Apo-2 ligand

Abstract

A novel cytokine, designated Apo-2 ligand, which induces mammalian cell apoptosis is provided. The Apo-2 ligand is believed to be a member of the TNF cytokine family. Compositions including Apo-2 ligand chimeras, nucleic acid encoding Apo-2 ligand, and antibodies to Apo-2 ligand are also provided. Methods of using Apo-2 ligand to induce apoptosis and to treat pathological conditions such as cancer, are further provided.

1 . Isolated biologically active human Apo-2 ligand comprising amino acid residues 114-281 of  FIG. 1A . 
     
     
         2 . The Apo-2 ligand of  claim 1  comprising amino acid residues 41-281 of  FIG. 1A . 
     
     
         3 . The Apo-2 ligand of  claim 2  comprising amino acid residues 15-281 of  FIG. 1A . 
     
     
         4 . The Apo-2 ligand of  claim 3  comprising amino acid residues 1-281 of  FIG. 1A . 
     
     
         5 . Isolated biologically active human Apo-2 ligand having amino acid residues 1-281 of  FIG. 1A . 
     
     
         6 . Isolated biologically active Apo-2 ligand having at least about 80% sequence identity with either of:
 (a) the full-length native human Apo-2 ligand comprising amino acid residues 1-281 of  FIG. 1A ;   (b) the extracellular region of native human Apo-2 ligand comprising amino acid residues 41-281 of  FIG. 1A ; or   (c) the extracellular region of native human Apo-2 ligand comprising amino acid residues 114-281 of  FIG. 1A .   
     
     
         7 . The Apo-2 ligand of  claim 6  wherein said ligand has at least about 90% sequence identity with either of (a), (b), or (c). 
     
     
         8 . The Apo-2 ligand of  claim 7  wherein said ligand has at least about 95% sequence identity with either of (a), (b), or (c). 
     
     
         9 . A chimeric polypeptide comprising the Apo-2 ligand of  claim 1  fused to a heterologous polypeptide sequence. 
     
     
         10 . The chimeric polypeptide of  claim 9  wherein said heterologous polypeptide sequence is a tag polypeptide sequence. 
     
     
         11 . An antibody which binds to Apo-2 ligand. 
     
     
         12 . The antibody of  claim 11  wherein said antibody is a monoclonal antibody. 
     
     
         13 . Isolated nucleic acid encoding Apo-2 ligand. 
     
     
         14 . The nucleic acid of  claim 13  wherein said nucleic acid encodes the Apo-2 ligand of  claim 1 . 
     
     
         15 . The nucleic acid of  claim 13  wherein said nucleic acid encodes the Apo-2 ligand of  claim 2 . 
     
     
         16 . The nucleic acid of  claim 13  wherein said nucleic acid encodes the Apo-2 ligand of  claim 5 . 
     
     
         17 . A vector comprising the nucleic acid of  claim 13 . 
     
     
         18 . A host cell comprising the vector of  claim 17 . 
     
     
         19 . A method of producing Apo-2 ligand comprising culturing the host cell of  claim 18  and recovering the Apo-2 ligand from the host cell culture. 
     
     
         20 . A composition comprising Apo-2 ligand and a pharmaceutically-acceptable carrier. 
     
     
         21 . The composition of  claim 20  wherein said Apo-2 ligand comprises the Apo-2 ligand of  claim 1 . 
     
     
         22 . A pharmaceutical composition useful for stimulating mammalian cell apoptosis comprising an effective amount of Apo-2 ligand in a pharmaceutically-acceptable carrier. 
     
     
         23 . A method of inducing apoptosis in mammalian cells comprising exposing mammalian cells to an effective amount of Apo-2 ligand. 
     
     
         24 . A method of treating a mammal having cancer, comprising administering to a mammal diagnosed as having cancer an effective amount of Apo-2 ligand. 
     
     
         25 . The method of  claim 24  wherein the Apo-2 ligand is administered to the mammal in combination with one or more other therapies. 
     
     
         26 . The method of  claim 25  wherein said one or more other therapies are selected from the group consisting of radiation therapy, chemotherapy, TNF-α, TNF-β, CD30 ligand, 4-1BB ligand, and Apo-1 ligand. 
     
     
         27 . The method of  claim 24  wherein said cancer is breast cancer, prostate cancer or ovarian cancer. 
     
     
         28 . An article of manufacture, comprising:
 a container;   a label on said container; and   a composition contained within said container;   
       wherein the composition includes an active agent effective for inducing apoptosis, the label on said container indicates that the composition can be used to induce apoptosis, and the active agent in said composition comprises Apo-2 ligand. 
     
     
         29 . The article of manufacture of  claim 28  further comprising instructions for administering the Apo-2 ligand to a mammal.