FGF23 c-tail fusion proteins
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.
1. A fusion protein comprising a fibroblast growth factor 23 c-tail (FGF23 c-tail) protein fused to a heterologous amino acid sequence, wherein the FGF23 c-tail protein comprises an amino acid sequence corresponding to the sequence beginning at residue 1 and ending at any one of residues 67 to 72 of SEQ ID NO:2, wherein the heterologous amino acid sequence comprises a human IgG1 Fc domain, and wherein said fusion protein modulates serum phosphate levels but does not substantially modulate serum 1,25-dihydroxycholecalciferol (1,25 VitD) levels.
2. The fusion protein of claim 1 , wherein the FGF23 c-tail protein comprises the sequence shown in SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO: 4, SEQ ID NO:5, SEQ ID NO:6 or SEQ ID NO:7.
3. The fusion protein of claim 1 , wherein the FGF23 c-tail protein comprises the sequence shown in SEQ ID NO:2.
4. The fusion protein of claim 1 , wherein the FGF23 c-tail protein is fused to the heterologous amino acid sequence via a linker.
5. The fusion protein of claim 4 , wherein the linker is a peptidyl linker comprising a sequence selected from:
(SEQ ID NO: 10)
a. GSGEGEGSEGSG;
(SEQ ID NO: 11)
b. GGSEGEGSEGGS;
and
(SEQ ID NO: 12)
c. GGGGS.
6. The fusion protein of claim 1 , wherein the Fc domain comprises the amino acid sequence of residues 1-231 shown in SEQ ID NO:13 or residues 1-231 shown in SEQ ID NO:14.
7. The fusion protein of claim 1 comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, and SEQ ID NO:20.
8. The fusion protein of claim 7 comprising the amino acid sequence shown in SEQ ID NO:15.
9. A pharmaceutical composition comprising the fusion protein of claim 1 and a pharmaceutically acceptable agent.
10. A method of increasing serum phosphate levels in a patient in need thereof, the method comprising administering to the patient the fusion protein of claim 1 .
11. The method of claim 10 , wherein the patient has renal phosphate wasting disorder.
12. The method of claim 10 , wherein the patient has a disease or disorder selected from the group consisting of autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemic rickets (XLH), tumor-induced osteomalacia (TIO), fibrous dysplasia (FD), and chronic kidney disease (CKD).
13. The method of claim 10 , wherein the patient has left ventricular hypertrophy or hyperparathyroidism.
14. An FGF23 c-tail Fc fusion protein comprising an amino acid sequence consisting of the amino acid sequence shown in SEQ ID NO:15.