Regulation of glucose metabolism using anti-cgrp antibodies

Abstract

The present disclosure provides methods for the prevention or treatment of metabolic disorders. In exemplary embodiments, methods of administering an anti-CGRP antibody are provided, optionally in combination with a second agent, wherein peripheral and/or hepatic glucose utilization is increased, thereby preventing or treating diseases and disorders associated with insulin resistance. Compositions comprising an anti-CGRP antibody are also provided, optionally in combination with a second agent, which are suitable for administration to increase peripheral and/or hepatic glucose utilization and thereby prevent or treat diseases and disorders associated with insulin resistance.

1 - 41 . (canceled) 
     
     
         42 . A method of identifying an anti-human CGRP antibody or antibody fragment that increases peripheral glucose utilization, comprising: administering an anti-human CGRP antibody or antibody fragment to a subject, measuring peripheral glucose utilization in said subject, and comparing the level of peripheral glucose utilization in said subject to the level of peripheral glucose utilization in at least one control subject. 
     
     
         43 . (canceled) 
     
     
         44 . The method of  claim 42 , wherein said subject is a human, mouse, rat, non-human primate, a non-human animal model of diabetes. 
     
     
         45 . The method of  claim 44 , wherein said non-human animal model of diabetes is selected from rats fed a high-fat diet and the Zucker diabetic fatty (ZDF) rat. 
     
     
         46 . The method of  claim 42 , wherein said anti-human CGRP antibody or antibody fragment increases peripheral glucose utilization by at least 10%, by at least 20%, or by at least 50% relative to said control subject. 
     
     
         47 . The method of  claim 42 , wherein said at least one control subject includes said subject prior to administration of said anti-human CGRP antibody or antibody fragment. 
     
     
         48 . A method of increasing peripheral and/or hepatic glucose utilization in a subject in need thereof, comprising administering an effective amount of a composition comprising an anti-human CGRP antibody or antibody fragment to said subject. 
     
     
         49 . The method of  claim 48 , wherein said anti-human CGRP antibody or antibody fragment specifically binds to the same linear or conformational epitope(s) and/or competes for binding to the same or overlapping linear or conformational epitope(s) on an intact CGRP polypeptide or fragment thereof as an anti-human CGRP antibody selected from the group consisting of:
 a. Ab1 comprising the V L  of SEQ ID NO:2 and the V H  of SEQ ID NO:4;   b. Ab2 comprising the V L  of SEQ ID NO:12 and the V H  of SEQ ID NO:14;   c. Ab3 comprising the V L  of SEQ ID NO:22 and the V H  of SEQ ID NO:24;   d. Ab4 comprising the V L  of SEQ ID NO:32 and the V H  of SEQ ID NO:34;   e. Ab5 comprising the V L  of SEQ ID NO:42 and the V H  of SEQ ID NO:44;   f. Ab6 comprising the V L  of SEQ ID NO:52 and the V H  of SEQ ID NO:54;   g. Ab7 comprising the V L  of SEQ ID NO:62 and the V H  of SEQ ID NO:64;   h. Ab8 comprising the V L  of SEQ ID NO:52 and the V H  of SEQ ID NO:54;   i. Ab9 comprising the V L  of SEQ ID NO:62 and the V H  of SEQ ID NO:64;   j. Ab10 comprising the V L  of SEQ ID NO:72 and the V H  of SEQ ID NO:74;   k. Ab11 comprising the V L  of SEQ ID NO:82 and the V H  of SEQ ID NO:84;   l. Ab12 comprising the V L  of SEQ ID NO:92 and the V H  of SEQ ID NO:94;   m. Ab13 comprising the V L  of SEQ ID NO:102 and the V H  of SEQ ID NO:104; and   n. Ab14 comprising the V L  of SEQ ID NO:112 and the V H  of SEQ ID NO:114.   
     
     
         50 . A composition suitable for use in a method according to  claim 48 , which comprises an effective amount of a composition comprising an anti-human CGRP antibody or antibody fragment and an anti-diabetic or anti-obesity agent other than an anti-human CGRP antibody or antibody fragment. 
     
     
         50 . The method of  claim 48 , wherein the anti-CGRP antibody V H  CDR1, CDR2 and CDR3 polypeptides having the amino acid sequences of SEQ ID NO:58, 59 and 60 respectively; and V L  CDR1, CDR2 and CDR3 polypeptides having the amino acid sequences of SEQ ID NO:55, 56 and 57 respectively. 
     
     
         51 . The method of  claim 50 , wherein the anti-CGRP antibody comprises a V H  polypeptide having the amino acid sequence of SEQ ID NO:53 and V L  polypeptide having the amino acid sequence of SEQ ID NO:51. 
     
     
         52 . The method of  claim 50 , wherein the anti-CGRP antibody comprises a heavy polypeptide having the amino acid sequence of SEQ ID NO:54 and a light chain polypeptide having the amino acid sequence of SEQ ID NO:52.