Anti-glucagon antibodies and uses thereof

Abstract

The present invention provides antibodies that bind to glucagon and methods of using the same. According to certain embodiments, the antibodies of the invention bind human GCG with high affinity. The antibodies of the invention may be fully human antibodies. The antibodies of the invention are useful for the treatment of various diseases or disorders characterized by elevated blood glucose levels, as well as other GCG-related disorders.

1 .- 18 . (canceled) 
     
     
         19 . A method for lowering blood glucose levels, or for treating a condition or disease associated with, or characterized in part by high blood glucose levels, or at least one symptom or complication associated with the condition or disease, the method comprising administering a pharmaceutical composition comprising an isolated antibody or antigen-binding fragment thereof that specifically binds to glucagon (GCG) and neutralizes GCG activity to a patient in need thereof, such that blood glucose 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,
 wherein the antibody or antigen-binding fragment thereof comprises: (a) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 130 and 146; and (b) three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 122, 138 and 154.   
     
     
         20 . The method of  claim 19 , 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, hyperglycemia in burn patients or in patients suffering from a myocardial infarct or another cardiac disorder, hyperinsulinemia, the metabolic syndrome, insulin resistance syndrome and impaired fasting glucose. 
     
     
         21 . The method of  claim 19 , wherein the pharmaceutical composition is administered to the patient in combination with a second therapeutic agent. 
     
     
         22 .- 25 . (canceled) 
     
     
         26 . The method of  claim 21 , wherein the second therapeutic agent is selected from the group consisting of insulin, a biguanide, a sulfonylurea, a PPAR gamma agonist, an alpha glucosidase inhibitor, a glucagon-like peptide 1 (GLP-1) agonist or analogue, a dipeptidyl peptidase IV (DPP-4) inhibitor, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, pramlintide, a glucagon receptor antagonist, and a second GCG antagonist. 
     
     
         27 . The method of  claim 26 , wherein the second therapeutic agent is a biguanide and the biguanide is metformin. 
     
     
         28 . The method of  claim 26 , wherein the second therapeutic agent is a sulfonylurea and the sulfonylurea is selected from the group consisting of glyburide and glipizide. 
     
     
         29 . The method of  claim 26 , wherein the second therapeutic agent is a PPAR gamma agonist and the PPAR gamma agonist is selected from the group consisting of pioglitazone and rosiglitazone. 
     
     
         30 . The method of  claim 26 , wherein the second therapeutic agent is an alpha glucosidase inhibitor and the alpha glucosidase inhibitor is selected from the group consisting of acarbose and voglibose. 
     
     
         31 . The method of  claim 26 , wherein the second therapeutic agent is a GLP-1 agonist or analogue and the GLP-1 agonist or analogue is selected from the group consisting of exenatide, liraglutide, albiglutide, dulaglutide, and lixisenatide. 
     
     
         32 . The method of  claim 26 , wherein the second therapeutic agent is a DPP-4 inhibitor and the DPP-4 inhibitor is selected from the group consisting of saxagliptin, sitaliptin, and vildagliptin. 
     
     
         33 . The method of  claim 26 , wherein the second therapeutic agent is a SGLT2 inhibitor and the SGLT2 inhibitor is selected from the group consisting of canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and tofogliflozin. 
     
     
         34 . The method of  claim 21 , wherein the second therapeutic agent is a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) inhibitor. 
     
     
         35 . The method of  claim 34 , wherein the HMG-CoA reductase inhibitor is a statin selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. 
     
     
         36 . The method of  claim 21 , wherein the second therapeutic agent is selected from the group consisting of an isolated antibody, or an antigen-binding fragment thereof, that specifically binds to angiopoietin-like protein 3 (ANGPTL3), angiopoietin-like protein 4 (ANGPTL4), angiopoietin-like protein 5 (ANGPTL5), angiopoietin-like protein 6 (ANGPTL6), angiopoietin-like protein 8 (ANGPTL8), and human proprotein convertase subtilisin/kexin type 9 (PCSK9). 
     
     
         37 . The method of  claim 19 , wherein the antibody or antigen-binding fragment thereof exhibits one or more of the following characteristics:
 (a) is a fully human monoclonal antibody;   (b) binds human GCG at 25° C. with a K D  ranging from about 50 pM to about 750 pM and from about 300 pM to about 5 nM at 37° C. as measured by surface plasmon resonance;   (c) lowers blood glucose levels by at least about 10% when administered to a mammal as a single dose, or as multiple doses of less than about 40 mg/kg; or   (d) inhibits GCG-mediated activation of cells expressing human glucagon receptor (GCGR) with an IC 50  ranging from about 7 pM to about 950 pM.   
     
     
         38 . The method of  claim 37 , wherein the antibody lowers blood glucose levels by about 10% to about 31% when administered to a mammal as a single dose, or as multiple doses ranging from about 3 mg/kg to about 30 mg/kg. 
     
     
         39 . The method of  claim 37 , wherein the antibody or an antigen-binding fragment thereof reduces blood glucose levels in a mammal when administered subcutaneously, intravenously, or intramuscularly. 
     
     
         40 . The method of  claim 19 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 130 and 146; and a LCVR having an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 122, 138 and 154. 
     
     
         41 . The method of  claim 19 , wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs contained within a HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 2/10; 18/26; 34/42; 50/58; 66/74; 82/90; 98/106; 114/122; 130/138 and 146/154. 
     
     
         42 . The method of  claim 19 , wherein the antibody or antigen-binding fragment thereof comprises a HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 2/10; 18/26; 34/42; 50/58; 66/74; 82/90; 98/106; 114/122; 130/138 and 146/154.