FGF9 as a specific ligand for FGFR3

Abstract

The present invention concerns fibroblast growth factor 9 (FGF9) as a high affinity ligand for fibroblast growth factor receptor 3 (FGFR3) which ligand is capable of binding and activating FGFR3 in a specific manner. The present invention is also directed to methods for detection of FGFR3 by utilizing FGF9, as well as to pharmaceutical compositions for modulating the activity of FGFR3 comprising as an active ingredient FGF9, antagonists thereof or FGF binding agents which are capable of neutralizing native circulating FGF9. The present invention further concerns novel recombinant mouse and chicken FGF9, expression vectors comprising these recombinant FGF9s and a transgenic animal transformed with said expression vectors.

1 . A method for the detection of fibroblast growth factor receptor 3 (FGFR3) in a sample or tissue comprising: 
 (i) contacting the sample or tissue with fibroblast growth factor 9 (FGF9) and allowing formation of receptor-ligand pairs; and    (ii) detecting the presence of FGFR3-FGF9 pairs, a positive detection indicating the presence of FGFR3 in the sample or tissue.    
     
     
         2 . A method according to  claim 1 , wherein the contact of sample or tissue with FGF9 is carried out in the presence of heparin.  
     
     
         3 . A pharmaceutical composition for modulating of the activity of FGFR3 comprising a pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective amount of FGF9.  
     
     
         4 . A pharmaceutical composition according to  claim 3  for increasing the activity of FGFR3.  
     
     
         5 . A pharmaceutical composition according to  claim 4  for stimulating bone and cartilage repair.  
     
     
         6 . A pharmaceutical composition for modulating of the activity of FGFR3 comprising a pharmaceutically acceptable carrier and as an active ingredient an antagonist of FGF9, or an FGF9 binding agent.  
     
     
         7 . A pharmaceutical composition according to  claim 6 , wherein the FGF9 binding agent is an antibody against FGF9.  
     
     
         8 . A pharmaceutical composition according to  claim 6  or  7  for decreasing the activity of FGFR3.  
     
     
         9 . A pharmaceutical composition according to  claim 8  for the treatment of a disease or a disorder selected from the group consisting of: 
 multiple or solitary hereditary exostosis, hallux vagus deformity, achondroplasia, synovial chondromatosis and endochondromas.  
 
     
     
         10 . A recombinant mouse FGF9 DNA having the nucleic acid sequence as depicted in FIG. 1.  
     
     
         11 . A recombinant chicken FGF9 DNA having the nucleic acid sequence as depicted in FIG. 2.  
     
     
         12 . A polypeptide comprising an amino acid sequence encoded by the recombinant mouse FGF9 DNA of  claim 10 .  
     
     
         13 . A polypeptide comprising an amino acid sequence encoded by the recombinant chicken FGF9 DNA of  claim 11 .  
     
     
         14 . An expression vector comprising the recombinant mouse FGF9 DNA sequence of  claim 10  or the recombinant chicken FGF9 DNA sequence of  claim 11  under the expression control of a strong promoter and/or a cartilage/bone tissue specific promoter.  
     
     
         15 . An expression vector according to  claim 14 , wherein the promoter is collagen type-2 promoter.  
     
     
         16 . A transgenic animal transfected with an expression vector according to  claim 14  or  15 .  
     
     
         17 . A method for the stimulation of cartilage or bone repair comprising: 
 administering to the site of desired repair a therapeutically effective amount of FGF9, optionally together with a pharmaceutically acceptable carrier.    
     
     
         18 . A method for the therapeutical treatment of a disease or disorder caused by an excess of FGF9 or over activity of FGFR3 comprising: 
 administering to a subject in need of such treatment a therapeutically effective amount of a FGF9-binding agent or an antagonist of FGF9.    
     
     
         19 . A method according to  claim 18 , wherein the FGF9-binding agent is an antibody against FGF9.  
     
     
         20 . A method according to  claim 13  or  19 , wherein the disease or disorder is selected from the group consisting of: 
 multiple or solitary hereditary exostosis, hallux vagus deformity, achondroplasia, synovial chondromatosis and endochondromas.