Interleukin-2 mutants with reduced toxicity

Abstract

Interleukin-2 (IL-2) mutants having reduced toxicity, which include full-length IL-2, truncated forms of IL-2 and forms of IL-2 that are linked to another molecule are disclosed herein. Particular substitutions within IL-2, particularly within the permeability enhancing peptide region of IL-2 achieve substantial reduction of vasopermeability activity as compared to a wildtype form of the mutant IL-2 while retaining many of the immune activating properties of IL-2. Invention IL-2 mutants can be used to stimulate the immune system of an animal and may be used in the treatment of various disorders and conditions.

1 . A method for stimulating the immune system of a subject in need thereof, said method comprising administering an effective amount of an interleukin-2 (IL-2) mutant to said subject, said mutant comprising a at least one mutation in the permeability enhancing peptide region of IL-2, said mutant characterized by substantially reduced vasopermeability activity and substantially similar binding affinity for an IL-2 receptor compared to a wildtype form of the IL-2 mutant.  
     
     
         2 . The method of  claim 1 , wherein said mutant further comprises a mutation outside the permeability enhancing peptide region of IL-2.  
     
     
         3 . The method of  claim 1 , wherein said IL-2 mutant is derived from human IL-2.  
     
     
         4 . The method of  claim 3 , wherein said mutation comprises a substitution of one or more non-wildtype amino acid residues located in position 22-58 of IL-2.  
     
     
         5 . The method of  claim 3 , wherein said IL-2 mutant comprises a substitution of a non wildtype amino acid residue at any one or more of amino acids positions 38, 39, 42, or 55 of IL-2, wherein said non-wildtype residue at position 38 is not alanine or glutamine while said non-wildtype residue at position 42 is not lysine.  
     
     
         6 . The method of  claim 3 , wherein said IL-2 mutant is selected from the group consisting W 38 , G 38 , Y 38 , L 39 , K 42  and Y 55 .  
     
     
         7 . The method of  claim 3 , wherein said IL-2 mutant is selected from the group consisting of W 38 R 88 , G 38  R 88 , Y 38  R 88 , L 39  R 88 , K 42  R 88  and Y 55  R 88 .  
     
     
         8 . The method of  claim 3 , wherein said mutant further comprises a mutation at one or more of positions 1-21 or 59-133 of IL-2.  
     
     
         9 . The method of  claim 8 , wherein said mutation results in a lysine at position 88.  
     
     
         10 . The method of  claim 1 , wherein said subject has cancer.  
     
     
         11 . The method of  claim 10 , wherein said cancer is renal cell carcinoma or melanoma.  
     
     
         12 . The method of  claim 1 , wherein said subject suffers from an immune deficiency.  
     
     
         13 . The method of  claim 12 , wherein said immune deficiency results from a human immunodeficiency virus.  
     
     
         14 . The method of  claim 12 , wherein the immune deficiency results from chemotherapy or radiation therapy.  
     
     
         15 . The method of  claim 1 , wherein said subject suffers from an autoimmune disorder.  
     
     
         16 . The method of  claim 1 , wherein said subject suffers from chronic infection.  
     
     
         17 . The method of  claim 1 , wherein said IL-2 mutant is administered in combination with a therapeutic agent.  
     
     
         18 . The method of  claim 1 , wherein said IL-2 mutant is administered as a component of a vaccine.