Peg-Modified Uricase

Abstract

The present invention is directed to uricase modified with polyethylene glycol and to methods of treating different illnesses characterized by increased circulating uric acid levels, including but not limited to, hyperuricemia and tumor lysis syndrome.

1 - 47 . (canceled)  
     
     
         48 . A compound comprising a uricase protein covalently bonded to polyethylene glycol, wherein polyethylene glycol is covalently attached to said uricase protein at one or more amino acid residues, wherein said polyethylene glycol has a total weight average molecular weight of about 12,000 to about 50,000 and wherein said uricase protein comprises 12 to about 30 polyethylene glycol molecules per uricase protein unit.  
     
     
         49 . The compound of  claim 48  wherein said uricase has an amino acid sequence comprising SEQ ID NO:6.  
     
     
         50 . The compound of  claim 49  wherein polyethylene glycol is covalently attached to uricase at amino acid residues other than Lys 12 , Lys 16 , Lys 28 , Lys 64 , Lys 72 , Lys 117 , Lys 156 , Lys 167 , and Lys 262 .  
     
     
         51 . The compound of  claim 49  wherein polyethylene glycol is covalently attached to uricase at amino acid residues other than Lys 156 .  
     
     
         52 . The compound of  claim 49  wherein polyethylene glycol is covalently attached to uricase at amino acid residues other than Lys 167 .  
     
     
         53 . The compound of  claim 49  wherein polyethylene glycol is covalently attached to uricase at amino acid residues other than Lys 12 .  
     
     
         54 . The compound of  claim 49  wherein polyethylene glycol is covalently attached to uricase at amino acid residues other than Lys 64 .  
     
     
         55 . The compound of  claim 49  wherein polyethylene glycol is covalently attached to uricase at amino acid residues other than Lys 262 .  
     
     
         56 . The compound of  claim 49  wherein polyethylene glycol is covalently attached to uricase at amino acid residues other than Lys 117 .  
     
     
         57 . The compound of  claim 49  wherein polyethylene glycol is covalently attached to uricase at amino acid residues other than Lys 16 , Lys 28 , and Lys 72 .  
     
     
         58 . A compound comprising a uricase protein covalently bonded via a linking group to polyethylene glycol, wherein the polyethylene glycol has a total weight average molecular weight of about 12,000 to about 50,000, wherein the linking group is selected from the group consisting of a succinimide group, an amide group, an imide group, a carbamate group, an ester group, an epoxy group, a carboxyl group, a hydroxyl group, a carbohydrate, a tyrosine group, a cysteine group, a histidine group and combinations thereof and wherein said uricase is a functional monomer comprises 12 to about 30 polyethylene glycol molecules per uricase protein.  
     
     
         59 . The compound of  claim 58 , wherein said linking group is a succinimide group.  
     
     
         60 . The compound of  claim 59 , wherein said succinimide group is succinimidyl succinate, succinimidyl propionate, succinimidyl carboxymethylate, succinimidyl succinamide, N-hydroxy succinimide or combinations thereof.  
     
     
         61 . The compound of  claim 60 , wherein said succinimide group is succinimidyl succinate, succinimidyl propionate or combinations thereof.  
     
     
         62 . The compound of  claim 58 , wherein said uricase is derived from a microorganism selected from the group consisting of  Asperigillus flavus, Candida utilis, Arthrobacter protoformiae , and combinations thereof.  
     
     
         63 . The compound of  claim 58  wherein said uricase protein unit is covalently bonded to 12 to about 25 polyethylene glycol molecules.  
     
     
         64 . The compound of  claim 58 , wherein said uricase protein unit is covalently bonded to about 18 to about 22 polyethylene glycol molecules.  
     
     
         65 . The compound of  claim 58 , wherein said uricase protein unit is covalently bonded to about 20 polyethylene glycol molecules.  
     
     
         66 . A method of reducing uric acid levels in a patient comprising administering to said patient a therapeutically effective amount of the compound of  claim 48 .  
     
     
         67 . A method of reducing uric acid levels in a patient comprising administering to said patient a therapeutically effective amount of the compound of  claim 58.