Title:
CHIMERIC FIBROBLAST GROWTH FACTOR 23 PROTEINS AND METHODS OF USE
Document Type and Number:
WIPO Patent Application WO/2013/184960
Kind Code:
A3
Abstract:
The present invention relates to a chimeric protein that includes an N-terminus coupled to a C-terminus, where the N-terminus includes a portion of a paracrine fibroblast growth factor ("FGF") and the C-terminus includes a C-terminal portion of an FGF23 molecule. The portion of the paracrine FGF is modified to decrease binding affinity for heparin and/or heparan sulfate compared to the portion without the modification. The present invention also relates to pharmaceutical compositions including chimeric proteins according to the present invention, methods for treating a subject suffering from a disorder, and methods of screening for compounds with enhanced binding affinity for the αKlotho-FGF receptor complex involving the use of chimeric proteins of the present invention.
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Inventors:
MOHAMMADI MOOSA (US)
GOETZ REGINA (US)
GOETZ REGINA (US)
Application Number:
PCT/US2013/044592
Publication Date:
March 13, 2014
Filing Date:
June 06, 2013
Export Citation:
Assignee:
UNIV NEW YORK (US)
MOHAMMADI MOOSA (US)
GOETZ REGINA (US)
MOHAMMADI MOOSA (US)
GOETZ REGINA (US)
International Classes:
A61K38/18; A61K38/00; A61K38/24; C07K5/00; C07K14/50; C12P21/04
Foreign References:
| US20110172401A1 | 2011-07-14 | |||
| US20100286042A1 | 2010-11-11 | |||
| US20110104152A1 | 2011-05-05 | |||
| EP0645451B1 | 2001-08-22 | |||
| US20110150901A1 | 2011-06-23 | |||
| US20110195077A1 | 2011-08-11 | |||
| US20100184665A1 | 2010-07-22 | |||
| US20100062984A1 | 2010-03-11 | |||
| US20100158914A1 | 2010-06-24 | |||
| US20110053841A1 | 2011-03-03 |
Other References:
GOETZ ET AL.: "Molecular Insights into the Klotho-Dependent, Endocrine Mode of Action of Fibroblast Growth Factor 19 Subfamily Members", MOLECULAR AND CELLULAR BIOLOGY, vol. 27, no. 9, May 2007 (2007-05-01), pages 3417 - 3428
BEENKEN ET AL.: "Plasticity in Interactions of Fibroblast Growth Factor 1 (FGF1) N Terminus with FGF Receptors Underlies Promiscuity of FGF1.", J BIOL CHEM., vol. 287, no. 5, January 2012 (2012-01-01), pages 3067 - 78
IGARASHI ET AL.: "Characterization of recombinant human fibroblast growth factor (FGF)-10 reveals functional similarities with keratinocyte growth factor (FGF-7).", J BIOL CHEM., vol. 273, no. 21, 1998, pages 13230 - 5
MOTOMURA ET AL.: "An FGF1:FGF2 chimeric growth factor exhibits universal FGF receptor specificity, enhanced stability and augmented activity useful for epithelial proliferation and radioprotection.", BIOCHIM BIOPHYS ACTA, vol. 1780, no. 12, 2008, pages 1432 - 40
ZAKRZEWSKA ET AL.: "Increased protein stability of FGF1 can compensate for its reduced affinity for heparin.", J BIOL CHEM., vol. 284, no. 37, 2009, pages 25388 - 403
GOETZ ET AL.: "Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23 -FGFR-Klotho complex formation.", PROC NATL ACAD SCI USA, vol. 107, no. 1, 4 December 2009 (2009-12-04), pages 407 - 412
GOETZ ET AL.: "Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands.", MOL CELL BIOL., vol. 32, no. 10, March 2012 (2012-03-01), pages 1944 - 1954
GOETZ ET AL.: "Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor.", J BIOL CHEM., vol. 287, no. 34, 25 June 2012 (2012-06-25), pages 29134 - 29146
BEENKEN ET AL.: "The structural biology of the FGF19 subfamily.", J. ADV EXP MED BIOL., vol. 728, 1 March 2012 (2012-03-01), pages 1 - 24, Retrieved from the Internet [retrieved on 20131030]
WU ET AL.: "C-terminal tail of FGF19 determines its specificity toward Klotho co-receptors.", J BIOL CHEM., vol. 283, no. 48, 28 November 2008 (2008-11-28), pages 33304 - 33309
BEENKEN ET AL.: "Plasticity in Interactions of Fibroblast Growth Factor 1 (FGF1) N Terminus with FGF Receptors Underlies Promiscuity of FGF1.", J BIOL CHEM., vol. 287, no. 5, January 2012 (2012-01-01), pages 3067 - 78
IGARASHI ET AL.: "Characterization of recombinant human fibroblast growth factor (FGF)-10 reveals functional similarities with keratinocyte growth factor (FGF-7).", J BIOL CHEM., vol. 273, no. 21, 1998, pages 13230 - 5
MOTOMURA ET AL.: "An FGF1:FGF2 chimeric growth factor exhibits universal FGF receptor specificity, enhanced stability and augmented activity useful for epithelial proliferation and radioprotection.", BIOCHIM BIOPHYS ACTA, vol. 1780, no. 12, 2008, pages 1432 - 40
ZAKRZEWSKA ET AL.: "Increased protein stability of FGF1 can compensate for its reduced affinity for heparin.", J BIOL CHEM., vol. 284, no. 37, 2009, pages 25388 - 403
GOETZ ET AL.: "Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23 -FGFR-Klotho complex formation.", PROC NATL ACAD SCI USA, vol. 107, no. 1, 4 December 2009 (2009-12-04), pages 407 - 412
GOETZ ET AL.: "Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands.", MOL CELL BIOL., vol. 32, no. 10, March 2012 (2012-03-01), pages 1944 - 1954
GOETZ ET AL.: "Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor.", J BIOL CHEM., vol. 287, no. 34, 25 June 2012 (2012-06-25), pages 29134 - 29146
BEENKEN ET AL.: "The structural biology of the FGF19 subfamily.", J. ADV EXP MED BIOL., vol. 728, 1 March 2012 (2012-03-01), pages 1 - 24, Retrieved from the Internet
WU ET AL.: "C-terminal tail of FGF19 determines its specificity toward Klotho co-receptors.", J BIOL CHEM., vol. 283, no. 48, 28 November 2008 (2008-11-28), pages 33304 - 33309
Attorney, Agent or Firm:
THISSE, Megan, L. et al. (A Professional Corporation70 Linden Oaks,Suite 21, Rochesterr NY, US)
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