US2011311534A1PendingUtilityA1

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

Individually held — no corporate assignee on recordPriority: Sep 8, 2006Filed: May 23, 2011Published: Dec 22, 2011

Est. expirySep 8, 2026(~0.1 yrs left)· nominal 20-yr term from priority

Inventors:James Ernst Paul Polakis Bonnee Rubinfeld Venita Dealmeida

A61P 43/00A61P 35/04A61P 35/00C07K 14/71C07K 14/4702A61K 38/00G01N 2333/71C07K 14/705A61K 38/17C12N 15/62G01N 33/50Y02A50/30

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References

Claims

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.

Claims

exact text as granted — not AI-modified

1 . A Wnt antagonist comprising:
 (a) a Frizzled domain component, and   (b) a Fc domain,   wherein the Frizzled domain component comprises a polypeptide derived from a polypeptide selected from the group consisting of (i) a Frizzled (Frz) protein, (ii) a secreted Frizzled Related Protein (sFRP) protein, and (iii) a Ror protein, and   further wherein the Wnt antagonist is active in vivo for at least 1 hour.   
     
     
         2 . The Wnt antagonist of any of  claim 1 , wherein the Wnt antagonist is active in vivo for at least 5 hours. 
     
     
         3 . The Wnt antagonist of  claim 1 , wherein the Frizzled domain component comprises a minimal CRD (ECD) domain from a Frz polypeptide selected from the group consisting of hFrz1 (SEQ ID NO: 18), hFrz2 (SEQ ID NO: 19), hFrz3 (SEQ ID NO: 20), hFrz4 (SEQ ID NO: 21), hFrz5 (SEQ ID NO: 22), hFrz6 (SEQ ID NO: 23), hFrz7 (SEQ ID NO: 24), hFrz8 (SEQ ID NO: 25), hFrz9 (SEQ ID NO: 26), and hFrz10 (SEQ ID NO: 27), and active variants thereof. 
     
     
         4 . The Wnt antagonist of  claim 1 , wherein the Frizzled domain component comprises a minimal CRD (ECD) domain from a sFRP polypeptide selected from the group consisting of sFRP1 (SEQ ID NO: 28), sFRP2 (SEQ ID NO: 29), sFRP3 (SEQ ID NO: 30), sFRP4 (SEQ ID NO: 31), and sFRP5 (SEQ ID NO: 32), and active variants thereof. 
     
     
         5 . The Wnt antagonist of  claim 1 , wherein the Frizzled domain component comprises a minimal CRD (ECD) domain from a Ror polypeptide selected from the group consisting of hRor1 (SEQ ID NO: 33), and hRor2 (SEQ ID NO: 34), and active variants thereof. 
     
     
         6 . The Wnt antagonist of  claim 1 , wherein the Frizzled domain component comprises a mature Frz polypeptide selected from the group consisting of hFrz1 (SEQ ID NO: 50), hFrz2 (SEQ ID NO: 51), hFrz3 (SEQ ID NO: 52), hFrz4 (SEQ ID NO: 53), hFrz5 (SEQ ID NO: 54), hFrz6 (SEQ ID NO: 55), hFrz7 (SEQ ID NO: 56), hFrz8 (SEQ ID NO: 57), hFrz9 (SEQ ID NO: 58), and hFrz10 (SEQ ID NO: 59), and active variants thereof. 
     
     
         7 . The Wnt antagonist of  claim 1 , wherein the Frizzled domain component comprises a mature sFrp polypeptide selected from the group consisting of sFRP1 (SEQ ID NO: 60), sFRP2 (SEQ ID NO: 61), sFRP3 (SEQ ID NO: 62), sFRP4 (SEQ ID NO: 63), and sFRP5 (SEQ ID NO: 64), and active variants thereof. 
     
     
         8 . The Wnt antagonist of  claim 1 , wherein the Frizzled domain component comprises a mature Ror polypeptide selected from the group consisting of hRor1 (SEQ ID NO: 65), and hRor2 (SEQ ID NO: 66), and active variants thereof. 
     
     
         9 . The Wnt antagonist of  claim 1 , wherein the Frizzled domain component comprises a pro-Frz polypeptide selected from the group consisting of hFrz1 (SEQ ID NO: 35), hFrz2 (SEQ ID NO: 36), hFrz3 (SEQ ID NO: 37), hFrz4 (SEQ ID NO: 38), hFrz5 (SEQ ID NO: 39), hFrz6 (SEQ ID NO: 40), hFrz7 (SEQ ID NO: 41), hFrz8 (SEQ ID NO: 42), hFrz9 (SEQ ID NO: 43), and hFrz10 (SEQ ID NO: 44), and active variants thereof. 
     
     
         10 . The Wnt antagonist of  claim 1 , wherein the Frizzled domain component comprises a pro-sFrp polypeptide selected from the group consisting of sFRP1 (SEQ ID NO: 45), sFRP2 (SEQ ID NO: 46), sFRP3 (SEQ ID NO: 47), sFRP4 (SEQ ID NO: 48), and sFRP5 (SEQ ID NO: 49), and active variants thereof. 
     
     
         11 . The Wnt antagonist of  claim 1 , wherein the Fc component is derived from an immunoglobulin selected from the group consisting of IgG1, IgG2, IgG3 and IgG4. 
     
     
         12 . The Wnt antagonist of  claim 11 , wherein the Fc is derived from an IgG1 immunoglobulin. 
     
     
         13 . The Wnt antagonist of  claim 12 , wherein the Fc comprises the Fc sequence shown in SEQ ID NO: 67 or SEQ ID NO: 68. 
     
     
         14 . The Wnt antagonist of  claim 1 , further comprising a linker connecting the Frizzled domain component to the Fc domain. 
     
     
         15 . The Wnt antagonist of  claim 14 , wherein the linker comprises a peptide selected from the group consisting of ESGGGGVT (SEQ ID NO: 69), LESGGGGVT (SEQ ID NO: 70), GRAQVT (SEQ ID NO: 71), WRAQVT (SEQ ID NO: 72), and ARGRAQVT (SEQ ID NO: 73). 
     
     
         16 . A Wnt antagonist comprising:
 (a) a Frizzled domain component, and   (b) a Fc domain,   wherein the Frizzled domain component comprises a polypeptide derived from a protein selected from the group consisting of (i) a Frizzled (Frz) protein, (ii) a secreted Frizzled Related Protein (sFRP) protein, and (iii) a Ror protein, and   further wherein the Wnt antagonist has an in vivo half-life of at least 1 day.   
     
     
         17 . The Wnt antagonist of  claim 16 , wherein the Wnt antagonist has an in vivo half-life of at least 2 days. 
     
     
         18 . A Wnt antagonist comprising a polypeptide selected from the group consisting of Frz8-Fc (SEQ ID NO: 74), Frz5-Fc (SEQ ID NO: 75), Frz1-Fc (SEQ ID NO: 76), Frz2-Fc (SEQ ID NO: 77), Frz3-Fc (SEQ ID NO: 78), Frz4-Fc (SEQ ID NO: 79), Frz6-Fc (SEQ ID NO: 80), Frz7-Fc (SEQ ID NO: 81), Frz9-Fc (SEQ ID NO: 82), Frz10-Fc (SEQ ID NO: 83), sFRP1-Fc (SEQ ID NO: 84), sFRP2 (SEQ ID NO: 85), sFRP3-Fc (SEQ ID NO: 86), sFRP4-Fc (SEQ ID NO: 87), and sFRPS-Fc (SEQ ID NO: 88). 
     
     
         19 . A composition comprising at least one pharmaceutically acceptable carrier or excipient and the Wnt antagonist of  claim 1 . 
     
     
         20 . A composition comprising at least one pharmaceutically acceptable carrier or excipient and the Wnt antagonist of  claim 16 . 
     
     
         21 . A method of inhibiting Wnt signaling in a cell comprising contacting the cell with an effective amount of a Wnt antagonist, the Wnt antagonist comprising:
 (a) a Frizzled domain component, and   (b) a Fc domain,   wherein the Frizzled domain component comprises a polypeptide derived from a polypeptide selected from the group consisting of (i) a Frizzled (Frz) protein, (ii) a secreted Frizzled Related Protein (sFRP) protein, and (iii) a Ror protein, and   further wherein the Wnt antagonist is active in vivo for at least 1 hour.   
     
     
         22 . The method of  claim 21 , wherein the cell is contained within a mammal and the amount administered is a therapeutically effective amount. 
     
     
         23 . The method of  claim 21 , wherein the inhibition of Wnt signaling results in the inhibition of growth of the cell. 
     
     
         24 . The method of  claim 21 , wherein the cell is a cancer cell. 
     
     
         25 . A method of treating a Wnt-mediated disorder in a mammal suffering therefrom, comprising administering to the mammal a therapeutically effective amount of a Wnt antagonist, the Wnt antagonist comprising:
 (a) a Frizzled domain component, and   (b) a Fc domain,   wherein the Frizzled domain component comprises a polypeptide derived from a polypeptide selected from the group consisting of (i) a Frizzled (Frz) protein, (ii) a secreted Frizzled Related Protein (sFRP) protein, and (iii) a Ror protein, and   further wherein the Wnt antagonist is active in vivo for at least 1 hour.   
     
     
         26 . The method of  claim 25 , wherein the disorder is a cell proliferative disorder associated with aberrant Wnt signaling activity. 
     
     
         27 . A method of modulating the expression of a Wnt target gene in a cell characterized by activated or excessive Wnt signaling, comprising contact the cell with an effective amount of a Wnt antagonist, the Wnt antagonist comprising:
 (a) a Frizzled domain component, and   (b) a Fc domain,   wherein the Frizzled domain component comprises a polypeptide derived from a polypeptide selected from the group consisting of (i) a Frizzled (Frz) protein, (ii) a secreted Frizzled Related Protein (sFRP) protein, and (iii) a Ror protein, and   further wherein the Wnt antagonist is active in vivo for at least 1 hour.   
     
     
         28 . A method of therapeutically treating a Wnt-mediated cancer, comprising administering a therapeutically effective amount of a Wnt antagonist, the Wnt antagonist comprising:
 (a) a Frizzled domain component, and   (b) a Fc domain,   wherein the Frizzled domain component comprises a polypeptide derived from a polypeptide selected from the group consisting of (i) a Frizzled (Frz) protein, (ii) a secreted Frizzled Related Protein (sFRP) protein, and (iii) a Ror protein, and   further wherein the Wnt antagonist is active in vivo for at least 1 hour.   
     
     
         29 . The method of  claim 28 , wherein the administration of the Wnt antagonist results in the reduction in size or severity of the cancer. 
     
     
         30 . The method of  claim 28 , wherein the administration of the Wnt antagonist results in the reduction in size or severity of the cancer. 
     
     
         31 . The method of  claim 28 , wherein the administration of the Wnt antagonist reduces the tumor burden of the cancer. 
     
     
         32 . The method of  claim 28 , wherein the administration of the Wnt antagonist kills the cancer.

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