Human Tumor Necrosis Factor TR21 and Methods Based Thereon

Abstract

The present invention relates to TR21 polypeptides. In particular, isolated nucleic acid molecules are provided encoding human TR21 protein. TR21 polypeptides are also provided as are vectors, host cells and recombinant methods for producing the same. The invention further relates to screening methods for identifying agonists and antagonists of TR21 activity.

1 . An isolated polypeptide comprising an amino acid sequence at least 90% identical to a sequence selected from the group consisting of:
 (a) amino acids from 2 to 81 in SEQ ID NO:2 ( FIG. 1 );   (b) amino acids from 2 to 38 in SEQ ID NO:2 ( FIG. 1 );   (c) amino acids from 2 to 46 in SEQ ID NO:2 ( FIG. 1 );   (d) amino acids from 2 to 62 in SEQ ID NO:2 ( FIG. 1 ); and   
       optionally, a heterologous polypeptide sequence 
     
     
         2 . An isolated nucleic acid molecule encoding the polypeptide of  claim 1 . 
     
     
         3 . A recombinant vector or a recombinant host cell comprising nucleic acid molecule of  claim 2 . 
     
     
         4 . An isolated antibody that binds specifically to a polypeptide consisting of amino acid residues selected from the group consisting of:
 (a) amino acids 2 to 81 in SEQ ID NO:2;   (b) amino acids 2 to 38 in SEQ ID NO:2;   (c) amino acids 2 to 46 in SEQ ID NO:2;   (d) amino acids 2 to 62 in SEQ ID NO:2;   (e) amino acids 3 to 15 in SEQ ID NO:2;   (f) amino acids 39 to 45 in SEQ ID NO:2;   (g) amino acids 51 to 53 in SEQ ID NO:2;   (h) amino acids 59 to 61 in SEQ ID NO:2;   (i) amino acids 104 to 112 in SEQ ID NO:2;   (j) amino acids 115 to 122 in SEQ ID NO:2;   (k) amino acids 136 to 138 in SEQ ID NO:2;   (l) amino acids 147 to 153 in SEQ ID NO:2; and   (m) amino acids 178 to 182 in SEQ ID NO:2.   
     
     
         5 . The antibody of  claim 4  which binds a polypeptide consisting of amino acids 2 to 38 of SEQ ID NO:2 and a polypeptide consisting of amino acids 2 to 81 of SEQ ID NO:2. 
     
     
         6 . A method of treating an autoimmune disease or condition associated with an autoimmune disease, comprising administering an effective amount of the polypeptide of  claim 1 , to a patient in need thereof; wherein said autoimmune disease is selected from the group consisting of:
 (a) rheumatoid arthritis;   (b) systemic lupus erythmatosus;   (c) multiple sclerosis;   (d) Sjogren's syndrome;   (e) IgA nephropathy;   (f) glomerulonephritis;   (g) diabetes mellitus; and   (h) myasthenia gravis.   
     
     
         7 . A method of treating an autoimmune disease or condition associated with an autoimmune disease comprising, administering an effective amount of the antibody of  claim 4 , to a patient in need thereof; wherein said autoimmune disease is selected from the group consisting of:
 (a) rheumatoid arthritis;   (b) systemic lupus erythmatosus;   (c) multiple sclerosis;   (d) Sjogren's syndrome;   (e) IgA nephropathy;   (f) glomerulonephritis;   (g) diabetes mellitus; and   (h) myasthenia gravis.   
     
     
         8 . A method of treating an immunodeficiency or condition associated with an immunodeficiency, comprising administering an effective amount of the antibody of  claim 4 , to a patient in need thereof; wherein said immunodeficiency is selected from the group consisting of:
 (a) common variable immunodeficiency (CVID);   (b) acquired immunodeficiency syndrome (AIDS);   (c) severe combined immunodeficiency (SCID);   (d) selective IgA deficiency;   (e) hypogammaglobulinemia; and   (f) Wiskott-Aldrich syndrome.   
     
     
         9 . A method of diagnosing an immunodeficiency or an autoimmune disease, comprising contacting the polypeptide of  claim 1  with cells or bodily fluids from an individual, and assaying for binding to said polypeptide. 
     
     
         10 . A method of diagnosing an immunodeficiency or an autoimmune disease, comprising contacting the antibody of  claim 4  with cells or bodily fluids from an individual, and assaying for binding to said antibody. 
     
     
         11 . A method of increasing B cell proliferation or immunoglobulin production, comprising administering an effective amount of the antibody of  claim 4 , to a patient in need thereof. 
     
     
         12 . A method of inhibiting B cell proliferation or immunoglobulin production, comprising administering an effective amount of the polypeptide of  claim 1  to a patient in need thereof. 
     
     
         13 . A method of inhibiting B cell proliferation or immunoglobulin production, comprising administering an effective amount of the antibody of  claim 4  to a patient in need thereof. 
     
     
         14 . A method of killing a cell that expresses TR21 polypeptide on its cell surface, comprising contacting said cell with an antibody or portion thereof that specifically binds a polypeptide consisting of amino acid residues 1-184 of SEQ ID NO:2; wherein said antibody or portion thereof is conjugated to a toxin. 
     
     
         15 . The method of  claim 14  performed in vivo. 
     
     
         16 . The method of  claim 14  wherein said antibody or portion thereof specifically binds to a polypeptide consisting of amino acid residues 1-81 of SEQ ID NO:2. 
     
     
         17 . The method of  claim 14  wherein the antibody or portion thereof is monoclonal, chimeric or human. 
     
     
         18 . The method of  claim 14  wherein the antibody or portion thereof is a single chain antibody or a Fab fragment. 
     
     
         19 . The method of  claim 14  wherein said cell is a lymphocyte. 
     
     
         20 . The method of  claim 19  wherein said lymphocyte is leukemic.