Use of interleukin-4 antagonists and compositions thereof

Abstract

Methods for treating medical conditions induced by interleukin-4 involve administering an IL-4 antagonist to a patient afflicted with such a condition. Suitable IL-4 antagonists include, but are not limited to, IL-4 receptors (such as a soluble human IL-4 receptor), antibodies that bind IL-4, antibodies that bind IL-4R, IL-4 muteins that bind to IL-4R but do not induce a biological response, molecules that inhibit IL-4-induced signal transduction, and other compounds that inhibit a biological effect that results from the binding of IL-4 to a cell surface IL-4R. Particular antibodies provided herein include human monoclonal antibodies generated by procedures involving immunization of transgenic mice. Such human antibodies may be raised against human IL-4 receptor. Certain of the antibodies inhibit both IL-4-induced and IL-13-induced biological activities.

1 . An isolated antibody that competes for binding to human IL-4 receptor with a fully human control antibody comprising the light chain variable region sequence (SEQ ID NO:10) and the heavy chain variable region sequence (SEQ ID NO:12) of antibody 12B5. 
     
     
         2 . The isolated antibody of  claim 1 , wherein when said control antibody is bound to human IL-4 receptor, binding of said isolated antibody to said human IL-4 receptor is inhibited. 
     
     
         3 . The isolated antibody of  claim 1 , wherein when said isolated antibody is bound to human IL-4 receptor, binding of said control antibody to said human IL-4 receptor is inhibited. 
     
     
         4 . The isolated antibody of  claim 1 , wherein said isolated antibody inhibits the binding of human IL-4 to human IL-4 receptor. 
     
     
         5 . The isolated antibody of  claim 1 , wherein said isolated antibody inhibits the binding of human IL-13 to human IL-13 receptor. 
     
     
         6 . The isolated antibody of  claim 1 , wherein said isolated antibody inhibits human IL-4 signaling through human IL-4 receptor. 
     
     
         7 . The isolated antibody of  claim 1 , wherein said isolated antibody inhibits human IL-13 signaling through human IL-13 receptor. 
     
     
         8 . The isolated antibody of  claim 1 , wherein said isolated antibody binds to human IL-4 receptor with a binding affinity (K a ) of at least 1×10 8 . 
     
     
         9 . The isolated antibody of  claim 1 , wherein said isolated antibody binds to human IL-4 receptor with a binding affinity (K a ) of at least 1×10 9 . 
     
     
         10 . The isolated antibody of  claim 1 , wherein said isolated antibody binds to human IL-4 receptor with a binding affinity (K a ) of at least 1×10 10 . 
     
     
         11 . The isolated antibody of  claim 1 , wherein said isolated antibody is a human, partially human, humanized, or chimeric antibody. 
     
     
         12 . The isolated antibody of  claim 1 , wherein said isolated antibody is a full-length antibody. 
     
     
         13 . The isolated antibody of  claim 1 , wherein said isolated antibody is an IgA antibody, an IgD antibody, an IgE antibody, IgG antibody, an IgG1 antibody, an IgG2 antibody, an IgG3, antibody, an IgG4 antibody, or an IgM antibody. 
     
     
         14 . The isolated antibody of  claim 1 , wherein said isolated antibody is a fragment of an antibody. 
     
     
         15 . The isolated antibody of  claim 1 , wherein said isolated antibody is a fusion protein. 
     
     
         16 . The isolated antibody of  claim 1 , wherein said isolated antibody is a single chain antibody (scFv). 
     
     
         17 . An isolated nucleic acid, wherein said isolated nucleic acid comprises a sequence encoding:
 a. the light chain variable domain of a first antibody,   b. the heavy chain variable domain of said first antibody, or   c. the light chain variable domain of said first antibody and the heavy chain variable domain of said first antibody,   
       wherein said first antibody competes for binding to human IL-4 receptor with a fully human control antibody comprising the light chain variable region sequence (SEQ ID NO:10) and the heavy chain variable region sequence (SEQ ID NO:12) of antibody 12B5. 
     
     
         18 . A vector, wherein said vector comprises said isolated nucleic acid of  claim 17 . 
     
     
         19 . The vector of  claim 18 , wherein said vector is an expression vector. 
     
     
         20 . An isolated cell, wherein said cell comprises a nucleic acid, said nucleic acid comprises a sequence encoding:
 a. the light chain variable domain of a first antibody,   b. the heavy chain variable domain of said first antibody, or   c. the light chain variable domain of said first antibody and the heavy chain variable domain of said first antibody,   said first antibody competes for binding to human IL-4 receptor with a fully human control antibody comprising the light chain variable region sequence (SEQ ID NO:10) and the heavy chain variable region sequence (SEQ ID NO:12) of antibody 12B5.   
     
     
         21 . The isolated cell of  claim 20 , wherein said isolated cell expresses said first antibody. 
     
     
         22 . A method of reducing IL-4 receptor-dependent signaling in a subject, comprising administering to said subject an effective amount of an isolated antibody, wherein said isolated antibody competes for binding to human IL-4 receptor with a fully human control antibody comprising the light chain variable region sequence (SEQ ID NO:10) and the heavy chain variable region sequence (SEQ ID NO:12) of antibody 12B5. 
     
     
         23 . The method of  claim 22 , wherein said method suppresses a T H 2-type immune response. 
     
     
         24 . The method of  claim 22 , wherein said subject has, or is at risk of developing, a condition responsive to inhibition of IL-4-dependent signaling and/or IL-13-dependent signaling. 
     
     
         25 . The method of  claim 24 , wherein said condition is an inflammatory condition. 
     
     
         26 . The method of  claim 24 , wherein said condition is an IgE mediated condition. 
     
     
         27 . The method of  claim 24 , wherein said condition is an allergic condition. 
     
     
         28 . The method of  claim 24 , wherein said condition is a condition in which IL-4 mediated epithelial barrier disruption plays a role. 
     
     
         29 . The method of  claim 24 , wherein said condition is asthma. 
     
     
         30 . The method of  claim 24 , wherein said condition is COPD. 
     
     
         31 . The method of  claim 24 , wherein said condition is pulmonary fibrosis. 
     
     
         32 . A method of making an antibody, comprising incubating a cell under conditions that allow it to express said antibody, wherein said cell comprises a first nucleic acid sequence encoding the light chain of said antibody and a second nucleic acid sequence encoding the heavy chain of said antibody, and said antibody competes for binding to human IL-4 receptor with a fully human control antibody comprising the light chain variable region sequence (SEQ ID NO:10) and the heavy chain variable region sequence (SEQ ID NO:12) of antibody 12B5. 
     
     
         33 . A composition comprising an isolated antibody, wherein said isolated antibody competes for binding to human IL-4 receptor with a fully human control antibody comprising the light chain variable region sequence (SEQ ID NO:10) and the heavy chain variable region sequence (SEQ ID NO:12) of antibody 12B5. 
     
     
         34 . The composition of  claim 33 , further comprising a pharmaceutically acceptable diluent, buffer, or excipient. 
     
     
         35 . A kit comprising an isolated antibody, wherein said isolated antibody competes for binding to human IL-4 receptor with a fully human control antibody comprising the light chain variable region sequence (SEQ ID NO:10) and the heavy chain variable region sequence (SEQ ID NO:12) of antibody 12B5.