Antagonist Antibodies Directed Against Calcitonin Gene-Related Peptide and Methods Using Same

Abstract

The invention features methods for preventing or treating CGRP associated disorders such as vasomotor symptoms, including headaches (e.g., migraine, cluster headache, and tension headache) and hot flushes, by administering an anti-CGRP antagonist antibody. Antagonist antibody G1 and antibodies derived from G1 directed to CGRP are also described.

1 . A method for reducing incidence of or treating cluster headache in an individual, comprising administering to the individual an effective amount of an anti-CGRP antagonist antibody, wherein the anti-CGRP antagonist antibody is a human or humanized antibody that blocks or decreases cyclic adenosine monophosphate (cAMP) activation in cells. 
     
     
         2 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody has a binding affinity (K D ) to human α-CGRP of 50 nM or less as measured by surface plasmon resonance at 37° C. 
     
     
         3 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody has a binding affinity (K D ) to human α-CGRP of 10 nM or less as measured by surface plasmon resonance at 37° C. 
     
     
         4 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody has a binding affinity (K D ) to human α-CGRP of 1 nM or less as measured by surface plasmon resonance at 37° C. 
     
     
         5 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody has a binding affinity (K D ) to human α-CGRP of 500 pM or less as measured by surface plasmon resonance at 37° C. 
     
     
         6 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody has a binding affinity (K D ) to human α-CGRP of 100 pM or less as measured by surface plasmon resonance at 37° C. 
     
     
         7 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody has a binding affinity (K D ) to human α-CGRP of 50 pM or less as measured by surface plasmon resonance at 37° C. 
     
     
         8 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody is a humanized antibody. 
     
     
         9 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody comprises a heavy chain constant region selected from the group consisting of: IgG, IgM, IgD, IgA and IgE. 
     
     
         10 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody comprises a heavy chain constant region derived from an IgG1 constant region. 
     
     
         11 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody comprises a heavy chain constant region derived from an IgG2 constant region. 
     
     
         12 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody comprises a heavy chain constant region derived from an IgG3 constant region. 
     
     
         13 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody comprises a heavy chain constant region derived from an IgG4 constant region. 
     
     
         14 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody comprises an Fc region with an impaired effector function. 
     
     
         15 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody binds a C-terminal fragment having amino acids 25-37 of human α-CGRP. 
     
     
         16 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody binds a C-terminal epitope within amino acids 25-37 of human α-CGRP. 
     
     
         17 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody is: (a) an antibody having a CDR H1 as set forth in SEQ ID NO: 3; a CDR H2 as set forth in SEQ ID NO: 4; a CDR H3 as set forth in SEQ ID NO: 5; a CDR L1 as set forth in SEQ ID NO: 6; a CDR L2 as set forth in SEQ ID NO: 7; and a CDR L3 as set forth in SEQ ID NO: 8; or (b) a variant of an antibody according to (a) as shown in Table 6. 
     
     
         18 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody comprises a V H  domain that is at least 90% identical in amino acid sequence to SEQ ID NO: 1 and a V L  domain that is at least 90% identical in amino acid sequence to SEQ ID NO: 2. 
     
     
         19 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody comprises a V H  domain comprising SEQ ID NO: 1 and a V L  domain comprising SEQ ID NO: 2. 
     
     
         20 . The method of  claim 1 , wherein the anti-CGRP antagonist antibody comprises a heavy chain sequence of SEQ ID NO: 11 and a light chain sequence of SEQ ID NO: 12. 
     
     
         21 .- 29 . (canceled)