Novel TNF receptor death domain ligand proteins and inhibitors of ligand binding

Abstract

Novel TNF receptor death domain (“TNF-R1-DD”) ligand proteins are disclosed. Polynucleotides encoding the TNF-R1-DD ligand protein are also disclosed, along with vectors, host cells, and methods of making the TNF-R1-DD ligand protein. Pharmaceutical compositions containing the TNF-R1-DD ligand protein, methods of treating inflammatory conditions, and methods of inhibiting TNF-R death domain binding are also disclosed. Methods of identifying inhibitors of TNF-R death domain binding and inhibitors identified by such methods are also disclosed.

1 - 46 . (canceled)  
     
     
         47 . A method of preventing or ameliorating an inflammatory disorder by administering to a mammal an antibody which specifically binds to a protein with the amino acid sequence of SEQ NO:2 or a fragment of said antibody.  
     
     
         48 . The method of  claim 47 , wherein said antibody is a neutralizing antibody.  
     
     
         49 . The method of  claim 47 , wherein said antibody blocks binding of TNF-R1-DD to a polypeptide TNF-R1-DD ligand protein with the amino acid sequence of SEQ ID NO:2.  
     
     
         50 . The method of  claim 47 , wherein said antibody is a polyclonal antibody.  
     
     
         51 . The method of  claim 47 , wherein said antibody is a monoclonal antibody.  
     
     
         52 . The method of  claim 47 , wherein said antibody specifically reacts with a protein comprising the amino acid sequence of SEQ ID NO:2.  
     
     
         53 . The method of  claim 47 , wherein said antibody specifically reacts with a protein comprising the amino acid sequence of SEQ ID NO:12.  
     
     
         54 . The method of  claim 47 , wherein said antibody specifically reacts with a protein comprising the amino acid sequence of SEQ ID NO:16.  
     
     
         55 . The method of  claim 47 , wherein said disorder is cachexia, autoimmune disease, graft-versus-host reaction, osteoporosis, colitis, myelogenous leukemia, diabetes, wasting, or atherosclerosis.  
     
     
         56 . A method of preventing or ameliorating an inflammatory disorder by administering to a mammal a neutralizing antibody that binds specifically to a protein with the amino acid sequence of SEQ ID NO:2, wherein said neutralizing antibody blocks binding of TNF-R1-DD to a TNF-R1-DD ligand protein with the amino acid sequence of SEQ ID NO:2, or a fragment of said neutralizing antibody.  
     
     
         57 . The method of  claim 56 , wherein said antibody is an isolated antibody.  
     
     
         58 . A method of preventing or ameliorating an inflammatory disorder by administering to a mammal an antibody that specifically binds to a protein with the amino acid sequence of SEQ ID NO:2, wherein said antibody is obtained using as an immunogen TNF-R1-DD ligand protein with the amino acid sequence of SEQ ID NO:2.  
     
     
         59 . The method of  claim 58 , wherein said antibody is obtained using as an immunogen a protein with tyrosine residues replaced with sulfated tyrosine residues.  
     
     
         60 . The method of  claim 58 , wherein said immunogen is conjugated to a hapten.  
     
     
         61 . The method of  claim 58 , wherein said hapten is keyhole limpet hemocyanin (KLH).