Method of inhibiting binding or activity of mif by administering a mif antagonist

Abstract

Methods and compositions for using the MHC class II invariant chain polypeptide, Ii (also known as CD74), as a receptor for macrophage migration inhibitory factor (MIF), are disclosed. These include methods and compositions for using this receptor, as well as agonists and antagonists of MIF which bind to this receptor, or which otherwise modulate the interaction of MIF with CD74 or the consequences of such interaction, in treatment of conditions characterized by locally or systemically altered MIF levels, particularly inflammatory conditions and cancer.

What is claimed is: 
     
         1 . A method for screening compounds for an agonist or antagonist of MIF comprising:
 contacting an MHC class II invariant chain (Ii) polypeptide with MIF in the presence and absence of a candidate compound, and   comparing the interaction of the MIF and said Ii polypeptide in the presence of said candidate compound with their interaction in the absence of said candidate compound, whereby
 a candidate compound that enhances the interaction of said MIF with said Ii polypeptide is identified as an agonist of MIF, and 
 a candidate compound that inhibits the interaction of said MIF with said Ii polypeptide is identified as an antagonist of MIF; 
   wherein said Ii polypeptide comprises the complete Ii amino acid sequence of  FIG. 5  (SEQ ID. NO:2) or an MIF-binding fragment thereof.   
     
     
         2 . An agonist or antagonist of MIF identified by the method of  claim 1 . 
     
     
         3 . An agonist or antagonist according to  claim 2  which is an antibody or antigen-binding fragment thereof. 
     
     
         4 . The agonist or antagonist according to  claim 3  wherein said antibody is an anti-CD74 antibody. 
     
     
         5 . An anti-CD74 antibody of  claim 4  selected from the group consisting of a monoclonal antibody, a human antibody, a humanized antibody and a chimeric antibody. 
     
     
         6 . A method of inhibiting an effect of MIF on a cell comprising on its surface an MHC class II invariant chain (Ii) polypeptide which binds MIF and thereby mediates said effect of MIF, said method comprising:
 contacting said cell with an antagonist of MIF wherein said antagonist inhibits binding of MIF to said Ii polypeptide.   
     
     
         7 . A method according to  claim 6  wherein said antagonist is an antibody or fragment thereof which binds to said Ii polypeptide. 
     
     
         8 . A method according to  claim 7 , wherein cell is present in a mammal and wherein said antagonist is administered to the mammal in a pharmaceutical composition. 
     
     
         9 . A method according to  claim 8 , wherein said mammal suffers from a condition characterized by systemic or local MIF levels elevated above the normal range in mammals not suffering from such a condition. 
     
     
         10 . A method according to  claim 9 , wherein said mammal suffers from an inflammatory disorder and said antagonist is administered in an amount effective to treat the disorder. 
     
     
         11 . A method according to  claim 9 , wherein the disorder is septic shock or arthritis. 
     
     
         12 . A method according to  claim 8 , wherein said mammal suffers from a cancer and said antagonist is administered in an amount effective to treat the cancer. 
     
     
         13 . A method of inhibiting an activity of MIF, said method comprising:
 contacting MIF with an antagonist of MIF, wherein said antagonist of MIF comprises a MHC class II invariant chain (Ii) polypeptide or a fragment thereof which binds to MIF.   
     
     
         14 . A method according to  claim 13 , wherein said MHC class II invariant chain (Ii) polypeptide or fragment thereof which binds to MIF is a soluble form of said polypeptide or fragment thereof. 
     
     
         15 . A method according to  claim 14 , wherein said soluble form of said polypeptide or fragment thereof comprises the extracellular binding domain of said polypeptide or a portion thereof. 
     
     
         16 . A method according to  claim 13 , wherein the MIF to be inhibited is in a mammal and wherein said antagonist of MIF is administered to the mammal in a pharmaceutical composition. 
     
     
         17 . A method according to  claim 16 , wherein said mammal suffers from a condition characterized by systemic or local MIF levels elevated above the normal range in mammals not suffering from such a condition. 
     
     
         18 . A method according to  claim 17 , wherein said mammal suffers from an inflammatory disorder and said antagonist is administered in an amount effective to treat the disorder. 
     
     
         19 . A method according to  claim 18 , wherein the disorder is septic shock or arthritis. 
     
     
         20 . A method according to  claim 16 , wherein said mammal suffers from a cancer and said antagonist is administered in an amount effective to treat the cancer. 
     
     
         21 . A method of purifying MIF comprising:
 contacting a sample comprising MIF with an MHC class II invariant chain (Ii) polypeptide or a fragment thereof which binds to MIF under conditions that promote the specific binding of MIF to the Ii polypeptide or fragment thereof, and   separating the MIF:Ii polypeptide complex or MIF:Ii polypeptide fragment complex thereby formed from materials which do not bind to the Ii polypeptide or fragment thereof.   
     
     
         22 . A method according to  claim 21 , wherein said Ii polypeptide or fragment thereof is immobilized on a solid support matrix. 
     
     
         23 . A method of assaying for the presence of MIF comprising:
 contacting a sample with an MHC class II invariant chain (Ii) polypeptide or a fragment thereof which binds to MIF under conditions that promote the specific binding of MIF to said Ii polypeptide or a fragment thereof, and   detecting any MIF:Ii polypeptide complex or MIF:Ii polypeptide fragment complex thereby formed.   
     
     
         24 . A method for reducing an effect of MIF on a cell comprising on its surface an MHC class II invariant chain (Ii) polypeptide which binds MIF and thereby mediates said effect of MIF, said method comprising:
 providing to said cell an antisense nucleic acid molecule in an amount effective to reduce the amount of said Ii polypeptide produced by said cell,   wherein said antisense nucleic acid molecule specifically binds to a portion of mRNA expressed from a gene encoding said MHC class II invariant chain (Ii) polypeptide and thereby decreases translation of said mRNA in said cell.   
     
     
         25 . A method according to  claim 24 , wherein the cell comprising an Ii polypeptide is in a mammal and wherein said antisense nucleic acid molecule is administered to the mammal in a pharmaceutical composition. 
     
     
         26 . A method according to  claim 25  wherein said antisense nucleic acid molecule is administered to the mammal in the form of an oligonucleotide. 
     
     
         27 . A method according to  claim 25  wherein said antisense nucleic acid molecule is administered to the mammal in the form of an recombinant construct that expresses said antisense nucleic acid molecule in said cell. 
     
     
         28 . A method according to  claim 25 , wherein said mammal suffers from a condition characterized by systemic or local MIF levels elevated above the normal range in mammals not suffering from such a condition.