Angiogenically effective unit dose of FGF-2 and method of use

Abstract

The present invention has multiple aspects. In particular, in one aspect, the present invention is directed to a unit dose composition comprising 0.2 μg/kg to 48 μg/kg of an FGF-2 of SEQ ID NO: 2, or an angiogenically active fragment or mutein thereof in a pharmaceutically acceptable carrier. In another aspect, the present invention is directed to a method for treating a human patient for coronary artery disease, comprising administering into one or more coronary vessels or a peripheral vein of a human patient in need of treatment for coronary artery disease a safe and angiogenically effective dose of a recombinant FGF-2, or an angiogenically active fragment or mutein thereof. The single unit dose composition of the present invention provides an angiogenic effect in a human CAD patient that lasts 2 months before re-treatment is required. In another aspect, the present invention is directed to a method of administration which optimizes patient's safety. In this embodiment, fluids, heparin and/or rate of infusion all play a role. In another aspect, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of FGF-2, alone or in combination with heparin, in a therapeutically effective carrier. The magnitude and duration of benefit were unexpected; in addition benefit with the IV route was unexpected.

What is claimed is:  
     
         1 . A unit dose composition for inducing angiogenesis in a human, comprising about 0.008 mg to about 7.2 mg of FGF-2 or an angiogenically active fragment or mutein thereof in a pharmaceutically acceptable carrier.  
     
     
         2 . The unit dose composition of  claim 1 , comprising 0.3 mg to 3.5 mg of FGF-2, or an angiogenically active fragment or mutein thereof.  
     
     
         3 . The unit dose composition of  claim 1 , wherein said FGF-2 has the amino acid sequence of SEQ ID NO: 2.  
     
     
         4 . The unit dose composition of  claim 3 , comprising 0.3 mg to 3.5 mg of an FGF-2 of SEQ ID NO: 2 or an angiogenically active fragment or mutein thereof in a pharmaceutically acceptable carrier.  
     
     
         5 . The unit dose composition of  claim 3 , comprising about 0.008 mg to about 7.2 mg of said angiogenically active mutein of said FGF-2 of SEQ ID NO: 2 in a pharmaceutically acceptable carrier.  
     
     
         6 . The unit dose composition of  claim 5 , comprising 0.3 mg to 3.5 mg of said angiogenically active mutein of said FGF-2 of SEQ ID NO: 2 in a pharmaceutically acceptable carrier.  
     
     
         7 . The unit dose composition of  claim 3 , comprising about 0.008 mg to about 7.2 mg of said angiogenically active fragment of said FGF-2 of SEQ ID NO: 2 in a pharmaceutically acceptable carrier.  
     
     
         8 . The unit dose composition of  claim 7 , comprising 0.3 mg to 3.5 mg of said angiogenically active fragment of said FGF-2 of SEQ ID NO: in a pharmaceutically acceptable carrier.  
     
     
         9 . The unit dose composition of  claim 3 , comprising about 0.008 mg to about 7.2 mg of FGF-2 of SEQ ID NO: 2 in a pharmaceutically acceptable carrier in a pharmaceutically acceptable carrier.  
     
     
         10 . A method for treating a human patient for coronary artery disease comprising, administering a safe and therapeutically effective amount of a recombinant FGF-2 or an angiogenically active fragment or mutein thereof to one or more coronary vessels or to a peripheral vein in a human patient in need of treatment for said coronary artery disease, said therapeutically effective amount being about 0.2 μg/kg to 48 μg/kg of patient weight.  
     
     
         11 . The method of  claim 10 , wherein said recombinant FGF-2 has the amino acid sequence of SEQ ID NO: 2.  
     
     
         12 . The method of  claim 11 , further comprising the step of administering to said human patient about 10 U/kg to 80 U/kg of heparin within about 0 to 30 minutes prior to administering said recombinant FGF-2 of SEQ ID NO: 2 or said angiogenically active fragment or mutein thereof.  
     
     
         13 . The method of  claim 12 , wherein said therapeutically effective amount of a recombinant FGF-2 of SEQ ID NO: 2 or an angiogenically active fragment or mutein thereof is administered to one or more coronary vessels.  
     
     
         14 . The method of  claim 13 , wherein said therapeutically effective amount of a recombinant FGF-2 of SEQ ID NO: 2 or an angiogenically active fragment or mutein thereof is about 24 μg/kg to 48 μg/kg.  
     
     
         15 . The method of  claim 12  wherein said therapeutically effective amount of a recombinant FGF-2 of SEQ ID NO: 2 or said angiogenically active fragment or mutein thereof is administered to a peripheral vein.  
     
     
         16 . The method of  claim 15 , wherein said therapeutically effective amount of a recombinant FGF-2 of SEQ ID NO: 2 or said angiogenically active fragment or mutein thereof is about 18 μg/kg to 36 μg/kg.  
     
     
         17 . A method for treating a human patient for coronary artery disease comprising, administering a single unit dose of a recombinant FGF-2 or an angiogenically active fragment or mutein thereof to one or more coronary vessels or to a peripheral vein in a human patient in need of treatment for coronary artery disease, said unit dose comprising from about 0.008 mg to 7.2 mg of a recombinant FGF-2 or an angiogenically active fragment or mutein thereof.  
     
     
         18 . The method of  claim 17 , wherein said FGF-2 has the amino acid sequence of SEQ ID NO: 2.  
     
     
         19 . The method of  claim 18 , wherein said single unit dose produces a therapeutic benefit in said human patient that lasts at least four months.  
     
     
         20 . The method of  claim 19 , wherein said single unit dose produces a therapeutic benefit in said human patient that lasts 6 months.  
     
     
         21 . The method of  claim 20 , wherein said single unit dose produces a therapeutic benefit of such magnitude and duration in said human patient such that administration of a second unit dose is not required for about 6 months.  
     
     
         22 . The method of  claim 20 , wherein said unit dose is administered to one or more coronary arteries.  
     
     
         23 . The method of  claim 20 , wherein said unit dose is administered to a peripheral vein.  
     
     
         24 . The method of  claim 20 , wherein said unit dose comprises 0.3 mg to 3.5 mg of a recombinant FGF-2 of SEQ ID NO: 2 or an angiogenically active fragment or mutein thereof.  
     
     
         25 . The method of  claim 19 , further comprising the step of administering 10 U/kg to 80 U/kg of heparin to said patient IV or IC about 0 to 30 minutes prior to administering said unit dose.  
     
     
         26 . A method for inducing angiogenesis in a heart of a human patient comprising, administering a single unit dose of a recombinant FGF-2 or an angiogenically active fragment or mutein thereof to one or more coronary vessels or to a peripheral vein in a human patient in need of treatment for coronary artery disease, said unit dose comprising from about 0.008 mg to 7.2 mg of a recombinant FGF-2 or an angiogenically active fragment or mutein thereof.  
     
     
         27 . The method of  claim 26 , wherein said FGF-2 has the amino acid sequence of SEQ ID NO: 2.  
     
     
         28 . The method of  claim 27  wherein said single unit dose produces an improvement in one or more clinical endpoints in said human patient that lasts at least four months.  
     
     
         29 . The method of  claim 28 , wherein said single unit dose produces an improvement in one or more clinical endpoints in said human patient that lasts 6 months.  
     
     
         30 . A method for treating a human patient for a myocardial infarction comprising, administering a single unit dose of a recombinant FGF-2 or an angiogenically active fragment or mutein thereof to one or more coronary vessels or to a peripheral vein in said human patient, said unit dose comprising from about 0.008 mg to 7.2 mg of a recombinant FGF-2 or an angiogenically active fragment or mutein thereof.  
     
     
         31 . The method of  claim 30 , further comprising the step of administering 10 U/kg to 80 U/kg of heparin to said patient IV or IC about 0 to 30 minutes prior to administering said unit dose.  
     
     
         32 . The method of  claim 31 , wherein FGF-2 has the amino acid sequence of the SEQ ID NO: 2.  
     
     
         33 . The method of  claim 30 , wherein said unit dose is administered to a peripheral vein.  
     
     
         34 . The method of  claim 30 , wherein said unit dose is administered into one or more coronary vessels of said patient.