Methods of treating neuroendocrine tumors using frizzled-binding agents

Abstract

Novel methods of treating neuroendocrine tumors are provided. In one embodiment, the method comprises administering to a subject in need thereof a therapeutically effective dose of a Wnt antagonist. In one embodiment, the Wnt antagonist is an anti-FZD antibody. In another embodiment, the Wnt antagonist is a soluble FZD receptor polypeptide. In a further embodiment, the Wnt antagonist is an anti-Wnt antibody.

1 - 6 . (canceled) 
     
     
         7 . A method of treating neuroendocrine cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a Wnt antagonist. 
     
     
         8 . The method of  claim 7 , wherein the subject is a human subject. 
     
     
         9 - 10 . (canceled) 
     
     
         11 . The method of  claim 7 , wherein the neuroendocrine tumor is selected from the group consisting of gastroenteropancreatic neuroendocrine tumor, carcinoid tumor, pheochromocytoma, paraganglioma, medullary thyroid cancer, pulmonary neuroendocrine tumor and thymic neuroendocrine tumor. 
     
     
         12 . The method of  claim 11 , wherein the neuroendocrine tumor is a carcinoid tumor or a pancreatic neuroendocrine tumor. 
     
     
         13 . The method  claim 7 , wherein the Wnt antagonist is an antibody that binds to at least one human frizzled receptor (FZD). 
     
     
         14 - 16 . (canceled) 
     
     
         17 . The method of  claim 13 , wherein the antibody specifically binds to at least one human FZD selected from the group consisting of FZD1, FZD2, FZD5, FZD7, and FZD8. 
     
     
         18 - 21 . (canceled) 
     
     
         22 . The method of  claim 17 , wherein the antibody specifically binds to FZD1, FZD2, FZD5, FZD7, and FZD8. 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 13 , wherein the antibody blocks Wnt binding to FZD or blocks the activation of FZD. 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 13 , wherein the antibody comprises:
 (a) a heavy chain CDR1 comprising GFTFSHYTLS (SEQ ID NO:31), a heavy chain CDR2 comprising VISGDGSYTYYADSVKG (SEQ ID NO:32), and a heavy chain CDR3 comprising NFIKYVFAN (SEQ ID NO:33); and/or   (b)
 (i) a light chain CDR1 comprising SGDNIGSFYVH (SEQ ID NO:34), a light chain CDR2 comprising DKSNRPSG (SEQ ID NO:35), and a light chain CDR3 comprising QSYANTLSL (SEQ ID NO:36); or 
 (ii) a light chain CDR1 comprising SGDKLGKKYAS (SEQ ID NO:41), a light chain CDR2 comprising EKDNRPSG (SEQ ID NO:42), and a light chain CDR3 comprising SSFAGNSLE (SEQ ID NO:43). 
   
     
     
         27 . The method of  claim 26 , wherein the antibody comprises:
 (a) a VH comprising the amino acid sequence of SEQ ID NO:37; and/or   (b) a VL comprising the amino acid sequence of SEQ ID NO:38 or 44.   
     
     
         28 . The method of  claim 26 , wherein the antibody comprises:
 (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:39; and/or   (b) a light chain comprising the amino acid sequence of SEQ ID NO:40 or 45.   
     
     
         29 . The method of  claim 13 , wherein the antibody is a monoclonal antibody. 
     
     
         30 . The method of  claim 29 , wherein the antibody is a recombinant antibody, a chimeric antibody, a humanized antibody, a human antibody, or an antibody fragment. 
     
     
         31 . The method of  claim 29 , wherein the antibody is a monospecific antibody or a bispecific antibody. 
     
     
         32 . (canceled) 
     
     
         33 . The method of  claim 13 , wherein the antibody is an IgG1 or IgG2 antibody. 
     
     
         34 . The method of  claim 7 , wherein the Wnt antagonist is a soluble FZD receptor that is capable of binding to Wnt. 
     
     
         35 - 36 . (canceled) 
     
     
         37 . The method of  claim 34 , wherein the soluble receptor comprises a fragment of the extracellular domain of the human FZD receptor, said fragment comprising the Fri domain of the human FZD receptor. 
     
     
         38 . (canceled) 
     
     
         39 . The method of  claim 37 , wherein the human FZD receptor is FZD8. 
     
     
         40 . The method of  claim 39 , wherein the FZD8 Fri domain comprises the amino acid sequence of SEQ ID NO: 28. 
     
     
         41 . The method of  claim 40 , wherein the soluble receptor further comprises a human Fc domain. 
     
     
         42 . The method of  claim 41 , wherein the human Fc domain comprises the amino acid sequence of SEQ ID NO: 95. 
     
     
         43 . The method of  claim 7 , which further comprises administering a second therapeutic agent to the subject. 
     
     
         44 . The method of  claim 43 , wherein the second therapeutic agent is a chemotherapeutic agent. 
     
     
         45 - 48 . (canceled) 
     
     
         49 . The method of  claim 7 , wherein the Wnt antagonist is OMP-18R5. 
     
     
         50 - 52 . (canceled) 
     
     
         53 . The method of  claim 7 , wherein the Wnt antagonist is OMP-54F28. 
     
     
         54 . The method of  claim 7 , wherein the neuroendocrine tumor is not small cell lung tumor (SCLC). 
     
     
         55 - 56 . (canceled)