Treatment of steroid-induced hyperglycemia with fibroblast growth factor (FGF) 1 analogs

Patent metadata

Field	Value
Publication number	US-10695404-B2
Application number	US-201815952516-A
Country	US
Kind code	B2
Filing date	Apr 13, 2018
Priority date	Oct 30, 2015
Publication date	Jun 30, 2020
Grant date	Jun 30, 2020

Abstract

Methods of using FGF1 analogs, such as FGF1 mutant proteins having an N-terminal deletion, point mutation(s), or combinations thereof, to reduce blood glucose levels in subjects with steroid-induced diabetes, hypercortisolemia, or diabetes due to treatment with an antipsychotic agent, are provided. Such mutant FGF1 proteins can be part of a chimeric protein that includes a β-Klotho-binding protein, an FGFR1-binding protein, a β-Klotho-binding protein and a FGFR1-binding protein, a C-terminal region from FGF19 or FGF21.

First claim

We claim:

1. A composition comprising:
(1) a mutant mature FGF1 protein, comprising:
at least 95% sequence identity to SEQ ID NO: 217; and
amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5, and

(2) a pharmaceutically acceptable carrier.

2. The composition of claim 1 , further comprising
a chemotherapy, a biologic, or combinations thereof; or
an antipsychotic agent.

3. The composition of claim 2 , wherein the composition comprises an antipsychotic agent.

4. The composition of claim 3 , wherein the antipsychotic agent is quetiapine, an olanzapine-fluoxetine combination, a phenothiazine or clozapine.

5. The composition of claim 2 , wherein the composition comprises a biologic.

6. The composition of claim 5 , wherein the biologic is a monoclonal antibody.

7. The composition of claim 1 , further comprising a glucocorticoid.

8. The composition of claim 7 , wherein the glucocorticoid is one or more of dexamethasone, prednisolone, hydrocortisone, cortisone, methylprednisolone, betamethasone, triamcinolone, and beclometasone.

9. The composition of claim 1 , wherein the mutant mature FGF1 protein comprises at least 96% sequence identity to SEQ ID NO: 217 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.

10. The composition of claim 1 , wherein the mutant mature FGF1 protein comprises at least 97% sequence identity to SEQ ID NO: 217 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.

11. The composition of claim 1 , wherein the mutant mature FGF1 protein comprises at least 98% sequence identity to SEQ ID NO: 217 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.

12. The composition of claim 1 , wherein the mutant mature FGF1 protein comprises at least 99% sequence identity to SEQ ID NO: 217 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.

13. The composition of claim 1 , wherein the mutant mature FGF1 protein comprises of SEQ ID NO: 217.

14. The composition of claim 1 , wherein the mutant mature FGF1 protein consists of SEQ ID NO: 217.

15. A composition comprising:
(1) a mutant mature FGF1 protein, comprising:
at least 95% sequence identity to SEQ ID NO: 218; and
amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5, and

(2) a pharmaceutically acceptable carrier.

16. The composition of claim 15 , further comprising
a chemotherapy, a biologic, or combinations thereof; or
an antipsychotic agent.

17. The composition of claim 16 , wherein the composition comprises an antipsychotic agent.

18. The composition of claim 17 , wherein the antipsychotic agent is quetiapine, an olanzapine-fluoxetine combination, a phenothiazine or clozapine.

19. The composition of claim 16 , wherein the composition comprises a biologic.

20. The composition of claim 19 , wherein the biologic is a monoclonal antibody.

21. The composition of claim 15 , further comprising a glucocorticoid.

22. The composition of claim 21 , wherein the glucocorticoid is one or more of dexamethasone, prednisolone, hydrocortisone, cortisone, methylprednisolone, betamethasone, triamcinolone, and beclometasone.

23. The composition of claim 15 , wherein the mutant mature FGF1 protein comprises at least 96% sequence identity to SEQ ID NO: 218 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.

24. The composition of claim 15 , wherein the mutant mature FGF1 protein comprises at least 97% sequence identity to SEQ ID NO: 218 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.

25. The composition of claim 15 , wherein the mutant mature FGF1 protein comprises at least 98% sequence identity to SEQ ID NO: 218 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.

26. The composition of claim 15 , wherein the mutant mature FGF1 protein comprises at least 99% sequence identity to SEQ ID NO: 218 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.

27. The composition of claim 15 , wherein the mutant mature FGF1 protein comprises of SEQ ID NO: 218.

28. The composition of claim 15 , wherein the mutant mature FGF1 protein consists of SEQ ID NO: 218.

Assignees

• Salk Inst For Biological Studi

Inventors

• Evans Ronald M
• Downes Michael
• Atkins Annette
• Yu Ruth T

Classifications

• C07K14/501

  acidic FGF [aFGF] · CPC title

• C07K2319/70

  containing domain for protein-protein interaction · CPC title

• C07K14/50

  Fibroblast growth factor [FGF] · CPC title

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title