Method of treating type I diabetes by administering a combination of a glucagon receptor antagonist and an anti-CD3 antibody
The present disclosure provides methods comprising a glucagon receptor antagonist in combination with an immunotherapeutic agent for treatment of disease.
1. A method of treating Type 1 diabetes in a human subject, the method comprising administering to the human subject a therapeutically effective amount of a glucagon receptor (GCGR) antagonist and a therapeutically effective amount of an immunotherapeutic agent, wherein the GCGR antagonist is an antibody that specifically binds human GCGR and wherein the immunotherapeutic agent is an anti-CD3 antibody.
2. The method of claim 1 , wherein the Type 1 diabetes is latent autoimmune diabetes of adults (LADA).
3. The method of claim 1 , wherein the antibody that specifically binds human GCGR comprises:
(a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFTNHWLG (SEQ ID NO:6), a heavy chain variable region CDR2 comprising the amino acid sequence DIYPGGYYINYNEKFKG (SEQ ID NO:7), and a heavy chain variable region CDR3 comprising the amino acid sequence HTNYGSDY (SEQ ID NO:8); and
(b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence RSSQSIVDSYGNTFLE (SEQ ID NO:9), a light chain variable region CDR2 comprising the amino acid sequence KVSNRLS (SEQ ID NO:10), and a light chain variable region CDR3 comprising the amino acid sequence FQGSHVPWT (SEQ ID NO:11).
4. The method of claim 3 , wherein:
(a) the heavy chain variable region of the antibody that specifically binds human GCGR comprises a sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:14; and/or
(b) the light chain variable region of the antibody that specifically binds human GCGR comprises a sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:15.
5. The method of claim 3 , wherein the heavy chain variable region of the antibody that specifically binds human GCGR comprises the amino acid sequence of SEQ ID NO:14 and the light chain variable region of the antibody that specifically binds human GCGR comprises the amino acid sequence of SEQ ID NO:15.
6. The method of claim 1 , wherein the antibody that specifically binds human GCGR comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:79 and a light chain comprising the amino acid sequence of SEQ ID NO:81.
7. The method of claim 3 , wherein the antibody that specifically binds human GCGR is a monoclonal antibody.
8. The method of claim 3 , wherein the antibody that specifically binds human GCGR is a humanized antibody.
9. The method of claim 3 , wherein the antibody that specifically binds human GCGR is an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody.
10. The method of claim 1 , wherein the treatment method:
(i) reduces blood glucose levels in the human subject;
(ii) increases C-peptide levels in the blood in the human subject;
(iii) increases C-peptide levels in the pancreas in the human subject;
(iv) reduces HbA1c in the blood in the human subject; and/or
(v) reduces supplemental insulin use by the human subject.
11. The method of claim 1 , which comprises administering at least one additional therapeutic agent to the human subject.
12. The method of claim 11 , wherein the at least one additional therapeutic agent is a diabetes or hyperglycemia drug.
13. The method of claim 11 , wherein the at least one additional therapeutic agent is an obesity drug, an appetite suppressant, or a weight loss drug.
14. The method of claim 3 , wherein the anti-CD3 antibody is a monoclonal antibody.
15. The method of claim 3 , wherein the anti-CD3 antibody is a humanized antibody.
16. The method of claim 3 , wherein the anti-CD3 antibody is an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody.
17. A method of improving beta cell function in a human subject, the method comprising administering to the human subject a therapeutically effective amount of a glucagon receptor (GCGR) antagonist and a therapeutically effective amount of an immunotherapeutic agent, wherein the GCGR antagonist is an antibody that specifically binds human GCGR and wherein the immunotherapeutic agent is an anti-CD3 antibody.
18. The method of claim 17 , wherein the improvement in beta cell function is indicated by:
(i) a reduction in blood glucose levels in the human subject;
(ii) an increase in C-peptide levels in the blood in the human subject;
(iii) an increase in C-peptide levels in the pancreas in the human subject;
(iv) a reduction of HbA1c in the blood in the human subject; and/or
(v) a reduction in supplemental insulin usage by the human subject.
19. The method of claim 17 , wherein the antibody that specifically binds human GCGR comprises:
(a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFTNHWLG (SEQ ID NO:6), a heavy chain variable region CDR2 comprising the amino acid sequence DIYPGGYYINYNEKFKG (SEQ ID NO:7), and a heavy chain variable region CDR3 comprising the amino acid sequence HTNYGSDY (SEQ ID NO:8); and
(b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence RSSQSIVDSYGNTFLE (SEQ ID NO:9), a light chain variable region CDR2 comprising the amino acid sequence KVSNRLS (SEQ ID NO:10), and a light chain variable region CDR3 comprising the amino acid sequence FQGSHVPWT (SEQ ID NO:11).
20. The method of claim 19 , wherein:
(a) the heavy chain variable region of the antibody that specifically binds human GCGR comprises a sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:14; and/or
(b) the light chain variable region of the antibody that specifically binds human GCGR comprises a sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:15.
21. The method of claim 19 , wherein the heavy chain variable region of the antibody that specifically binds human GCGR comprises the amino acid sequence of SEQ ID NO:14 and the light chain variable region of the antibody that specifically binds human GCGR comprises the amino acid sequence of SEQ ID NO:15.
22. The method of claim 17 , wherein the antibody that specifically binds human GCGR comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:79 and a light chain comprising the amino acid sequence of SEQ ID NO:81.
23. The method of claim 19 , wherein the antibody that specifically binds human GCGR is a monoclonal antibody.
24. The method of claim 19 , wherein the antibody that specifically binds human GCGR is a humanized antibody.
25. The method of claim 19 , wherein the antibody that specifically binds human GCGR is an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody.
26. The method of claim 17 , which comprises administering at least one additional therapeutic agent to the human subject.
27. The method of claim 26 , wherein the at least one additional therapeutic agent is a diabetes or hyperglycemia drug.
28. The method of claim 26 , wherein the at least one additional therapeutic agent is an obesity drug, an appetite suppressant, or a weight loss drug.
29. The method of claim 19 , wherein the anti-CD3 antibody is a monoclonal antibody.
30. The method of claim 19 , wherein the anti-CD3 antibody is a humanized antibody.
31. The method of claim 19 , wherein the anti-CD3 antibody is an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody.