Antibodies that modulate insulin receptor signaling are provided.
1. An IgG antibody that binds insulin receptor with an affinity of 10 −7 M or less, and that comprises
(a) a first heavy chain CDR, a second heavy chain CDR, and a third heavy chain CDR set out in SEQ ID NO: 195, and
(b) a first light chain CDR, a second light chain CDR, and a third light chain CDR set out in SEQ ID NO: 77.
2. An IgG antibody that binds insulin receptor and that comprises a heavy chain variable region of SEQ ID NO: 195 and a light chain variable region of SEQ ID NO: 77.
3. The antibody of claim 1 or 2 , wherein the antibody binds to insulin receptor with an affinity of 10 −8 M or less.
4. The antibody of claim 1 or 2 , wherein the IgG is a human IgG1 or IgG3 heavy chain constant region.
5. The antibody of claim 1 or 2 , wherein the IgG is a human IgG2 or IgG4 heavy chain constant region.
6. The antibody of claim 1 or 2 , further comprising a human light chain constant region.
7. The antibody of claim 1 or 2 , wherein the antibody reduces fasting blood glucose levels in a subject having elevated blood glucose toward normal glucose levels.
8. The antibody of claim 1 or 2 , wherein said antibody is a human antibody.
9. A method of treating hyperglycemia, comprising administering an antibody of claim 1 or 2 in an amount effective to treat hyperglycemia.
10. A method for reducing blood glucose levels in a subject comprising administering an antibody of claim 1 or 2 in an amount effective to reduce blood glucose levels.
11. A method of preparing a sterile pharmaceutical composition, comprising adding a sterile pharmaceutically acceptable diluent to an antibody of claim 1 or 2 .
12. A sterile composition comprising the antibody of claim 1 or 2 and a sterile pharmaceutically acceptable diluent.
13. A method of treating diabetes, comprising administering an antibody of claim 1 or 2 in an amount effective to treat diabetes.
14. The method of claim 13 , wherein the diabetes is Type 1 diabetes or Type 2 diabetes mellitus.
15. The method of claim 14 , wherein the treatment reduces blood glucose levels.
16. The method of claim 14 , wherein the treatment results in a decrease in HbA1c levels compared to an untreated subject.
17. The method of claim 13 , wherein the treatment results in an improved glucose tolerance test, or reduced 2-hour glucose level during a glucose tolerance test.
18. The method of claim 13 , wherein the treatment results in an improvement in a symptom associated with diabetes selected from the group consisting of dyslipidemia, plasma triglycerides, HOMA-IR, plasma unesterified cholesterol, plasma total cholesterol, plasma insulin, non-HDL/HDL cholesterol ratio, total/HDL cholesterol ratio, beta cell function and plasma leptin levels.
19. The method of claim 13 , wherein the disorder is Type 1 diabetes.
20. The method of claim 13 , wherein the disorder is Type 2 diabetes mellitus.