with atrial fibrillation, unstable angina pectoris, venous thrombo-embolism, prosthetic heart valve, ischemic heart disease, ischemic cerebral disease, a vascular graft, diffuse intravascular coagulation, sepsis, or a patient undergoing prostate or orthopaedic surgery, wherein the binding molecule is administered no more than once per 2 weeks. 
     
     
         14 . A binding molecule according to  claim 13 , wherein the binding molecule has a half life of at least 6 days and a Kd that is less than 1 nM.