Anti MIF Antibodies

Abstract

The present invention relates to monoclonal antibodies and antigen-binding portions thereof that specifically bind to the C-terminal or the center region of macrophage migration inhibitory factor (MIF). These anti-MIF antibodies and antigen-binding portions thereof further inhibit human MIF biological function. The invention also relates to isolated heavy and light chain immunoglobulins derived from anti-MIF antibodies and nucleic acid molecules encoding such immunoglobulins. The present invention also relates to a method of identifying anti-MIF antibodies, pharmaceutical compositions comprising these antibodies and a method of using these antibodies and compositions for the treatment of MIF-related conditions.

1 . A monoclonal antibody or an antigen-binding portion thereof that specifically binds to the C-terminal or the center region of MIF and inhibits human MIF biological function. 
     
     
         2 . The monoclonal antibody or antigen-binding portion according to  claim 1 , wherein said antibody or antigen-binding portion possesses at least one of the following properties:
 a) inhibits glucocorticoid overriding (GCO) activity   b) inhibits proliferation of cancer cells or fibroblasts   c) binds to active MIF   d) does not bind to non-active MIF   e) competes mouse anti-MIF antibody III.D.9.   
     
     
         3 . The monoclonal antibody or antigen-binding portion according to  claim 1 , wherein said antibody or antigen-binding portion binds human MIF with a K D  less than 500 nM. 
     
     
         4 . The monoclonal antibody or antigen-binding portion according to  claim 1 , wherein said antibody or said antigen-binding portion binds to active MIF. 
     
     
         5 . The monoclonal antibody according to  claim 1 , wherein said antibody is selected from the group consisting of antibody Bax8, antibody Bax69, antibody Bax74, antibody Bax94, antibody Bax152 and antibody BaxA10. 
     
     
         6 . The monoclonal antibody according to  claim 5 , wherein said antibody is an IgG4 sub-format antibody. 
     
     
         7 . The monoclonal antibody according to  claim 6 , wherein said IgG4 sub-format has a single mutation, whereby the CPSC sub-sequence in the Fc region of IgG4 becomes CPPC. 
     
     
         8 . The monoclonal antibody or the antigen-binding portion according to  claim 1 , wherein said antibody or antigen-binding portion comprises:
 a) a heavy chain CDR1, CDR2 and CDR3 independently selected from the heavy chain of an antibody selected from the group consisting of antibody Bax8, antibody Bax69, antibody Bax74, antibody Bax94, antibody Bax152 and antibody BaxA10   b) a light chain CDR1, CDR2 and CDR3 independently selected from the light chain of an antibody selected from the group consisting of antibody Bax8, antibody Bax69, antibody Bax74, antibody Bax94, antibody Bax152 and antibody BaxA10.   
     
     
         9 . The monoclonal antibody according to  claim 1 , wherein the antibody comprises:
 c) a heavy chain amino acid sequence that is at least 90% identical to the heavy chain amino acid sequence of antibody Bax8, antibody Bax69, antibody Bax74, antibody Bax94, antibody Bax152 and antibody BaxA10;   d) a light chain amino acid sequence that is at least 90% identical to the light chain amino acid sequence of antibody Bax8, antibody Bax69, antibody Bax74, antibody Bax94, antibody Bax152 and antibody BaxA10.   
     
     
         10 . The monoclonal antibody or the antigen-binding portion according to  claim 1 , for use in treating an immunological disease, wherein said immunological disease is an inflammatory disease or a hyperproliferative disorder. 
     
     
         11 . The monoclonal antibody or the antigen-binding portion according to  claim 10 , wherein said inflammatory disease is selected from the group consisting of vasculitis, arthritis, sepsis, septic shock, endotoxic shock, toxic shock syndrome, acquired respiratory distress syndrome, glomerulonephritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, peritonitis, nephritis and psoriasis. 
     
     
         12 . A pharmaceutical composition, comprising the monoclonal antibody or the antigen-binding portion according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the monoclonal antibody is an antibody selected from the group consisting of antibody Bax8, antibody Bax69, antibody Bax74, antibody Bax94, antibody Bax152 and antibody BaxA10. 
     
     
         14 . A method for treating an immunological disease selected from inflammatory disease or a hyperproliferative disorder in a subject, including a human, comprising the step of administering to said subject in need thereof a therapeutically effective amount of the monoclonal antibody or the antigen-binding portion according to  claim 1 , wherein said antibody or said antigen binding portion further inhibits human MIF biological function. 
     
     
         15 . The method according to  claim 14 , wherein said inflammatory disease is selected from the group consisting of vasculitis, arthritis, sepsis, septic shock, endotoxic shock, toxic shock syndrome, acquired respiratory distress syndrome, glomerulonephritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, peritonitis, nephritis and psoriasis. 
     
     
         16 . An isolated cell line that produces the monoclonal antibody or the antigen-binding portion according to  claim 1 . 
     
     
         17 . An isolated nucleic acid molecule comprising a nucleotide sequence that encodes the heavy chain, or the light chain, of the monoclonal antibody or the antigen-binding portion according to  claim 1 . 
     
     
         18 . A vector comprising the nucleic acid molecule according to  claim 17 , wherein the vector optionally comprises an expression control sequence operably linked to said nucleic acid molecule. 
     
     
         19 . A host cell comprising the nucleic acid molecule according to  claim 17 . 
     
     
         20 . A host cell comprising a nucleic acid molecule encoding the heavy chain and a nucleic acid molecule encoding the light chain of the monoclonal antibody or the antigen-binding portion according to  claim 1 . 
     
     
         21 . A method of producing a monoclonal antibody or an antigen-binding portion thereof, comprising culturing the host cell according to  claim 19  under suitable conditions and recovering said antibody or antigen-binding portion thereof. 
     
     
         22 . A process for the identification of anti-MIF antibodies capable of inhibiting human MIF biological function and inducing a beneficial effect in an animal model by carrying out the following steps:
 a) selecting an antibody that binds to active MIF and does not bind to non-active MIF   b) testing said antibody in in-vitro assays   c) selecting an antibody, which inhibits GCO and/or cell proliferation.