Method of reducing the severity of stress hyperglycemia with human antibodies to the glucagon receptor

• US 8,771,696 B2
• Filed: 05/22/2013
• Issued: 07/08/2014
• Est. Priority Date: 11/23/2010
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Harp, Joyce, Okamoto, Haruka
• Primary Examiner(s): LANDSMAN, ROBERT S
• Application Number:
  US13/900,275
• Publication Number:
  US 20130251728A1
• Time in Patent Office: 412 Days
• Field of Search: None
• US Class Current: 424/143.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 39/39541 against normal tissues, cells
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07K 16/2869 against hormone receptors for antibodies against neuromediator receptors C07K16/286
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The present invention provides antibodies that bind to the human glucagon receptor, designated GCGR and methods of using same. According to certain embodiments of the invention, the antibodies are fully human antibodies that bind to human GCGR. The antibodies of the invention are useful for lowering blood glucose levels and blood ketone levels and are also useful for the treatment of diseases and disorders associated with one or more GCGR biological activities, including the treatment of diabetes, diabetic ketoacidosis, long-term complications associated with diabetes, or other metabolic disorders characterized in part by elevated blood glucose levels, including stress hyperglycemia.

Claims

1. A method of reducing the severity of stress hyperglycemia in a patient, or for treating a patient suffering from stress hyperglycemia wherein the patient exhibits elevated levels of blood glucose caused or exacerbated by one or more stress-inducing stimulus or glucose-elevating stimulus, the method comprising administering to a patient a therapeutically effective amount of a composition comprising a glucagon receptor antagonist, wherein the glucagon receptor antagonist is an isolated human monoclonal antibody, or an antigen binding fragment thereof, specific for the human glucagon receptor, and wherein the isolated human monoclonal antibody or the antigen-binding fragment thereof is capable of blocking the binding of glucagon to the glucagon receptor such that the patient'"'"'s blood glucose level is lowered.

2. The method of claim 1, wherein the patient is identified on the basis of having a blood glucose level greater than about 140 mg/dL.

3. The method of claim 1, wherein the stress-inducing stimulus or glucose elevating stimulus is selected from the group consisting of pre-existing type 1 or type 2 diabetes, hypertonic dehydration, infusion of catecholamine pressors, parenteral nutrition, enteral nutrition, glucocorticoid therapy, obesity, aging, excessive dextrose administration, pancreatitis, sepsis, stroke, traumatic head injury, hypothermia, hypoxemia, uremia, cirrhosis, anesthesia, pre-operative or post-operative hospital stays, peri-operative hyperglycemia, admission to an emergency room, a trauma center, or an intensive care unit, prolonged hospital stays, surgical procedures, an infection and a chronic illness.

4. The method of claim 1, wherein the isolated human monoclonal antibody or antigen-binding fragment thereof comprises the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR), wherein the HCVR has an amino acid sequence of SEQ ID NO:

86; and

the CDRs of a light chain variable region (LCVR), wherein the LCVR has an amino acid sequence of SEQ ID NO;

88.

5. The method of claim 4, wherein the isolated human monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO:

86.

6. The method of claim 4, wherein the isolated human monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable region (LCVR) having an amino acid sequence of SEQ ID NO:

88.

7. The method of claim 4, wherein the isolated human monoclonal antibody or antigen-binding fragment thereof comprises:

(a) a HCVR having an amino acid sequence of SEQ ID NO;

86; and

(b) a LCVR having an amino acid sequence of SEQ ID NO;

88.

8. The method of claim 4, wherein the isolated human monoclonal antibody or antigen-binding fragment thereof comprises:

(a) a HCDR1 domain having an amino acid sequence of SEQ ID NO;

72;

(b) a HCDR2 domain having an amino acid sequence of SEQ ID NO;

74;

(c) a HCDR3 domain having an amino acid sequence of SEQ ID NO;

76;

(d) a LCDR1 domain having an amino acid sequence of SEQ ID NO;

80;

(f) a LCDR2 domain having an amino acid sequence of SEQ ID NO;

82; and

(g) a LCDR3 domain having an amino acid sequence of SEQ ID NO;

84.

9. The method of claim 4, wherein the isolated human monoclonal antibody or antigen-binding fragment comprises a HCVR/LCVR sequence pair of SEQ ID NO:

86/88.

10. The method of claim 1, wherein the patient is a diabetic patient.

11. The method of claim 10, wherein the diabetic patient is a critically ill diabetic patient.

12. The method of claim 10, wherein the diabetic patient is a non-critically ill diabetic patient.

13. The method of claim 10, wherein the diabetic patient is administered one or more additional therapeutic agents selected from the group consisting of insulin, a biguanide (metformin), a sulfonylurea (glyburide, glipizide), a PPAR gamma agonist (pioglitazone, rosiglitazone), an alpha glucosidase inhibitor (acarbose, voglibose), an amylin mimetic or agonist (pramlintide), any GLP-1 compound, or an analog, an agonist, a derivative, or a secretagogue thereof, and a dipeptidyl peptidase IV inhibitor.

14. The method of claim 1, wherein the patient is a non-diabetic patient.

15. The method of claim 14, wherein the non-diabetic patient is a critically ill non-diabetic patient.

16. The method of claim 14, wherein the non-diabetic patient is a non-critically ill non-diabetic patient.

17. The method of claim 14, wherein the non-diabetic patient is administered insulin as a second therapeutic agent.

18. The method of claim 1, wherein the administering of the antibody results in lowering the blood glucose level to between about 80 mg/dL to about 140 mg/dL.

19. The method of claim 18, wherein the administering of the antibody results in lowering the blood glucose level to between about 80 mg/dL to about 110 mg/dL.

20. The method of claim 18, wherein the administering of the antibody results in lowering the blood glucose level to between about 100 mg/dL to about 140 mg/dL.

21. The method of claim 1, wherein the administering results in lowering blood glucose levels without the risk of inducing hypoglycemia.

22. The method of claim 1, wherein the composition decreases the risk for infection, organ failure, disability from stroke, arrhythmia, or death.