Tiki inhibitors

Abstract

Modulators of Wnt activity, e.g., Wnt inhibitors, that act on TIKI proteins and inhibit TIKI-mediated cleavage of Wnt proteins, as well as methods of identifying such modulators and methods of use thereof.

1 . An isolated antibody or antigen-binding fragment thereof that binds to a TIKI protein and inhibits TIKI-mediated cleavage of a Wnt protein. 
     
     
         2 . The antibody or antigen-binding fragment thereof of  claim 1  that binds specifically to human TIKI1, human TIKI2, or both human TIKI1 and human TIKI2. 
     
     
         3 . The antigen-binding fragment of  claim 1 , wherein the fragment comprises an F(ab), F(ab′)2, or scFv fragment. 
     
     
         4 . The antibody or antigen-binding fragment of  claim 1  that inhibits cleavage of one or more of Wnt2B, 3, 3A, 4, 5A, 5B, 6, 7A, 7B, 8A, 8B, or 16. 
     
     
         5 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment is murine, chimeric, human or humanized. 
     
     
         6 . A peptide antigen for use in generating an antibody that binds specifically to human TIKI1, TKIK2, or both TIKI1 and TIKI2, and inhibits TIKI-mediated cleavage of a Wnt, comprising at least one amino acid corresponding to H58, E85, E205, or H331, of SEQ ID NO:2. 
     
     
         7 . The peptide antigen of  claim 6 , wherein the peptide comprises at least one amino acid corresponding to H58, E85, E205, or H331 of SEQ ID NO:2 plus up to 25 amino acids from SEQ ID NO:2 on either side. 
     
     
         8 . A method of generating an inhibitory antibody that binds to TIKI, comprising immunizing an animal with a peptide antigen of  claim 6 . 
     
     
         9 . An antibody or antigen-binding fragment thereof that binds specifically to human TIKI1, TKIK2, or both TIKI1 and TIKI2, and inhibits TIKI-mediated cleavage of a Wnt, made by the method of  claim 8 . 
     
     
         10 . An antibody or antigen-binding fragment thereof that binds specifically to human TIKI1, TKIK2, or both TIKI1 and TIKI2, and inhibits TIKI-mediated cleavage of a Wnt, wherein the antibody binds to an epitope comprising at least one amino acid corresponding to H58, E85, E205 and H331 of SEQ ID NO:2. 
     
     
         11 . A method of treating a subject having or at risk of developing a disorder associated with a loss of bone density, the method comprising administering to the subject an antibody or antigen-binding fragment thereof according to  claim 1 . 
     
     
         12 . (canceled) 
     
     
         16 . The method of  claim 11 , wherein the Wnt protein is Wnt3a and the N-terminal amino acids comprise at least one sequence selected from the group consisting of SYPIWWSL, SYPIWWSLAVGPQYS and SYPIWWSLAVGPQYSS. 
     
     
         17 . The method of  claim 11 , wherein the Wnt protein is Wnt8 and the N-terminal amino acids comprise at least one sequence selected from the group consisting of AWSVNNFLMTGPKAYLT and AWSVNNFLMTGPKAYLTYSA. 
     
     
         18 . A method of decreasing bone loss or resorption, or increasing bone growth and/or density, in a patient in need thereof, the method comprising administering a therapeutically effective amount of a TIKI inhibitor wherein the inhibitor inhibits TIKI-mediated of the N-terminal amino acids of a Wnt protein and thereby inhibits or prevents inactivation of the Wnt protein, thereby increasing Wnt signaling and thereby decreasing bone loss or resorption. 
     
     
         19 . The method of  claim 18  wherein the TIKI inhibitor is selected from the group consisting of an antibody or antigen binding fragment thereof that specifically binds TIKI, and an inhibitory nucleic acid. 
     
     
         20 . The method of  claim 19 , wherein the inhibitory nucleic acid is selected from the group consisting of a siRNA, an antisense oligonucleotide, a ribozyme, and an aptamer. 
     
     
         21 .- 23 . (canceled)