TIE ligands

Abstract

The present invention concerns isolated nucleic acid molecules encoding the novel TIE ligands NL1, NL5 and NL8, the proteins encoded by such nucleic acid molecules, as well as methods and means for making and using such nucleic acid and protein molecules.

1 . An isolated nucleic acid molecule encoding a mammalian TIE ligand, 
 (a) selected from the group consisting of human NL-1 (SEQ. ID. NO: 2), human NL-5 (SEQ. ID. NO: 4), human NL8 (SEQ. ID. NO: 6), and homologs thereof in a non-human mammalian species; or    (b) a biologically active functional derivative thereof,    provided that if the functional derivative is an amino acid sequence variant, it has at least about 90% sequence identify with the fibrinogen-like domain of a human NL-1, human NL-5 or human NL8 ligand.    
     
     
         2 . The isolated nucleic acid molecule of  claim 1  which comprises the coding region of SEQ. ID. NO: 1; SEQ. ID. NO: 3; or SEQ. ID. NO: 5.  
     
     
         3 . The isolated nucleic acid molecule of  claim 1  which comprises the fibrinogen-like domain of SEQ. ID. NO: 1; SEQ. ID. NO:3; or SEQ. ID. NO: 5.  
     
     
         4 . A vector which comprises a nucleic acid molecule of  claim 1 .  
     
     
         5 . A recombinant host cell transformed with a nucleic acid molecule according to  claim 1 .  
     
     
         6 . The recombinant host cell of  claim 5  which is a prokaryotic cell.  
     
     
         7 . The recombinant host cell of  claim 5  which is a eukaryotic cell.  
     
     
         8 . An isolated mammalian TIE ligand, 
 (a) selected from the group consisting of human NL-1 (SEQ. ID. NO: 2), human NL-5 (SEQ. ID NO: 4), human NL8 (SEQ. ID. NO: 6), and homologs thereof in a non-human mammalian species; or    (b) a biologically active functional derivative thereof,    provided that if the functional derivative is an amino acid sequence variant, it has at least about 90% sequence identity with the fibrinogen-like region of a human NL-1, human NL-5 or human NL-8 ligand.    
     
     
         9 . An antibody which specifically binds the TIE ligand according to  claim 8 .  
     
     
         10 . The antibody of  claim 9  which is a monoclonal antibody.  
     
     
         11 . The antibody of  claim 10  which is an antagonist of the TIE-2 receptor.  
     
     
         12 . The antibody of  claim 10  which is an agonist of the TIE-2 receptor.  
     
     
         13 . A composition comprising a TIE ligand according to  claim 8  or an antibody according to  claim 9 , in association with a carrier.  
     
     
         14 . A conjugate comprising a TIE ligand according to  claim 8  or an antibody according to  claim 9 , fused to a further therapeutic or cytotoxic agent.  
     
     
         15 . The conjugate of  claim 14  wherein the further therapeutic agent is a toxin, another TIE ligand, or a member of the vascular endothelial growth factor (VEGF) family.  
     
     
         16 . A method for identifying a cell expressing a TIE receptor comprising contacting the cell with a detectably labeled TIE ligand according to  claim 8  under conditions permitting the binding of said TIE ligand to the TIE receptor, and monitoring the binding.  
     
     
         17 . A method for identifying an antagonist of a TIE receptor, comprising contacting cells expressing the TIE receptor with a TIE ligand according to  claim 8  and a test compound, under conditions permitting the binding of said TIE ligand to the TIE receptor, and determining whether the test compound is capable of interfering with the binding of the TIE ligand to the TIE receptor.  
     
     
         18 . A method for imaging the presence of antiogenesis, which comprises administering to a patient a detectably labeled TIE ligand according to  claim 8 , or antibody agonist according to  claim 9  of a TIE receptor, and monitoring angiogenesis.  
     
     
         19 . A method for inhibiting vasculogenesis, comprising administering to a patient an effective amount of a TIE ligand according to  claim 8 .  
     
     
         20 . The method of  claim 19  wherein said TIE ligand is a native human NL8 molecule.  
     
     
         21 . A method of inhibiting tumor growth, comprising administering to a patient an effective amount of a TIE ligand according to  claim 8 .  
     
     
         22 . A method for promoting bone development, maturation or growth, comprising administering to a patient in need an effective amounf of TIE ligand according to  claim 8.