T-cell selective interleukin-4 agonists

Abstract

This invention realizes a less toxic IL-4 mutant that allows greater therapeutic use of interleukin 4. Further, the invention is directed to IL-4 muteins having single and double mutations represented by the designators R121E and T13D/R121E, numbered in accordance with wild type IL-4 (His=1). The invention also includes polynucleotides coding for the muteins of the invention, vectors containing the polynucleotides, transformed host cells, pharmaceutical compositions comprising the muteins, and therapeutic methods of treatment.

We claim:  
     
         1 . A polypeptide comprising a human IL-4 mutein numbered in accordance with wild-type IL-4, said mutein having the substitution R121E, wherein said substitution substantially preserves native T cell activating ability but substantially reduces endothelial cell activating ability on the resulting IL-4 mutein, relative to wild-type.  
     
     
         2 . A polypeptide comprising a human IL-4 mutein numbered in accordance with wild-type IL-4, said mutein having at least both substitutions T13D and R121E, wherein said substitutions substantially preserve native T cell activating ability but substantially reduce endothelial cell activating ability on the resulting IL-4 mutein, relative to wild-type.  
     
     
         3 . A pharmaceutical composition comprising the human IL-4 mutein of  claim 1  in combination with a pharmaceutically acceptable carrier.  
     
     
         4 . A pharmaceutical composition comprising the human IL-4 mutein of  claim 2  in combination with a pharmaceutically acceptable carrier.  
     
     
         5 . A polynucleotide molecule comprising a polynucleic acid encoding the human IL-4 mutein of  claim 1  and degenerate variants thereof.  
     
     
         6 . A polynucleotide molecule comprising a polynucleic acid encoding the human IL-4 mutein of  claim 2  and degenerate variants thereof.  
     
     
         7 . A host cell transformed with the polynucleotide of  claim 5 .  
     
     
         8 . A host cell transformed with the polynucleotide of  claim 6 .  
     
     
         9 . A method of treating a patient afflicted with an IL-4 treatable condition by administering a therapeutically effective amount of a human IL-4 mutein of  claim 1  or  2 .  
     
     
         10 . The method of  claim 9  wherein said IL-4 treatable condition is an autoimmune disorder.  
     
     
         11 . The method of  claim 10  wherein said autoimmune condition is Multiple Sclerosis.  
     
     
         12 . The method of  claim 10  wherein said autoimmune condition is Rheumatoid Arthritis.  
     
     
         13 . The method of  claim 10  wherein said autoimmune condition is Insulin Dependent Diabetes Melitus.  
     
     
         14 . The method of  claim 10  wherein said autoimmune condition is Systemic Lupus Erythematosus.  
     
     
         15 . The method of  claim 9  wherein said IL-4 treatable condition is an infectious disease.  
     
     
         16 . The method of  claim 15  wherein said infectious disease is Lyme Disease.  
     
     
         17 . The method of  claim 9  wherein said IL-4 treatable condition is a Th1-polarized disease.  
     
     
         18 . The method of  claim 17  wherein said Th1 -polarized disease is Psoriasis.  
     
     
         19 . The method of  claim 9  wherein said IL-4 treatable condition is a cancer.  
     
     
         20 . The method of  claim 19  wherein said cancer is selected from the group consisting of acute lymphoblastic leukemia, and non-Hodgkins Lymphoma.  
     
     
         21 . The method of  claim 9  wherein said IL-4 treatable condition is a cartilagenous disorder.  
     
     
         22 . The method of  claim 21  wherein said cartilagenous disorder is osteoarthritis.