New York University

Pfizer Corporation

The Salk Institute for Biological Studies

Sugen Incorporated

University of Cincinnati

Moosa Mohammadi

Regina Goetz

Joseph Schlessinger

Stevan R Hubbard

Anna V Eliseenkova

Ronald Mark Evans

Michael Downes

Jae Myoung Suh

Claudio Basilico

Xiang-peng Kong

Jeanne Sue Magram

Alexander Plotnikov

Kristen Leigh Johnson

Zhongtao Zhang

Jo El J Schultz

Disclosed herein are modified soluble α-Klotho proteins and isolated fragments of wildtype soluble α-Klotho protein. Also disclosed are pharmaceutical compositions including the modified soluble α-Klotho proteins and/or isolated fragments of soluble α-Klotho protein and methods of their use in treating a subject.

Soluble alpha-Klotho proteins, protein fragments, and uses thereof

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 FGF21 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 diabetes, obesity, or metabolic syndrome, and methods of screening for compounds with enhanced binding affinity for the &#x3b2;Klotho-FGF receptor complex involving the use of chimeric proteins of the present invention.

Chimeric fibroblast growth factor 21 proteins and methods of use

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 FGF19 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 diabetes, obesity, or metabolic syndrome, and methods of screening for compounds with enhanced binding affinity for the &#x3b2;Klotho-FGF receptor complex involving the use of chimeric proteins of the present invention.

Chimeric fibroblast growth factor 19 proteins and methods of use

Disclosed herein are FGF23 c-tail fusion proteins, pharmaceutical compositions comprising the FGF23 c-tail fusion proteins, and methods of treatment using the FGF23 c-tail fusion proteins. This application discloses fusion proteins comprising a FGF-23 c-tail protein fused to a heterologous amino acid sequence, wherein said fusion protein modulates serum phosphate levels but does not substantially modulate serum 1, 25 VitD levels. In some embodiments, the FGF-23 c-tail protein is fused to the heterologous amino acid sequence via a linker. This invention also encompasses vectors comprising the nucleic acids disclosed herein, and a host cell comprising the vector or polynucleotides encoding the proteins of the invention.

FGF23 c-tail fusion proteins

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 &#x3b1;Klotho-FGF receptor complex involving the use of chimeric proteins of the present invention.

Chimeric fibroblast growth factor 23 proteins and methods of use

The present invention relates to chimeric proteins that include an N-terminus coupled to a C-terminus, where the N-terminus includes an N-terminal portion of fibroblast growth factor 21 ('FGF21') and the C-terminus includes a C-terminal portion of fibroblast growth factor 19 ('FGF19'). The present invention also relates to pharmaceutical compositions including chimeric proteins according to the present invention, as well as methods for treating a subject suffering from diabetes, obesity, or metabolic syndrome, methods of treating a subject in need of increased FGF21-&#x3b2;Klotho-FGF receptor complex formation, methods of causing increased FGF21 receptor agonist-&#x3b2;Klotho-FGF receptor complex formation, and methods of screening for compounds with enhanced binding affinity for the &#x3b2;Klotho-FGF receptor complex involving the use of chimeric proteins of the present invention.

FGF21 protein with enhanced binding affinity for &#x3b2;-Klotho for the treatment of type II diabetes, obesity, and related metabolic disorders

The present invention is directed to a method of treating chronic kidney disease. This method involves selecting a subject with chronic kidney disease and administering to the selected subject an inhibitor of FGF23-Klotho-FGF receptor complex formation under conditions effective to treat the chronic kidney disease. The present invention is also directed to a method of treating or preventing chronic kidney disease symptoms and/or complications, which involves selecting a subject with a chronic kidney disease symptom and/or complication and and administering to the selected subject an inhibitor of FGF23-Klotho-FGF receptor complex formation under conditions effective to treat the chronic kidney disease.

Inhibiting binding of FGF23 to the binary FGFR-Klotho complex for the treatment of chronic kidney disease and symptoms and/or complications thereof

The present invention relates to an isolated chimeric protein. The isolated chimeric protein includes an N-terminus coupled to a C-terminus, where the N-terminus includes an N-terminal portion from a fibroblast growth factor ('FGF') 23 molecule and the C-terminus includes a C-terminal portion from an FGF19 molecule. The present invention also relates to a pharmaceutical composition including an isolated chimeric protein and a pharmaceutically acceptable carrier. The isolated chimeric protein includes an N-terminus coupled to a C-terminus, where the N-terminus includes an N-terminal portion from a fibroblast growth factor ('FGF') 23 molecule and the C-terminus includes a C-terminal portion from an FGF19 molecule, and a pharmaceutically-acceptable carrier. Yet another aspect of the present invention relates to a method for treating a subject suffering from a disorder. This method includes selecting a subject suffering from the disorder and administering to the subject a therapeutically effective amount of a chimeric protein according to the present invention.

Chimeric fibroblast growth factor 23/fibroblast growth factor 19 proteins and methods of use

Chimeric FGF21 proteins with enhanced binding affinity for &#x3b2;-klotho for the treatment of type II diabetes, obesity, and related metabolic disorders

The present invention is directed to a pharmaceuticalm composition comprising a peptide comprising at least a portion corresponding to the C-terminus of FGF23 and an additive selected from the group consisting of vitamin D and a vitamin D receptor agonist.

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Scarsdale, NY, United States of America

Moosa Mohammadi