FGF21 protein with enhanced binding affinity for β-Klotho for the treatment of type II diabetes, obesity, and related metabolic disorders
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-βKlotho-FGF receptor complex formation, methods of causing increased FGF21 receptor agonist-βKlotho-FGF receptor complex formation, and methods of screening for compounds with enhanced binding affinity for the βKlotho-FGF receptor complex involving the use of chimeric proteins of the present invention.
1. A β-Klotho binding agent comprising:
a fibroblast growth factor 21 (FGF21) protein comprising the amino acid sequence of amino acid residues 29 to 209 of SEQ ID NO: 152.
2. The agent according to claim 1 , wherein the FGF21 protein consists of the amino acid sequence of amino acid residues 29 to 209 SEQ ID NO: 152.
3. The agent according to claim 2 , wherein the agent consists of said FGF21 protein.
4. A pharmaceutical composition comprising:
the agent of claim 1 and
a pharmaceutically-acceptable carrier.
5. The pharmaceutical composition of claim 4 further comprising:
an anti-inflammatory agent, an antifibrotic agent, an antihypertensive agent, an antidiabetic agent, a triglyceride-lowering agent, and/or a cholesterol-lowering agent.
6. A method for decreasing blood glucose level in a subject, said method comprising:
selecting a subject and
administering to said selected subject an effective amount of the agent of claim 1 to decrease blood glucose level in the selected subject.
7. The method according to claim 6 , wherein the selected subject has diabetes, obesity, or metabolic syndrome.
8. The method according to claim 7 , wherein the selected subject has diabetes.
9. The method according to claim 8 , wherein the selected subject has type II diabetes, gestational diabetes, or drug-induced diabetes.
10. The method according to claim 8 , wherein the selected subject has type I diabetes.
11. The method according to claim 7 , wherein the selected subject has obesity.
12. The method according to claim 7 , wherein the selected subject has metabolic syndrome.
13. The method according to claim 6 , wherein said administering is carried out 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.
14. The method according to claim 6 , wherein the protein is administered with a pharmaceutically-acceptable carrier.
15. The method according to claim 6 , wherein the selected subject is a mammal.
16. The method according to claim 15 , wherein the selected subject is a human.
17. A β-Klotho binding agent comprising:
a fibroblast growth factor 21 (FGF21) protein comprising the amino acid sequence of amino acid residues 29 to 209 of SEQ ID NO: 152 having a proline to valine substitution at amino acid residue 171.
18. The agent according to claim 17 , wherein the FGF21 protein consists of the amino acid sequence of amino acid residues 29 to 209 SEQ ID NO: 152 having a proline to valine substitution at amino acid residue 171.
19. The agent according to claim 18 , wherein the agent consists of said FGF21 protein.
20. A pharmaceutical composition comprising:
the agent of claim 17 and
a pharmaceutically-acceptable carrier.
21. The pharmaceutical composition of claim 20 further comprising:
an anti-inflammatory agent, an antifibrotic agent, an antihypertensive agent, an antidiabetic agent, a triglyceride-lowering agent, and/or a cholesterol-lowering agent.
22. A method for decreasing blood glucose level in a subject, said method comprising:
selecting a subject and
administering to said selected subject an effective amount of the agent of claim 17 to decrease blood glucose level in the selected subject.
23. The method according to claim 22 , wherein the selected subject has diabetes, obesity, or metabolic syndrome.
24. The method according to claim 23 , wherein the selected subject has diabetes.
25. The method according to claim 24 , wherein the selected subject has type II diabetes, gestational diabetes, or drug-induced diabetes.
26. The method according to claim 24 , wherein the selected subject has type I diabetes.
27. The method according to claim 23 , wherein the selected subject has obesity.
28. The method according to claim 23 , wherein the selected subject has metabolic syndrome.
29. The method according to claim 22 , wherein said administering is carried out 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.
30. The method according to claim 22 , wherein the protein is administered with a pharmaceutically-acceptable carrier.
31. The method according to claim 22 , wherein the selected subject is a mammal.
32. The method according to claim 31 , wherein the selected subject is a human.