Monoclonal antibodies against HMGB1

1 . An antibody or antigen-binding fragment thereof that specifically binds to a mammalian high mobility group box (HMGB1) A box but does not specifically bind to non-A box epitopes of HMGB, wherein said antibody or antigen-binding fragment inhibits release of a proinflammatory cytokine from a vertebrate cell treated with a high mobility group protein and wherein said antibody or antigen-binding fragment is selected from the group consisting of 6H9 HMGB1 mAb and 10D4 HMGB1 mAb. 
     
     
         2 . The antibody or antigen-binding fragment of  claim 1  wherein the binding of said antibody or said antigen-binding fragment to said high mobility group box (HMGB) A box can be inhibited by an antibody selected from the group consisting of 6H9 HMGB1 mAb and 10D4 HMGB1 mAb. 
     
     
         3 . The antibody or antigen-binding fragment of  claim 1  wherein said antibody or antigen-binding fragment has the epitopic specificity of 6H9 HMGB1 mAb and/or 10D4 HMGB1 mAb. 
     
     
         4 . The antibody or antigen-binding fragment of  claim 1  wherein said antibody or antigen-binding fragment has the epitopic specificity of 6H9 HMGB1 mAb. 
     
     
         5 . The antibody produced by murine hybridoma 6H9 HMGB1 mAb, deposited as ATCC Accession Number PTA-5434, or an antigen-binding fragment thereof. 
     
     
         6 . The antibody produced by murine hybridoma 10D4 HMGB1 mAb, deposited as ATCC Accession Number PTA-5435, or an antigen-binding fragment thereof. 
     
     
         7 . Murine hybridoma 6H9 HMGB1 mAb, deposited as ATCC Accession Number PTA-5434. 
     
     
         8 . Murine hybridoma 10D4 HMGB1 mAb, deposited as ATCC Accession Number PTA-5435. 
     
     
         9 . The antibody or antigen-binding fragment of  claim 1  wherein said antibody or antigen-binding fragment is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody and an antigen-binding fragment of any of the foregoing. 
     
     
         10 . An isolated cell that produces an antibody or antigen-binding fragment thereof that specifically binds to a vertebrate high mobility group box (HMGB) A box but does not specifically bind to non-A box epitopes of HMGB, wherein said antibody or antigen-binding fragment is selected from the group consisting of 6H9 HMGB1 mAb and 10D4 HMGB1 mAb. 
     
     
         11 . An isolated cell that produces an antibody or antigen-binding fragment thereof that specifically binds to a vertebrate high mobility group box (HMGB) A box but does not specifically bind to non-A box epitopes of HMGB, wherein the binding of said antibody or said antigen-binding fragment to said high mobility group box (HMGB) A box can be inhibited by an antibody selected from the group consisting of 6H9 HMGB1 mAb and 10D4 HMGB1 mAb. 
     
     
         12 . An isolated cell that produces an antibody or antigen-binding fragment thereof that specifically binds to a vertebrate high mobility group box (HMGB) A box but does not specifically bind to non-A box epitopes of HMGB, wherein said antibody or antigen-binding fragment has the epitopic specificity of an antibody selected from the group consisting of 6H9 HMGB1 mAb and 10D4 HMGB1 mAb. 
     
     
         13 . The antibody produced by murine hybridoma 2G7 HMGB1 mAb, deposited as ATCC Accession Number PTA-5432, or an antigen-binding fragment thereof. 
     
     
         14 . An antibody or antigen-binding fragment thereof, wherein the binding of said antibody or said antigen-binding fragment to a vertebrate high mobility group box (HMGB) polypeptide can be inhibited by 2G7 HMGB1 mAb. 
     
     
         15 . An antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment has the epitopic specificity of 2G7 HMGB1 mAb. 
     
     
         16 . Murine hybridoma 2G7 HMGB1 mAb, deposited as ATCC Accession Number PTA-5432. 
     
     
         17 . An isolated cell that produces 2G7 HMGB1 mAb. 
     
     
         18 . The isolated cell of  claim 17  wherein said isolated cell is selected from the group consisting of an immortalized B cell, a hybridoma and a recombinant cell comprising one or more exogenous nucleic acid molecules that encode said antibody or antigen-binding fragment thereof. 
     
     
         19 . An isolated cell that produces an antibody or antigen-binding fragment thereof, wherein the binding of said antibody or said antigen-binding fragment to a vertebrate high mobility group box (HMGB) polypeptide can be inhibited by 2G7 HMGB1 mAb. 
     
     
         20 . The isolated cell of  claim 19  wherein said isolated cell is selected from the group consisting of an immortalized B cell, a hybridoma and a recombinant cell comprising one or more exogenous nucleic acid molecules that encode said antibody or antigen-binding fragment thereof. 
     
     
         21 . An isolated cell that produces an antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment has the epitopic specificity of 2G7 HMGB1 mAb. 
     
     
         22 . The isolated cell of  claim 21  wherein said isolated cell is selected from the group consisting of an immortalized B cell, a hybridoma and a recombinant cell comprising one or more exogenous nucleic acid molecules that encode said antibody or antigen-binding fragment thereof. 
     
     
         23 . An antibody or antigen-binding fragment, wherein the binding of said antibody or said antigen-binding fragment to a peptide consisting of amino acid residues 61to 78 of SEQ ID NO:1 can be inhibited by 6H9 HMGB1 mAb. 
     
     
         24 . An antibody or antigen-binding fragment, wherein the binding of said antibody or said antigen-binding fragment to a peptide consisting of amino acid residues 46to 63 of SEQ ID NO:1 can be inhibited by 2G7 HMGB1 mAb. 
     
     
         25 . An antibody or antigen-binding fragment thereof wherein said antibody or fragment comprises the light chain CDRs (CDR1, CDR2 and CDR3) and the heavy chain CDRs (CDR1, CDR2 and CDR3) of an antibody selected from the group consisting of 6H9 HMGB1 mAb, 10D4 HMGB1 mAb and 2G7 HMGB1 mAb. 
     
     
         26 . The antibody or antigen-binding fragment of  claim 25  wherein said antibody or antigen-binding fragment further comprises a human framework region. 
     
     
         27 . The antibody or antigen-binding fragment of  claim 1  wherein said antibody or antigen-binding fragment is an antigen-binding fragment selected from the group consisting of a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment and a Fv fragment. 
     
     
         28 . A composition comprising the antibody or antigen-binding fragment of  claim 1  and a pharmaceutically-acceptable excipient. 
     
     
         29 . A composition comprising an antibody or antigen-binding fragment thereof and a pharmaceutically-acceptable excipient, wherein said antibody or antigen-binding fragment is selected from the group consisting of 6H9 HMGB1 mAb, 2G7 HMGB1 mAb, 10D4 HMGB1 mAb, and an antigen-binding fragment of any of the foregoing. 
     
     
         30 . The antibody or antigen-binding fragment of  claim 1  wherein said antibody or antigen-binding fragment is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody and an antigen-binding fragment of any of the foregoing. 
     
     
         31 . An antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment is selected from the group consisting of:
 a) 6H9 HMGB1 mAb;   b) 2G7 HMGB1 mAb;   c) 10D4 HMGB1 mAb;   d) an antibody having the epitopic specificity of 6H9 HMGB1 mAb, 2G7 HMGB1 mAb, and/or 10D4 HMGB1 mAb;   e) an antibody that can compete with 6H9 HMGB1 mAb, 2G7 HMGB1 mAb, and/or 10D4 HMGB1 mAb for binding to a vertebrate high mobility group box (HMGB) polypeptide; and   f) an antigen-binding fragment of a), b), c), d) or e).   
     
     
         32 . The antibody or antigen-binding fragment of  claim 31  wherein said antibody or antigen-binding fragment is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody and an antigen-binding fragment of any of the foregoing. 
     
     
         33 . A method of detecting and/or identifying an agent that binds to a vertebrate high mobility group box (HMGB) polypeptide comprising combining:
 i) an antibody or antigen-binding fragment that binds HMGB;   ii) a test agent; and   iii) a composition comprising a vertebrate HMGB polypeptide;   
       and detecting or measuring the formation of a complex between said antibody or antigen-binding fragment and said HMGB polypeptide, wherein a decrease in the formation of said complex relative to a suitable control indicates that said test agent binds to said HMGB polypeptide, 
       wherein said antibody or antigen-binding fragment is selected from the group consisting of:
 a) 6H9 HMGB1 mAb; 
 b) 2G7 HMGB1 mAb; 
 c) 10D4 HMGB1 mAb; 
 d) an antibody having the epitopic specificity of 6H9 HMGB1 mAb, 2G7 HMGB1 mAb and/or 10D4 HMGB1 mAb; 
 e) an antibody that can compete with 6H9 HMGB1 mAb, 2G7 HMGB1 mAb and/or 10D4 HMGB1 mAb for binding to a vertebrate high mobility group box (HMGB) polypeptide; and 
 f) an antigen-binding fragment of a), b), c), d) or e). 
 
     
     
         34 . A method of treating a condition in a subject characterized by activation of an inflammatory cytokine cascade comprising administering to the subject an antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment is selected from the group consisting of:
 a) 6H9 HMGB1 mAb;   b) 2G7 HMGB1 mAb;   c) 10D4 HMGB1 mAb;   d) an antibody having the epitopic specificity of 6H9 HMGB1 mAb, 2G7 HMGB1 mAb and/or 10D4 HMGB1 mAb;   e) an antibody that can compete with 6H9 HMGB1 mAb, 2G7 HMGB1 mAb and/or 10D4 HMGB1 mAb for binding to a vertebrate high mobility group box (HMGB) polypeptide; and   f) an antigen-binding fragment of a), b), c), d), or e).   
     
     
         35 . The method of  claim 34  wherein said condition is selected from the group consisting of sepsis, allograft rejection, arthritis, asthma, lupus, adult respiratory distress syndrome, chronic obstructive pulmonary disease, psoriasis, pancreatitis, peritonitis, burns, ischemia, Behcet's disease, graft versus host disease, inflammatory bowel disease, multiple sclerosis, and cachexia. 
     
     
         36 . A method of treating a subject with sepsis comprising administering to the subject an antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment is selected from the group consisting of:
 a) 6H9 HMGB1 mAb;   b) 2G7 HMGB1 mAb;   c) 10D4 HMGB1 mAb;   d) an antibody having the epitopic specificity of 6H9 HMGB1 mAb, 2G7 HMGB1 mAb and/or 10D4 HMGB1 mAb;   e) an antibody that can compete with 6H9 HMGB1 mAb, 2G7 HMGB1 mAb and/or 10D4 HMGB1 mAb for binding to a vertebrate high mobility group box (HMGB) polypeptide; and   f) an antigen-binding fragment of a), b), c), d) or e).   
     
     
         37 . A method of treating a subject with arthritis comprising administering to the subject an antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment is selected from the group consisting of:
 a) 6H9 HMGB1 mAb;   b) 2G7 HMGB1 mAb;   c) 10D4 HMGB1 mAb;   d) an antibody having the epitopic specificity of 6H9 HMGB1 mAb, 2G7 HMGB1 mAb and/or 10D4 HMGB1 mAb;   e) an antibody that can compete with 6H9 HMGB1 mAb, 2G7 HMGB1 mAb and/or 10D4 HMGB1 mAb for binding to a vertebrate high mobility group box (HMGB) polypeptide; and   f) an antigen-binding fragment of a), b), c), d) or e).   
     
     
         38 . A method of treating a subject with lupus comprising administering to the subject an antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment is selected from the group consisting of:
 a) 6H9 HMGB1 mAb;   b) 2G7 HMGB1 mAb;   c) 10D4 HMGB1 mAb;   d) an antibody having the epitopic specificity of 6H9 HMGB1 mAb, 2G7 HMGB1 mAb and/or 10D4 HMGB1 mAb;   e) an antibody that can compete with 6H9 HMGB1 mAb, 2G7 HMGB1 mAb and/or 10D4 HMGB1 mAb for binding to a vertebrate high mobility group box (HMGB) polypeptide; and   f) an antigen-binding fragment of a), b), c), d) or e).   
     
     
         39 . A method of detecting a vertebrate high mobility group box (HMGB) polypeptide in a sample comprising:
 a) contacting a sample with an antibody or antigen-binding fragment of  claim 26 , under conditions suitable for binding of said antibody or fragment to said HMGB polypeptide present in said sample; and   b) detecting antibody-HMGB complexes or antigen-binding fragment-HMGB complexes,   
       wherein detection of said antibody-HMGB complexes or antigen-binding fragment-HMGB complexes is indicative of the presence of HMGB polypeptide in said sample. 
     
     
         40 . The method of  claim 39  wherein said antibody or antigen-binding fragment is selected from the group consisting of 6H9 HMGB1 mAb, 2G7 HMGB1 mAb, 10D4 HMGB1 mAb and an antigen-binding fragment of any of the foregoing. 
     
     
         41 . The method of  claim 39 , wherein said antibody or antigen-binding fragment comprises a detectable label. 
     
     
         42 . The method of  claim 39  wherein said detecting of antibody-HMGB complexes or antigen-binding fragment-HMGB complexes is by immunoassay. 
     
     
         43 . The method of  claim 42  wherein said immunoassay is an ELISA. 
     
     
         44 . A test kit for use in detecting the presence of a vertebrate high mobility group box (HMGB) polypeptide or portion thereof in a sample comprising:
 a) an antibody or antigen-binding fragment of  claim 26 ; and   b) one or more ancillary reagents suitable for detecting the presence of a complex between said antibody or antigen-binding fragment and said HMGB polypeptide or portion thereof.