Saxatilin-fc fusion protein and use thereof

Abstract

The present invention relates to a saxatilin derivative having an increased half life and a use thereof. The saxatilin derivative of the present invention has thrombolytic ability similar to that of saxatilin, which is the mother protein, a remarkably increased protein half life, and efficiently dissolves, for long period of time, blood clots already formed in blood vessels of an animal model with a FeCl 3 -induced carotid by using the same. Therefore, a composition containing, as an active ingredient, the saxatilin derivative of the present invention does not cause reocclusion after penetration and effectively opens to microvessels, and is thus very useful for treating angiostenosis or occlusive diseases (for example, cerebrovascular diseases, cardiovascular diseases, arteriosclerotic vascular diseases, coronary artery diseases, and peripheral vascular diseases).

What is claimed is: 
     
         1 . A saxatilin derivative comprising saxatilin, which is composed of the amino acid sequence of SEQ ID NO: 2, conjugated to an immunoglobulin Fc region. 
     
     
         2 . The saxatilin derivative of  claim 1 , wherein the immunoglobulin Fc region is conjugated to the N-terminal or C-terminal of the saxatilin. 
     
     
         3 . The saxatilin derivative of  claim 1 , wherein the saxatilin derivative comprises a leader sequence further conjugated to the N-terminal. 
     
     
         4 . The saxatilin derivative of  claim 1 , wherein the saxatilin derivative has a half-life, which is increased by 4- to 6.5-fold when compared with naturally occurring saxatilin. 
     
     
         5 . The saxatilin derivative of  claim 1 , wherein the saxatilin derivative has a similar thrombolytic ability to naturally occurring saxatilin. 
     
     
         6 . The saxatilin derivative of  claim 5 , wherein the saxatilin derivative has an IC 50  value of 100-500 nM, with respect to platelet aggregation. 
     
     
         7 . (canceled) 
     
     
         8 . The saxatilin derivative of  claim 1 , wherein the saxatilin derivative binds to integrins existing in a thrombus to break up the thrombus. 
     
     
         9 . The saxatilin derivative of  claim 8 , wherein the saxatilin derivative binds to glycoprotein (GP) Ilb-Ilia on the surface of platelets constituting the thrombus to break up the thrombus. 
     
     
         10 . The saxatilin derivative of  claim 1 , wherein the saxatilin derivative has a binding affinity (dissociation constant (Kd)) of 1×10 −8  to 1×10 −10  M to integrin α M β 2  existing in neutrophils. 
     
     
         11 . The saxatilin derivative of  claim 1 , wherein the saxatilin derivative has a binding affinity (dissociation constant (Kd)) of 1×10 −8  to 1×10 −10  M to integrin α L β 2  existing in neutrophils. 
     
     
         12 - 15 . (canceled) 
     
     
         16 . A pharmaceutical composition for preventing or treating vascular stenosis or occlusive disease, the pharmaceutical composition containing: (a) a pharmaceutically effective amount of the saxatilin derivative of  claim 1 ; and (b) a pharmaceutically acceptable carrier. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein a blood vessel in the vascular stenosis include main arteries, carotid arteries, subclavian arteries, celiac arteries, mesenteric arteries, renal arteries, iliac arteries, arterioles, capillaries, and venulas. 
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein the vascular stenosis or occlusive disease is selected from the group consisting of stroke, cerebral infarction, cerebral thrombosis, cerebral embolism, lacunar infarction, acute coronary syndrome, angina, aortic stenosis, myocardial infarction, migraine, bundle branch block, ischemia, acute ischemic arteriovascular event, thrombophlebitis, venous thromboembolism, deep vein thrombosis, pulmonary embolism, peripheral vascular disease, vascular headache, atherosclerosis, vascular spasm, restenosis, restenosis after balloon angioplasty, and vascular occlusion by vasculitis. 
     
     
         19 . The pharmaceutical composition of  claim 16 , wherein the pharmaceutical composition is administered through a direct injection into the blood vessel. 
     
     
         20 . The pharmaceutical composition of  claim 16 , wherein the pharmaceutical composition is administered to a patient with vascular occlusion due to thrombi. 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein the occlusion is partial occlusion or complete occlusion. 
     
     
         22 . The pharmaceutical composition of  claim 16 , wherein the pharmaceutical composition contains no plasminogen activator. 
     
     
         23 . A method for preventing or treating vascular stenosis or occlusive disease, the method comprising administering a pharmaceutically effective amount of the saxatilin derivative of  claim 1  to a subject. 
     
     
         24 . The method of  claim 23 , wherein the vascular stenosis or occlusive disease is selected from the group consisting of stroke, cerebral infarction, cerebral thrombosis, cerebral embolism, lacunar infarction, acute coronary syndrome, angina, aortic stenosis, myocardial infarction, migraine, bundle branch block, ischemia, acute ischemic arteriovascular event, thrombophlebitis, venous thromboembolism, deep vein thrombosis, pulmonary embolism, peripheral vascular disease, vascular headache, atherosclerosis, vascular spasm, restenosis, restenosis after balloon angioplasty, and vascular occlusion by vasculitis.