Beta klotho-binding proteins and methods of use thereof
The present disclosure provides binding proteins, such as antibodies, that bind beta klotho, including human beta klotho, and methods of their use.
1. A method of reducing blood glucose levels in a subject comprising administering to the subject an effective amount of an antibody or binding fragment thereof that binds human beta klotho, wherein the antibody or binding fragment comprises:
(a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3; and
(b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:6.
2. The method of claim 1 , wherein the heavy chain variable region comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:271 and the light chain variable region comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:276.
3. The method of claim 2 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:271 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:276.
4. The method of claim 1 , wherein the antibody or binding fragment thereof is a monoclonal antibody.
5. The method of claim 1 , wherein the antibody or binding fragment thereof is a humanized antibody.
6. The method of claim 1 , wherein the subject has Type 2 diabetes, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), obesity, dyslipidemia, cardiovascular disease, and/or metabolic syndrome.
7. The method of claim 1 , wherein the method comprises administering at least one additional therapeutic agent.
8. The method of claim 7 , wherein the at least one additional therapeutic agent is selected from the group consisting of: biguanides, sulphonylureas, thiazolidinediones, GLP-1 analogs, PPAR gamma agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, bromocriptine, bile acid sequestrants, insulin, alpha glucosidase inhibitors, metformin, SGLT-2 inhibitors, appetite suppressants, and weight loss drugs.
9. The method of claim 1 , wherein the antibody is an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody.
10. The method of claim 1 , wherein the subject is human.
11. A method of reducing blood glucose levels in a subject, comprising administering to the subject an effective amount of an antibody that binds human beta klotho, wherein the antibody comprises a heavy chain comprising amino acids 23-472 of SEQ ID NO:317 and a light chain comprising amino acids 23-240 of SEQ ID NO:319.
12. The method of claim 11 , wherein the subject has Type 2 diabetes, NASH, NAFLD, obesity, dyslipidemia, cardiovascular disease, and/or metabolic syndrome.
13. The method of claim 11 , wherein the subject is human.
14. The method of claim 11 , wherein the method comprises administering at least one additional therapeutic agent.
15. The method of claim 14 , wherein the at least one additional therapeutic agent is selected from the group consisting of: biguanides, sulphonylureas, thiazolidinediones, GLP-1 analogs, PPAR gamma agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, bromocriptine, bile acid sequestrants, insulin, alpha glucosidase inhibitors, metformin, SGLT-2 inhibitors, appetite suppressants, and weight loss drugs.
16. A method of treating Type 2 diabetes in a subject, comprising administering to the subject an effective amount of an antibody or binding fragment thereof that binds human beta klotho, wherein the antibody or binding fragment comprises:
(a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3; and
(b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:6.
17. The method of claim 16 , wherein the heavy chain variable region comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:271 and the light chain variable region comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:276.
18. The method of claim 16 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:271 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:276.
19. The method of claim 16 , wherein the antibody or binding fragment thereof is a monoclonal antibody.
20. The method of claim 16 , wherein the antibody or binding fragment thereof is a humanized antibody.
21. The method of claim 16 , wherein the method comprises administering at least one additional therapeutic agent.
22. The method of claim 21 , wherein the at least one additional therapeutic agent is selected from the group consisting of: biguanides, sulphonylureas, thiazolidinediones, GLP-1 analogues, PPAR gamma agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, bromocriptine, bile acid sequestrants, insulin, alpha glucosidase inhibitors, metformin, SGLT-2 inhibitors, appetite suppressants, and weight loss drugs.
23. The method of claim 16 , wherein the antibody is an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody.
24. The method of claim 16 , wherein the subject is human.
25. A method of treating Type 2 diabetes in a subject, comprising administering to the subject an effective amount of an antibody that binds human beta klotho, wherein the antibody comprises a heavy chain comprising amino acids 23-472 of SEQ ID NO:317 and a light chain comprising amino acids 23-240 of SEQ ID NO:319.
26. The method of claim 25 , wherein the subject is human.
27. The method of claim 25 , wherein the method comprises administering at least one additional therapeutic agent.
28. The method of claim 27 , wherein the at least one additional therapeutic agent is selected from the group consisting of: biguanides, sulphonylureas, thiazolidinediones, GLP-1 analogs, PPAR gamma agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, bromocriptine, bile acid sequestrants, insulin, alpha glucosidase inhibitors, metformin, SGLT-2 inhibitors, appetite suppressants, and weight loss drugs.