Inhibiting binding of FGF23 to the binary FGFR-Klotho complex for the treatment of hypophosphatemia

• US 8,889,621 B2
• Filed: 10/29/2010
• Issued: 11/18/2014
• Est. Priority Date: 10/30/2009
• Status: Active Grant

• Current Assignee: New York University
• Original Assignee: New York University
• Inventors: Mohammadi, Moosa, Goetz, Regina, Eliseenkova, Anna V.
• Primary Examiner(s): Saoud, Christine J
• Application Number:
  US12/915,801
• Publication Number:
  US 20110190207A1
• Time in Patent Office: 1,481 Days
• Field of Search: None
• US Class Current: 514/9.1
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: G01N 21/84 Systems specially adapted for particular applications
• CPC Class Codes: G01N 30/00 Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation G01N3/00, G01N5/00, G01N7/00, G01N9/00, G01N11/00, G01N13/00, G01N15/00, G01N17/00, G01N19/00, G01N21/00, G01N22/00, G01N23/00, G01N24/00, G01N25/00, G01N27/00, G01N29/00 take precedence
• CPC Class Codes: G01N 33/573 for enzymes or isoenzymes
• CPC Class Codes: G01N 33/68 involving proteins, peptides or amino acids involving lipoproteins G01N33/92

Abstract

The present invention is directed to a method of treating hypophosphatemia in a subject. This method involves selecting a subject with hypophosphatemia associated with elevated or normal FGF23 and administering to the selected subject an inhibitor of FGF23-Klotho-FGF receptor complex formation under conditions effective to treat the hypophosphatemia.

Claims

1. A method of treating hypophosphatemia in a subject, said method comprising:

selecting a subject with hypophosphatemia associated with elevated or normal FGF23 and

administering to the selected subject an inhibitor of FGF23-Klotho-FGF receptor ternary complex formation under conditions effective to treat the hypophosphatemia, wherein the inhibitor is a peptide consisting of the amino acid sequence of SEQ ID NO;

12 or amino acid residues 1 to 21 of SEQ ID NO;

11.

2. The method according to claim 1, wherein Klotho has the amino acid sequence of SEQ ID NO:

7.

3. The method according to claim 1, wherein the FGF23 has the amino acid sequence of SEQ ID NO:

3.

4. The method according to claim 1, wherein the FGF receptor has the amino acid sequence of SEQ ID NO:

9.

5. The method according to claim 1, wherein said administering is carried out orally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by implantation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, transdermally, or by application to mucous membranes.

6. The method according to claim 1, wherein the inhibitor is administered with a pharmaceutically-acceptable carrier.

7. The method according to claim 1, wherein the subject is a mammal.

8. The method according to claim 7, wherein the subject is a human.

9. The method according to claim 1, wherein the hypophosphatemia is due to autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemia (XLH), autosomal recessive hypophosphatemic rickets (ARHR), fibrous dysplasia (FD), McCune-Albright syndrome complicated by fibrous dysplasia (MAS/FD), Jansen'"'"'s metaphyseal chondrodysplasia (Jansen'"'"'s Syndrome), tumor-induced osteomalacia (TIO), autosomal dominant polycystic kidney disease (ADPKD), chronic metabolic acidosis, or any other inherited or acquired renal phosphate wasting disorder.

10. The method according to claim 1, wherein the hypophosphatemia is due to alcoholic and diabetic ketoacidosis, acute asthma, chronic obstructive pulmonary disease, drug treatment of asthma, drug treatment of chronic obstructive pulmonary disease, mechanical ventilation, sepsis, recovery from kidney transplantation, parenteral iron administration, salicylate intoxication, severe trauma, chronic treatment with sucralfate and/or antacids, refeeding syndrome, or an eating disorder.

11. The method according to claim 1, wherein the hypophosphatemia is due to anorexia nervosa or bulimia nervosa.

12. The method according to claim 1, wherein the inhibitor is the peptide consisting of the amino acid sequence of SEQ ID NO:

12.

13. The method according to claim 1, wherein the inhibitor is the peptide consisting of the amino acid sequence of amino acid residues 1 to 21 of SEQ ID NO:

11.

14. A method of treating hypophosphatemia in a subject, said method comprising:

selecting a subject with hypophosphatemia associated with elevated or normal FGF23 and

administering to the selected subject an inhibitor of FGF23-Klotho-FGF receptor ternary complex formation under conditions effective to treat the hypophosphatemia, wherein the inhibitor comprises an FGF23 C-terminal fragment consisting of the amino acid sequence of SEQ ID NO;

12 or amino acid residues 1 to 21 of SEQ ID NO;

11.

15. The method according to claim 14, wherein Klotho has the amino acid sequence of SEQ ID NO:

7.

16. The method according to claim 14, wherein the FGF23 has the amino acid sequence of SEQ ID NO:

3.

17. The method according to claim 14, wherein the FGF receptor has the amino acid sequence of SEQ ID NO:

9.

18. The method according to claim 14, wherein said administering is carried out orally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by implantation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, transdermally, or by application to mucous membranes.

19. The method according to claim 14, wherein the inhibitor is administered with a pharmaceutically-acceptable carrier.

20. The method according to claim 14, wherein the subject is a mammal.

21. The method according to claim 20, wherein the subject is a human.

22. The method according to claim 14, wherein the hypophosphatemia is due to autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemia (XLH), autosomal recessive hypophosphatemic rickets (ARHR), fibrous dysplasia (FD), McCune-Albright syndrome complicated by fibrous dysplasia (MAS/FD), Jansen'"'"'s metaphyseal chondrodysplasia (Jansen'"'"'s Syndrome), tumor-induced osteomalacia (TIO), autosomal dominant polycystic kidney disease (ADPKD), chronic metabolic acidosis, or any other inherited or acquired renal phosphate wasting disorder.

23. The method according to claim 14, wherein the hypophosphatemia is due to alcoholic and diabetic ketoacidosis, acute asthma, chronic obstructive pulmonary disease, drug treatment of asthma, drug treatment of chronic obstructive pulmonary disease, mechanical ventilation, sepsis, recovery from kidney transplantation, parenteral iron administration, salicylate intoxication, severe trauma, chronic treatment with sucralfate and/or antacids, refeeding syndrome, or an eating disorder.

24. The method according to claim 14, wherein the hypophosphatemia is due to anorexia nervosa or bulimia nervosa.

25. The method according to claim 14, wherein the FGF23 C-terminal fragment consists of the amino acid sequence of SEQ ID NO:

12.

26. The method according to claim 14, wherein the FGF23 C-terminal fragment consists of the amino acid sequence of amino acid residues 1 to 21 of SEQ ID NO:

11.