Methods and Pharmaceutical Compositions for the Treatment of Diseases Mediated by the NRP-1/OBR Complex Signaling Pathway

Abstract

The present invention relates to methods and pharmaceutical compositions for the treatment of diseases mediated by the NRP-1/OBR complex signaling pathway. In particular, the present invention relates to a method for treating a disease selected from the group consisting of cancers, obesity and obesity related diseases, anorexia, autoimmune diseases and infectious diseases in a subject in need thereof comprising administering the subject with a therapeutically effective amount of an antagonist of the NRP-1/OBR signaling pathway.

1 . A method for treating a disease selected from the group consisting of cancers, obesity and obesity related diseases, cachexia, anorexia, ureteral obstructive kidney disease, autoimmune diseases and infectious diseases in a subject in need thereof comprising administering to the subject with a therapeutically effective amount of an antagonist of the NRP-1/OBR signaling pathway. 
     
     
         2 . The method of  claim 1  wherein the antagonist of the NRP-1/OBR signaling pathway is selected from the group consisting of antibodies, small organic molecules, polypeptides and aptamers. 
     
     
         3 . The method of  claim 1  wherein the antagonist of the NRP-1/OBR signaling pathway is a CK2 inhibitor. 
     
     
         4 . The method of  claim 3  wherein the CK2 inhibitor is an allosteric CK2 inhibitor. 
     
     
         5 . The method of  claim 1  wherein the antagonist of the NRP-1/OBR signaling pathway is an antibody having an ability to block interaction between NRP-1 and OBR or an ability to block interaction between one or both of NRP-1 and Leptin. 
     
     
         6 . The method of  claim 5  wherein the antibody is directed to an extracellular domain of NRP-1 or OBR or a domain of Leptin. 
     
     
         7 . The method of  claim 1  wherein the antagonist of the NRP-1/OBR signaling pathway is combined with an anti-VEGF agent. 
     
     
         8 . A method for the treatment of cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an anti-VEGF agent and a therapeutically effective amount of a CK2 inhibitor. 
     
     
         9 . A method for preventing or reducing an adaptive-evasive response induced by a prolonged exposure to anti-VEGF treatment in a subject having a cancer comprising administering to the subject a therapeutically effective amount of an antagonist of the NRP-1/OBR/Leptin signaling pathway. 
     
     
         10 . The method of  claim 9  wherein the antagonist of the NRP-1/OBR/Leptin signaling pathway is a CK2 inhibitor. 
     
     
         11 . A method for screening a plurality of test substances useful for prevention or treatment of a disease selected from the group consisting of cancers, obesity and obesity related diseases, cachexia, anorexia, ureteral obstructive kidney disease, autoimmune diseases and infectious diseases comprising (a) testing each of the plurality of test substances for its ability to inhibit the NRP-1/OBR/Leptin signaling pathway and (b) and positively selecting test substances capable of inhibiting said NRP-1/OBR/Leptin signaling pathway. 
     
     
         12 . The method of  claim 11  wherein step (a) comprises determining whether each of the plurality of test substances i) inhibits formation of a complex between NRP-1 and OBR or Leptin, ii) inhibits phosphorylation of OBR and NRP1 induced by CK2, iii) inhibits nuclear translocation of NRP-1/OBR complexes and iv) inhibits expression of genes which are under control of the NRP-1/OBR/Leptin signaling pathway. 
     
     
         13 . The method of  claim 11  wherein step a) comprises:
 a1) contacting a test substance with a mixture of a first NRP-1 polypeptide or a substantially homologous or substantially similar amino acid sequence thereof and (2) a second OBR polypeptide or a substantially homologous or substantially similar amino acid sequence thereof, and 
 a2) determining the ability of said test substance to modulate binding between said NRP-1 polypeptide or said substantially homologous or substantially similar amino acid sequence thereof and said second OBR polypeptide or said substantially homologous or substantially similar amino acid sequence thereof. 
 
     
     
         14 . The method of  claim 11  wherein step a) comprises:
 a1) contacting a test substance with a mixture of a first NRP-1 polypeptide or a substantially homologous or substantially similar amino acid sequence thereof and (2) a second Leptin polypeptide or a substantially homologous or substantially similar amino acid sequence thereof, and 
 a2) determining the ability of said test substance to modulate binding between said NRP-1 polypeptide and said second Leptin polypeptide. 
 
     
     
         15 . The method of  claim 11  wherein step a) comprises:
 a1) contacting a test substance with a mixture of a first NRP-1 or OBR polypeptide or a substantially homologous or substantially similar amino acid sequence thereof and (2) a second CK2 alpha polypeptide or a substantially homologous or substantially similar amino acid sequence thereof, and 
 a2) determining the ability of said test substance to modulate binding between said first NRP-1 or OBR polypeptide or said substantially homologous or substantially similar amino acid sequence thereof and said second CK2α polypeptide or said substantially homologous or substantially similar amino acid sequence thereof. 
 
     
     
         16 . The method of  claim 11  wherein step a) comprises:
 a1) contacting a test substance with a mixture of a first NRP-1 or Leptin polypeptide or a substantially homologous or substantially similar amino acid sequence thereof and (2) a second CK2 alpha polypeptide or a substantially homologous or substantially similar amino acid sequence thereof, and 
 a2) determining the ability of said test substance to modulate binding between said NRP-1 or Leptin polypeptide or said substantially homologous or substantially similar amino acid sequence thereof and said second CK2 alpha polypeptide or said substantially homologous or substantially similar amino acid sequence thereof. 
 
     
     
         17 . The method of  claim 12 , wherein step (a) comprises determining whether each of the plurality of test substances inhibits interaction between extracellular domains of NRP1 and OBR and a domain of Leptin that interacts with NRP-1.