Anti-PACAP antibodies and uses thereof
View Patent ↗The present invention is directed to antibodies and antigen binding fragments thereof having binding specificity for PACAP. The antibodies and antigen binding fragments thereof comprise the sequences of the V H , V L , and CDR polypeptides described herein, and the polynucleotides encoding them. Antibodies and antigen binding fragments described herein bind to and/or compete for binding to the same linear or conformational epitope(s) on human PACAP as an anti-PACAP antibody. The invention contemplates conjugates of anti-PACAP antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. Methods of making said anti-PACAP antibodies and antigen binding fragments thereof are also contemplated. Other embodiments of the invention contemplate using 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, photophobia, mast cell degranulation, and/or neuronal activation, would be therapeutically beneficial.
1. An anti-pituitary adenylate cyclase-activating peptide (anti-PACAP) antibody or antigen-binding fragment thereof comprising: (a) a heavy chain variable region comprising an amino acid sequence with at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1042 and comprising the complementarity-determining region 1 (CDR1) sequence consisting of the amino acid sequence of SEQ ID NO: 1044; a complementarity-determining region 2 (CDR2) sequence consisting of the amino acid sequence of SEQ ID NO: 1046; and a complementarity-determining region 3 (CDR3) sequence consisting of the amino acid sequence of SEQ ID NO: 1048; and (b) a light chain variable region comprising an amino acid sequence with at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1062 and comprising the CDR1 sequence consisting of the amino acid sequence of SEQ ID NO: 1064; a CDR2 sequence consisting of the amino acid sequence of SEQ ID NO: 1066; and a CDR3 sequence consisting of the amino acid sequence of SEQ ID NO: 1068.
2. The anti-PACAP antibody or antigen-binding fragment thereof of claim 1 , wherein said heavy chain variable region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1042 and comprising a CDR1 consisting of the amino acid sequence of SEQ ID NO: 1044; a CDR2 consisting of the amino acid sequence of SEQ ID NO: 1046; and a CDR3 consisting of the amino acid sequence of SEQ ID NO: 1048.
3. The anti-PACAP antibody or antigen-binding fragment thereof of claim 1 , wherein said light chain variable region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1062 and comprising a CDR1 consisting of the amino acid sequence of SEQ ID NO: 1064; a CDR2 consisting of the amino acid sequence of SEQ ID NO: 1066; and a CDR3 consisting of the amino acid sequence of SEQ ID NO: 1068.
4. The anti-PACAP antibody or antigen-binding fragment thereof of claim 1 , wherein said light chain variable region comprises the amino acid sequence of SEQ ID NO: 1042, and said light chain variable region comprises the amino acid sequence of SEQ ID NO: 1062.
5. The anti-PACAP antibody or antigen-binding fragment thereof of claim 1 , wherein said heavy chain comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1041 and comprising a CDR1 consisting of the amino acid sequence of SEQ ID NO: 1044; a CDR2 consisting of the amino acid sequence of SEQ ID NO: 1046; and a CDR3 consisting of the amino acid sequence of SEQ ID NO: 1048; and said light chain comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1061 and comprising a CDR1 consisting of the amino acid sequence of SEQ ID NO: 1064; a CDR2 consisting of the amino acid sequence of SEQ ID NO: 1066; and a CDR3 consisting of the amino acid sequence of SEQ ID NO: 1068.
6. An anti-PACAP antibody or antigen-binding fragment thereof comprising the heavy chain amino acid sequence of SEQ ID NO: 1041 and the light chain amino acid sequence of SEQ ID NO: 1061.
7. The anti-PACAP antibody or antigen-binding fragment thereof of claim 1 , which is an antigen binding fragment selected from the group consisting of scFvs, fragment antigen binding (“Fab”) fragments, Fab′ fragments, monovalent antigen binding fragments and F(ab′)2 fragments.
8. The anti-PACAP antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or antigen binding fragment lacks N-glycosylation and/or O-glycosylation.
9. The anti-PACAP antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or antigen binding fragment comprises a human IgG1, IgG2, IgG3, or IgG4 constant domain.
10. The anti-PACAP antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or antigen binding fragment comprises an Fc region that has been modified to increase or decrease at least one of effector function, half-life, proteolysis, or glycosylation.
11. The anti-PACAP antibody or antigen-binding fragment thereof of claim 10 , wherein said Fc region comprises the sequence of any of the amino acid sequence of SEQ ID NO:1244, 1245 or 1246.
12. The anti-PACAP antibody or antigen-binding fragment thereof of claim 1 , herein said antibody or antigen binding fragment binds to human pituitary adenylate cyclase-activating peptide (PACAP) with a binding affinity (K D ) of less than or equal to 5×10 −10 M as determined by surface plasmon resonance at 25° C.
13. The anti-PACAP antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or antigen binding fragment binds to pituitary adenylate cyclase-activating peptide (PACAP) with an off-rate (k d ) of less than or equal to 5×10 −4 s −1 .
14. The anti-PACAP antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or antigen binding fragment is directly or indirectly attached to a detectable label or therapeutic agent.
15. The anti-PACAP antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or antigen binding fragment has stronger affinity for human pituitary adenylate cyclase-activating peptide (PACAP) than human vasoactive intestinal peptide (VIP).
16. The anti-PACAP antibody or antigen-binding fragment thereof of claim 1 , wherein the binding affinity (K D ) of said antibody or antigen binding fragment to human pituitary adenylate cyclase-activating peptide (PACAP) is at least 10-fold stronger than the binding affinity of said antibody or antigen binding fragment to human vasoactive intestinal peptide (VIP).
17. A composition comprising at least one anti-PACAP antibody or antigen binding fragment according to claim 1 and a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, or mixture thereof.
18. The composition according to claim 17 , wherein said composition is suitable for subcutaneous, intravenous, or intramuscular administration.
19. The composition according to claim 17 , wherein said composition is lyophilized, stabilized, and/or formulated for administration by injection.