Neurturin receptor

Abstract

NTNRα, NTNRα extracellular domain (ECD), NTNRα variants, chimeric NTNRα (e.g., NTNRα immunoadhesion), and antibodies which bind thereto (including agonist and neutralizing antibodies) are disclosed. Various uses for these molecules are described, including methods to modulate cell activity and survival by response to NTNRα-ligands, for example NTN, by providing NTNRα to the cell.

What is claimed is:  
     
         1 . A polypeptide comprising a sequence selected from the group consisting of: 
 (a) a human NTNRα extracellular domain amino acid sequence;    (b) an allelic variant or mammalian homolog of (a);    (c) a sequence encoded by nucleic acid which hybridizes under stringent conditions to a nucleic acid encoding (a) or (b);    (d) a sequence derived from (a) or (b) by substitution, deletion, or addition of one or several amino acids in the amino acid sequence of (a) or (b); and,    (e) a sequence encoding at least 16 contiguous amino acids from (a), (b) or (c).    
     
     
         2 . The polypeptide of  claim 1 , comprising the amino acid sequence of NTNRα ECD from SEQ ID NO: 3 or SEQ ID NO: 6.  
     
     
         3 . The polypeptide of  claim 2 , comprising the amino acid sequence of mature NTNRα from SEQ ID NO: 3 or SEQ ID NO: 6.  
     
     
         4 . The polypeptide of  claim 3 , which specifically binds neurturin.  
     
     
         5 . The polypeptide of  claim 4 , which is conjugated with, or fused to, a molecule which increases the serum half-life thereof.  
     
     
         6 . The polypeptide of  claim 1  that is soluble NTNRα.  
     
     
         7 . A composition comprising the polypeptide of  claim 1  and a physiologically acceptable carrier.  
     
     
         8 . The NTNRα of  claim 1  that is chimeric NTNRα 
     
     
         9 . The chimeric NTNRα of  claim 8 , comprising a NTNRα amino acid sequence fused to an immunoglobulin sequence.  
     
     
         10 . The chimeric NTNRα of  claim 8 , comprising a NTNRα amino acid sequence fused to an epitope tag.  
     
     
         11 . A method for identifying a molecule which binds to the NTNRα, comprising exposing the NTNRα to the molecule suspected of binding thereto and determining binding of the molecule to the NTNRα.  
     
     
         12 . The method of  claim 11 , wherein the NTNRα is soluble NTNRα.  
     
     
         13 . A method for identifying a molecule which activates NTNRα, comprising exposing the NTNRα to a molecule suspected of being capable of activating NTNRα and measuring activation of NTNRα.  
     
     
         14 . A method for purifying a molecule which binds to NTNRα, comprising adsorbing the molecule to NTNRα immobilized on a solid phase and recovering the molecule from the immobilized NTNRα.  
     
     
         15 . The method of  claim 14  wherein the NTNRα is chimeric NTNRα, comprising a fusion of a NTNRα extracellular domain sequence to an immunoglobulin constant domain sequence.  
     
     
         16 . An antibody that specifically binds to NTNRα of  claim 1 .  
     
     
         17 . The antibody of  claim 16 , which is a monoclonal antibody.  
     
     
         18 . A composition comprising the antibody of  claim 17  and a physiologically acceptable carrier.  
     
     
         19 . The composition of  claim 18  further comprising a cytokine or a neurotrophic factor.  
     
     
         20 . A method for activating NTNRα in a cell, comprising exposing the NTNRα to an amount of an agonist antibody of  claim 16  which is effective for activating NTNRα.  
     
     
         21 . A method for modulating a physiological response of a cell to NTN, comprising contacting the cell with an amount of a NTNRα effective for modulating the response of the cell to NTN.  
     
     
         22 . A method for activating Ret on the surface of a cell, comprising administering to the cell a Ret-activating effective amount of soluble NTNRα or soluble GDNFRα.  
     
     
         23 . A method for determining the presence of NTNRα, comprising exposing a test sample suspected of containing the NTNRα to the antibody of  claim 16  and determining binding of said antibody to the test sample.  
     
     
         25 . An isolated nucleic acid molecule comprising a sequence encoding a polypeptide of  claim 1 .  
     
     
         26 . An isolated nucleic acid molecule comprising a sequence encoding a polypeptide of  claim 2 .  
     
     
         27 . An isolated nucleic acid molecule encoding the polypeptide of  claim 8 .  
     
     
         28 . The isolated nucleic acid molecule of  claim 25 , further comprising a promoter operably linked to the nucleic acid molecule.  
     
     
         29 . An expression vector comprising the nucleic acid molecule of  claim 25  operably linked to control sequences recognized by a host cell transformed with the vector.  
     
     
         30 . A host cell comprising the vector of  claim 29 .  
     
     
         31 . A process of using a nucleic acid molecule encoding NTNRα to effect production of NTNRα, comprising culturing the host cell of  claim 30  under conditions allowing expression of NTNRα.  
     
     
         32 . The process of  claim 31  further comprising recovering the NTNRα from the host cell culture.  
     
     
         33 . A non-human, transgenic animal which contains cells that express nucleic acid comprising the polypeptide of  claim 1 .  
     
     
         34 . The animal of  claim 33  which is a mouse.  
     
     
         35 . A non-human, transgenic animal which contains cells having an altered NTNRα gene.  
     
     
         36 . The animal of  claim 35  which is a mouse.