Anti-PACAP antibodies
The present invention is directed to antagonistic antibodies and antigen binding fragments thereof having binding specificity for PACAP. These antibodies inhibit, block or neutralize at least one biological effect associated with PACAP, e.g., vasodilation. In exemplary embodiments these antibodies and antigen binding fragments thereof may comprise specific V H , V L , and CDR polypeptides described herein. In some embodiments these antibodies and antigen binding fragments thereof bind to and/or compete for binding to specific epitope(s) on human PACAP. The invention is further directed to using these antagonistic anti-PACAP antibodies, and binding fragments thereof, for the diagnosis, assessment, and treatment of diseases and disorders associated with PACAP and conditions where antagonism of PACAP-related activities, such as vasodilation, mast cell degranulation, and/or neuronal activation, are therapeutically beneficial, e.g., headache and migraine indications.
1. A human, humanized or chimerized anti-human Pituitary Adenylate Cyclase-Activating Polypeptide (“PACAP”) antibody or antigen-binding antibody fragment that binds to an epitope comprising at least three of residues 19, 22, 23 and 27 of the human PACAP polypeptide of SEQ ID NO: 1241, wherein the antibody or fragment has the ability to neutralize an activity of the human PACAP polypeptide of SEQ ID NO: 1241.
2. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 , wherein said antibody is humanized.
3. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 , wherein said antibody specifically competes for binding to the human PACAP of SEQ ID NO: 1241 with (a) the anti-human PACAP antibody comprising the Ab10 variable heavy chain region of SEQ ID NO: 402 and the Ab10 variable light chain region of SEQ ID NO: 422 and/or (b) the anti-human PACAP antibody comprising the Ab20variable heavy chain region of SEQ ID NO: 442 and the Ab20 variable light chain region of SEQ ID NO: 462.
4. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 , wherein said antibody or antigen-binding antibody fragment binds to the human PACAP polypeptide of SEQ ID NO: 1241 with a disassociation constant (“K D ”) that is at least 10-fold lower (stronger) than the K D of said antibody or antibody fragment binding to the human vasoactive intestinal peptide (“VIP”) polypeptide of SEQ ID NO: 1243.
5. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 , wherein said antibody or antigen-binding antibody fragment binds to the human PACAP polypeptide of SEQ ID NO: 1241 with a disassociation constant (“K D ”) that is at least 100-fold lower (stronger) than the K D of said antibody or antibody fragment binding to the human vasoactive intestinal peptide (“VIP”) polypeptide of SEQ ID NO: 1243.
6. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 , wherein said antibody or antigen-binding antibody fragment inhibits, blocks or prevents PACAP activation of at least one of pituitary adenylate cyclase-activating polypeptide type I receptor (“PAC1-R”), vasoactive intestinal peptide receptor type 1(“VPAC1-R”), and/or vasoactive intestinal peptide receptor type 2 (“VPAC2-R”).
7. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 , wherein said antibody or antigen-binding antibody fragment inhibits, blocks or prevents PACAP-induced cyclic adenosine monophosphate (“cAMP”) production by a cell expressing at least one of pituitary adenylate cyclase-activating polypeptide type I receptor (“PAC1-R”), vasoactive intestinal peptide receptor type 1 (“VPAC1-R”), and/or vasoactive intestinal peptide receptor type 2 (“VPAC2-R”) and/or said antibody or antigen-binding antibody fragment inhibits PACAP-mediated binding of such antibody to the cell surface and/or said antibody or antigen-binding antibody fragment inhibits PACAP binding to the surface of a cell.
8. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 , wherein said antibody or antigen-binding antibody fragment, when administered to a subject, reduces PACAP-induced vasodilation.
9. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 , wherein said antibody or antigen-binding antibody fragment comprises a variable heavy chain comprising complementarity determining regions (CDRs) consisting of the CDR1 sequence consisting of SEQ ID NO: 404; the CDR2 sequence consisting of SEQ ID NO: 406; and the CDR3 sequence consisting of SEQ ID NO: 408.
10. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 9 , wherein said variable heavy chain has at least 90% sequence identity to the Ab10 variable heavy chain polypeptide of SEQ ID NO: 402.
11. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 , wherein said antibody or antigen-binding antibody fragment comprises a variable light chain comprising complementarity determining regions (CDRs) consisting of the CDR1 sequence consisting of SEQ ID NO: 424; the CDR2 sequence consisting of SEQ ID NO: 426; and the CDR3 sequence consisting of SEQ ID NO: 428.
12. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 11 , wherein said variable heavy chain has at least 90% sequence identity to the Ab10 variable light chain polypeptide of SEQ ID NO: 422.
13. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 , wherein said antibody or antigen-binding antibody fragment comprises an scFv, Fab, Fab′, or A(ab′) 2 antibody fragment.
14. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 , wherein said antibody or antigen-binding antibody fragment comprises a human IgG1, IgG2, IgG3, or IgG4 constant region.
15. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 , wherein said antibody or antigen-binding antibody fragment comprises an Fc region containing at least one mutation that alters or eliminates N- and/or O-linked glycosylation.
16. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 , wherein said antibody or antigen-binding antibody fragment binds to the human PACAP polypeptide of SEQ ID NO: 1241 with a disassociation constant (“K D ”) of less than or equal to 50 nM.
17. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 , wherein said antibody or antigen-binding antibody fragment is directly or indirectly attached to a detectable label or therapeutic agent.
18. A composition comprising the anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 and a pharmaceutically acceptable carrier.
19. The composition of claim 18 , that further comprises at least one agent selected from an analgesic, an anti-inflammatory, an antiemetic, a non-steroidal anti-inflammatory drug, an opioid analgesic, another antibody, a non-antibody biologic, an anti-Nerve Growth Factor (“NGF”) antibody or antigen binding fragment thereof, an anti-Calcitonin Gene-Related Peptide (“CGRP”) antibody or antigen binding fragment thereof, a cyclooxygenase 1 inhibitor, or a cyclooxygenase 2 inhibitor.
20. The anti-human PACAP antibody or antigen-binding antibody fragment of claim 1 , wherein said antibody or antigen-binding antibody fragment comprises:
(a) a variable heavy chain comprising the CDR1 sequence consisting of SEQ ID NO: 404, the CDR2 sequence consisting of SEQ ID NO: 406, and the CDR3 sequence consisting of SEQ ID NO: 408; and a variable light chain comprising the CDR1sequence consisting of SEQ ID NO: 424, the CDR2 sequence consisting of SEQ ID NO: 426, and the CDR3 sequence consisting of SEQ ID NO: 428;
(b) a variable heavy chain comprising the CDR1 sequence consisting of SEQ ID NO: 444, the CDR2 sequence consisting of SEQ ID NO: 446, and the CDR3 sequence consisting of SEQ ID NO: 448; and a variable light chain comprising the CDR1sequence consisting of SEQ ID NO: 464, the CDR2 sequence consisting of SEQ ID NO: 466, and the CDR3 sequence consisting of SEQ ID NO: 468;
(c) a variable heavy chain comprising the CDR1 sequence consisting of SEQ ID NO: 844, the CDR2 sequence consisting of SEQ ID NO: 846, and the CDR3 sequence consisting of SEQ ID NO: 848; and a variable light chain comprising the CDR1 sequence consisting of SEQ ID NO: 864, the CDR2 sequence consisting of SEQ ID NO: 866, and the CDR3 sequence consisting of SEQ ID NO: 868; or
(d) a variable heavy chain comprising the CDR1 sequence consisting of SEQ ID NO: 884, the CDR2 sequence consisting of SEQ ID NO: 866, and the CDR3 sequence consisting of SEQ ID NO: 888; and a variable light chain comprising the CDR1sequence consisting of SEQ ID NO: 904, the CDR2 sequence consisting of SEQ ID NO: 906, and the CDR3 sequence consisting of SEQ ID NO: 908.