# US 8,771,696 B2 · Method of reducing the severity of stress hyperglycemia with human antibodies to the glucagon receptor > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,771,696 B2 - Document ID: US8771696B2 - Status: Granted - Kind: B2 - Application number: 13/900,275 - Filed: 2013-05-22 - Published: 2013-09-26 - Granted: 2014-07-08 - Earliest claimed: 2010-11-23 - Assignees: Regeneron Pharmaceuticals, Inc. - Applicants: Regeneron Pharmaceuticals, Inc. - Inventors: Joyce Harp; Haruka Okamoto - Web page: https://patentgrep.com/patent/US8771696B2 ## CPC - C07K 16/2869: {against hormone receptors (for antibodies against neuromediator receptors C07K16/286)} - A61K 38/28: Insulins - A61K 39/39541: {against normal tissues, cells} - A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines} - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - C07K 16/40: against enzymes - A61K 2039/505: {comprising antibodies} - A61K 2039/507: {Comprising a combination of two or more separate antibodies} - C07K 2317/21: from primates, e.g. man - C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity - C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues - C07K 2317/56: variable (Fv) region, i.e. VH and/or VL - C07K 2317/565: Complementarity determining region [CDR] - C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding - C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## 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 ### Claim 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. ### Claim 2 (depends on 1) 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. ### Claim 3 (depends on 1) 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. ### Claim 4 (depends on 1) 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. ### Claim 5 (depends on 4) 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. ### Claim 6 (depends on 4) 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. ### Claim 7 (depends on 4) 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. ### Claim 8 (depends on 4) 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. ### Claim 9 (depends on 4) 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. ### Claim 10 (depends on 1) The method of claim 1, wherein the patient is a diabetic patient. ### Claim 11 (depends on 10) The method of claim 10, wherein the diabetic patient is a critically ill diabetic patient. ### Claim 12 (depends on 10) The method of claim 10, wherein the diabetic patient is a non-critically ill diabetic patient. ### Claim 13 (depends on 10) 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. ### Claim 14 (depends on 1) The method of claim 1, wherein the patient is a non-diabetic patient. ### Claim 15 (depends on 14) The method of claim 14, wherein the non-diabetic patient is a critically ill non-diabetic patient. ### Claim 16 (depends on 14) The method of claim 14, wherein the non-diabetic patient is a non-critically ill non-diabetic patient. ### Claim 17 (depends on 14) The method of claim 14, wherein the non-diabetic patient is administered insulin as a second therapeutic agent. ### Claim 18 (depends on 1) 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. ### Claim 19 (depends on 18) 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. ### Claim 20 (depends on 18) 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. ### Claim 21 (depends on 1) The method of claim 1, wherein the administering results in lowering blood glucose levels without the risk of inducing hypoglycemia. ### Claim 22 (depends on 1) The method of claim 1, wherein the composition decreases the risk for infection, organ failure, disability from stroke, arrhythmia, or death.