Compositions and methods of treating inflammatory and autoimmune diseases

Abstract

Described herein are immunosuppressive molecules including immunosuppressive variants of IL-2, and use of such molecules to treat inflammatory and autoimmune disorders.

1 . A method of treating an inflammatory disorder in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of an IL-2 variant, wherein said IL-2 variant
 (a) comprises a sequence of amino acids at least 80% identical to SEQ ID NO:1;   (b) stimulates STAT5 phosphorylation in FOXP3-positive regulatory T cells; and   (c) has a reduced ability compared to the polypeptide set forth as SEQ ID NO:1 to induce phosphorylation of STAT5 in FOXP3-negative T cells.   
     
     
         2 . The method of  claim 1 , wherein the inflammatory disorder is selected from the group consisting of asthma, diabetes, arthritis, allergy, organ graft rejection and graft-versus-host disease. 
     
     
         3 . The method of  claim 1 , wherein said IL-2 variant comprises a sequence of amino acids at least 90% identical to SEQ ID NO:1. 
     
     
         4 . The method of  claim 1 , wherein said IL-2 variant comprises a sequence of amino acids at least 95% identical to SEQ ID NO:1. 
     
     
         5 . The method of  claim 1 , wherein the IL-2 variant has a higher affinity for IL-2Rα than does the polypeptide set forth as SEQ ID NO:1; 
     
     
         6 . The method of  claim 1 , wherein the IL-2 variant promotes FOXP3-positive regulatory T cell growth or survival in vitro. 
     
     
         7 . The method of  claim 1 , wherein the IL-2 variant comprises a mutation in the polypeptide sequence set forth in SEQ ID NO:1 at a position selected from the group consisting of amino acid 30, amino acid 31, amino acid 35, amino acid 69, and amino acid 74. 
     
     
         8 . The method of  claim 7 , wherein the mutation at position 30 is N30S. 
     
     
         9 . The method of  claim 7 , wherein the mutation at position 31 is Y31H. 
     
     
         10 . The method of  claim 7 , wherein the mutation at position 35 is K35R. 
     
     
         11 . The method of  claim 7 , wherein the mutation at position 69 is V69A. 
     
     
         12 . The method of  claim 7 , wherein the mutation at position 74 is Q74P. 
     
     
         13 . The method of  claim 1 , wherein the IL-2 variant induces STAT5 phosphorylation in ex vivo FOXP3-positive T cells comprising a functional IL-2 receptor complex but has a reduced ability to induce phosphorylation of STAT5. 
     
     
         14 . The method of  claim 13 , wherein the IL-2 variant comprises a mutation in the polypeptide sequence set forth in SEQ ID NO:1 at position 88. 
     
     
         15 . The method of  claim 14 , wherein the mutation at position 88 is N88D. 
     
     
         16 . The method of  claim 1 , wherein the IL-2 variant is conjugated to a chemical or polypeptide that extends the serum half-life of said IL-2 variant in vivo. 
     
     
         17 . A method of promoting FOXP3-postive regulatory T cell growth or survival, said method comprising contacting a FOXP3-positive regulatory T cell with an IL-2 variant, wherein said IL-2 variant
 (a) comprises a sequence of amino acids at least 80% identical to SEQ ID NO:1;   (b) stimulates STAT5 phosphorylation in said FOXP3-positive regulatory T cells; and   (c) has a reduced ability compared to the polypeptide set forth as SEQ ID NO:1 to induce phosphorylation of STAT5 in FOXP3-negative T cells.   
     
     
         18 . The method of  claim 16 , wherein the FOXP3-positive regulatory T cell is contacted in vitro. 
     
     
         19 . The method of  claim 18 , wherein the IL-2 variant is conjugated to a chemical or polypeptide that extends the serum half-life of said IL-2 variant in vivo. 
     
     
         20 . Use of an IL-2 variant in the preparation of a medicament for the treatment of an inflammatory disease, wherein said IL-2 variant
 (a) comprises a sequence of amino acids at least 80% identical to SEQ ID NO:1;   (b) stimulates STAT5 phosphorylation in FOXP3-positive regulatory T cells; and   (c) has a reduced ability compared to the polypeptide set forth as SEQ ID NO:1 to induce phosphorylation of STAT5 in FOXP3-negative T cells.   
     
     
         21 . The method of  claim 20 , wherein the IL-2 variant is conjugated to a chemical or polypeptide that extends the serum half-life of said IL-2 variant in vivo.