Human antibodies to the glucagon receptor and methods of use thereof

• US 9,587,029 B2
• Filed: 08/07/2015
• Issued: 03/07/2017
• Est. Priority Date: 11/23/2010
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Okamoto, Haruka, Sleeman, Mark, Harp, Joyce
• Primary Examiner(s): LANDSMAN, ROBERT S
• Application Number:
  US14/821,652
• Publication Number:
  US 20150337045A1
• Time in Patent Office: 578 Days
• US Class Current: 1/1
• 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 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: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/12 for cataracts
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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 16/468 : Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/30 : characterized by aspects of specificity or valency
• CPC Class Codes: C07K 2317/31 : multispecific
• 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
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: C12N 15/1137 : against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 15/64 : General methods for preparing the vector, for introducing it into the cell or for selecting the vector-containing host
• CPC Class Codes: C12N 15/70 : Vectors or expression systems specially adapted for E. coli
• CPC Class Codes: C12N 2310/11 : Antisense
• CPC Class Codes: C12N 2310/14 : interfering N.A.
• CPC Class Codes: C12N 2320/31 : Combination therapy

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 and long-term complications associated with diabetes, or other metabolic disorders characterized in part by elevated blood glucose levels.

Claims

1. An isolated human antibody or antigen-binding fragment thereof that specifically binds human glucagon receptor (hGCGR), comprising the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR), wherein the HCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs:

2, 18, 34, 50, 66, 70, 90, 106, 110, 126, 130 and 146; and

the CDRs of a light chain variable region (LCVR), wherein the LCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs;

10, 26, 42, 58, 68, 78, 98, 108, 118, 128, 138 and 148.

2. The isolated antibody or antigen-binding fragment thereof of claim 1, comprising a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NO:

2, 18, 34, 50, 66, 70, 90, 106, 110, 126, 130 and 146.

3. The isolated antibody or antigen-binding fragment thereof of claim 1, comprising a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NO:

10, 26, 42, 58, 68, 78, 98, 108, 118, 128, 138 and 148.

4. The isolated human antibody or antigen-binding fragment thereof of claim 1, comprising:

(a) a HCVR having an amino acid sequence selected from the group consisting of SEQ ID NO;

2, 18, 34, 50, 66, 70, 90, 106, 110, 126, 130 and 146; and

(b) a LCVR having an amino acid sequence selected from the group consisting of SEQ ID NO;

10, 26, 42, 58, 68, 78, 98, 108, 118, 128, 138 and 148.

5. The isolated antibody or antigen-binding fragment thereof of claim 1, comprising:

(a) a HCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NO;

4, 20, 36, 52, 92, 112 and 132;

(b) a HCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NO;

6, 22, 38, 54, 94, 114 and 134;

(c) a HCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs;

8, 24, 40, 56, 96, 116 and 136;

(d) a LCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NO;

12, 28, 44, 60, 100, 120 and 140;

(f) a LCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NO;

14, 30, 46, 62, 102, 122 and 142; and

(g) a LCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NO;

16, 32, 48, 64, 104, 124 and 144.

6. The isolated antibody or antigen-binding fragment of claim 1, comprising a HCVR/LCVR sequence pair selected from the group consisting of SEQ ID NO:

2/10, 18/26, 34/42, 50/58, 66/68, 70/78, 90/98, 106/108, 110/118, 126/128, 130/138, and 146/148.

7. The isolated antibody or antigen-binding fragment of claim 6, comprising a HCVR/LCVR sequence pair selected from the group consisting of SEQ ID NO:

34/42, 70/78, 110/118 and 126/128.

9. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier or diluent.

10. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof of claim 1, and a second therapeutic agent comprising an isolated antibody, or an antigen-binding fragment thereof, that specifically binds to PCSK9, and a pharmaceutically acceptable carrier or diluent.

11. A method for lowering blood glucose or ketone levels, or for treating a condition or disease associated with, or characterized in part by high blood glucose or ketone levels, or at least one symptom or complication associated with the condition or disease, the method comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 9, to a patient in need thereof, such that blood glucose or ketone levels are lowered or that the condition or disease is mediated, or at least one symptom or complication associated with the condition or disease is alleviated or reduced in severity.

12. The method of claim 11, wherein the condition or disease is selected from the group consisting of diabetes, impaired glucose tolerance, obesity, nephropathy, neuropathy, retinopathy, cataracts, stroke, atherosclerosis, impaired wound healing, diabetic ketoacidosis, hyperglycemia, hyperglycemic hyperosmolar syndrome, perioperative hyperglycemia, hyperglycemia in the intensive care unit patient, hyperinsulinemia, the metabolic syndrome, insulin resistance syndrome and impaired fasting glucose.

13. The method of claim 11, wherein the pharmaceutical composition is administered to the patient in combination with a second therapeutic agent.

14. The method of claim 13, wherein the second therapeutic agent is 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, glucagon-like peptide 1, pramlintide, a glucagon antagonist, and a second GCGR antagonist.

15. The method of claim 13, wherein the second therapeutic agent is a nucleic acid that inhibits the activity of PCSK9 and is selected from an anti-sense molecule, a double stranded RNA, or an siRNA.

16. The method of claim 13, wherein the second therapeutic agent is a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) inhibitor.

17. The method of claim 16, wherein the HMG-CoA reductase inhibitor is a statin selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.

18. The method of claim 13, wherein the second therapeutic agent is an isolated antibody, or an antigen-binding fragment thereof, that specifically binds to human proprotein convertase subtilisin/kexin type 9 (PCSK9).

19. The method of claim 13, wherein the second therapeutic agent is an inhibitor of angiopoietin-like protein 3, and inhibitor of angiopoietin-like protein 4, angiopoietin-like protein 5, or angiopoietin-like protein 6.

8. An antibody or antigen-binding fragment thereof that competes for specific binding to hGCGR with an antibody or antigen-binding fragment comprising the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR), wherein the HCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs:

2, 18, 34, 50, 66, 70, 90, 106, 110, 126, 130 and 146; and

the CDRs of a light chain variable region (LCVR), wherein the LCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs;

10, 26, 42, 58, 68, 78, 98, 108, 118, 128, 138 and 148.