Methods For Treating Obesity And Nonalcoholic Fatty Liver Disease Or Nonalcoholic Steatohepatitis Using Glucagon Receptor Antagonistic Antibodies

Abstract

The present disclosure relates to methods for treating or preventing obesity and/or nonalcoholic fatty liver diseases (NAFLDs) and/or nonalcoholic steatohepatitis (NASH) using a glucagon receptor blocking agent. In various embodiments, the present disclosure relates to methods for treating or preventing NAFLD/NASH using antigen binding and antagonizing proteins, e.g., fully human antibodies, that specifically bind to and antagonize the function of the human glucagon receptor.

What is claimed is: 
     
         1 . A method for treating nonalcoholic steatohepatitis (NASH) in a subject comprising administering to a subject diagnosed with NASH a therapeutically effective amount of an isolated antagonistic antigen binding protein that specifically binds to the human glucagon receptor. 
     
     
         2 . A method according to  claim 1 , wherein the isolated antagonistic antigen binding protein comprises an isolated antagonistic antibody or antibody fragment selected from the group consisting of a fully human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a Fab, a Fab′, a Fab 2 , a Fab′ 2 , a IgG, a IgM, a IgA, a IgE, a scFv, a dsFv, a dAb, a nanobody, a unibody, a diabody, and a hemibody, and wherein the isolated antagonistic antibody or antibody fragment specifically binds to a human glucagon receptor with a dissociation constant (KD) of at least about 1×10 −7  M, at least about 1×10 −8  M, at least about 1×10 −9  M, at least about 1×10 −10  M, at least about 1×10 −11  M, or at least about 1×10 −12  M. 
     
     
         3 . A method according to  claim 2 , wherein the isolated antagonistic antibody is a fully human antibody. 
     
     
         4 . A method according to  claim 3 , wherein the fully human antibody comprises a human anti-GCGR antibody which comprises the amino acid sequence encoding the heavy chain variable region of SEQ ID NO: 2 and the amino acid sequence encoding the light chain variable region of SEQ ID NO: 3. 
     
     
         5 . A method according to  claim 3 , wherein the fully human antibody comprises a human anti-GCGR antibody which comprises the amino acid sequence encoding the heavy chain variable region of SEQ ID NO: 4 and the amino acid sequence encoding the light chain variable region of SEQ ID NO: 5. 
     
     
         6 . A method according to  claim 3 , wherein the fully human antibody comprises a human anti-GCGR antibody which comprises the amino acid sequence encoding the heavy chain variable region of SEQ ID NO: 6 and the amino acid sequence encoding the light chain variable region of SEQ ID NO: 7. 
     
     
         7 . A method according to  claim 3 , wherein the fully human antibody comprises a heavy chain variable region having the amino acid sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, and SEQ ID NO: 28. 
     
     
         8 . A method according to  claim 3 , wherein the fully human antibody comprises a light chain variable region having the amino acid sequence selected from the group consisting of SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, and SEQ ID NO: 47. 
     
     
         9 . A method according to  claim 3 , wherein the fully human antibody comprises a human anti-GCGR antibody which comprises the amino acid sequence encoding the heavy chain variable region of SEQ ID NO: 28 and the amino acid sequence encoding the light chain variable region of SEQ ID NO: 47. 
     
     
         10 . A method according to  claim 1 , wherein the therapeutically effective amount of the isolated antagonistic antigen binding protein is selected from the group consisting of 0.001 to 100 mg/kg, 0.001 to 90 mg/kg, 0.001 to 80 mg/kg, 0.001 to 70 mg/kg, 0.001 to 60 mg/kg, 0.001 to 50 mg/kg, 0.001 to 40 mg/kg, 0.001 to 30 mg/kg, 0.001 to 20 mg/kg, 0.001 to 10 mg/kg, 0.001 to 5 mg/kg, 0.001 to 4 mg/kg, 0.001 to 3 mg/kg, 0.001 to 2 mg/kg, and 0.001 to 1 mg/kg body weight per week. 
     
     
         11 . A method according to  claim 10 , wherein the therapeutically effective amount of the isolated antagonistic antigen binding protein is 0.01 to 10 mg/kg body weight per week. 
     
     
         12 . A method according to  claim 1 , said method further comprising administering an anti-obesity agent to said subject, wherein the anti-obesity agent is selected from gut-selective MTP inhibitors, CCKa agonists, 5HT2c agonists, MCR4 agonists, lipase inhibitors, opioid antagonists, oleoyl-estrone, obinepitide, pramlintide (SYMLIN®), tesofensine, leptin, bromocriptine, orlistat, AOD-9604, and sibutramine. 
     
     
         13 . A method for treating nonalcoholic fatty liver disease (NAFLD) in a subject comprising administering to a subject diagnosed with NAFLD a therapeutically effective amount of an isolated antagonistic antigen binding protein that specifically binds to the human glucagon receptor. 
     
     
         14 . A method according to  claim 13 , said method further comprising administering an anti-obesity agent to said subject, wherein the anti-obesity agent is selected from gut-selective MTP inhibitors, CCKa agonists, 5HT2c agonists, MCR4 agonists, lipase inhibitors, opioid antagonists, oleoyl-estrone, obinepitide, pramlintide (SYMLIN®), tesofensine, leptin, bromocriptine, orlistat, AOD-9604, and sibutramine. 
     
     
         15 . A method of treating a subject classified as obese (e.g., having a body mass index (BMI) of 30 kg/m 2  or more) comprising administering to the subject a therapeutically effective amount of an isolated antagonistic antigen binding protein that specifically binds to the human glucagon receptor. 
     
     
         16 . A method according to  claim 15 , said method further comprising administering an anti-obesity agent to said subject, wherein the anti-obesity agent is selected from gut-selective MTP inhibitors, CCKa agonists, 5HT2c agonists, MCR4 agonists, lipase inhibitors, opioid antagonists, oleoyl-estrone, obinepitide, pramlintide (SYMLIN®), tesofensine, leptin, bromocriptine, orlistat, AOD-9604, and sibutramine.