Modified il-4 mutein receptor antagonists

Abstract

This invention relates to modified IL-4 mutein receptor antagonists comprising an IL-4 mutein receptor antagonist coupled to polyethylene glycol. Related formulations and dosages and methods of administration thereof for therapeutic purposes are also provided. These modified IL-4 mutein receptor antagonists, compositions and methods provide a treatment option for those individuals afflicted with a respiratory disorder such as asthma by inhibiting IL-4 and IL-13-mediated airway hyperresponsiveness and eosinophilia. More particularly, these antagonists have an increased duration of effect versus unmodified IL-4RA by virtue of a greater plasma half-life.

1 . A modified IL-4 mutein receptor antagonist coupled to a non-protein polymer at an amino acid residue at position 37, 38, or 104 of IL-4, wherein the amino acids at positions 13, 121 and 124 are aspartic acid, and wherein the non-protein polymer is polyethylene glycol, polypropylene glycol or a polyoxyalkylene. 
     
     
         2 . The modified IL-4 mutein receptor antagonist of  claim 1 , comprising the amino acid sequence as set forth in SEQ ID NO: 32. 
     
     
         3 . The modified IL-4 mutein receptor antagonist of  claim 1 , wherein the non-protein polymer is polyethylene glycol, polypropylene glycol or a polyoxyalkylene. 
     
     
         4 . The modified IL-4 mutein receptor antagonist of  claim 1 , wherein the non-protein polymer is polyethylene glycol. 
     
     
         5 . The modified IL-4 mutein receptor antagonist of  claim 4 , wherein the polyethylene glycol is linear. 
     
     
         6 . The modified IL-4 mutein receptor antagonist of  claim 4 , wherein the polyethylene glycol is branched. 
     
     
         7 . The modified IL-4 mutein receptor antagonist of  claim 6 , wherein the polyethylene glycol is about 3 kD to 50 kD. 
     
     
         8 . The modified IL-4 mutein receptor antagonist of  claim 7 , wherein the polyethylene glycol is 40 kD. 
     
     
         9 . A pharmaceutical composition comprising:
 a) the modified IL-4 mutein receptor antagonist of  claim 1 ; and   b) a pharmaceutically acceptable carrier.   
     
     
         10 . A pharmaceutical composition comprising:
 a) the modified IL-4 mutein receptor antagonist of  claim 8 ; and   b) a pharmaceutically acceptable carrier.   
     
     
         11 . The modified IL-4 mutein receptor antagonist of  claim 1 , wherein the modified mutein receptor antagonist binds to the IL-4 receptor alpha chain with a K d  of about 0.1 nM to about 10 μM, about 0.5 nM to about 1 μM, or about 1.0 nM to about 100 nM. 
     
     
         12 . The modified IL-4 mutein receptor antagonist of  claim 1 , wherein the modified IL-4 mutein receptor antagonist inhibits the proliferative response of TF-1 cells to IL-4 with an IC 50  of about 0.1 nM to about 10 μM, about 0.5 nM to about 1 or about 1.0 nM to about 100 nM. 
     
     
         13 . The modified IL-4 mutein receptor antagonist of  claim 1 , wherein the modified IL-4 mutein receptor antagonist inhibits the proliferative response of TF-1 cells to IL-13 with an IC 50  of about 0.1 nM to about 10 μM, about 0.5 nM to about 1 μM, or about 1.0 nM to about 100 nM. 
     
     
         14 . The modified IL-4 mutein receptor antagonist of  claim 1 , wherein the modified IL-4 mutein receptor antagonist inhibits the proliferative response of human B cells to IL-4 with an IC 50  of about 0.1 nM to about 10 μM, about 0.5 nM to about 1 μM, or about 1.0 nM to about 100 nM. 
     
     
         15 . The modified IL-4 mutein receptor antagonist of  claim 1 , wherein the modified IL-4 mutein receptor antagonist inhibits the proliferative response of human T cells to IL-4 with an IC 50  of about 0.1 nM to about 10 μM, about 0.5 nM to about 1 μM, or about 1.0 nM to about 100 nM. 
     
     
         16 . The modified IL-4 mutein receptor antagonist of  claim 1 , wherein the modified IL-4 mutein receptor antagonist has a plasma half-life which is at least about 2-10 fold greater than that of an unmodified IL-4 receptor antagonist. 
     
     
         17 . A purified polynucleotide encoding the polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 32.