Wnt antagonists and their use in the diagnosis and treatment of wnt-mediated disorders

Abstract

The present invention provides for chimeric Wnt antagonists comprising a Frz domain component derived from a Frizzled protein, a secreted Frizzled related protein or Ror protein and an Fc immunoglobulin component, and their use in the treatment and diagnostic detection of cellular Wnt signaling and Wnt-mediated disorders, including cancer.

1 .- 32 . (canceled) 
     
     
         33 . A soluble receptor comprising (a) a fragment of an extracellular domain of a human Frizzled (Frz) receptor and (b) a human Fc domain, wherein the fragment of the extracellular domain of the human Frz receptor consists essentially of an amino acid sequence selected from the group consisting of amino acid residues 1 to 156 of SEQ ID NO:42, amino acid residues 1 to 129 of SEQ ID NO:25, amino acid residues 1 to 155 of SEQ ID NO:39; and amino acid residues 1 to 129 of SEQ ID NO:22, wherein the soluble receptor has a longer half-life in vivo than a soluble receptor comprising the extracellular domain of the Frz receptor and the human Fc domain. 
     
     
         34 . The soluble receptor of  claim 33  wherein the human Fc is human IgG1 Fc comprising the amino acid sequence of SEQ ID NO:67. 
     
     
         35 . A pharmaceutical composition comprising the soluble receptor of  claim 33 . 
     
     
         36 . A kit comprising the soluble receptor of  claim 33 . 
     
     
         37 . The soluble receptor of  claim 33 , wherein the soluble receptor inhibits the Wnt-dependant growth of solid tumor cells. 
     
     
         38 . The soluble receptor of  claim 33 , wherein the soluble receptor inhibits the Wnt-dependant growth of breast tumor cells. 
     
     
         39 . An isolated polypeptide comprising an amino acid sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of amino acid residues 1 to 129 of SEQ ID NO:25 and amino acid residues 1 to 129 of SEQ ID NO:22, wherein said polypeptide is a soluble receptor that inhibits the Wnt-dependent growth of solid tumor cells. 
     
     
         40 . A soluble receptor comprising (a) a fragment of an extracellular domain of a human Frizzled (Frz) receptor and (b) a human Fc domain, wherein the fragment of the extracellular domain of the human Frz receptor consists essentially of an amino acid sequence selected from the group consisting of amino acid residues 1 to 156 of SEQ ID NO:42 and amino acid residues 1 to 155 of SEQ ID NO:39, and wherein the soluble receptor has a half-life in vivo of at least 24 hours in mice following i.p. injection. 
     
     
         41 . A soluble receptor comprising (a) a fragment of an extracellular domain of a human Frizzled (Frz) receptor and (b) a human Fc domain, wherein the fragment of the extracellular domain of the human Frz receptor consists essentially of an amino acid sequence selected from the group consisting of amino acid residues 1 to 156 of SEQ ID NO:42 and amino acid residues 1 to 155 of SEQ ID NO:39, and wherein the soluble receptor is detectable in serum at least 24 hours following i.p. injection in mice. 
     
     
         42 . A method of inhibiting the growth of solid tumor cells in a subject in need thereof, the method comprising administering to the subject the soluble receptor of  claim 33  in an amount effective to inhibit the Wnt-dependent growth of solid tumor cells. 
     
     
         43 . A method of inhibiting the growth of solid tumor cells in a subject in need thereof, the method comprising administering to the subject the soluble receptor of  claim 40  in an effective amount to inhibit the Wnt-dependent growth of solid tumor cells. 
     
     
         44 . A method of inhibiting the growth of solid tumor cells in a subject in need thereof, the method comprising administering to the subject the soluble receptor of  claim 41  in an effective amount to inhibit the Wnt-dependent growth of solid tumor cells. 
     
     
         45 . The method of  claim 42 , wherein the soluble receptor is administered with radiation therapy. 
     
     
         46 . The method of  claim 42 , wherein the soluble receptor is administered with chemotherapy. 
     
     
         47 . The method of  claim 42 , wherein the solid tumor cells are from a breast tumor, colorectal tumor, lung tumor, pancreatic tumor, prostate tumor, or a head and neck tumor.