Antibody Fragments Against the Insulin Receptor and Uses Thereof to Treat Hypoglycemia

1 . An antibody or fragment thereof comprising three heavy chain CDRs having the amino acid sequence set out in SEQ ID NOs: 5-7, 8-10 and 50-112 and three light chain CDRs have the amino acid sequences set out in SEQ ID NOs: 14-16 or SEQ ID NOs: 20-28 wherein the antibody or fragment thereof binds to i) insulin receptor or (ii) a complex comprising insulin and insulin receptor, or both (i) and (ii).

2 . An antibody or fragment thereof of claim 1 wherein the heavy chain variable region amino acid sequence is set out in SEQ ID NOs: 1, 2 or 29-49, and the light chain variable region amino acid sequence is set out in SEQ ID NOs: 4 or 17-19.

3 . An antibody or fragment thereof comprising three heavy chain CDRs having the amino acid sequence set out in SEQ ID NOs: 8-10 and three light chain CDRs have the amino acid sequences set out in SEQ ID NOs: 14-16, wherein the antibody or fragment thereof binds to i) insulin receptor or (ii) a complex comprising insulin and insulin receptor, or both (i) and (ii).

4 . The antibody or fragment thereof of claim 3 wherein the heavy chain variable region amino acid sequence is set out in SEQ ID NO: 2 and the light chain variable region amino acid sequence is set out in SEQ ID NO: 4.

5 . An antibody fragment comprising three heavy chain CDRs having the amino acid sequences set out in SEQ ID NOs: 5-7 or 8-10 and three light chain CDRs having the amino acid sequences set out in SEQ ID NOs: 11-13 or 14-16, wherein the antibody fragment binds to i) insulin receptor or (ii) a complex comprising insulin and insulin receptor, or both (i) and (ii).

6 . The antibody fragment of claim 3 wherein the heavy chain variable region amino acid sequence is set out in SEQ ID NO: 1 or 2 and the light chain variable region amino acid sequence is set out in SEQ ID NO: 3 or 4.

7 . The antibody fragment of claim 5 wherein the three heavy chain CDRs have the amino acid sequences set out in SEQ ID NOs: 8-10 and three light chain CDRs have the amino acid sequences set out in SEQ ID NOs: 14-16.

8 . The antibody fragment of claim 5 wherein the heavy chain variable region amino acid sequence is set out in SEQ ID NO: 2 and the light chain variable region amino acid sequences is set out in SEQ ID NO: 4.

9 . The antibody fragment of claim 1 which is a Fab fragment.

10 . The antibody fragment of claim 1 wherein the antibody or antibody fragment binds to (i) insulin receptor or (ii) a complex comprising insulin and insulin receptor, or both (i) and (ii), with an equilibrium dissociation constant KD of 10-5M or less that is capable of weakening the binding affinity between insulin and insulin receptor by at least about 1.5-fold, optionally up to 1000-fold.

11 . (canceled)

12 . The antibody or antibody fragment of claim 1 , wherein the antibody increases the EC50 of insulin signaling activity by about 2-fold to 1000-fold, optionally in a pAKT assay.

13 . (canceled)

14 . The antibody or antibody fragment of claim 1 , wherein said antibody is a human antibody.

15 . (canceled)

16 . A method of preparing a sterile pharmaceutical composition, comprising adding a sterile pharmaceutically acceptable diluent to an antibody of claim 1 .

17 . A sterile composition comprising the antibody of claim 1 and a sterile pharmaceutically acceptable diluent.

18 . A method of treating hypoglycemia, comprising administering to a subject in need thereof an antibody fragment according to claim 1 that is a negative modulator of insulin binding to the insulin receptor and/or insulin action at the insulin receptor in an amount effective to ameliorate hypoglycemia.

19 . The method of claim 18 , wherein the hypoglycemia is selected from the group consisting of sulfonylurea-induced hypoglycemia, insulin-induced hypoglycemia, nocturnal hypoglycemia, hypoglycemia following post-bariatric surgery, and hypoglycemia in subjects with inherited metabolic and insulin sensitivity disorders.

20 . A method for treating or preventing nocturnal hypoglycemia comprising administering to a subject in need thereof an antibody fragment according to claim 1 that is a negative modulator of insulin binding to the insulin receptor and/or insulin action at the insulin receptor in an amount effective to ameliorate nocturnal hypoglycemia.

21 . The method of claim 18 , wherein the antibody fragment binds to (i) insulin receptor or (ii) a complex comprising insulin and insulin receptor, or both (i) and (ii), with an equilibrium dissociation constant KD of 10-5 M or less that is capable of weakening the binding affinity between insulin and insulin receptor by at least about 1.5-fold, optionally up to 1000-fold.

22 . The method of claim 21 , wherein the antibody fragment increases the EC50 of insulin signaling activity by about 2-fold to 1000-fold, optionally in a pAKT assay.

23 . The method of claim 18 wherein the antibody fragment comprises three heavy chain CDRs set out in SEQ ID NOs: 5-7, 8-10 or 50-112 and three light chain CDRs set out in SEQ ID NOs: 11-13, 14-16 or 20-28.

24 . (canceled)

25 . The method of claim 18 , wherein the antibody fragment comprises a heavy chain variable region selected from the group consisting of SEQ ID NO: 1 or 2 and a light chain variable region selected from the group consisting of SEQ ID NO: 3 or 4.

26 . The method of claim 18 wherein the antibody fragment comprises three heavy chain CDRs set out in SEQ ID NO: 8-10 and three light chain CDRs set out in SEQ ID NO: 14-16.

27 . The method of claim 18 , wherein the antibody fragment comprises a variable heavy chain amino acid sequence set out in SEQ ID NO: 2 and variable light chain amino acid sequence set out in SEQ ID NO: 4.

28 . (canceled)

29 . The method of claim 18 , wherein the antibody fragment is from a human antibody.

30 . The method of claim 18 , wherein the antibody fragment is a Fab fragment.

31 . (canceled)

32 . The method of claim 18 , wherein the antibody fragment is in a pharmaceutical composition.

33 . The method of claim 18 , wherein the antibody fragment reduces hyperinsulinemia or excess insulin signaling in the subject.

34 . The method of claim 18 , wherein the subject has a blood glucose level of less than 70 mg/dL prior to administration.

35 . The method of claim 18 , wherein the antibody fragment is administered at a dose of from about 0.1 to 25 mg/kg, from about 0.05 to 10 mg/kg, from about 0.3 to 6.0 mg/kg, or from about 0.1 to 3 mg/kg.

36 . (canceled)

37 . The method of claim 18 , wherein the antibody fragment is administered in a single bolus, once every 12 hours or once per day, until hypoglycemia is eliminated.

38 . The method of claim 18 , wherein the antibody is administered intravenously, intraarterially, intraperitoneally, intramuscularly, intradermally, subcutaneously or orally.

39 . The method of claim 18 , wherein administration increases blood glucose in the subject by 1.5 to 10 fold or by 10 to 40%, optionally wherein administration increases blood glucose in the subject by at least 10 mg/dL.

40 . (canceled)

41 . The method of claim 18 , wherein the subject is also on a restricted diet regimen.

42 . The method of claim 18 , further comprising administering a second agent, optionally wherein the second agent is glucagon and/or insulin.

43 . The method of claim 18 , wherein the administration prevents or ameliorates one or more symptoms of hypoglycemia selected from the group consisting of pancreatic nesidioblastosis, islet cell enlargement, islet cell hyperplasia, β cell budding, tachycardia, diaphoresis, flushing and reduced cognitive function.

44 . The method of claim 18 , wherein the administration reduces or eliminates hypoglycemia within 20 minutes, optionally within 15 minutes.

45 . The method of claim 18 , wherein the antibody fragment has a duration of action of approximately 4 hours.

46 . The method of claim 18 , wherein the subject is non-responsive to dextrose or glucagon therapy.