Compositions and methods for preventing erythropoietin-associated hypertension

Abstract

The inventors have discovered that both soluble erythropoietin-binding protein and antibodies against the erythropoietin-binding protein, when they are administered to a mammal along with erythropoietin (Epo), prevent or reduce the blood pressure increase normally caused by erythropoietin, while not affecting the hematocrit increase that is the purpose of Epo treatment. The invention provides a method of treating anemia in a mammal involving: administering erythropoietin (Epo) to the mammal; and administering to the mammal an agent selected from a soluble Epo-binding protein (Epo-bp), a recognition protein that binds Epo receptor on an extracellular soluble portion of the Epo receptor, and a combination thereof. The invention also provides a method of reducing hypertension in a mammal receiving Epo, and pharmaceutical compositions containing a soluble Epo-bp and/or a recognition protein that binds Epo receptor on an extracellular soluble portion of the Epo receptor

1 . A method of treating anemia in a mammal comprising: 
 administering erythropoietin (Epo) to the mammal; and    administering to the mammal an agent selected from a soluble Epo-binding protein (Epo-bp), a recognition protein that binds Epo receptor on an extracellular soluble portion of the Epo receptor, and a combination thereof.    
     
     
         2 . The method of  claim 1  wherein the agent is a soluble Epo-bp.  
     
     
         3 . The method of  claim 2  wherein the soluble Epo-bp comprises a fragment of a soluble portion of a mammalian Epo receptor.  
     
     
         4 . The method of  claim 3  wherein the soluble Epo-bp comprises a fragment of at least 30 residues of SEQ ID NO:2.  
     
     
         5 . The method of  claim 4  wherein the soluble Epo-bp is a fragment of at least 30 residues of SEQ ID NO:2.  
     
     
         6 . The method of  claim 2  wherein the soluble Epo-bp comprises SEQ ID NO:2.  
     
     
         7 . The method of  claim 6  wherein the soluble Epo-bp is SEQ ID NO:2.  
     
     
         8 . The method of  claim 1  wherein the agent is a recognition protein that binds Epo receptor on an extracellular soluble portion of the Epo receptor.  
     
     
         9 . The method of  claim 8  wherein the recognition protein binds SEQ ID NO:2.  
     
     
         10 . The method of  claim 8  wherein the recognition protein is an antibody.  
     
     
         11 . The method of  claim 10  wherein the antibody is an antibody fragment.  
     
     
         12 . The method of  claim 11  wherein the antibody fragment is Fab.  
     
     
         13 . The method of  claim 1  wherein Epo and the agent are administered together.  
     
     
         14 . The method of  claim 1  wherein Epo and the agent are administered separately.  
     
     
         15 . The method of  claim 1  wherein the amount of agent administered is at least equimolar with the amount of Epo administered.  
     
     
         16 . The method of  claim 1  wherein the amount of agent administered is about equimolar with the amount of Epo administered.  
     
     
         17 . The method of  claim 1  wherein the agent reduces an erythropoietin-induced blood pressure rise in the mammal.  
     
     
         18 . A method of reducing hypertension in a mammal receiving erythropoietin (Epo), the method comprising: 
 administering to the mammal an effective amount of an agent selected from a soluble erythropoietin-binding protein (Epo-bp), a recognition protein that binds Epo receptor on an extracellular soluble portion of the Epo receptor, and a combination thereof.    
     
     
         19 . A pharmaceutical composition comprising: 
 erythropoietin (Epo); and    an agent selected from a soluble Epo-binding protein (Epo-bp), a recognition protein that binds Epo receptor on an extracellular soluble portion of the Epo receptor, and a combination thereof.    
     
     
         20 . The pharmaceutical composition of  claim 19  wherein the recognition protein is an antibody against SEQ ID NO:2.  
     
     
         21 . The pharmaceutical composition of  claim 19  wherein the Epo-bp is SEQ ID NO:2.  
     
     
         22 . A pharmaceutical composition comprising: 
 a recognition protein that binds erythropoietin (Epo) receptor on an extracellular soluble portion of the Epo receptor.    
     
     
         23 . The pharmaceutical composition of  claim 22  wherein the recognition protein is an antibody against SEQ ID NO:2.  
     
     
         24 . A pharmaceutical composition comprising: 
 a soluble erythropoietin-binding protein (Epo-bp).    
     
     
         25 . The pharmaceutical composition of  claim 24  wherein the Epo-bp is SEQ ID NO:2.  
     
     
         26 . The pharmaceutical composition of  claim 24  wherein the Epo-bp is a product of a process comprising: 
 expressing a fusion protein consisting of:    (a) a first polypeptide segment having an amino terminus and a carboxyl terminus, said segment having SEQ ID NO:7 at its carboxyl terminus; and    (b) a second polypeptide segment consisting of SEQ ID NO:2, the second polypeptide segment covalently coupled to the carboxyl terminus of the first polypeptide segment; and    cleaving the fusion protein with thrombin.