US20160362488A1 - Anti-pacap antibodies and uses thereof - Google Patents

Anti-pacap antibodies and uses thereof Download PDF

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US20160362488A1
US20160362488A1 US15/130,263 US201615130263A US2016362488A1 US 20160362488 A1 US20160362488 A1 US 20160362488A1 US 201615130263 A US201615130263 A US 201615130263A US 2016362488 A1 US2016362488 A1 US 2016362488A1
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pacap
seq
antibody
human
amino acid
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Maria-Cristina Loomis
Leon F. Garcia-Martinez
Benjamin H. Dutzar
Daniel S. Allison
Lee Hendricks
Ethan W. Ojala
Pei FAN
Jeffrey T.L. Smith
John A. Latham
Charlie KARASEK
Jenny MULLIGAN
Michelle Scalley-Kim
Erica STEWART
Vanessa Lisbeth Rubin
Jens J. Billgren
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H Lundbeck AS
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Alder Biopharmaceuticals Inc
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Assigned to ALDER BIOPHARMACEUTICALS, INC., reassignment ALDER BIOPHARMACEUTICALS, INC., ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ALLISON, DANIEL S., BILLGREN, Jens J., FAN, PEI, HENDRIX, Katherine Lee, KARASEK, Charlie, LATHAM, JOHN A., MULLIGAN, Jenny, OJALA, ETHAN W., RUBIN, Vanessa Lisbeth, SMITH, JEFFREY T. L.
Priority to US16/242,792 priority patent/US11254741B2/en
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Priority to US17/553,280 priority patent/US20220289836A1/en
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    • C07K16/26—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against hormones ; against hormone releasing or inhibiting factors
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Definitions

  • This invention generally pertains to antibodies and antigen binding fragments thereof, preferably humanized, chimerized, and human antibodies and antigen binding fragments thereof, and compositions containing such antibodies and antigen binding fragments thereof, wherein such antibodies and antigen binding fragments thereof specifically bind to Pituitary Adenylate Cyclase-Activating Polypeptide (“PACAP”) and therapeutic and diagnostic uses for the antibodies, antigen binding fragments, and compositions thereof.
  • PACAP Pituitary Adenylate Cyclase-Activating Polypeptide
  • PACAP Pituitary Adenylate Cyclase-Activating Polypeptide
  • VIP secretin/vasoactive intestinal peptide
  • GHRH growth hormone-releasing hormone
  • PACAP is a multifunctional vasodilatory peptide that exists in two ⁇ -amidated active forms, one with 38 amino acids (PACAP38; SEQ ID NO: 1241) and the other with 27 amino acids (PACAP27; SEQ ID NO: 1242). Both peptides have the same N-terminal 27 amino acids and are synthesized from the same precursor protein, preproPACAP (See, Moody et al., Curr. Opin. Endocrinol. Diabetes Obes., 18(1):61-67, 2011).
  • PACAP38 is the more prevalent active form, representing up to 90% of PACAP forms in mammalian tissues (See, Kaiser and Russo, Neuropeptides, 47:451-461, 2013).
  • the sequence of PACAP38 is identical in all mammals and differs from the avian and amphibian orthologs by only one amino acid (See, Vaudry et al., Pharmacol. Rev., 52:269-324, 2000).
  • the secretin/VIP/GHRH family includes mammalian peptide histidine methioneamide (“PHM”), secretin, glucagon, glucagon-like peptide-1 (“GLP1”), glucagon-like peptide-2 (“GLP2”), glucose-dependent-insulinotrophic-polypeptide (“GIP”), and growth-hormone-releasing-factor (“GRF”).
  • PLM mammalian peptide histidine methioneamide
  • GLP1 glucagon-like peptide-1
  • GLP2 glucagon-like peptide-2
  • GIP glucose-dependent-insulinotrophic-polypeptide
  • GRF growth-hormone-releasing-factor
  • PACAP27 has 68% sequence identity to VIP at the amino acid level (See, Vaudry et al. 2000).
  • PACAP is widely distributed in the brain and peripheral organs, e.g., the endocrine system, gonads, sympathetic neurons, respiratory system, gastrointestinal tract, cardiovascular system, and urogenital tracts (See, Schytz et al., Neurotherapeutics, 7:191-196, 2010).
  • PACAP is expressed throughout the nervous system, including a presence in the trigeminovascular system, trigeminal ganglia, spinal cord, hypothalamus, and pituitary.
  • PACAP has roles in neurodevelopment, neuroprotection, neuromodulation, neurogenic inflammation, and nociception with multiple actions (See, Kaiser and Russo (2013)).
  • PACAP exerts pleiotropic effects including modulation of neurotransmitter release, vasodilation, bronchodilation, and activation of intestinal motility, increase of insulin and histamine secretion, as well as stimulation of cell proliferation and/or differentiation.
  • PACAP has been shown to act as a hormone, a neurohormone, a neurotransmitter, and a trophic factor in a number of tissues (See, Vaudry et al., Pharmacological Rev., 52(2):269-324, 2000).
  • VPAC1-R vasoactive intestinal peptide receptor type 1
  • VPAC2-R vasoactive intestinal peptide receptor type 2
  • VPAC1-R expression has been detected in the nervous system (e.g., cerebral cortex and hippocampus), smooth muscle cells of lung, liver, intestine, megakaryocytes, and platelets. VPAC1-R associates with receptor-associated membrane protein (“RAMP”, specifically RAMP2) (See, Christopoulos et al., J. Biol. Chem., 278:3293-3297, 2002).
  • RAMP receptor-associated membrane protein
  • VPAC2-R expression profile includes the nervous (e.g., thalamus, hippocampus, brain stem, and dorsal root ganglia (“DRG”)), cardiovascular system, gastrointestinal system, pancreas, and reproductive systems (See, Usdin et al., Endocrin., 135:2662-2680, 1994; Sheward et al., Neurosci., 67:409-418, 1995).
  • nervous e.g., thalamus, hippocampus, brain stem, and dorsal root ganglia (“DRG”)
  • DRG dorsal root ganglia
  • PAC1-R is selective for PACAP38 and PACAP27.
  • PAC1-R binds to PACAP with 100-1000-fold greater affinity than VIP, i.e., K D ⁇ 0.5 nM for PACAP27/PACAP38 vs. K D ⁇ 500 nM for VIP.
  • VPAC1-R and VPAC2-R have equal affinities for PACAP and VIP (K D ⁇ 1 nM) (See Schytz et al. (2010)).
  • these receptors Upon activation, these receptors are all capable of causing downstream production of cyclic adenosine monophosphate (“cAMP”), and/or activation of phospholipase C (“PLC”), and/or modulation of phospholipase D (“PLD”).
  • cAMP cyclic adenosine monophosphate
  • PLC phospholipase C
  • PLD modulation of phospholipase D
  • PAC1-R is coupled to dual signal transduction pathways acting through cAMP and Ca 2+
  • VPAC1-R and VPAC2-R are coupled principally to adenylyl cyclase.
  • PAC1-R is coupled to G s protein, which activates adenylyl cyclase to form cAMP that in turn activates protein kinase A.
  • PAC1-R also couples to Gq and thereby activates PLC, which produces inositol phosphate, which increases cytosolic calcium release from intra-cellular calcium stores.
  • PLC protein-based phospholipase
  • PACAP PACAP signaling pathway results in the elevation of intra-cellular sodium levels via activation of nonselective cation channels (See Roy et al., American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 304(12):R1070-R1084, 2013).
  • PACAP is hypothesized to play a role in a multitude of diseases and disorders, including but not limited to migraine, headache, and pain, though such a role for PACAP has not been clinically demonstrated.
  • Migraines are believed to have a neurovascular component. Migraines affect approximately 10% of the adult population in the U.S. and are typically accompanied by intense headaches. Approximately 20-30% of migraine sufferers experience aura, comprising focal neurological phenomena that precede and/or accompany the event.
  • PACAP-induced vasodilation may play a role in neurogenic inflammation (see, Kaiser and Russo, Neuropeptides, 47:451-461, 2013); and (4) PACAP-induced migraines are associated with photophobia, phonophobia, nausea, and respond to triptans (see, Amin et al., Brain, 32:140-149 2012).
  • PACAP has also been shown to induce vasodilation, photophobia, as well as mast cell degranulation and neuronal activation (See, Markovics et al., Neurobiology of Disease, 45:633-644 2012; Baun et al., Cephalalgia, 32(4):337-345, 2012; Chan et al., Pharmacology & Therapeutics, 129:332-351, 2011).
  • triptans which are a family of tryptamine-based drugs, including sumatriptan and rizatriptan.
  • Members of this family have an affinity for multiple serotonin receptors, including 5-HT 1B , 5-HT 1D , and 5-HT 1F .
  • Members of this family of drugs selectively constrict cerebral vessels, but also cause vasoconstrictive effects on coronary vessels (See Durham, New Eng. J. Med., 350 (11):1073-75, 2004).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • the administration of these treatments often has negative consequences.
  • NSAIDs have the potential to cause kidney failure, intestinal bleeding, and liver dysfunction.
  • Narcotics have the potential to cause nausea, vomiting, impaired mental functioning, and addiction. Therefore, it is desirable to identify alternative treatments for pain in order to avoid certain of these negative consequences.
  • PACAP may also be involved in diseases and disorders other than migraine, headache, and pain.
  • PACAP may correlate to or even play a causal role in anxiety disorders (WO 2012/106407); thrombocytopenia (WO 2004/062684); and inflammatory skin diseases (WO 2010/007175).
  • PACAP and PAC1-R polymorphisms are associated with post-traumatic stress syndrome (“PTSD”) in females, major depressive disorder, and generalized anxiety disorder, suggesting a role for PACAP in these conditions.
  • PTSD post-traumatic stress syndrome
  • trisomy 18 patients have excess PACAP and exhibit defective megakaryocyte maturation (See, Schytz et al. 2010; and Moody et al., Curr. Opin. Endocrinol. Diabetes Obes., 18(1):61-67, 2011).
  • PACAP and other neuropeptides such as Calcitonin Gene-Related Peptide (“CGRP”), substance P, neurokinin A, bradykinin, and endothelin-1
  • CGRP Calcitonin Gene-Related Peptide
  • substance P substance P
  • neurokinin A neurokinin A
  • bradykinin and endothelin-1
  • LUT lower urinary tract
  • UTI urinary tract infection
  • UTI urinary tract infection
  • nocturia urinary urgency
  • urinary incontinence overactive bladder, and the pain associated with such conditions.
  • PACAP and PACAP receptors have also been suggested to modulate inflammatory and neuropathic pain and have been implicated in both pronociception and antinociception (See, Davis-Taber et al., J. Pain, 9(5):449-56 2008). PACAP has also been reported to be required for spinal desensitization and the induction of neuropathic pain (See, Mabuchi et al., J. Neurosci., 24(33):7283-91, 2004). Additionally, morphine withdrawal behavior is reportedly modified in PACAP-receptor deficient mice further suggesting the role of PACAP in morphine withdrawal anxiolytic response (See, Martin et al., Mol. Brain Res., 110(1):109-18 2003).
  • the present invention in general relates to anti-PACAP antibodies and antigen binding fragments thereof, preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, that antagonize, inhibit, neutralize, or block at least one biological effect associated with human PACAP.
  • the anti-PACAP antibodies and antigen binding fragments thereof inhibit or neutralize at least one biological effect elicited by PACAP, which includes PACAP27 and/or PACAP38, as discussed infra.
  • the anti-PACAP antibodies and antigen binding fragments thereof neutralize or inhibit PACAP activation of at least one of PAC1-R, VPAC1-R, and/or VPAC2-R; neutralize or inhibit PACAP activation of each of PAC1-R, VPAC1-R, and VPAC2-R; and/or neutralize or inhibit PACAP activation of PAC1-R; and/or inhibits PACAP binding to the cell surface, e.g., via a glycosaminoglycan (“GAG”).
  • GAG glycosaminoglycan
  • the anti-PACAP antibodies and antigen binding fragments thereof are capable of inhibiting PACAP binding to at least one of PAC1-R, VPAC1-R, and/or VPAC2-R; are capable of inhibiting PACAP binding to each of PAC1-R, VPAC1-R, and/or VPAC2-R; or are capable of inhibiting PACAP binding to PAC1-R.
  • the anti-PACAP antibodies and antigen binding fragments thereof inhibit PACAP-induced cAMP production.
  • the anti-PACAP antibodies and antigen binding fragments thereof when administered to a subject, e.g., a human, reduce PACAP-induced vasodilation, photophobia, mast cell degranulation, and/or neuronal activation.
  • a subject e.g., a human
  • the human or humanized anti-PACAP antibodies and antigen binding fragments thereof are suitable for treating a human subject having an acute, episodic or chronic condition associated with increased vasodilation, photophobia, mast cell degranulation, and/or neuronal activation.
  • the method provides a eukaryotic host cell that is mammalian selected from the group consisting of baby hamster kidney (“BHK”) cells; chinese hamster ovary (“CHO”) cells; mouse sertoli cells (“TM4” cells); African green monkey kidney cells (“VERO-76” cells); human cervical carcinoma (“HELA”) cells; canine kidney cells (“MDCK”); buffalo rat liver (“BRL”) cells; human lung cells; human liver (“Hep G2”) cells; mouse mammary tumor (“MMT”) cells; TRI cells; MRC 5 cells; and FS4 cells.
  • BHK baby hamster kidney
  • CHO chinese hamster ovary
  • TM4 African green monkey kidney cells
  • HELA human cervical carcinoma
  • BRL buffalo rat liver
  • MMT mouse mammary tumor
  • TRI cells MRC 5 cells
  • FS4 cells mammalian host cell that is mammalian selected from the group consisting of baby hamster kidney (“BHK”) cells; chinese hamster
  • the anti-PACAP antibodies and antigen binding fragments thereof do not substantially interact with (bind) to VIP.
  • the present invention also encompasses the therapeutic use (as a monotherapy or combination therapy) and diagnostic use of such anti-PACAP antibodies and antigen binding fragments thereof.
  • anti-PACAP antibodies and antigen binding fragments thereof according to the invention can include human, humanized, and chimerized antibodies and fragments thereof, as well as scFvs, camelbodies, shark antibodies, nanobodies, Immunoglobulin New Antigen Receptor (“IgNAR”), fragment antigen binding (“Fab”) fragments, Fab′ fragments, MetMab like antibodies, bispecific antibodies, monovalent antibody fragments, and F(ab′) 2 fragments.
  • anti-PACAP antibodies and antigen binding fragments thereof according to the invention can substantially or entirely lack N-glycosylation and/or O-glycosylation.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise a human constant domain, e.g., that of IgG1, IgG2, IgG3, or IgG4 antibody or a fragment thereof.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise an Fc region that has been modified to alter (enhance or impair) at least one of effector function, half-life, proteolysis, or glycosylation.
  • the Fc region may contain one or more mutations that alters or eliminates N- and/or O-glycosylation.
  • anti-PACAP antibodies and antigen binding fragments thereof bind to PACAP with a K D of less than or equal to 5 ⁇ 10 ⁇ 5 M, 10 ⁇ 5 M, 5 ⁇ 10 ⁇ 6 M, 10 ⁇ 6 M, 5 ⁇ 10 ⁇ 7 M, 10 ⁇ 7 M, 5 ⁇ 10 ⁇ 8 M, 10 ⁇ 8 M, 5 ⁇ 10 ⁇ 9 M, 10 ⁇ 9 M, 5 ⁇ 10 ⁇ 10 M, 10 ⁇ 10 M, 5 ⁇ 10 ⁇ 11 M, 10 ⁇ 11 M, 5 ⁇ 10 ⁇ 12 M, 10 ⁇ 12 M, 5 ⁇ 10 ⁇ 13 M, or 10 ⁇ 13 M, e.g., as determined by ELISA, bio-layer interferometry (“BLI”), Kinetic Exclusion Assay (KINEXA®, Sapidyne Instruments, Boise, Id.), or SPR, e.g., at 25° or 37° C.
  • K D K D of less than or equal to 5 ⁇ 10 ⁇ 5 M, 10 ⁇ 5 M, 5
  • the human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof bind to PACAP with a K D of less than or equal to 5 ⁇ 10 ⁇ 10 M, 10 ⁇ 10 M, 5 ⁇ 10 ⁇ 11 M, 10 ⁇ 11 M, 5 ⁇ 10 ⁇ 12 M, or 10 ⁇ 12 M.
  • the human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof bind to PACAP with a K D that is less than about 100 nM, less than about 40 nM, less than about 1 nM, less than about 100 pM, less than about 50 pM, or less than about 25 pM.
  • the anti-PACAP antibodies and antigen binding fragments thereof bind to PACAP with a K D that is between about 10 pM and about 100 pM.
  • the human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof bind to PACAP with an off-rate (k off ) of less than or equal to 5 ⁇ 10 ⁇ 4 s ⁇ 1 , 10 ⁇ 4 s ⁇ 1 , 5 ⁇ 10 ⁇ 5 s ⁇ 1 , or 10 ⁇ 5 s ⁇ 1 .
  • the invention embraces anti-PACAP antibodies and antigen binding fragments thereof that specifically bind to the same linear or conformational epitope(s) on human PACAP as an anti-PACAP antibody selected from the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • an anti-PACAP antibody selected from the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • the epitope(s) are determined using alanine scanning mutation strategy.
  • the anti-PACAP antibodies and antigen binding fragments thereof include human, humanized or chimerized anti-PACAP antibodies or antibody fragments which bind to the identical epitopes as any one of Ab1, Ab2, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab1.H, Ab5, Ab7, Ab11, Ab12, Ab4, Ab3, Ab6, Ab8, and Ab9 or a binding fragment of any one of the foregoing.
  • the anti-PACAP antibodies and antigen binding fragments thereof include human, humanized or chimerized anti-PACAP antibodies or antibody fragments that specifically bind to an epitope on human PACAP or a fragment or variant thereof containing the corresponding amino acid residues wherein said epitope is selected from the group consisting of:
  • xii at least one of residues 5, 6, 9, 10, 12, 13, 14, and 17 of a human PACAP;
  • xiv. at least one of residues 8, 9, 10, 11, 12, 13, 14, 17, and 21 of a human PACAP;
  • xv. at least one of residues 4, 5, 6, 8, 9, 10, 12, 13, 14, and 17 of a human PACAP;
  • anti-PACAP antibodies or antigen binding fragments thereof include human, humanized or chimerized anti-PACAP antibodies or antibody fragments that specifically bind to an epitope on human PACAP, or a fragment or variant thereof that may contain the corresponding amino acid residues that may include residues 8 and/or 14 of human PACAP.
  • the anti-PACAP antibodies and antigen binding fragments thereof include human, humanized or chimerized anti-PACAP antibodies or antibody fragments that specifically bind to an epitope on human PACAP or a fragment or variant thereof containing the corresponding amino acid residues that is present in human wild-type PACAP38 but not human wild-type human PACAP27.
  • the anti-PACAP antibodies and antigen binding fragments thereof include human, humanized or chimerized anti-PACAP antibodies or antibody fragments that specifically bind to an which specifically binds to an epitope on human PACAP or a fragment or variant thereof containing the corresponding amino acid residues, wherein said epitope is identified by alanine scanning, e.g., as disclosed in Example 12 or another art-recognized method.
  • the anti-PACAP antibodies and antigen binding fragments thereof include human, humanized or chimerized anti-PACAP antibodies or antibody fragments that specifically bind to an epitope on human PACAP or a fragment or variant thereof containing the corresponding amino acid residues, wherein said epitope consists of the residues of any one of (i)-(xv) as described above.
  • the anti-PACAP antibodies and antigen binding fragments thereof include human, humanized or chimerized anti-PACAP antibodies or antibody fragments which specifically binds to an epitope on human PACAP or a fragment or variant thereof containing the corresponding amino acid residues that is present in human wild-type PACAP38 and in human wild-type human PACAP27.
  • the anti-PACAP antibodies and antigen binding fragments thereof include human, humanized or chimerized anti-PACAP antibodies or antibody fragments that specifically bind to human wild-type human PACAP38 but which does not bind or appreciably bind to human wild-type human PACAP27.
  • the anti-PACAP antibodies and antigen binding fragments thereof include human, humanized or chimerized anti-PACAP antibodies or antibody fragments which has a K D for human PACAP38 which is at least 10 fold, 100 fold, 1,000 fold, 10,000 fold, or 100,000 fold lower (stronger) than the K D of said antibody or antibody fragment to human PACAP27.
  • the anti-PACAP antibodies and antigen binding fragments thereof include human, humanized or chimerized anti-PACAP antibodies or antibody fragments which do not bind to or does not appreciably bind to human Vasoactive Intestinal Peptide (“VIP”).
  • VIP Vasoactive Intestinal Peptide
  • the anti-PACAP antibodies and antigen binding fragments thereof include human, humanized or chimerized anti-PACAP antibodies or antibody fragments which have a K D for human PACAP which is at least 10, 100, 1,000, 10,000 or 100,000 fold less (weaker) than the K D of said antibody or antibody fragment to human VIP.
  • the present invention provides an anti-PACAP antibodies and antigen binding fragments thereof, are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, comprising at least 2 complementarity determining regions (“CDRs”), or at least 3 CDRs, or at least 4 CDRs, or at least 5 CDRs, or all six CDRs of an anti-PACAP antibody selected from the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • CDRs complementarity determining regions
  • the antibodies and antigen binding fragments thereof comprise the variable heavy (“V H ”) chain and/or the variable light (“V L ”) chain of one of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, or Ab1.H.
  • anti-PACAP antibodies and antigen binding fragments thereof comprise human, humanized, or chimerized anti-PACAP antibodies or antigen binding fragments thereof, which comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 4; a CDR2 sequence consisting of SEQ ID NO: 6; and a CDR3 sequence consisting of SEQ ID NO: 8; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 24; a CDR2 sequence consisting of SEQ ID NO: 26; and a CDR3 sequence consisting of SEQ ID NO: 28.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 2, and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 22.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 2, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 22.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 21.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 44; a CDR2 sequence consisting of SEQ ID NO: 46; and a CDR3 sequence consisting of SEQ ID NO: 48; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 64; a CDR2 sequence consisting of SEQ ID NO: 66; and a CDR3 sequence consisting of SEQ ID NO: 68.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 42, and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 62.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 42, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 62.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 41, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 61.
  • anti-PACAP antibodies and antigen binding fragments thereof according to the invention may comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 84; a CDR2 sequence consisting of SEQ ID NO: 86; and a CDR3 sequence consisting of SEQ ID NO: 88; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 104; a CDR2 sequence consisting of SEQ ID NO: 106; and a CDR3 sequence consisting of SEQ ID NO: 108.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 82, and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 102.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 82, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 102.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 81, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 101.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention may comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 124; a CDR2 sequence consisting of SEQ ID NO: 126; and a CDR3 sequence consisting of SEQ ID NO: 128; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 144; a CDR2 sequence consisting of SEQ ID NO: 146; and a CDR3 sequence consisting of SEQ ID NO: 148.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 122 and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 142.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 122, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 142. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 121, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 141.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention may comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 164; a CDR2 sequence consisting of SEQ ID NO: 166; and a CDR3 sequence consisting of SEQ ID NO: 168; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 184; a CDR2 sequence consisting of SEQ ID NO: 186; and a CDR3 sequence consisting of SEQ ID NO: 188.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 162, and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 182.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 162, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 182. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 161, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 181.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 204; a CDR2 sequence consisting of SEQ ID NO: 206; and a CDR3 sequence consisting of SEQ ID NO: 208; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 224; a CDR2 sequence consisting of SEQ ID NO: 226; and a CDR3 sequence consisting of SEQ ID NO: 228.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 202 and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 222.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 202, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 222. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 201, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 221.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 244; a CDR2 sequence consisting of SEQ ID NO: 246; and a CDR3 sequence consisting of SEQ ID NO: 248; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 264; a CDR2 sequence consisting of SEQ ID NO: 266; and a CDR3 sequence consisting of SEQ ID NO: 268.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 242 and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 262.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 242, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 262. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 241, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 261.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 284; a CDR2 sequence consisting of SEQ ID NO: 286; and a CDR3 sequence consisting of SEQ ID NO: 288; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 304; a CDR2 sequence consisting of SEQ ID NO: 306; and a CDR3 sequence consisting of SEQ ID NO: 308.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 282, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 302.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 282, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 302. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 281, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 301.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 324; a CDR2 sequence consisting of SEQ ID NO: 326; and a CDR3 sequence consisting of SEQ ID NO: 328; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 344; a CDR2 sequence consisting of SEQ ID NO: 346; and a CDR3 sequence consisting of SEQ ID NO: 348.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 322, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 342.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 322, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 342. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 321, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 341.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 364; a CDR2 sequence consisting of SEQ ID NO: 366; and a CDR3 sequence consisting of SEQ ID NO: 368; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 384; a CDR2 sequence consisting of SEQ ID NO: 386; and a CDR3 sequence consisting of SEQ ID NO: 388.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 362, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 382.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 362, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 382. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 361, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 381.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 484; a CDR2 sequence consisting of SEQ ID NO: 486; and a CDR3 sequence consisting of SEQ ID NO: 488; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 504; a CDR2 sequence consisting of SEQ ID NO: 506; and a CDR3 sequence consisting of SEQ ID NO: 508.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 482, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 502.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 482, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 502. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 481, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 501.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 524; a CDR2 sequence consisting of SEQ ID NO: 526; and a CDR3 sequence consisting of SEQ ID NO: 528; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 544; a CDR2 sequence consisting of SEQ ID NO: 546; and a CDR3 sequence consisting of SEQ ID NO: 548.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 522, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 542.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 522, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 542. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 521, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 541.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 564; a CDR2 sequence consisting of SEQ ID NO: 566; and a CDR3 sequence consisting of SEQ ID NO: 568; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 584; a CDR2 sequence consisting of SEQ ID NO: 586; and a CDR3 sequence consisting of SEQ ID NO: 588.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 562, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 582.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 562, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 582. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 561, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 581.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 604; a CDR2 sequence consisting of SEQ ID NO: 606; and a CDR3 sequence consisting of SEQ ID NO: 608; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 624; a CDR2 sequence consisting of SEQ ID NO: 626; and a CDR3 sequence consisting of SEQ ID NO: 628.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 602, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 622.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 602, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 622. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 601, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 621.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 644; a CDR2 sequence consisting of SEQ ID NO: 646; and a CDR3 sequence consisting of SEQ ID NO: 648; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 664; a CDR2 sequence consisting of SEQ ID NO: 666; and a CDR3 sequence consisting of SEQ ID NO: 668.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 642, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 662.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 642, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 662. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 641, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 661.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 684; a CDR2 sequence consisting of SEQ ID NO: 686; and a CDR3 sequence consisting of SEQ ID NO: 688; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 704; a CDR2 sequence consisting of SEQ ID NO: 706; and a CDR3 sequence consisting of SEQ ID NO: 708.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 682, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 702.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 682, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 702. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 681, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 701.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 724; a CDR2 sequence consisting of SEQ ID NO: 726; and a CDR3 sequence consisting of SEQ ID NO: 728; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 744; a CDR2 sequence consisting of SEQ ID NO: 746; and a CDR3 sequence consisting of SEQ ID NO: 748.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 722, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 742.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 722, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 742. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 721, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 741.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 764; a CDR2 sequence consisting of SEQ ID NO: 766; and a CDR3 sequence consisting of SEQ ID NO: 768; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 784; a CDR2 sequence consisting of SEQ ID NO: 786; and a CDR3 sequence consisting of SEQ ID NO: 788.
  • the anti-PACAP antibodies and antigen binding fragments thereof fragment can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 762, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 782.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 762, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 782.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 761, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 781.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 804; a CDR2 sequence consisting of SEQ ID NO: 806; and a CDR3 sequence consisting of SEQ ID NO: 808; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 824; a CDR2 sequence consisting of SEQ ID NO: 826; and a CDR3 sequence consisting of SEQ ID NO: 828.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 802, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 822.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 802, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 822. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 801, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 821.
  • the anti-PACAP antibodies and antigen binding fragments may comprise sequence variants of any of the disclosed antibodies which are modified by mutagenesis, e.g., affinity maturation to alter one or more properties such as binding affinity or immunogenicity.
  • the anti-PACAP antibodies and antigen binding fragments thereof are directly or indirectly attached to another moiety, such as a detectable label or therapeutic agent.
  • the anti-PACAP antibodies and antigen binding fragments thereof inhibit or neutralize at least one biological effect elicited by PACAP; neutralize or inhibit PACAP activation of at least one of PAC1-R, VPAC1-R, and/or VPAC2-R; neutralize or inhibit PACAP activation of each of PAC1-R, VPAC1-R, and VPAC2-R; neutralize or inhibit PACAP activation of PAC1-R; are capable of inhibiting PACAP binding to at least one of PAC1-R, VPAC1-R, and/or VPAC2-R; are capable of inhibiting PACAP binding to each of PAC1-R, VPAC1-R, and/or VPAC2-R; are capable of inhibiting PACAP binding to PAC1-R; and/or inhibits PACAP binding to the cell surface, e.g., via a GAG; inhibit PACAP-induced cAMP production; and/or when administered to a subject reduce PACAP-induced vasodilation, photophobia, mast cell degranulation
  • the human, or humanized, anti-PACAP antibodies and antigen binding fragments thereof are suitable for treating a human subject having an acute, episodic, or chronic condition associated with increased vasodilation, photophobia, mast cell degranulation, and/or neuronal activation.
  • the anti-PACAP antibodies and antigen binding fragments thereof do not substantially interact with (i.e., bind to) VIP.
  • the anti-PACAP antibodies and antigen binding fragments thereof have stronger affinity for PACAP as compared to VIP, i.e., although there is some cross-reactivity, the antibodies preferentially bind to PACAP as compared to VIP.
  • the affinity of said antibodies and antigen binding fragments thereof to PACAP is at least 10-fold, 30-fold, 100-fold, 300-fold, 1000-fold, 3000-fold, 10000-fold, 30000-fold, 100000-fold, 300000-fold, 1000000-fold, 3000000-fold, 10000000-fold, 30000000-fold, or stronger than the affinity of said antibodies and antigen binding fragments thereof to VIP (e.g., the K D of said antibody or fragment for binding to human PACAP is 10-fold, 30-fold, 100-fold, 300-fold, 1000-fold, 3000-fold, 10000-fold, 30000-fold, 100000-fold, 300000-fold, 1000000-fold, 3000000-fold, 10000000-fold, or 30000000-fold lower than the K D for binding to VIP).
  • the anti-PACAP antibodies and antigen binding fragments thereof are attached to at least one effector moiety, e.g., which comprises a chemical linker.
  • the anti-PACAP antibodies and antigen binding fragments thereof are attached to one or more detectable moieties, e.g., which comprise a fluorescent dye, enzyme, substrate, bioluminescent material, radioactive material, chemiluminescent moiety, or mixtures thereof.
  • the anti-PACAP antibodies and antigen binding fragments thereof are attached to one or more functional moieties.
  • the invention also contemplates antibodies, e.g., anti-idiotypic antibodies, produced against an anti-PACAP antibodies and antigen binding fragments thereof as described above. Furthermore, the invention provides a method of using the anti-idiotypic antibody to monitor the in vivo levels of said anti-PACAP antibodies and antigen binding fragments thereof in a subject or to neutralize said anti-PACAP antibody in a subject being administered said anti-PACAP antibody or antigen binding fragment thereof.
  • the present invention encompasses a composition suitable for therapeutic, prophylactic, or a diagnostic use comprising a therapeutically, prophylactically, or diagnostically effective amount of at least one anti-PACAP antibody or antigen binding fragment as described herein.
  • compositions and dosage forms containing the subject anti-PACAP antibodies or binding fragments thereof for use in treating or preventing migraine or other headache indications are provided herein.
  • dosage forms containing the subject anti-PACAP antibodies or binding fragments thereof for use in treating or preventing photophobia are provided herein.
  • the composition may be suitable for subcutaneous administration, intra-muscular administration, and/or intravenous administration.
  • the composition may be lyophilized.
  • the composition further comprises a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, or mixture thereof.
  • the composition further comprises another active agent, e.g., a chemotherapeutic, an analgesic, an anti-inflammatory, an immunosuppressant, a cytokine, an antiproliferative, and an antiemetic.
  • the other therapeutic agent is an analgesic, e.g., an NSAID, an opioid analgesic, an antibody (e.g., an anti-human Nerve Growth Factor (“NGF”) antibody or antibody fragment; or an anti-human CGRP or anti-human CGRP-receptor antibody or antibody fragment); or a non-antibody biologic, such as an NGF or CGRP polypeptide fragment or conjugate; or BOTOX® (Botulinum toxin).
  • NGF Nerve Growth Factor
  • Suitable NSAIDs for use in combination with the subject anti-PACAP antibodies include, but are not limited to, a cyclooxygenase 1 and/or cyclooxygenase 2 inhibitor; propionic acid derivatives including ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen; acetic acid derivatives including tolmetin and sulindac; fenamic acid derivatives including mefenamic acid and meclofenamic acid; biphenylcarboxylic acid derivatives including diflunisal and flufenisal; and oxicams including piroxim, sudoxicam, and isoxicam.
  • a cyclooxygenase 1 and/or cyclooxygenase 2 inhibitor propionic acid derivatives including ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen
  • acetic acid derivatives including tolmetin and sulindac
  • Suitable opioid analgesics for use in combination with the subject anti-PACAP antibodies include, e.g., codeine, dihydrocodeine, morphine or a morphine derivative or pharmaceutically acceptable salt thereof, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanil, meperidine, methadone, nalbuphine, propoxyphene, and pentazocine, or pharmaceutically acceptable salts thereof.
  • the combined administration of the opioid analgesic and the anti-PACAP antibody or antigen binding fragment thereof may increase the analgesic effect elicited thereby.
  • the present invention further contemplates an isolated nucleic acid sequence or nucleic acid sequences encoding an anti-PACAP antibody or antigen binding fragment described herein, as well as a vector or vectors containing these isolated nucleic acid sequence or sequences.
  • the invention provides a host cell comprising these isolated nucleic acid sequence or sequences or the vector or set forth above.
  • the host cell may be a eukaryotic host cell that is mammalian, selected from the group consisting of baby hamster kidney (“BHK”) cells; chinese hamster ovary (“CHO”) cells; mouse sertoli cells (“TM4” cells); African green monkey kidney cells (“VERO-76” cells); human cervical carcinoma (“HELA”) cells; canine kidney cells (“MDCK”); buffalo rat liver (“BRL”) cells; human lung cells; human liver (“Hep G2”) cells; mouse mammary tumor (“MMT”) cells; TRI cells; MRC 5 cells; and FS4 cells.
  • BHK baby hamster kidney
  • CHO chinese hamster ovary
  • TM4 mouse sertoli cells
  • HELA human cervical carcinoma
  • MDCK canine kidney cells
  • BRL buffalo rat liver
  • MMT mouse mammary tumor
  • TRI cells MRC 5 cells
  • the mammalian host cell is a CHO cell. More preferably, the mammalian host cell is a CHO K1 cell.
  • the host cell may be a prokaryotic cell, i.e., bacterial cell, or a eukaryotic cell, including a mammalian, fungal, yeast, avian, or insect cell.
  • the host cell is a filamentous fungus or is a yeast cell.
  • the yeast species is of the genus Pichia . Most preferably, the species of Pichia is selected from Pichia pastoris, Pichia methanolica , and Hansenula polymorpha ( Pichia angusta ).
  • the invention further provides a method of expressing anti-PACAP antibodies and antigen binding fragments thereof, typically human, humanized, or chimeric antibodies and antigen binding fragments thereof, the method comprising culturing the host cell described herein under conditions that provide for expression of said antibody or antigen binding fragment thereof.
  • the host cell may be a cell culture, such as a Chinese hamster ovary (“CHO”) cell or a polyploid yeast culture that stably expresses and secretes into the culture medium at least 10-25 mg/liter of said antibody or antigen binding fragment thereof.
  • the polyploid yeast may be made by a method that comprises: (i) introducing at least one expression vector containing one or more heterologous polynucleotides encoding said antibody operably linked to a promoter and a signal sequence into a haploid yeast cell; (ii) producing by mating or spheroplast fusion a polyploid yeast from said first and/or second haploid yeast cell; (iii) selecting polyploid yeast cells that stably express said antibody; and (iv) producing stable polyploid yeast cultures from said polyploid yeast cells that stably express said antibody into the culture medium.
  • the yeast species is of the genus Pichia.
  • the mammalian cell culture may be made by a method that comprises: (i) introducing at least one expression vector containing one or more heterologous polynucleotides encoding said antibody operably linked to a promoter and a signal sequence into a mammalian cell; (ii) producing single cells for culturing to express one or more heterologous polynucleotides encoding said antibody; (iii) selecting a mammalian cell that stably expresses said antibody; and (iv) producing cell cultures from said mammalian cell that stably expresses said antibody into the culture medium.
  • the mammalian species are CHO cells.
  • the invention further relates to the therapeutic and diagnostic uses of anti-PACAP antibodies and antigen binding fragments thereof, preferably a human antibody, humanized antibody, or chimeric antibody, or a fragment thereof.
  • the invention provides a method for blocking, inhibiting, or neutralizing one or more biological effects associated with PACAP in a subject comprising administering to a subject an effective amount of a human or humanized or chimerized anti-PACAP antibody or antigen binding fragment thereof that antagonizes, inhibits, neutralizes, or blocks at least one biological effect associated with human PACAP.
  • the method employs an anti-PACAP antibody or antigen binding fragment thereof that specifically binds to the same or overlapping linear or conformational epitope(s) and/or competes for binding to the same or overlapping linear or conformational epitope(s) on human PACAP as an anti-PACAP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • an anti-PACAP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • the invention provides a method for blocking, inhibiting, or neutralizing one or more biological effects associated with PACAP in a subject comprising administering to a subject an effective amount of a human, humanized, or chimerized anti-PACAP antibody or antigen binding fragment thereof that antagonizes, inhibits, neutralizes, or blocks at least one biological effect associated with human PACAP and that does not substantially interact with (bind) VIP, e.g., the anti-PACAP antibody or antigen binding fragment thereof has stronger affinity for PACAP as compared to VIP, i.e., although there is some cross-reactivity, the antibodies preferentially bind to PACAP as compared to VIP.
  • a human, humanized, or chimerized anti-PACAP antibody or antigen binding fragment thereof that antagonizes, inhibits, neutralizes, or blocks at least one biological effect associated with human PACAP and that does not substantially interact with (bind) VIP, e.g., the anti-PACAP antibody or antigen binding fragment thereof has stronger affinity for PACAP as compared to VIP
  • the affinity of said antibody or antigen binding fragment thereof to PACAP is at least 10-fold, 30-fold, 100-fold, 300-fold, 1000-fold, 3000-fold, 10000-fold, 30000-fold, 100000-fold, 300000-fold, 1000000-fold, 3000000-fold, 10000000-fold, 30000000-fold, or higher than the affinity of said antibody or antigen binding fragment thereof to VIP (e.g., the K D of said antibody or fragment for binding to human PACAP is 10-fold, 30-fold, 100-fold, 300-fold, 1000-fold, 3000-fold, 10000-fold, 30000-fold, 100000-fold, 300000-fold, 1000000-fold, 3000000-fold, 10000000-fold, 30000000-fold, or lower than the K D for binding to VIP).
  • the method employs an anti-PACAP antibody or antigen binding fragment thereof that specifically binds to the same or overlapping linear or conformational epitope(s) and/or competes for binding to the same or overlapping linear or conformational epitope(s) on human PACAP as an anti-PACAP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • an anti-PACAP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • the invention provides a method for blocking, inhibiting, or neutralizing one or more biological effects associated with PACAP in a subject comprising administering to a subject an effective amount of a human, humanized, or chimerized anti-PACAP antibody or antigen binding fragment thereof that inhibits or neutralizes at least one biological effect elicited by PACAP; neutralizes or inhibits PACAP activation of at least one of PAC1-R, VPAC1-R, and/or VPAC2-R; neutralizes or inhibits PACAP activation of each of PAC1-R, VPAC1-R, and VPAC2-R; neutralizes or inhibits PACAP activation of PAC1-R; is capable of inhibiting PACAP binding to at least one of PAC1-R, VPAC1-R, and/or VPAC2-R; is capable of inhibiting PACAP binding to each of PAC1-R, VPAC1-R, and/or VPAC2-R; is capable of inhibiting PACAP binding to PAC1-R; and/or is
  • the method employs an anti-PACAP antibody or antigen binding fragment thereof that specifically binds to the same or overlapping linear or conformational epitope(s) and/or competes for binding to the same or overlapping linear or conformational epitope(s) on human PACAP as an anti-PACAP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • an anti-PACAP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • the invention provides a method for treating or preventing the onset, frequency, severity, or duration of headache or migraine in a subject comprising administering to a subject an effective amount of a human, humanized, or chimerized anti-PACAP antibody or antigen binding fragment thereof that inhibits or neutralizes at least one biological effect elicited by PACAP; neutralizes or inhibits PACAP activation of at least one of PAC1-R, VPAC1-R, and/or VPAC2-R; neutralizes or inhibits PACAP activation of each of PAC1-R, VPAC1-R, and VPAC2-R; neutralizes or inhibits PACAP activation of PAC1-R; is capable of inhibiting PACAP binding to at least one of PAC1-R, VPAC1-R, and/or VPAC2-R; is capable of inhibiting PACAP binding to each of PAC1-R, VPAC1-R, and/or VPAC2-R; is capable of inhibiting PACAP binding to PAC1-R; and/or is
  • the method employs an anti-PACAP antibody or antigen binding fragment thereof that specifically binds to the same or overlapping linear or conformational epitope(s) and/or competes for binding to the same or overlapping linear or conformational epitope(s) on human PACAP as an anti-PACAP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • the epitope can be identified using an alanine scanning mutation strategy, for example.
  • the headache or migraine treated and/or prevented by administration of the subject anti-PACAP antibodies and antigen binding fragments thereof is selected from migraine with or without aura, hemiplegic migraine, cluster headache, migrainous neuralgia, chronic headache, and tension headache.
  • the subject has a ocular disorder associated with photophobia selected from the group consisting of achromatopsia, aniridia, photophobia caused by an anticholinergic drug, aphakia (absence of the lens of the eye), buphthalmos (abnormally narrow angle between the cornea and iris), cataracts, cone dystrophy, congenital abnormalities of the eye, viral conjunctivitis (“pink eye”), corneal abrasion, corneal dystrophy, corneal ulcer, disruption of the corneal epithelium, ectopia lentis, endophthalmitis, eye trauma caused by disease, injury, or infection such as chalazion, episcleritis, glaucoma, keratoconus, or optic nerve hypoplasia, hydrophthalmos, or congenital glaucoma blinkis, optic neuritis, pigment dispersion syndrome, pupillary dilation (naturally or chemically induced), retinal detachment, scarring of the cornea or sclera,
  • the subject has a nervous system-related or neurological condition associated with photophobia selected from the group consisting of autism spectrum disorders, Canali malformation, dyslexia, encephalitis including myalgic encephalomyelitis (also known as “chronic fatigue syndrome”), meningitis, subarachnoid hemorrhage, tumor of the posterior cranial fossa, ankylosing spondylitis, albinism, ariboflavinosis, benzodiazepines (long term use of or withdrawal from benzodiazepines), chemotherapy, chikungunya, cystinosis, Ehlers-Danlos syndrome, hangover, influenza, infectious mononucleosis, magnesium deficiency, mercury poisoning, migraine, rabies, and tyrosinemia type II (also known as “Richner-Hanhart syndrome”).
  • a nervous system-related or neurological condition associated with photophobia selected from the group consisting of autism spectrum disorders, Canali malformation, dyslexia, encephalitis including my
  • the subject has a photophobia-associated disorder selected from the group consisting of migraine (with or without aura), crizo, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, glabra, glabras, glabras, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra,
  • the invention provides a method for neutralizing PACAP-induced PAC1-R, VPAC1-R, and/or VPAC2-R signaling, comprising administering to a subject in need thereof an effective amount of an anti-PACAP antibody or antigen binding fragment thereof that specifically binds to the same or overlapping linear or conformational epitope(s) and/or competes for binding to the same or overlapping linear or conformational epitope(s) on human PACAP as an anti-PACAP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • an anti-PACAP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • the invention provides a method for inhibiting PACAP-induced cAMP production, comprising administering to a subject in need thereof an effective amount of an anti-PACAP antibody or antigen binding fragment thereof that specifically binds to the same or overlapping linear or conformational epitope(s) and/or competes for binding to the same or overlapping linear or conformational epitope(s) on human PACAP as an anti-PACAP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • an anti-PACAP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • the invention provides a method for inhibiting PACAP-induced vasodilation, photophobia, mast cell degranulation, and/or neuronal activation, comprising administering to a subject in need thereof an effective amount of an anti-PACAP antibody or antigen binding fragment thereof that specifically binds to the same or overlapping linear or conformational epitope(s) and/or competes for binding to the same or overlapping linear or conformational epitope(s) on human PACAP as an anti-PACAP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • an anti-PACAP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • the invention provides a method for treating or preventing a condition associated with elevated PACAP levels in a subject, comprising administering to a subject in need thereof an effective amount of an anti-PACAP antibody or antigen binding fragment thereof that specifically binds to the same or overlapping linear or conformational epitope(s) and/or competes for binding to the same or overlapping linear or conformational epitope(s) on human PACAP as an anti-PACAP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, and Ab1.H.
  • the epitope can be identified using an alanine scanning mutation strategy, for example.
  • Exemplary anti-PACAP antibodies and antigen binding fragments thereof suitable for use in this invention comprise a V H chain having an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, 99 or 100% sequence identity to a V H chain selected from SEQ ID NOs: 2; 42; 82; 122; 162; 202; 242; 282; 322; 362; 482; 522; 562; 602; 642; 682; 722; 762; and 802, and/or a V L chain having an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% sequence identity to a V L chain selected from selected from SEQ ID NOs: 22; 62; 102; 142; 182; 222; 262; 302; 342; 382; 502; 542; 582; 622; 662; 702; 742; 782; and 822, and/or at least 2, 3, 4, 5, or all 6 CDRs comprised
  • anti-PACAP antibodies and antigen binding fragments thereof employed in the methods according to the invention may include human, humanized, and chimerized antibodies and fragments thereof, as well as scFvs, camelbodies, shark antibodies, nanobodies, IgNAR, Fab fragments, Fab′ fragments, MetMab like antibodies, bispecific antibodies, monovalent antibody fragments, and F(ab′) 2 fragments.
  • the anti-PACAP antibody or antigen binding fragment thereof employed by the methods according to the invention may substantially or entirely lack N-glycosylation and/or O-glycosylation.
  • the anti-PACAP antibody or antigen binding fragment thereof used in the encompassed methods comprises a human constant domain, e.g., an IgG1, IgG2, IgG3, or IgG4 antibody.
  • the anti-PACAP antibody or antigen binding fragment thereof comprises an Fc region that has been modified to alter (enhance or impair) at least one of effector function, half-life, proteolysis, or glycosylation.
  • the Fc region may contain one or more mutations that alters or eliminates N- and/or O-glycosylation.
  • the subject methods employ an anti-PACAP antibody or antigen binding fragment thereof that binds to PACAP with a K D of less than or equal to 5 ⁇ 10 ⁇ 5 M, 10 ⁇ 5 M, 5 ⁇ 10 ⁇ 6 M, 10 ⁇ 6 M, 5 ⁇ 10 ⁇ 7 M, 10 ⁇ 7 M, 5 ⁇ 10 ⁇ 8 M, 10 ⁇ 8 M, 5 ⁇ 10 ⁇ 9 M, 10 ⁇ 9 M, 5 ⁇ 10 ⁇ 10 M, 10 ⁇ 10 M, 5 ⁇ 10 ⁇ 11 M, 10 ⁇ 11 M, 5 ⁇ 10 ⁇ 12 M, 10 ⁇ 12 M, 5 ⁇ 10 ⁇ 13 M, or 10 ⁇ 13 M.
  • the human, humanized, or chimerized anti-PACAP antibody or antigen binding fragment thereof binds to PACAP with a K D of less than or equal to 5 ⁇ 10 ⁇ 10 M, 10 ⁇ 10 M, 5 ⁇ 10 ⁇ 11 M, 10 ⁇ 11 M, 5 ⁇ 10 ⁇ 12 M, or 10 ⁇ 12 M. More preferably, the methods employ a human, humanized, or chimerized anti-PACAP antibody or antigen binding fragment thereof that binds to PACAP with a K D that is less than about 100 nM, less than about 40 nM, less than about 1 nM, less than about 100 pM, less than about 50 pM, or less than about 25 pM.
  • the anti-PACAP antibody or antigen binding fragment thereof binds to PACAP with a K D that is between about 10 pM and about 100 pM.
  • the human, humanized or chimerized anti-PACAP antibody or antigen binding fragment thereof binds to PACAP with an off-rate (k off ) of less than or equal to 5 ⁇ 10 ⁇ 4 s ⁇ 1 , 10 ⁇ 4 s ⁇ 1 , 5 ⁇ 10 ⁇ 5 s ⁇ 1 , or 10 ⁇ 5 s ⁇ 1 .
  • the anti-PACAP antibody or antigen binding fragment thereof used in the subject methods is directly or indirectly attached to another moiety, such as a detectable label or therapeutic agent; is attached to at least one effector moiety, e.g., which comprises a chemical linker; and/or is attached to one or more detectable moieties, e.g., which comprises a fluorescent dye, enzyme, substrate, bioluminescent material, radioactive material, chemiluminescent moiety, or mixtures thereof; and/or is attached to one or more functional moieties.
  • a detectable label or therapeutic agent is attached to at least one effector moiety, e.g., which comprises a chemical linker; and/or is attached to one or more detectable moieties, e.g., which comprises a fluorescent dye, enzyme, substrate, bioluminescent material, radioactive material, chemiluminescent moiety, or mixtures thereof; and/or is attached to one or more functional moieties.
  • the method further comprises administering separately or co-administering another agent, e.g., selected from a chemotherapeutic, an analgesic, an anti-inflammatory, an immunosuppressant, a cytokine, an antiproliferative, and an antiemetic.
  • another agent e.g., selected from a chemotherapeutic, an analgesic, an anti-inflammatory, an immunosuppressant, a cytokine, an antiproliferative, and an antiemetic.
  • the other therapeutic agent is an analgesic, e.g., an NSAID (such as a cyclooxygenase 1 and/or cyclooxygenase 2 inhibitor; propionic acid derivatives including ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen; acetic acid derivatives including tolmetin and sulindac; fenamic acid derivatives including mefenamic acid and meclofenamic acid; biphenylcarboxylic acid derivatives including diflunisal and flufenisal; and oxicams including piroxim, sudoxicam, and isoxicam), an opioid analgesic (such as morphine or a morphine derivative or pharmaceutically acceptable salt thereof; codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol,
  • the combined administration of the opioid analgesic and the anti-PACAP antibody or antigen binding fragment thereof increase the analgesic effect as compared to either the opioid analgesic or the anti-PACAP antibody or antigen binding fragment thereof administered alone.
  • the subject has previously been treated (“a treated subject”) and received an anti-CGRP or anti-CGRP-R antibody or antibody fragment thereof.
  • the treated subject may be a migraineur who did not adequately respond to anti-CGRP or anti-CGRP-R antibody treatment (“poor responder”).
  • the treated subject may have previously received at least one anti-CGRP or anti-CGRP-R antibody or antibody fragment thereof administration, and has elicited an immune response to said antibody or antibody fragment thereof.
  • Exemplary anti-CGRP and anti-CGRP-R antibodies and antibody fragments thereof are disclosed in U.S. Pat. Nos. 9,102,731; 9,115,194; 8,734,802; 8,623,366; 8,597,649; and 8,586,045; and U.S. Patent Application Publication No.'s 20120294822, 20120294802, and 20120294797, the contents of each which are incorporated by reference in their entireties herein.
  • anti-PACAP antibodies and antigen binding fragments thereof may include human, humanized or chimerized anti-PACAP antibodies or antibody fragments thereof that specifically compete for binding to human PACAP with an antibody selected from the group consisting of Ab1, Ab2, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab1.H, Ab5, Ab7, Ab11, Ab12, Ab4, Ab3, Ab6, Ab8, and Ab9, or an antigen-binding fragment thereof.
  • the anti-PACAP antibodies and antigen binding fragments of the invention may include human, humanized or chimerized anti-PACAP antibodies or antibody fragments that may specifically bind to at least one linear or conformational epitope bound by an anti-PACAP antibody selected from the group consisting of Ab1, Ab2, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab1.H, Ab5, Ab7, Ab11, Ab12, Ab4, Ab3, Ab6, Ab8, and Ab9 or an antigen-binding fragment thereof.
  • the epitope may be identified by alanine scanning, e.g., as disclosed in Example 12, or another art-recognized method.
  • the anti-PACAP antibodies and antigen binding fragments thereof of the invention may include human, humanized or chimerized anti-PACAP antibodies or antibody fragments thereof which may bind to the identical epitopes as any one of Ab1, Ab2, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab1.H, Ab5, Ab7, Ab11, Ab12, Ab4, Ab3, Ab6, Ab8, and Ab9 or an antigen-binding fragment thereof.
  • the epitope may be identified by alanine scanning, e.g., as disclosed in Example 12, or another art-recognized method.
  • the anti-PACAP antibodies or antigen binding fragments thereof of the invention may include human, humanized or chimerized anti-PACAP antibodies or antibody fragments which may specifically bind to an epitope on human PACAP or a fragment or variant thereof containing the corresponding amino acid residues wherein said epitope includes one or more of the following:
  • xii at least one of residues 5, 6, 9, 10, 12, 13, 14, and 17 of a human PACAP;
  • xiii at least one of residues 6, 8, 10, 11, 13, 14, 18, and 22 of a human PACAP
  • xiv. at least one of residues 8, 9, 10, 11, 12, 13, 14, 17, and 21 of a human PACAP;
  • xv. at least one of residues 4, 5, 6, 8, 9, 10, 12, 13, 14, and 17 of a human PACAP;
  • anti-PACAP antibodies or antigen binding fragments thereof of the invention may include human, humanized or chimerized anti-PACAP antibodies or antibody fragments which specifically bind to an epitope on human PACAP, or a fragment or variant thereof that may contain the corresponding amino acid residues that may include residues 8 and/or 14 of human PACAP.
  • the anti-PACAP antibodies or antigen binding fragments thereof may include a human, humanized or chimerized anti-PACAP antibodies or antibody fragments thereof, which specifically bind to an epitope on human PACAP (or a fragment or variant thereof containing the corresponding amino acid residues that may be present in human wild-type PACAP38) but not human wild-type human PACAP27.
  • the epitope may be identified by alanine scanning, e.g., as disclosed in Example 12 or another art-recognized method.
  • anti-PACAP antibodies or antigen binding fragments thereof of the invention may include human, humanized or chimerized anti-PACAP antibodies or antibody fragments thereof which may specifically bind to an epitope on human PACAP or a fragment or variant thereof that contain the corresponding amino acid residues, wherein said epitope may consist of the residues of any one of (i)-(xv) as described above.
  • the epitope may be identified by alanine scanning, e.g., as disclosed in Example 12, or another art-recognized method.
  • anti-PACAP antibodies or antigen binding fragments thereof may include human, humanized or chimerized anti-PACAP antibodies or antibody fragment which specifically bind to an epitope on human PACAP (or a fragment or variant thereof that may contain the corresponding amino acid residues) that may be present in human wild-type PACAP38 and in human wild-type human PACAP27.
  • the anti-PACAP antibodies or antigen binding fragments thereof may include human, humanized or chimerized anti-PACAP antibodies or antibody fragments thereof, which may specifically bind to human wild-type human PACAP38 but which may not bind or appreciably bind to human wild-type human PACAP27.
  • the invention may also embody anti-PACAP antibodies or antigen binding fragments thereof that may include human, humanized or chimerized anti-PACAP antibodies or antibody fragments thereof which may specifically interact with residues 28 and 31 of human PACAP38.
  • the anti-PACAP antibodies and antigen binding fragments thereof of the invention may include human, humanized or chimerized anti-PACAP antibodies or antibody fragments thereof which may have a K D for human PACAP38 which may be at least 10, 100, 1000, 10,000 or 100,000 fold lower (stronger) than the K D of said antibody or antibody fragment to human PACAP27.
  • the anti-PACAP antibodies and antigen binding fragments thereof of the invention may include human, humanized or chimerized anti-PACAP antibodies or antibody fragments thereof which do not bind to or do not appreciably bind to human Vasoactive Intestinal Peptide (“VIP”).
  • VIP Vasoactive Intestinal Peptide
  • Said anti-PACAP antibodies or antibody fragments thereof may have a KD for human PACAP which may be at least 10, 100, 1000, 10,000 or 100,000 fold lower (stronger) than the KD of said antibody or antibody fragment to human VIP.
  • a human, humanized or chimerized anti-PACAP antibody or antibody fragment as disclosed herein may inhibit or may neutralize at least one biological effect elicited by human PACAP.
  • the anti-PACAP antibodies and antigen binding fragments thereof of the invention may include human, humanized or chimerized anti-PACAP antibodies or antibody fragments thereof that may comprise one or more of the following properties: (a) inhibit, block or prevent PACAP activation of at least one of PAC1 receptor (“PAC1-R”), vasoactive intestinal peptide receptor type 1 (“VPAC1-R”), and/or vasoactive intestinal peptide receptor type 2 (“VPAC2-R”); (b) inhibit, block or prevent PACAP activation of each of PAC1-R, VPAC1-R, and VPAC2-R; (c) inhibit, block or prevent PACAP activation of PAC1-R; (d) are capable of inhibiting PACAP binding to at least one of PAC1-R, VPAC1-R, and/or VPAC2-R; (e) are capable of inhibiting PACAP binding to each of PAC1-R, VPAC1-R, and/or VPAC2-R; (f) may be capable of inhibiting PACAP binding to
  • GAG glycosaminoglycan
  • j do not inhibit PACAP-mediated binding of such antibody to the cell surface, e.g., via a GAG
  • GAG glycosaminoglycan
  • k do inhibit PACAP-mediated binding of such antibody to the cell surface, e.g., via a glycosaminoglycan (“GAG”)
  • (1) inhibit, block or prevent PACAP-induced cAMP production
  • m when administered to a subject reduce PACAP-induced vasodilation, photophobia, mast cell degranulation and/or neuronal activation.
  • the invention may also pertain to anti-PACAP antibodies and antigen binding fragments thereof that may be preferably human, humanized or chimerized anti-PACAP antibodies or antibody fragments which may be substantially non-immunogenic in human subjects.
  • the invention may also relate to anti-PACAP antibodies and antigen binding fragments thereof that may be preferably human, humanized or chimerized anti-PACAP antibodies or antibody fragments, which may be suitable for treating a human subject having an acute, episodic or chronic condition associated with increased vasodilation, photophobia, mast cell degranulation and/or neuronal activation.
  • the invention may also embody anti-PACAP antibodies and antigen binding fragments thereof that may be preferably human, humanized or chimerized anti-PACAP antibodies or antibody fragments that may comprise at least 2 complementarity determining regions (“CDRs”) of an anti-PACAP antibody that may be selected from Ab1, Ab2, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab1.H, Ab5, Ab7, Ab11, Ab12, Ab4, Ab3, Ab6, Ab8, or Ab9, preferably including the VH CDR3 and/or the VL CDR3.
  • CDRs complementarity determining regions
  • Another additional embodiment of the invention may include anti-PACAP antibodies and antigen binding fragments thereof that may be preferably human, humanized or chimerized anti-PACAP antibodies or antibody fragments that may comprise at least 3, at least 4, at least 5, or all 6 CDRS of an anti-PACAP antibody selected from Ab1, Ab2, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab1.H, Ab5, Ab7, Ab11, Ab12, Ab4, Ab3, Ab6, Ab8, or Ab9. In instances where all 6 CDRs may not be present, preferably at least the VH CDR3 and the VL CDR3 may be present.
  • anti-PACAP antibodies and antigen binding fragments thereof may comprise a sequence variant of any of the antibodies or antibody fragments of the invention that may contain one or more modifications that may putatively alter binding affinity or immunogenicity.
  • anti-PACAP antibodies and antigen binding fragments thereof comprise human, humanized, or chimerized anti-PACAP antibodies or antigen binding fragments thereof, which comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 4; a CDR2 sequence consisting of SEQ ID NO: 6; and a CDR3 sequence consisting of SEQ ID NO: 8; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 24; a CDR2 sequence consisting of SEQ ID NO: 26; and a CDR3 sequence consisting of SEQ ID NO: 28.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 2, and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 22.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 2, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 22.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 21.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 44; a CDR2 sequence consisting of SEQ ID NO: 46; and a CDR3 sequence consisting of SEQ ID NO: 48; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 64; a CDR2 sequence consisting of SEQ ID NO: 66; and a CDR3 sequence consisting of SEQ ID NO: 68.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 42, and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 62.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 42, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 62.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 41, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 61.
  • anti-PACAP antibodies and antigen binding fragments thereof according to the invention may comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 84; a CDR2 sequence consisting of SEQ ID NO: 86; and a CDR3 sequence consisting of SEQ ID NO: 88; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 104; a CDR2 sequence consisting of SEQ ID NO: 106; and a CDR3 sequence consisting of SEQ ID NO: 108.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 82, and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 102.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 82, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 102.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 81, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 101.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention may comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 124; a CDR2 sequence consisting of SEQ ID NO: 126; and a CDR3 sequence consisting of SEQ ID NO: 128; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 144; a CDR2 sequence consisting of SEQ ID NO: 146; and a CDR3 sequence consisting of SEQ ID NO: 148.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 122 and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 142.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 122, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 142. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 121, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 141.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention may comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 164; a CDR2 sequence consisting of SEQ ID NO: 166; and a CDR3 sequence consisting of SEQ ID NO: 168; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 184; a CDR2 sequence consisting of SEQ ID NO: 186; and a CDR3 sequence consisting of SEQ ID NO: 188.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 162, and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 182.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 162, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 182. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 161, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 181.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 204; a CDR2 sequence consisting of SEQ ID NO: 206; and a CDR3 sequence consisting of SEQ ID NO: 208; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 224; a CDR2 sequence consisting of SEQ ID NO: 226; and a CDR3 sequence consisting of SEQ ID NO: 228.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 202 and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 222.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 202, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 222. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 201, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 221.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 244; a CDR2 sequence consisting of SEQ ID NO: 246; and a CDR3 sequence consisting of SEQ ID NO: 248; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 264; a CDR2 sequence consisting of SEQ ID NO: 266; and a CDR3 sequence consisting of SEQ ID NO: 268.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 242 and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 262.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 242, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 262. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 241, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 261.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 284; a CDR2 sequence consisting of SEQ ID NO: 286; and a CDR3 sequence consisting of SEQ ID NO: 288; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 304; a CDR2 sequence consisting of SEQ ID NO: 306; and a CDR3 sequence consisting of SEQ ID NO: 308.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 282, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 302.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 282, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 302. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 281, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 301.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 324; a CDR2 sequence consisting of SEQ ID NO: 326; and a CDR3 sequence consisting of SEQ ID NO: 328; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 344; a CDR2 sequence consisting of SEQ ID NO: 346; and a CDR3 sequence consisting of SEQ ID NO: 348.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 322, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 342.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 322, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 342. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 321, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 341.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 364; a CDR2 sequence consisting of SEQ ID NO: 366; and a CDR3 sequence consisting of SEQ ID NO: 368; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 384; a CDR2 sequence consisting of SEQ ID NO: 386; and a CDR3 sequence consisting of SEQ ID NO: 388.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 362, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 382.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 362, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 382. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 361, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 381.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 484; a CDR2 sequence consisting of SEQ ID NO: 486; and a CDR3 sequence consisting of SEQ ID NO: 488; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 504; a CDR2 sequence consisting of SEQ ID NO: 506; and a CDR3 sequence consisting of SEQ ID NO: 508.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 482, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 502.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 482, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 502. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 481, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 501.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 524; a CDR2 sequence consisting of SEQ ID NO: 526; and a CDR3 sequence consisting of SEQ ID NO: 528; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 544; a CDR2 sequence consisting of SEQ ID NO: 546; and a CDR3 sequence consisting of SEQ ID NO: 548.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 522, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 542.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 522, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 542. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 521, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 541.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 564; a CDR2 sequence consisting of SEQ ID NO: 566; and a CDR3 sequence consisting of SEQ ID NO: 568; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 584; a CDR2 sequence consisting of SEQ ID NO: 586; and a CDR3 sequence consisting of SEQ ID NO: 588.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 562, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 582.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 562, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 582. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 561, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 581.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 604; a CDR2 sequence consisting of SEQ ID NO: 606; and a CDR3 sequence consisting of SEQ ID NO: 608; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 624; a CDR2 sequence consisting of SEQ ID NO: 626; and a CDR3 sequence consisting of SEQ ID NO: 628.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 602, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 622.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 602, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 622. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 601, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 621.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 644; a CDR2 sequence consisting of SEQ ID NO: 646; and a CDR3 sequence consisting of SEQ ID NO: 648; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 664; a CDR2 sequence consisting of SEQ ID NO: 666; and a CDR3 sequence consisting of SEQ ID NO: 668.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 642, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 662.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 642, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 662. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 641, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 661.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 724; a CDR2 sequence consisting of SEQ ID NO: 726; and a CDR3 sequence consisting of SEQ ID NO: 728; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 744; a CDR2 sequence consisting of SEQ ID NO: 746; and a CDR3 sequence consisting of SEQ ID NO: 748.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 722, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 742.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 722, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 742. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 721, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 741.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 764; a CDR2 sequence consisting of SEQ ID NO: 766; and a CDR3 sequence consisting of SEQ ID NO: 768; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 784; a CDR2 sequence consisting of SEQ ID NO: 786; and a CDR3 sequence consisting of SEQ ID NO: 788.
  • the anti-PACAP antibodies and antigen binding fragments thereof fragment can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 762, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 782.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 762, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 782.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 761, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 781.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 804; a CDR2 sequence consisting of SEQ ID NO: 806; and a CDR3 sequence consisting of SEQ ID NO: 808; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 824; a CDR2 sequence consisting of SEQ ID NO: 826; and a CDR3 sequence consisting of SEQ ID NO: 828.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 802, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 822.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 802, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 822. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 801, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 821.
  • An additional embodiment of the invention relates to anti-PACAP antibodies and antigen binding fragments, preferably human, humanized or chimerized anti-PACAP antibodies or antibody fragments, wherein said antibodies or antibody fragments may comprise an Fc region that may have been modified to alter at least one of effector function, half-life, proteolysis, or glycosylation, e.g., wherein the Fc region may contain one or more mutations that may alter or eliminate N- and/or O-glycosylation.
  • anti-PACAP antibodies and antigen binding fragments may bind to PACAP with a binding affinity (KD) of less than or equal to 5 ⁇ 10 ⁇ 5 M, 10 ⁇ 5 M, 5 ⁇ 10 ⁇ 6 M, 10 ⁇ 6 M, 5 ⁇ 10 ⁇ 7 M, 10 ⁇ 7 M, 5 ⁇ 10 ⁇ 8 M, 10 ⁇ 8 M, 5 ⁇ 10 ⁇ 9 M, 10 ⁇ 9 M, 5 ⁇ 10 ⁇ 10 M, 10 ⁇ 10 M, 5 ⁇ 10 ⁇ 11 M, 10 ⁇ 11 M, 5 ⁇ 10 ⁇ 12 M, 10 ⁇ 12 M, 5 ⁇ 10 ⁇ 13 M, or 10 ⁇ 13 M, e.g., as may determined by ELISA, bio-layer interferometry (“BLI”), KINEXA or surface plasmon resonance at 25° or 37° C.
  • KD binding affinity
  • anti-PACAP antibodies and antigen binding fragments preferably human, humanized or chimerized anti-PACAP antibodies or antibody fragments, wherein said antibodies or antibody fragments may bind to PACAP with a binding affinity (KD) of less than or equal to 5 ⁇ 10 ⁇ 10 M, 10 ⁇ 10 M, 5 ⁇ 10 ⁇ 11 M, 10 ⁇ 11 M, 5 ⁇ 10 ⁇ 12 M, or 10 ⁇ 12 M.
  • KD binding affinity
  • the anti-PACAP antibodies and antigen binding fragments, preferably human, humanized or chimerized anti-PACAP antibodies or antibody fragments, of the invention may neutralize or may inhibit PACAP activation of at least one of PAC1-R, VPAC1-R, or VPAC2-R; may neutralize or may inhibit PACAP activation of each of PAC1-R, VPAC1-R, and VPAC2-R; may neutralize or may inhibit PACAP activation of PAC1-R; may be capable of inhibiting or preventing PACAP binding to at least one of PAC1-R, VPAC1-R, or VPAC2-R; may be capable of inhibiting or preventing PACAP binding to each of PAC1-R, VPAC1-R, and VPAC2-R; may be capable of inhibiting or preventing PACAP binding to PAC1-R-expressing cells, VPAC1-R-expressing cells, and/or VPAC2-R-expressing cells; may inhibit or block PACAP-induced cAMP production; may, when administered to a subject, may reduce PACAP
  • anti-PACAP antibodies and antigen binding fragments may bind to PACAP with a K D that may be less than about 100 nM; with a K D that may be less than about 40 nM; with a K D that may be less than about 100 pM; with a K D that may be less than about 50 pM; with a K D that may be less than about 25 pM; or with a K D that may be between about 10 pM and about 100 pM.
  • the invention also embraces anti-PACAP antibodies and antigen binding fragments, preferably human, humanized or chimerized anti-PACAP antibodies or antibody fragments, that may have stronger binding affinity for PACAP as compared to VIP and/or that may not bind to VIP, e.g., wherein said antibodies or antibody fragments thereof may have an affinity to PACAP that may be at least 10-fold, 30-fold, 100-fold, 300-fold, 1000-fold, 3000-fold, 10000-fold, 30000-fold, 100000-fold, 300000-fold, 1000000-fold, 3000000-fold, 10000000-fold, 30000000-fold or more stronger than the affinity of said antibody or antibody fragment to VIP.
  • the invention pertains to anti-PACAP antibodies and antigen binding fragments, preferably human, humanized or chimerized anti-PACAP antibodies or antibody fragments, that may be attached to at least one effector moiety, e.g., wherein said effector moiety may comprise a chemical linker.
  • the invention pertains to anti-PACAP antibodies and antigen binding fragments, preferably human, humanized or chimerized anti-PACAP antibodies or antibody fragments, that may be attached to one or more detectable moieties, e.g., wherein said detectable moieties may comprise a fluorescent dye, enzyme, substrate, bioluminescent material, radioactive material, chemiluminescent moiety, and/or mixtures thereof.
  • the anti-PACAP antibodies and antigen binding fragments of the invention preferably human, humanized or chimerized anti-PACAP antibodies or antibody fragments, may be attached to one or more functional moieties.
  • Another embodiment of the invention relates to anti-idiotypic antibodies that may be produced against anti-PACAP antibodies or antibody fragments, wherein said anti-idiotypic antibodies optionally may neutralize one or more biological effects of the anti-PACAP antibody to which it may bind.
  • This embodiment of the invention may also relate to a method of using said anti-idiotypic antibody to monitor the in vivo levels of said anti-PACAP antibody or antibody fragment in a subject or to neutralize the in vivo effects of said anti-PACAP antibody in a subject.
  • composition of at least one anti-PACAP antibody or antibody fragment or anti-idiotypic antibody may be lyophilized; and/or wherein said composition may comprise a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, or mixture thereof.
  • Said composition of the invention may further comprise at least one other active agent, e.g., wherein the other active agent may be selected from the group consisting of a chemotherapeutic, an analgesic, an anti-inflammatory, an immunosuppressant, a cytokine, an antiproliferative, an antiemetic and/or a cytotoxin.
  • Said composition may also be lyophilized, stabilized, and/or may be formulated for administration by injection.
  • a further embodiment of the invention embraces an isolated nucleic acid sequence or nucleic acid sequences that may encode an anti-PACAP antibody or antibody fragment or anti-idiotypic antibody, and wherein said isolated nucleic acid sequence or nucleic acid sequences may be contained within a vector or vectors.
  • a host cell may comprise said isolated nucleic acid sequence or sequences, wherein said host cell may be a mammalian, bacterial, fungal, yeast, avian, amphibian, plant or insect cell; and/or said host cell may be a filamentous fungus or a yeast.
  • said host cell may be a yeast cell
  • the yeast may be selected from the following genera: Arxiozyma; Ascobotryozyma; Citeromyces; Debaryomyces; Dekkera; Eremothecium; Issatchenkia; Kazachstania; Kluyveromyces; Kodamaea; Lodderomyces; Pachysolen; Pichia; Saccharomyces; Saturnispora; Tetrapisispora; Torulaspora; Williopsis; and Zygosaccharomyces ; or the yeast may be genus Pichia .
  • the yeast host cell may be selected from Pichia pastoris, Pichia methanolica and Hansenula polymorpha ( Pichia angusta ).
  • the invention also relates to a method of expressing an anti-PACAP antibody or antibody fragment that may comprise culturing any of but not limited to the host cells disclosed herein under conditions that may provide for expression of said antibody or antibody fragment. Additionally, the invention pertains to said method wherein the host cell may be a yeast cell or CHO cell that may stably express and may secrete said antibody or antibody fragment.
  • the invention pertains to a method that may block, inhibit, block or neutralize one or more biological effects associated with PACAP in a subject that may comprise administering to said subject a therapeutically or prophylactically effective amount of a human, humanized or chimerized anti-PACAP antibody or antibody fragment that may antagonize, inhibit, neutralize or block at least one biological effect associated with human PACAP.
  • Another aspect of the invention relates to a method that may block, inhibit, or neutralize one or more biological effects associated with PACAP in a subject that may comprise administering to a subject a therapeutically or prophylactically effective amount of a human, humanized or chimerized anti-PACAP antibody or antibody fragment that may antagonize, inhibit, neutralize or block at least one biological effect associated with human PACAP and that may not substantially interact with (bind) VIP.
  • Another aspect of the invention generally relates to a method that may block, inhibit, or neutralize one or more biological effects, e.g., vasomotor effects, associated with PACAP in a subject that may comprise administering to a subject a therapeutically or prophylactically effective amount of a human, humanized or chimerized anti-PACAP antibody or antibody fragment that may comprise one or more of the following: inhibits, blocks or neutralizes at least one biological effect elicited by PACAP; neutralizes or inhibits PACAP activation of at least one of PAC1-R, VPAC1-R, and/or VPAC2-R; inhibits, blocks or neutralizes PACAP activation of each of PAC1-R, VPAC1-R, and VPAC2-R; neutralizes or inhibits PACAP activation of PAC1-R; inhibits PACAP binding to at least one of PAC1-R, VPAC1-R, and/or VPAC2-R; inhibits PACAP binding to each of PAC1-R, VPAC1-R,
  • GAG glycosaminoglycan
  • Another embodiment of the invention relates to a method that may block, inhibit, or neutralize vasodilation, e.g., vasodilation of the dural arteries, which may be associated with or may be elicited by PACAP in a subject that may comprise administering to a subject a therapeutically or prophylactically effective amount of a human, humanized or chimerized anti-PACAP antibody or antibody fragment that may block, inhibit, or neutralize vasodilation associated with, or elicited by PACAP.
  • Yet another embodiment of the invention pertains to a method that may treat or prevent the onset, frequency, severity or duration of headache or migraine, e.g., wherein said headache or migraine may be selected from migraine with aura, migraine without aura, hemiplegic migraine, cluster headache, migrainous neuralgia, chronic headache, chronic migraine, medication overuse headache, and tension headache, in a subject that may comprise administering to a subject in need thereof an effective amount of a human, humanized or chimerized anti-human PACAP antibody or antibody fragment that may elicit one or more of the following effects: inhibits or neutralizes at least one biological effect elicited by PACAP; neutralizes or inhibits PACAP activation of at least one of PAC1-R, VPAC1-R, and/or VPAC2-R; neutralizes or inhibits PACAP activation of each of PAC1-R, VPAC1-R, and VPAC2-R; neutralizes or inhibits PACAP activation of PAC1-R; inhibits PACAP binding to at least
  • GAG glycosaminoglycan
  • cAMP cyclic adenosine monophosphate
  • Another embodiment of the invention relates to a method of treating a human subject that may have an acute, episodic or chronic condition that may be associated with at least one of increased vasodilation, photophobia, mast cell degranulation and neuronal activation or a combination of said conditions that may comprise administering to a subject in need thereof an effective amount of an antagonistic human, humanized or chimerized anti-human PACAP antibody or antibody fragment.
  • the invention also pertains to any of the methods disclosed herein that may be effected by the administration of a therapeutically or prophylactically effective amount of at least one human, humanized or chimerized anti-PACAP antibody or antibody fragment; and/or wherein said anti-PACAP antibody may be a human antibody or antibody fragment; and/or wherein said anti-PACAP antibody may be a humanized antibody or antibody fragment; and/or wherein said anti-PACAP antibody may be a chimeric antibody or antibody fragment.
  • Another embodiment of the invention also relates to a method wherein an anti-PACAP antibody or antibody fragment of the invention may bind to PACAP27 and/or PACAP38 and may block PACAP27 and/or PACAP38 binding to PAC1-R, VPAC1-R, and/or VPAC2-R.
  • Another embodiment of the invention pertains to a method wherein said anti-PACAP antibody or antibody fragment may bind to PACAP27 and/or PACAP38 and may block PACAP27 and/or PACAP38 binding to each of PAC1-R, VPAC1-R, and VPAC2-R.
  • Yet another embodiment of the invention relates to a method wherein said anti-PACAP antibody or antibody fragment may bind to PACAP27 and/or PACAP38 and may block PACAP27 and/or PACAP38 binding to PAC1-R-expressing cells. Additionally, said anti-PACAP antibody or antibody fragment of the invention may have an affinity to PACAP that may be at least 10-fold, 30-fold, 100-fold, 300-fold, 1000-fold, 3000-fold, 10000-fold, 30000-fold, 100000-fold, 300000-fold, 1000000-fold, 3000000-fold, 10000000-fold, 30000000-fold or more stronger than the affinity of said antibody or antibody fragment to VIP.
  • the invention embraces a method that may block, inhibit, block or neutralize one or more biological effects associated with PACAP in a subject that may comprise administering to said subject a therapeutically or prophylactically effective amount of a human, humanized or chimerized anti-PACAP antibody or antibody fragment that may antagonize, inhibit, neutralize or blocks at least one biological effect associated with human PACAP, and wherein said subject may have a condition selected from the group consisting of migraine with aura, migraine without aura, hemiplegic migraines, cluster headaches, migrainous neuralgia, chronic headaches, tension headaches, general headaches, hot flush, photophobia, chronic paroxysmal hemicrania, secondary headaches due to an underlying structural problem in the head, secondary headaches due to an underlying structural problem in the neck, cranial neuralgia, sinus headaches, headache associated with sinusitis, allergy-induced headaches, allergy-induced migraines, trigeminal neuralgia, post-herpetic neuralgia, phantom limb pain
  • said subject may have a condition selected from the group consisting of migraine, headache and a pain associated disease or condition, wherein said headache or migraine may selected from the group consisting of migraine with aura, migraine without aura, hemiplegic migraine, cluster headache, migrainous neuralgia, chronic headache, chronic migraine, medication overuse headache, and tension headache.
  • said subject may have a ocular disorder associated with photophobia that may be selected from the group consisting of achromatopsia, aniridia, photophobia caused by an anticholinergic drug, aphakia, buphthalmos, cataracts, cone dystrophy, congenital abnormalities of the eye, viral conjunctivitis, corneal abrasion, corneal dystrophy, corneal ulcer, disruption of the corneal epithelium, ectopia lentis, endophthalmitis, eye trauma caused by disease, eye trauma caused by injury, eye trauma caused by infection, chalazion, episcleritis, glaucoma, keratoconus, optic nerve hypoplasia, hydrophthalmos, congenital glaucoma ulceris, optic neuritis, pigment dispersion syndrome, pupillary dilation, retinal detachment, scarring of the cornea, sclera and uveitis.
  • a ocular disorder associated with photophobia may be selected from the group consisting of achromat
  • said subject may have a nervous system-related or neurological condition associated with photophobia that may be selected from the group consisting of autism spectrum disorders, Chiari malformation, dyslexia, encephalitis, meningitis, subarachnoid hemorrhage, tumor of the posterior cranial fossa, ankylosing spondylitis, albinism, ariboflavinosis, benzodiazepines, chemotherapy, chikungunya, cystinosis, Ehlers-Danlos syndrome, hangover, influenza, infectious mononucleosis, magnesium deficiency, mercury poisoning, migraine, rabies, and tyrosinemia type II.
  • a nervous system-related or neurological condition associated with photophobia may be selected from the group consisting of autism spectrum disorders, Chiari malformation, dyslexia, encephalitis, meningitis, subarachnoid hemorrhage, tumor of the posterior cranial fossa, ankylosing spondylitis, albinism, a
  • said subject may have a photophobia associated disorder that may be selected from the group consisting of migraine with aura, migraine without aura, crizo, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, rhinitis, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, glabra, r
  • the invention also embraces any of the methods disclosed herein wherein the method relates to an antibody or antibody fragment that may be a human, humanized, or chimerized anti-PACAP antibody or antibody fragment; and/or wherein the antibody or antibody fragment may a human, humanized, or chimerized anti-PACAP antibody or antibody fragment; and/or wherein the antibody or antibody fragment may be an anti-PACAP antibody or antibody fragment that may comprise the same CDRs as an anti-PACAP antibody that may be selected from Ab1, Ab2, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab1.H, Ab5, Ab7, Ab11, Ab12, Ab4, Ab3, Ab6, Ab8, or Ab9.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise human, humanized, or chimerized anti-PACAP antibodies or antigen binding fragments thereof, which comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 4; a CDR2 sequence consisting of SEQ ID NO: 6; and a CDR3 sequence consisting of SEQ ID NO: 8; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 24; a CDR2 sequence consisting of SEQ ID NO: 26; and a CDR3 sequence consisting of SEQ ID NO: 28.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 2, and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 22.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 2, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 22.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 21.
  • the invention also embraces any of the methods disclosed herein wherein the anti-PACAP antibodies and antigen binding fragments thereof according to the invention, preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 44; a CDR2 sequence consisting of SEQ ID NO: 46; and a CDR3 sequence consisting of SEQ ID NO: 48; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 64; a CDR2 sequence consisting of SEQ ID NO: 66; and a CDR3 sequence consisting of SEQ ID NO: 68.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 42, and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 62.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 42, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 62.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 41, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 61.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention may comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 84; a CDR2 sequence consisting of SEQ ID NO: 86; and a CDR3 sequence consisting of SEQ ID NO: 88; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 104; a CDR2 sequence consisting of SEQ ID NO: 106; and a CDR3 sequence consisting of SEQ ID NO: 108.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 82, and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 102.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 82, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 102.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 81, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 101.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention may comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 124; a CDR2 sequence consisting of SEQ ID NO: 126; and a CDR3 sequence consisting of SEQ ID NO: 128; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 144; a CDR2 sequence consisting of SEQ ID NO: 146; and a CDR3 sequence consisting of SEQ ID NO: 148.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 122 and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 142.
  • the anti-PACAP antibodies and antigen binding fragments thereof may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 122, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 142. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 121, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 141.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention may comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 164; a CDR2 sequence consisting of SEQ ID NO: 166; and a CDR3 sequence consisting of SEQ ID NO: 168; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 184; a CDR2 sequence consisting of SEQ ID NO: 186; and a CDR3 sequence consisting of SEQ ID NO: 188.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 162, and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 182.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 162, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 182. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 161, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 181.
  • the anti-PACAP antibodies and antigen binding fragments thereof are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 204; a CDR2 sequence consisting of SEQ ID NO: 206; and a CDR3 sequence consisting of SEQ ID NO: 208; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 224; a CDR2 sequence consisting of SEQ ID NO: 226; and a CDR3 sequence consisting of SEQ ID NO: 228.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 202 and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 222.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 202, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 222. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 201, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 221.
  • the anti-PACAP antibodies and antigen binding fragments thereof are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 244; a CDR2 sequence consisting of SEQ ID NO: 246; and a CDR3 sequence consisting of SEQ ID NO: 248; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 264; a CDR2 sequence consisting of SEQ ID NO: 266; and a CDR3 sequence consisting of SEQ ID NO: 268.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 242 and/or (b) a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 262.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 242, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 262. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 241, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 261.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 284; a CDR2 sequence consisting of SEQ ID NO: 286; and a CDR3 sequence consisting of SEQ ID NO: 288; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 304; a CDR2 sequence consisting of SEQ ID NO: 306; and a CDR3 sequence consisting of SEQ ID NO: 308.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 282, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 302.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 282, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 302. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 281, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 301.
  • the anti-PACAP antibodies and antigen binding fragments thereof are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 324; a CDR2 sequence consisting of SEQ ID NO: 326; and a CDR3 sequence consisting of SEQ ID NO: 328; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 344; a CDR2 sequence consisting of SEQ ID NO: 346; and a CDR3 sequence consisting of SEQ ID NO: 348.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 322, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 342.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 322, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 342. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 321, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 341.
  • the anti-PACAP antibodies and antigen binding fragments thereof are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 364; a CDR2 sequence consisting of SEQ ID NO: 366; and a CDR3 sequence consisting of SEQ ID NO: 368; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 384; a CDR2 sequence consisting of SEQ ID NO: 386; and a CDR3 sequence consisting of SEQ ID NO: 388.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 362, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 382.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 362, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 382. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 361, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 381.
  • the invention also embraces any of the methods disclosed herein wherein the anti-PACAP antibodies and antigen binding fragments thereof according to the invention, are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 484; a CDR2 sequence consisting of SEQ ID NO: 486; and a CDR3 sequence consisting of SEQ ID NO: 488; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 504; a CDR2 sequence consisting of SEQ ID NO: 506; and a CDR3 sequence consisting of SEQ ID NO: 508.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 482, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 502.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 482, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 502. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 481, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 501.
  • the anti-PACAP antibodies and antigen binding fragments thereof are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 524; a CDR2 sequence consisting of SEQ ID NO: 526; and a CDR3 sequence consisting of SEQ ID NO: 528; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 544; a CDR2 sequence consisting of SEQ ID NO: 546; and a CDR3 sequence consisting of SEQ ID NO: 548.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 522, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 542.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 522, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 542. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 521, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 541.
  • the anti-PACAP antibodies and antigen binding fragments thereof are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 564; a CDR2 sequence consisting of SEQ ID NO: 566; and a CDR3 sequence consisting of SEQ ID NO: 568; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 584; a CDR2 sequence consisting of SEQ ID NO: 586; and a CDR3 sequence consisting of SEQ ID NO: 588.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 562, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 582.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 562, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 582. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 561, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 581.
  • the anti-PACAP antibodies and antigen binding fragments thereof are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 604; a CDR2 sequence consisting of SEQ ID NO: 606; and a CDR3 sequence consisting of SEQ ID NO: 608; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 624; a CDR2 sequence consisting of SEQ ID NO: 626; and a CDR3 sequence consisting of SEQ ID NO: 628.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 602, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 622.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 602, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 622. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 601, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 621.
  • the anti-PACAP antibodies and antigen binding fragments thereof are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 644; a CDR2 sequence consisting of SEQ ID NO: 646; and a CDR3 sequence consisting of SEQ ID NO: 648; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 664; a CDR2 sequence consisting of SEQ ID NO: 666; and a CDR3 sequence consisting of SEQ ID NO: 668.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 642, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 662.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 642, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 662. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 641, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 661.
  • the anti-PACAP antibodies and antigen binding fragments thereof are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 684; a CDR2 sequence consisting of SEQ ID NO: 686; and a CDR3 sequence consisting of SEQ ID NO: 688; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 704; a CDR2 sequence consisting of SEQ ID NO: 706; and a CDR3 sequence consisting of SEQ ID NO: 708.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 682, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 702.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 682, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 702. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 681, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 701.
  • the invention also embraces any of the methods disclosed herein wherein the anti-PACAP antibodies and antigen binding fragments thereof according to the invention, are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 724; a CDR2 sequence consisting of SEQ ID NO: 726; and a CDR3 sequence consisting of SEQ ID NO: 728; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 744; a CDR2 sequence consisting of SEQ ID NO: 746; and a CDR3 sequence consisting of SEQ ID NO: 748.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 722, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 742.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 722, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 742. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 721, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 741.
  • the anti-PACAP antibodies and antigen binding fragments thereof according to the invention are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 764; a CDR2 sequence consisting of SEQ ID NO: 766; and a CDR3 sequence consisting of SEQ ID NO: 768; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 784; a CDR2 sequence consisting of SEQ ID NO: 786; and a CDR3 sequence consisting of SEQ ID NO: 788.
  • the anti-PACAP antibodies and antigen binding fragments thereof fragment can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 762, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 782.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 762, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 782.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 761, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 781.
  • the anti-PACAP antibodies and antigen binding fragments thereof are preferably human, humanized, or chimerized anti-PACAP antibodies and antigen binding fragments thereof, and comprise (a) a variable heavy chain comprising a CDR1 sequence consisting of SEQ ID NO: 804; a CDR2 sequence consisting of SEQ ID NO: 806; and a CDR3 sequence consisting of SEQ ID NO: 808; and/or (b) a variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 824; a CDR2 sequence consisting of SEQ ID NO: 826; and a CDR3 sequence consisting of SEQ ID NO: 828.
  • the anti-PACAP antibodies and antigen binding fragments thereof can comprise a variable heavy chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 802, and/or a variable light chain comprising an amino acid sequence with at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 822.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 802, and/or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 822. More specifically, the anti-PACAP antibodies and antigen binding fragments thereof can comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 801, and/or (b) a light chain having the amino acid sequence of SEQ ID NO: 821.
  • the invention also relates to any of the methods disclosed herein wherein the anti-PACAP antibodies or antibody fragments may be selected from the group consisting of scFvs, camelbodies, nanobodies, Immunoglobulin New Antigen Receptor (“IgNAR”), fragment antigen binding (“Fab”) fragments, Fab′ fragments, MetMab like antibodies, monovalent antibody fragments, and F(ab′) 2 fragments. Additionally, the invention relates to any of the methods disclosed herein wherein the anti-PACAP antibody or antibody fragment may substantially or entirely lack N-glycosylation and/or O-glycosylation. Also, the invention pertains to any of the methods disclosed herein wherein the anti-PACAP antibody or antibody fragment may comprise a human constant domain, e.g., that of an IgG1, IgG2, IgG3, or IgG4 antibody.
  • the anti-PACAP antibody or antibody fragment may comprise an Fc region that may have been modified to alter at least one of effector function, half-life, proteolysis, or glycosylation, e.g., the Fc region may contain one or more mutations that alters or eliminates N- and/or O-glycosylation.
  • a further aspect of the invention relates to any of the methods disclosed herein wherein the anti-PACAP antibody or antibody fragment may bind to PACAP with a binding affinity (K D ) of less than or equal to 5 ⁇ 10 ⁇ 5 M, 10 ⁇ 5 M, 5 ⁇ 10 ⁇ 6 M, 10 ⁇ 6 M, 5 ⁇ 10 ⁇ 7 M, 10 ⁇ 7 M, 5 ⁇ 10 ⁇ 8 M, 10 ⁇ 8 M, 5 ⁇ 10 ⁇ 9 M, 10 ⁇ 9 M, 5 ⁇ 10 ⁇ 10 M, 10 ⁇ 10 M, 5 ⁇ 10 ⁇ 11 M, 10 ⁇ 11 M, 5 ⁇ 10 ⁇ 12 M, 10 ⁇ 12 M, 5 ⁇ 10 ⁇ 13 M, or 10 ⁇ 13 M.
  • K D binding affinity
  • said anti-PACAP antibody or antibody fragment of any of the methods disclosed herein may bind to PACAP with a binding affinity (K D ) of less than or equal to 5 ⁇ 10 ⁇ 10 M, 10 ⁇ 10 M, 5 ⁇ 10 ⁇ 11 M, 10 ⁇ 11 M, 5 ⁇ 10 ⁇ 12 M, or 10 ⁇ 12 M.
  • K D binding affinity
  • Another embodiment of the invention pertains any of the methods disclosed herein wherein the anti-PACAP antibody or antibody fragment may bind to PACAP with an off-rate (k off ) of less than or equal to 5 ⁇ 10 ⁇ 4 s ⁇ 1 , 10 ⁇ 4 s ⁇ 1 , 5 ⁇ 10 ⁇ 5 s ⁇ 1 , or 10 ⁇ 5 s ⁇ 1 .
  • the invention embraces any of the methods disclosed herein wherein the anti-PACAP antibody or antibody fragment may be directly or indirectly attached to a detectable label or therapeutic agent. Also, the invention relates to any of the methods disclosed herein wherein the anti-PACAP antibody or antibody fragment may bind to PACAP with a KD that may be less than about 100 nM, less than about 40 nM, less than about 1 nM, less than about 100 pM, less than about 50 pM, or less than about 25 pM. Also, the invention embraces any of the methods disclosed herein wherein the anti-PACAP antibody or antibody fragment may bind to PACAP with a KD that may be between about 10 pM and about 100 pM.
  • the invention further pertains to any of the methods disclosed herein wherein the method may further comprise administering separately or co-administering another agent, e.g., wherein the other agent may be selected from a chemotherapeutic, an analgesic, an anti-inflammatory, an immunosuppressant, a cytokine, an antiproliferative, an antiemetic or a cytotoxin.
  • another agent e.g., wherein the other agent may be selected from a chemotherapeutic, an analgesic, an anti-inflammatory, an immunosuppressant, a cytokine, an antiproliferative, an antiemetic or a cytotoxin.
  • the invention embraces any of the methods disclosed herein wherein the other therapeutic agent may be an analgesic, and said analgesic may be a non-steroidal anti-inflammatory drug (“NSAID”), an opioid analgesic, another antibody or a non-antibody biologic, and further wherein said other antibody may be an anti-NGF antibody or antibody fragment; and/or may be an anti-Calcitonin Gene-Related Peptide (“CGRP”) antibody or antibody fragment and/or an anti-CGRP receptor antibody or antibody fragment.
  • NSAID non-steroidal anti-inflammatory drug
  • CGRP anti-Calcitonin Gene-Related Peptide
  • the invention also pertains to any of the methods disclosed herein wherein said NSAID may be a cyclooxygenase 1 and/or cyclooxygenase 2 inhibitor; and/or wherein said NSAID may be selected from the group consisting of (1) propionic acid derivatives including ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen; (2) acetic acid derivatives including tolmetin and sulindac; (3) fenamic acid derivatives including mefenamic acid and meclofenamic acid; (4) biphenylcarboxylic acid derivatives including diflunisal and flufenisal; and (5) oxicams including piroxim, sudoxicam, and isoxicam.
  • propionic acid derivatives including ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen
  • acetic acid derivatives including tolmetin and sulindac
  • the invention further relates to any of the methods disclosed herein wherein said opioid analgesic may be selected from the group consisting of codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanil, meperidine, methadone, nalbuphine, propoxyphene, pentazocine, and pharmaceutically acceptable salts thereof; and/or wherein the opioid analgesic may be morphine or a morphine derivative or pharmaceutically acceptable salt thereof; and/or wherein the combined administration of the opioid analgesic and the anti-PACAP antibody or antigen binding fragment may increase the analgesic effect as compared to either the opioid analgesic or the anti-PACAP antibody or antigen binding fragment administered alone.
  • said opioid analgesic may be selected from the group consisting of codeine, dihydrocodeine, diacetylmorph
  • the invention relates to any of the methods disclosed herein wherein a subject of any of the methods disclosed herein may have previously received an anti-CGRP antibody or antibody fragment and/or an anti-CGRP receptor antibody or antibody fragment; and/or wherein said subject may be a migraineur who may have not adequately responded to anti-CGRP antibody and/or an anti-CGRP receptor antibody or antibody fragment treatment; and/or wherein said subject may have previously received at least one anti-CGRP antibody or antibody fragment and/or an anti-CGRP receptor antibody or antibody fragment administration that may have elicited an immune response to the anti-CGRP antibody or antibody fragment and/or the anti-CGRP receptor antibody or antibody fragment.
  • the invention embraces any of the methods disclosed herein wherein the antibody or antigen binding fragment thereof of the invention may ameliorate or treat one or more conditions associated with PACAP expression in a subject in need thereof, said condition may be selected from the group consisting of: migraine with aura, migraine without aura, hemiplegic migraines, cluster headaches, migrainous neuralgia, chronic headaches, tension headaches, general headaches, hot flush, photophobia, chronic paroxysmal hemicrania, secondary headaches due to an underlying structural problem in the head, secondary headaches due to an underlying structural problem in the neck, cranial neuralgia, sinus headaches, headache associated with sinusitis, allergy-induced headaches, allergy-induced migraines, trigeminal neuralgia, post-herpetic neuralgia, phantom limb pain, fibromyalgia, reflex sympathetic dystrophy, pain, chronic pain, inflammatory pain, post-operative incision pain, post-surgical pain, trauma-related pain, lower back pain, eye pain, tooth pain
  • an anti-PACAP antibody or antibody fragment or a method as disclosed herein may inhibit the effects of PACAP on vasodilation; and/or may inhibit the effects of PACAP on cAMP production; and/or may inhibit the effects of PACAP on PLC resulting in reduced Ca++ and PLD levels; and/or may inhibit the effects of PACAP on adenylate cyclase activity; and/or may inhibit the effects of PACAP on its binding to any or all of PAC1-R, VPAC1-R or VPAC2-R; and/or may inhibit the effects of PACAP on neurodevelopment; may inhibit the effects of PACAP on neuroprotection; and/or may inhibit the effects of PACAP on neuromodulation; and/or may inhibit the effects of PACAP on neurogenic inflammation; and/or may inhibit the effects of PACAP on nociception; and/or may modulate the interaction of PACAP with binding the cell surface, e.g.
  • At least one GAG may comprise one or more of heparin, chondroitin, keratin, and hyaluronic acid
  • said antibody or antibody fragment or method may block or inhibit receptor-independent cellular uptake of PACAP3 8 and/or PACAP27 and/or may inhibit or may block GAG-dependent uptake of PACAP38 and/or PACAP27 by cells.
  • a further embodiment of the invention relates to method of therapy or prophylaxis that may comprise the administration of an anti-PACAP antibody or antibody fragment of the invention.
  • the invention pertains to a composition that may be used in human therapy that may contain an anti-PACAP antibody or antibody fragment of the invention.
  • Said composition may contain another active agent, e.g., wherein the other agent may selected from a chemotherapeutic, an analgesic, an anti-inflammatory, an immunosuppressant, a cytokine, an antiproliferative, an antiemetic or a cytotoxin.
  • said other agent may be an analgesic
  • said analgesic may be a NSAID, an opioid analgesic, another antibody or a non-antibody biologic.
  • the other agent may be an analgesic that may be another antibody
  • the other antibody may be an anti-NGF antibody or antibody fragment
  • the other antibody may be an anti-Calcitonin Gene-Related Peptide (“CGRP”) antibody or antibody fragment and/or an anti-CGRP receptor antibody or antibody fragment.
  • CGRP Gene-Related Peptide
  • said other agent may be a NSAID
  • said NSAID may be a cyclooxygenase 1 and/or cyclooxygenase 2 inhibitor
  • said NSAID may be selected from the group consisting of (1) propionic acid derivatives including ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen; (2) acetic acid derivatives including tolmetin and sulindac; (3) fenamic acid derivatives including mefenamic acid and meclofenamic acid; (4) biphenylcarboxylic acid derivatives including diflunisal and flufenisal; and (5) oxicams including piroxim, sudoxicam, and isoxicam.
  • said other agent may be an opioid analgesic
  • said opioid analgesic may be selected from the group consisting of codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanil, meperidine, methadone, nalbuphine, propoxyphene, pentazocine, and pharmaceutically acceptable salts thereof; and/or said opioid analgesic may be morphine or a morphine derivative or pharmaceutically acceptable salt thereof; and/or said opioid analgesic and an anti-PACAP antibody or antigen binding fragment according to the invention may increase the analgesic effect as compared to either the opioid analgesic or the anti-PACAP antibody or antigen binding fragment administered alone.
  • an anti-PACAP antibody or fragment or composition according to the invention wherein the anti-PACAP antibody or fragment and another active agent may be combined therewith or may be administered in combination, may elicit a synergistic or additive effect on the treatment or prevention of a PACAP associated effect, e.g., migraine or on pain.
  • Another embodiment of the invention additionally embraces an anti-PACAP antibody or fragment or composition according the invention that may be used in therapy or diagnosis, e.g., migraine treatment or prophylaxis.
  • a further embodiment of the invention relates to an anti-PACAP antibody or fragment or composition according to the invention that may be used for treating one or more of hot flush, migraine with or without aura, hemiplegic migraine, cluster headache, migrainous neuralgia, chronic headache, chronic migraine, medication overuse headache or tension headache.
  • Another embodiment of the invention pertains an anti-PACAP antibody or fragment or composition according to the invention that may be used for ameliorating, controlling, reducing incidence of, or delaying the development or progression of headache, e.g., migraine with or without aura, hemiplegic migraine, cluster headache, migrainous neuralgia, chronic headache, chronic migraine, medication overuse headache or tension headache.
  • headache e.g., migraine with or without aura, hemiplegic migraine, cluster headache, migrainous neuralgia, chronic headache, chronic migraine, medication overuse headache or tension headache.
  • the use may be for a subject who may have previously received or may be receiving an anti-CGRP antibody or antibody fragment and/or an anti-CGRP receptor antibody or antibody fragment, and further wherein said subject may be a migraineur who may not have adequately responded to anti-CGRP antibody or antibody fragment and/or anti-CGRP receptor antibody or antibody fragment treatment; and/or wherein said subject may have previously received at least one anti-CGRP antibody or antibody fragment and/or anti-CGRP receptor antibody or antibody fragment administration that may have elicited an immune response to the anti-CGRP antibody or antibody fragment and/or anti-CGRP receptor antibody or antibody fragment.
  • FIG. 1A-1B provides the polypeptide sequences of the variable heavy chain region for antibodies Ab1, Ab1.H, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab22, and Ab23 (SEQ ID NOs: 2; 42; 82; 682; 642; 482; 722; 522; 762; 802; 562; 602; 122; 162; 202; 242; 282; 322; 362; 882; and 922, respectively) aligned by their FRs and CDRs.
  • FIG. 2A-2B provides the polypeptide sequences of the variable light chain region for antibodies Ab1, Ab1.H, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab22, and Ab23 (SEQ ID NOs: 22; 62; 102; 702; 662; 502; 742; 542; 782; 822; 582; 622; 142; 182; 222; 262; 302; 342; 382; 902; and 942, respectively) aligned by their FRs and CDRs.
  • FIG. 3A-3F provides the polynucleotide sequences encoding the variable heavy chain region for antibodies Ab1, Ab1.H, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab22, and Ab23 (SEQ ID NOs: 12; 52; 92; 692; 652; 492; 732; 532; 772; 812; 572; 612; 132; 172; 212; 252; 292; 332; 372; 892; and 932, respectively) aligned by their FRs and CDRs.
  • FIG. 4A-4E provide the polynucleotide sequences encoding the variable light chain region for antibodies Ab1, Ab1.H, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab22, and Ab23 (SEQ ID NOs: 32; 72; 112; 712; 672; 512; 752; 552; 792; 832; 592; 632; 152; 192; 232; 272; 312; 352; 392; 912; and 952, respectively) aligned by their FRs and CDRs.
  • FIG. 5 provides the polypeptide sequence coordinates for certain antibody heavy chain protein sequence features including the variable region and CDRs of the heavy chain for antibodies Ab1, Ab1.H, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab22, and Ab23.
  • FIG. 6 provides the polypeptide sequence coordinates for certain antibody heavy chain protein sequence features including the constant region and framework regions FRs of the heavy chain for antibodies Ab1, Ab1.H, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab22, and Ab23.
  • FIG. 7 provides the polypeptide sequence coordinates for certain antibody light chain protein sequence features including the variable region and CDRs of the light chain for antibodies Ab1, Ab1.H, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab22, and Ab23.
  • FIG. 8 provides the polypeptide sequence coordinates for certain antibody light chain protein sequence features including the constant region and framework regions FRs of the light chain for antibodies Ab1, Ab1.H, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab22, and Ab23.
  • FIG. 9 provides the polynucleotide sequence coordinates for certain antibody heavy chain DNA sequence features including the variable region and CDRs of the heavy chain for antibodies Ab1, Ab1.H, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab22, and Ab23.
  • FIG. 10 provides the polynucleotide sequence coordinates for certain antibody heavy chain DNA sequence features including the constant region and FRs of the heavy chain for antibodies Ab1, Ab1.H, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab22, and Ab23.
  • FIG. 11 provides the polynucleotide sequence coordinates for certain antibody light chain DNA sequence features including the variable region and CDRs of the light chain for antibodies Ab1, Ab1.H, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab22, and Ab23.
  • FIG. 12 provides the polynucleotide sequence coordinates for certain antibody light chain DNA sequence features including the constant region and FRs of the light chain for antibodies Ab1, Ab1.H, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab22, and Ab23.
  • FIG. 13A-V provides representative competitive binding data for Ab1 ( FIG. 13A ), Ab2 ( FIG. 13B ), Ab3 ( FIG. 13C ), Ab4 ( FIG. 13D ), Ab5 ( FIG. 13E ), Ab6 ( FIG. 13F ), Ab7 ( FIG. 13G ), Ab8 ( FIG. 13H ), Ab9 ( FIG. 13I ), Ab10 ( FIG. 13J ), Ab11 ( FIG. 13K ), Ab12 ( FIG. 13L ), Ab13 ( FIG. 13M ), Ab14 ( FIG. 13N ), Ab15 ( FIG. 13O ), Ab16 ( FIG. 13P ), Ab17 ( FIG. 13Q ), Ab18 ( FIG. 13R ), Ab19 ( FIG. 13S ), Ab1.H, ( FIG. 13T ), Ab22 ( FIG. 13U ), and Ab23 ( FIG. 13V ), respectively, obtained following the protocol in Example 1 infra.
  • FIG. 14A -BB provides representative data showing Ab1-mediated ( FIG. 14A ), Ab2-mediated ( FIG. 14B ), Ab3-mediated ( FIG. 14C ), Ab4-mediated ( FIG. 14D ), Ab5-mediated ( FIG. 14E ), Ab6-mediated ( FIG. 14F ), Ab7-mediated ( FIG. 14G ), Ab8-mediated ( FIG. 14H ), Ab9-mediated ( FIG. 14I ), Ab10-mediated ( FIG. 14J ), Ab11-mediated ( FIG. 14K ), Ab12-mediated ( FIG. 14L ), Ab13-mediated ( FIG. 14M ), Ab14-mediated ( FIG. 14N ), Ab15-mediated ( FIG. 14O ), Ab16-mediated ( FIG.
  • FIG. 14P Ab17-mediated ( FIG. 14Q ), Ab18-mediated ( FIG. 14R ), Ab19-mediated ( FIG. 14S ), Ab1.H-mediated ( FIG. 14T ), Ab10.H-mediated ( FIG. 14U ), Ab22-mediated ( FIG. 14V ), Ab23-mediated ( FIG. 14W ), Ab3.H-mediated ( FIG. 14X ), Ab4.H-mediated ( FIG. 14Y ), Ab5.H-mediated ( FIG. 14Z ), Ab9.H-mediated ( FIG. 14AA ), and Ab12.H-mediated ( FIG. 14BB ) inhibition of PACAP38 binding to PAC1-R-expressing PC-12 cells obtained following the protocol in Example 5 infra.
  • FIG. 15A-J provides representative data showing Ab1.H ( FIG. 15A ), Ab3.H ( FIG. 15B ), Ab4.H ( FIG. 15C ), Ab5.H ( FIG. 15D ), Ab9.H ( FIG. 15E ), Ab12.H ( FIG. 15F ), Ab10 ( FIG. 15G ), Ab10.H ( FIG. 15H ), Ab22 ( FIG. 15I ), and Ab23 ( FIG. 15J ) binding to PAC1-R-expressing PC-12 cells in the presence of PACAP38 obtained following the protocol in Example 6 infra.
  • FIG. 16A -BB provides representative data showing Ab1-mediated ( FIG. 16A ), Ab2-mediated ( FIG. 16B ), Ab3-mediated ( FIG. 16C ), Ab4-mediated ( FIG. 16D ), Ab5-mediated ( FIG. 16E ), Ab6-mediated ( FIG. 16F ), Ab7-mediated ( FIG. 16G ), Ab8-mediated ( FIG. 16H ), Ab9-mediated ( FIG. 16I ), Ab10-mediated ( FIG. 16J ), Ab11-mediated ( FIG. 16K ), Ab12-mediated ( FIG. 16L ), Ab13-mediated ( FIG. 16M ), Ab14-mediated ( FIG. 16N ), Ab15-mediated ( FIG. 16O ), Ab16-mediated ( FIG.
  • FIG. 16P Ab17-mediated ( FIG. 16Q ), Ab18-mediated ( FIG. 16R ), Ab19-mediated ( FIG. 16S ), Ab1.H-mediated ( FIG. 16T ), Ab10.H-mediated ( FIG. 16U ), Ab22-mediated ( FIG. 16V ), Ab23-mediated ( FIG. 16W ), Ab3.H-mediated ( FIG. 16X ), Ab4.H-mediated ( FIG. 16Y ), Ab5.H-mediated ( FIG. 16Z ), Ab9.H-mediated ( FIG. 16AA ), and Ab12.H-mediated ( FIG. 16BB ) inhibition of PACAP38-driven cAMP production via PAC1-R-expressing PC-12 cells obtained following the protocol in Example 1 infra.
  • FIG. 17A -BB provides representative data showing Ab1-mediated ( FIG. 17A ), Ab2-mediated ( FIG. 17B ), Ab3-mediated ( FIG. 17C ), Ab4-mediated ( FIG. 17D ), Ab5-mediated ( FIG. 17E ), Ab6-mediated ( FIG. 17F ), Ab7-mediated ( FIG. 17G ), Ab8-mediated ( FIG. 17H ), Ab9-mediated ( FIG. 17I ), Ab10-mediated ( FIG. 17J ), Ab11-mediated ( FIG. 17K ), Ab12-mediated ( FIG. 17L ), Ab13-mediated ( FIG. 17M ), Ab14-mediated ( FIG. 17N ), Ab15-mediated ( FIG. 17O ), Ab16-mediated ( FIG.
  • FIG. 17P Ab17-mediated ( FIG. 17Q ), Ab18-mediated ( FIG. 17R ), Ab19-mediated ( FIG. 17S ), Ab1.H-mediated ( FIG. 17T ), Ab10.H-mediated ( FIG. 17U ), Ab22-mediated ( FIG. 17V ), Ab23-mediated ( FIG. 17W ), Ab3.H-mediated ( FIG. 17X ), Ab4.H-mediated ( FIG. 17Y ), Ab5.H-mediated ( FIG. 17Z ), Ab9.H-mediated ( FIG. 17AA ), and Ab12.H-mediated ( FIG. 17BB ) inhibition of PACAP27-driven cAMP production via PAC1-R-expressing PC-12 cells obtained following the protocol in Example 1 infra.
  • FIG. 18A -BB provides representative data showing Ab1-mediated ( FIG. 18A ), Ab2-mediated ( FIG. 18B ), Ab3-mediated ( FIG. 18C ), Ab4-mediated ( FIG. 18D ), Ab5-mediated ( FIG. 18E ), Ab6-mediated ( FIG. 18F ), Ab7-mediated ( FIG. 18G ), Ab8-mediated ( FIG. 18H ), Ab9-mediated ( FIG. 18I ), Ab10-mediated ( FIG. 18J ), Ab11-mediated ( FIG. 18K ), Ab12-mediated ( FIG. 18L ), Ab13-mediated ( FIG. 18M ), Ab14-mediated ( FIG. 18N ), Ab15-mediated ( FIG. 18O ), Ab16-mediated ( FIG.
  • FIG. 18P Ab17-mediated ( FIG. 18Q ), Ab18-mediated ( FIG. 18R ), Ab19-mediated ( FIG. 18S ), Ab1.H-mediated ( FIG. 18T ), Ab10.H-mediated ( FIG. 18U ), Ab22-mediated ( FIG. 18V ), Ab23-mediated ( FIG. 18W ), Ab3.H-mediated ( FIG. 18X ), Ab4.H-mediated ( FIG. 18Y ), Ab5.H-mediated ( FIG. 18Z ), Ab9.H-mediated ( FIG. 18AA ), and Ab12.H-mediated ( FIG. 18BB ) inhibition of PACAP38-driven cAMP production via VPAC1-R-expressing CHO-K1 cells obtained following the protocol in Example 3 infra.
  • FIG. 19A -BB provides representative data showing Ab1-mediated ( FIG. 19A ), Ab2-mediated ( FIG. 19B ), Ab3-mediated ( FIG. 19C ), Ab4-mediated ( FIG. 19D ), Ab5-mediated ( FIG. 19E ), Ab6-mediated ( FIG. 19F ), Ab7-mediated ( FIG. 19G ), Ab8-mediated ( FIG. 19H ), Ab9-mediated ( FIG. 19I ), Ab10-mediated ( FIG. 19J ), Ab11-mediated ( FIG. 19K ), Ab12-mediated ( FIG. 19L ), Ab13-mediated ( FIG. 19M ), Ab14-mediated ( FIG. 19N ), Ab15-mediated ( FIG. 19O ), Ab16-mediated ( FIG.
  • FIG. 19P Ab17-mediated ( FIG. 19Q ), Ab18-mediated ( FIG. 19R ), Ab19-mediated ( FIG. 19S ), Ab1.H-mediated ( FIG. 19T ), Ab10.H-mediated ( FIG. 19U ), Ab22-mediated ( FIG. 19V ), Ab23-mediated ( FIG. 19W ), Ab3.H-mediated ( FIG. 19X ), Ab4.H-mediated ( FIG. 19Y ), Ab5.H-mediated ( FIG. 19Z ), Ab9.H-mediated ( FIG. 19AA ), and Ab12.H-mediated ( FIG. 19BB ) inhibition of PACAP38-driven cAMP production via VPAC2-R-expressing CHO-K1 cells obtained following the protocol in Example 4 infra.
  • FIG. 20 provides representative data showing a reduction in vasodilation obtained by administering Ab1.H following PACAP38 administration in a rabbit model, relative to a vehicle control, obtained following the protocol in Example 7 infra.
  • FIG. 21 provides representative data showing a reduction in vasodilation obtained by administering Ab10 following PACAP38 administration in a rabbit model, relative to an isotype antibody control, obtained following the protocol in Example 8 infra.
  • FIG. 22A provides epitope binning data for labeled Ab1 and unlabeled Ab10 obtained following the protocol in Example 9 infra.
  • FIG. 22B provides epitope binning data for unlabeled Ab1 and labeled Ab10 obtained following the protocol in Example 9 infra.
  • FIG. 23 provides representative data showing the in vivo effect of the administration of PACAP and an anti-PACAP antibody Ab1.H in a rodent photophobia model, which model detects the amount of time treated animals (mice) spend in the light per 5 minute intervals compared to appropriate control animals obtained following the protocol in Example 11 infra.
  • FIG. 24 provides representative data showing the in vivo effect of the administration of PACAP and anti-PACAP antibody Ab1.H in a rodent photophobia animal model, which detects the average amount of time treated animals (mice) spend in the light compared to appropriate control animals obtained following the protocol in Example 11 infra.
  • FIG. 25 provides representative data showing the in vivo effect of the administration of PACAP and an anti-PACAP antibody Ab10.H in a rodent photophobia model, which model detects the amount of time treated animals (mice) spend in the light compared to appropriate control animals obtained following the protocol in Example 11 infra
  • FIG. 26A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab1 to PACAP alanine scanning mutants 5A, 6A, 8A, 10A, and 13A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 26B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab1 to PACAP alanine scanning mutants 1A-4A, 7A, 9A, 11A, 12A, and 14A-38A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 27A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab2 to PACAP alanine scanning mutants 5A, 6A, 8A, 9A, 10A, 13A, and 14A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 27B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab2 to PACAP alanine scanning mutants 1A-4A, 7A, 11A, 12A, and 15A-38A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 28A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab13 to PACAP alanine scanning mutants 6A, 8A, 9A, 10A, and 13A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 28B presents results of binding kinetics measurements for binding of anti-PACAP antibody Ab13 to PACAP alanine scanning mutants 1A-5A, 7A, 11A, 12A, and 14A-38A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 29A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab14 to PACAP alanine scanning mutants 5A, 6A, 8A, 9A, 10A, and 13A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 29B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab14 to PACAP alanine scanning mutants 1A-4A, 7A, 11A, 12A, and 14A-38A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 30A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab15 to PACAP alanine scanning mutants 5A, 6A, 8A, 9A, 10A, 12A, 13A, and 14A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 30B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab15 to PACAP alanine scanning mutants 1A-4A, 7A, 11A, and 15A-38A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 31A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab16 to PACAP alanine scanning mutants 6A, 8A, 10A, and 13A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 31B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab16 to PACAP alanine scanning mutants 1A-5A, 7A, 9A, 11A, 12A, and 14A-38A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 32A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab17 to PACAP alanine scanning mutants 5A, 6A, 8A, 10A, and 13A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 32B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab17 to PACAP alanine scanning mutants 1A-4A, 7A, 9A, 11A, 12A, and 14A-38A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 33A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab18 to PACAP alanine scanning mutants 5A, 6A, 8A, 9A, 10A, 12A, and 13A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 33B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab18 to PACAP alanine scanning mutants 1A-4A, 7A, 11A, and 14A-38A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 34A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab19 to PACAP alanine scanning mutants 4A, 5A, 6A, 8A, 9A, 10A, 12A, 13A, 14A, and 17A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 35A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab5 to PACAP alanine scanning mutants 3A, 4A, 5A, 6A, 7A, 10A, 13A, and 14A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 36B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab7 to PACAP alanine scanning mutants 1A-5A, 7A, 9A, 12A, 15A-17A, and 19A-38A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 37A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab11 to PACAP alanine scanning mutants 6A, 8A, 10A, 11A, 13A, 14A, 18V, and 22A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 37B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab11 to PACAP alanine scanning mutants 1A-5A, 7A, 9A, 12A, 15A-17A, 19A-21A, and 23A-38A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 38B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab12 to PACAP alanine scanning mutants 1A-5A, 7A, 9A, 12A, 15A-17A, and 19A-38A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 39A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab4 to PACAP alanine scanning mutants 8A, 9A, 10A, 13A, 14A, 17A, and 18V, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 39B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab4 to PACAP alanine scanning mutants 1A-7A, 11A, 12A, 15A, 16A, and 19A-38A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 40A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab3 to PACAP alanine scanning mutants 8A, 9A, 10A, 11A, 12A, 13A, 14A, 17A, and 21A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 41A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab6 to PACAP alanine scanning mutants 5A, 6A, 9A, 10A, 12A, 13A, 14A, and 17A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 41B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab6 to PACAP alanine scanning mutants 1A-4A, 7A, 8A, 11A, 15A, 16A, and 18V-38A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 42B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab8 to PACAP alanine scanning mutants 1A-6A, 8A, 9A, 11A, 12A, and 15A-38A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 43A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab9 to PACAP alanine scanning mutants 7A, 10A, 12A, 13A, 14A, and 17A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 43B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab9 to PACAP alanine scanning mutants 1A-6A, 8A, 9A, 11A, 15A, 16A, and 18V-38A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 44B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab22 to PACAP alanine scanning mutants 1A-21A, 24V-26A, 29A, and 30A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 45A presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab23 to PACAP alanine scanning mutants 12A, 20A, 23A, 24V, 26A, 27A, and 28A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 45B presents results of surface plasmon resonance-based binding kinetics measurements for binding of anti-PACAP antibody Ab23 to PACAP alanine scanning mutants 1A-11A, 13A-19A, 21A, 22A, 25V, and 29A-31A, along with controls including wild-type PACAP (labelled huPACAP (1-38)) (positive control) and 1 ⁇ running buffer (negative control) obtained following the protocol in Example 12 infra.
  • wild-type PACAP labelled huPACAP (1-38)
  • 1 ⁇ running buffer negative control
  • FIG. 46B presents a summary of the effects of PACAP alanine scanning mutants on antibody binding.
  • VIP residue 28 is listed in column 1 of FIG. 46B .
  • PACAP residues are listed in the order of their spatial arrangement along the PACAP primary sequence from amino acid residues 28-38.
  • Column 3 of FIG. 46B provides the number corresponding to residue 28 for VIP and each of residues 28-38 for PACAP, as arranged spatially along their primary polypeptide sequences.
  • FIG. 47A presents a summary of the effects of PACAP alanine scanning mutants on antibody binding.
  • VIP residues are listed in the order of their spatial arrangement along the VIP primary sequence from amino acid residues 1-27.
  • PACAP residues are listed in the order of their spatial arrangement along the PACAP primary sequence from amino acid residues 1-27.
  • Column 3 of FIG. 47A provides the number corresponding to each residue from 1-27 for both VIP and PACAP, as arranged spatially along their primary polypeptide sequences.
  • FIG. 47B presents a summary of the effects of PACAP alanine scanning mutants on antibody binding.
  • VIP residue 28 is listed in column 1 of FIG. 47B .
  • PACAP residues are listed in the order of their spatial arrangement along the PACAP primary sequence from amino acid residues 28-38.
  • Column 3 of FIG. 47B provides the number corresponding to residue 28 for VIP and for each of 28-38 for PACAP, as arranged spatially along their primary polypeptide sequences.
  • PACAP includes any mammalian form of PACAP, and in particular encompasses the following Homo sapiens PACAP27 and Homo sapiens PACAP38 amino acid sequences:
  • HSDGIFTDSYSRYRKQMAVKKYLAAVL (SEQ ID NO: 1242), wherein the C-terminal leucine is amidated; but also any mutants, splice variants, isoforms, orthologs, homologs, and variants of this sequence.
  • Photophobia herein refers to a symptom of abnormal intolerance to visual perception of light, sometimes additionally defined by abnormal or irrational fear of light, or by presence of actual physical photosensitivity of the eyes.
  • photophobia includes in particular light aversion associated with migraine, cluster headaches and other neurological causes of light aversive behavior that can trigger a migraine or cluster headache.
  • Patients/subjects can develop photophobia as a result of several different medical conditions, related to the eye or the nervous system.
  • Photophobia can be caused by an increased response to light starting at any step in the visual system such as: (i) too much light entering the eye, (ii) too much light can enter the eye if it is damaged, such as with corneal abrasion and retinal damage, or if a pupil(s) is unable to normally constrict (seen with damage to the oculomotor nerve), (iii) overstimulation of the photoreceptors in the retina, (iv) excessive electric impulses to the optic nerve, and (v) excessive response in the central nervous system.
  • Effective treatment or prevention of photophobia refers to inhibiting light aversive behavior or photophobia or inhibiting the onset of light aversive behavior or photophobia in a subject in need thereof, e.g., a subject having an active migraine attack or cluster headache or a subject prone to migraine or cluster headaches, or one of the other photophobia-associated disorders identified herein after administration of an effective amount of an anti-PACAP antibody or antigen binding fragment thereof according to the invention.
  • the treatment may be effected as a monotherapy or in association with another active agent such as topiramate or dihydroergotamine by way of example.
  • migraine refers to a complex and disabling neurological disorder that may progress during four stages: prodrome, aura, headache, and postdrome.
  • a migraine is defined by the International Headache Society as a headache that lasts for 4-72 hours and is characterized by at least two of the following: unilateral localization, pulsating quality, moderate to severe pain intensity; and aggravation by movement such as walking.
  • the headache must be accompanied by at least one of the following: nausea and/or vomiting, photophobia, or phonophobia.
  • a migraine may also be accompanied by aura, which typically precedes the deadline during the premonition or prodrome phase, and often results in visual changes, e.g., a scintillating scotoma that moves across the visual field.
  • headache refers to pain in any region of the head. Headaches may occur on one or both sides of the head, be isolated to a certain location, radiate across the head from one point, or have a vise-like quality. A headache may be a sharp pain, throbbing sensation or dull ache. Headaches may appear gradually or suddenly, and they may last less than an hour or for several days.
  • Pain associated disease or condition refers to any disease or condition defined, in whole or in part, by acute and/or chronic pain. Pain is generally defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Pain may be classified as neurogenic, neuropathic, inflammatory, or nociceptic.
  • opioid analgesic refers to all drugs, natural or synthetic, with morphine-like actions.
  • the synthetic and semi-synthetic opioid analgesics are derivatives of five chemical classes of compound: phenanthrenes; phenylheptylamines; phenylpiperidines; morphinans; and benzomorphans, all of which are within the scope of the term.
  • NSAID refers to a non-steroidal anti-inflammatory compound. NSAIDs are categorized by virtue of their ability to inhibit cyclooxygenase. Cyclooxygenase 1 and cyclooxygenase 2 are two major isoforms of cyclooxygenase and most standard NSAIDs are mixed inhibitors of the two isoforms.
  • NSAIDs fall within one of the following five structural categories: (1) propionic acid derivatives, such as ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen; (2) acetic acid derivatives, such as tolmetin and sulindac; (3) fenamic acid derivatives, such as mefenamic acid and meclofenamic acid; (4) biphenylcarboxylic acid derivatives, such as diflunisal and flufenisal; and (5) oxicams, such as piroxim, sudoxicam, and isoxicam.
  • propionic acid derivatives such as ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen
  • acetic acid derivatives such as tolmetin and sulindac
  • fenamic acid derivatives such as mefenamic acid and meclofenamic acid
  • biphenylcarboxylic acid derivatives such as diflunisal and
  • COX-2 inhibitors have been described, e.g., in U.S. Pat. Nos. 5,616,601; 5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,475,995; 5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and 5,130,311, all of which are hereby incorporated by reference.
  • COX-2 inhibitors include celecoxib (SC-58635), DUP-697, flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid (6-MNA), rofecoxib, MK-966, nabumetone (prodrug for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations thereof.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: improvement in any aspect of PACAP-related conditions such as migraine or headache.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: improvement in any aspect of PACAP-related conditions such as migraine or headache.
  • this includes lessening severity, alleviation of pain intensity, and other associated symptoms, reducing frequency of recurrence, increasing the quality of life of those suffering from the headache, and decreasing dose of other medications required to treat the headache.
  • migraine other associated symptoms include, but are not limited to, nausea, vomiting, and sensitivity to light, sound, and/or movement.
  • cluster headache other associated symptoms include, but are not limited to swelling under or around the eyes, excessive tears, red eye, rhinorrhea or nasal congestion, and red flushed face.
  • Reducing incidence or “prophylaxis” or “prevention” means any of reducing severity for a particular disease, condition, symptom, or disorder (the terms disease, condition, and disorder are used interchangeably throughout the application).
  • Reduction in severity includes reducing drugs and/or therapies generally used for the condition by, for example, reducing the need for, amount of, and/or exposure to drugs or therapies.
  • Reduction in severity also includes reducing the duration, and/or frequency of the particular condition, symptom, or disorder (including, for example, delaying or increasing time to next episodic attack in an individual).
  • “Ameliorating” headache or one or more symptoms of headache or migraine or other PACAP-related condition means a lessening or improvement of one or more symptoms of the condition, e.g., headache or migraine as compared to not administering an anti-PACAP antagonist antibody. “Ameliorating” also includes shortening or reduction in duration of a symptom.
  • controlling headache or “controlling migraine” or “controlling” another PACAP-related condition refers to maintaining or reducing severity or duration of one or more symptoms of the condition, e.g., headache or migraine or frequency of headache or migraine attacks in an individual (as compared to the level before treatment).
  • the duration or severity of head pain, or frequency of attacks is reduced by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% in the individual as compared to the level before treatment.
  • the reduction in the duration or severity of head pain, or frequency of attacks can last for any length of time, e.g., 2 weeks, 4 weeks (1 month), 8 weeks (2 months), 16 weeks (3 months), 4 months, 5 months, 6 months, 9 months, 12 months, etc.
  • “delaying” the development of a PACAP-related condition such as migraine or headache means to defer, hinder, slow, retard, stabilize, and/or postpone progression of the condition or disease. This delay can be of varying lengths of time, depending on the history of the condition or disease and/or individuals being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop headache (e.g., migraine).
  • a method that “delays” development of the symptom is a method that reduces probability of developing the symptom in a given time frame and/or reduces extent of the symptoms in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects.
  • “Development” or “progression” of a PACAP-related condition such as migraine or headache means initial manifestations and/or ensuing progression of the disorder. Development of headache or migraine can be detectable and assessed using standard clinical techniques as well known in the art. However, development also refers to progression that may be undetectable. For purpose of this invention, development, or progression refers to the biological course of the symptoms. “Development” includes occurrence, recurrence, and onset. As used herein “onset” or “occurrence” of a condition such as headache or migraine includes initial onset and/or recurrence.
  • an “effective dosage” or “effective amount” of drug, compound, or pharmaceutical composition is an amount sufficient to effect beneficial or desired results.
  • beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the outset of the disease, including biochemical, histological, and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
  • beneficial or desired results include clinical results such as reducing pain intensity, duration, or frequency of headache attack, and decreasing one or more symptoms resulting from headache (biochemical, histological, and/or behavioral), including its complications and intermediate pathological phenotypes presenting during development of the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication, and/or delaying the progression of the disease of patients.
  • An effective dosage can be administered in one or more administrations.
  • an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly.
  • an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.
  • an “effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
  • a “suitable host cell” or “host cell” generally includes any cell wherein the subject anti-PACAP antibodies and antigen binding fragments thereof can be produced recombinantly using techniques and materials readily available.
  • the anti-PACAP antibodies and antigen binding fragments thereof of the present invention can be produced in genetically engineered host cells according to conventional techniques.
  • Suitable host cells are those cell types that can be transformed or transfected with exogenous DNA and grown in culture, and include bacteria, fungal cells (e.g., yeast), and cultured higher eukaryotic cells (including cultured cells of multicellular organisms), particularly cultured mammalian cells, e.g., human or non-human mammalian cells.
  • these antibodies may be expressed in CHO cells.
  • the antibodies may be expressed in mating competent yeast, e.g., any haploid, diploid or tetraploid yeast that can be grown in culture.
  • Yeast useful in fermentation expression methods may exist in a haploid, diploid, or other polyploid form.
  • the cells of a given ploidy may, under appropriate conditions, proliferate for an indefinite number of generations in that form. Diploid cells can also sporulate to form haploid cells. Sequential mating can result in tetraploid strains through further mating or fusion of diploid strains.
  • the present invention contemplates the use of haploid yeast, as well as diploid or other polyploid yeast cells produced, for example, by mating or spheroplast fusion.
  • such yeast may include members of the Saccharomycetaceae family, which includes the genera Arxiozyma; Ascobotryozyma; Citeromyces; Debaryomyces; Dekkera; Eremothecium; Issatchenkia; Kazachstania; Kluyveromyces; Kodamaea; Lodderomyces; Pachysolen; Pichia; Saccharomyces; Saturnispora; Tetrapisispora; Torulaspora; Williopsis ; and Zygosaccharomyces .
  • Other types of yeast potentially useful in the invention include Yarrowia; Rhodosporidium; Candida; Hansenula; Filobasium; Sporidiobolus; Bullera; Leucosporidium and Filobasidella.
  • the mating competent yeast used for antibody expression may comprise a member of the genus Pichia .
  • the mating competent yeast of the genus Pichia is one of the following species: Pichia pastoris, Pichia methanolica , and Hansenula polymorpha ( Pichia angusta ).
  • the mating competent yeast of the genus Pichia is the species Pichia pastoris.
  • a “selectable marker” herein refers to a gene or gene fragment that confers a growth phenotype (physical growth characteristic) on a cell receiving that gene as, for example through a transformation event.
  • the selectable marker allows that cell to survive and grow in a selective growth medium under conditions in which cells that do not receive that selectable marker gene cannot grow.
  • Selectable marker genes generally fall into several types, including positive selectable marker genes such as a gene that confers on a cell resistance to an antibiotic or other drug, temperature when two temperature sensitive (“ts”) mutants are crossed or a is mutant is transformed; negative selectable marker genes such as a biosynthetic gene that confers on a cell the ability to grow in a medium without a specific nutrient needed by all cells that do not have that biosynthetic gene, or a mutagenized biosynthetic gene that confers on a cell inability to grow by cells that do not have the wild type gene; and the like. Suitable markers include but are not limited to: ZEO; G418; LYS3; MET1; MET3a; ADE1; ADE3; URA3; and the like.
  • an “expression vector” herein refers to DNA vectors containing elements that facilitate manipulation for the expression of a foreign protein within the target host cell, e.g., a bacterial, insect, yeast, plant, amphibian, reptile, avian, or mammalian cell, and most typically a yeast or mammalian cell, e.g., a CHO cell.
  • a bacterial host e.g. E. coli
  • vectors will include sequences to facilitate such manipulations, including a bacterial origin of replication and appropriate bacterial selection marker. Selection markers encode proteins necessary for the survival or growth of transformed host cells grown in a selective culture medium.
  • Selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media.
  • Exemplary vectors and methods for transformation of yeast are described, for example, in Burke, D., Dawson, D., & Stearns, T., Methods in yeast genetics: a Cold Spring Harbor Laboratory course manual , Plainview, N.Y.: Cold Spring Harbor Laboratory Press (2000).
  • Expression vectors for use in the methods of the invention may include yeast or mammalian specific sequences, including a selectable auxotrophic or drug marker for identifying transformed host strains. A drug marker may further be used to amplify copy number of the vector in a yeast host cell.
  • the polypeptide coding sequence of interest is operably linked to transcriptional and translational regulatory sequences that provide for expression of the polypeptide in the desired host cells, e.g., yeast or mammalian cells.
  • These vector components may include, but are not limited to, one or more of the following: an enhancer element, a promoter, and a transcription termination sequence. Sequences for the secretion of the polypeptide may also be included, e.g. a signal sequence, and the like.
  • An origin of replication e.g., a yeast origin of replication, is optional, as expression vectors are often integrated into the host cell genome.
  • the polypeptide of interest is operably linked, or fused, to sequences providing for optimized secretion of the polypeptide from yeast diploid cells.
  • Nucleic acids are “operably linked” when placed into a functional relationship with another nucleic acid sequence.
  • DNA for a signal sequence is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence.
  • “operably linked” means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers do not have to be contiguous.
  • Linking is accomplished by ligation at convenient restriction sites or alternatively via a PCR/recombination method familiar to those skilled in the art (GATEWAY® Technology; Invitrogen, Carlsbad Calif.). If such sites do not exist, the synthetic oligonucleotide adapters or linkers are used in accordance with conventional practice.
  • Promoters are untranslated sequences located upstream (5′) to the start codon of a structural gene (generally within about 100 to 1000 bp) that control the transcription and translation of particular nucleic acid sequences to which they are operably linked. Such promoters fall into several classes: inducible, constitutive, and repressible promoters (that increase levels of transcription in response to absence of a repressor). Inducible promoters may initiate increased levels of transcription from DNA under their control in response to some change in culture conditions, e.g., the presence or absence of a nutrient or a change in temperature.
  • the promoter fragment may also serve as the site for homologous recombination and integration of the expression vector into the same site in the host cell, e.g., yeast cell, genome; alternatively, a selectable marker may be used as the site for homologous recombination.
  • a selectable marker may be used as the site for homologous recombination.
  • Pichia transformation is described in Cregg et al., Mol. Cell. Biol., 5:3376-3385 (1985). Suitable promoters for use in different eukaryotic and prokaryotic cells are well known and commercially available.
  • the polypeptides of interest may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, e.g. a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide.
  • a heterologous polypeptide e.g. a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide.
  • the signal sequence may be a component of the vector, or it may be a part of the polypeptide coding sequence that is inserted into the vector.
  • the heterologous signal sequence selected preferably is one that is recognized and processed through one of the standard pathways available within the host cell, e.g., a mammalian cell, an insect cell, or a yeast cell. Additionally, these signal peptide sequences may be engineered to provide for enhanced secretion in expression systems.
  • Secretion signals of interest also include mammalian and yeast signal sequences, which may be heterologous to the protein being secreted, or may be a native sequence for the protein being secreted.
  • Signal sequences include pre-peptide sequences, and in some instances may include propeptide sequences.
  • Many such signal sequences are known in the art, including the signal sequences found on immunoglobulin chains, e.g., K28 preprotoxin sequence, PHA-E, FACE, human MCP-1, human serum albumin signal sequences, human Ig heavy chain, human Ig light chain, and the like. For example, see Hashimoto et. al., Protein Eng., 11(2):75 (1998); and Kobayashi et. al., Therapeutic Apheresis, 2(4):257 (1998)).
  • Transcription may be increased by inserting a transcriptional activator sequence into the vector.
  • These activators are cis-acting elements of DNA, usually about from 10 to 300 bp, which act on a promoter to increase its transcription.
  • Transcriptional enhancers are relatively orientation and position independent, having been found 5′ and 3′ to the transcription unit, within an intron, as well as within the coding sequence itself. The enhancer may be spliced into the expression vector at a position 5′ or 3′ to the coding sequence, but is preferably located at a site 5′ from the promoter.
  • Expression vectors used in eukaryotic host cells may also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from 3′ to the translation termination codon, in untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA.
  • Plasmids from the transformants are prepared, analyzed by restriction endonuclease digestion, and/or sequenced.
  • recombination methods based on specific attachment (“att”) sites and recombination enzymes may be used to insert DNA sequences into a vector.
  • att specific attachment
  • Such methods are described, for example, by Landy, Ann. Rev. Biochem., 58:913-949 (1989); and are known to those of skill in the art.
  • Such methods utilize intermolecular DNA recombination that is mediated by a mixture of lambda and E. coli —encoded recombination proteins. Recombination occurs between att sites on the interacting DNA molecules.
  • att sites see Weisberg and Landy, Site - Specific Recombination in Phage Lambda , in Lambda II , p.
  • the DNA segments flanking the recombination sites are switched, such that after recombination, the att sites are hybrid sequences comprised of sequences donated by each parental vector.
  • the recombination can occur between DNAs of any topology.
  • Att sites may be introduced into a sequence of interest by ligating the sequence of interest into an appropriate vector; generating a PCR product containing att B sites through the use of specific primers; generating a cDNA library cloned into an appropriate vector containing att sites; and the like.
  • Folding refers to the three-dimensional structure of polypeptides and proteins, where interactions between amino acid residues act to stabilize the structure. While non-covalent interactions are important in determining structure, usually the proteins of interest will have intra- and/or intermolecular covalent disulfide bonds formed by two cysteine residues. For naturally occurring proteins and polypeptides or derivatives and variants thereof, the proper folding is typically the arrangement that results in optimal biological activity, and can conveniently be monitored by assays for activity, e.g. ligand binding, enzymatic activity, etc.
  • assays based on biological activity will be less meaningful.
  • the proper folding of such molecules may be determined on the basis of physical properties, energetic considerations, modeling studies, and the like.
  • the expression host may be further modified by the introduction of sequences encoding one or more enzymes that enhance folding and disulfide bond formation, i.e. foldases, chaperonins, etc.
  • sequences may be constitutively or inducibly expressed in the yeast host cell, using vectors, markers, etc. as known in the art.
  • sequences, including transcriptional regulatory elements sufficient for the desired pattern of expression are stably integrated in the yeast genome through a targeted methodology.
  • the eukaryotic protein disulfide isomerase (“PDI”) is not only an efficient catalyst of protein cysteine oxidation and disulfide bond isomerization, but also exhibits chaperone activity. Co-expression of PDI can facilitate the production of active proteins having multiple disulfide bonds. Also of interest is the expression of immunoglobulin heavy chain binding protein (“BIP”); cyclophilin; and the like.
  • BIP immunoglobulin heavy chain binding protein
  • each of the haploid parental strains expresses a distinct folding enzyme, e.g. one strain may express BIP, and the other strain may express PDI or combinations thereof.
  • Cultured mammalian cells are also preferred exemplary hosts for production of the disclosed anti-PACAP antibodies and antigen binding fragments thereof.
  • CHO cells are particularly suitable for expression of antibodies.
  • Many procedures are known in the art for manufacturing monoclonal antibodies in mammalian cells. (See, Galfre, G. and Milstein, C., Methods Enzym., 73:3-46, 1981; Basalp et al., Turk. J. Biol., 24:189-196, 2000; Wurm, F. M., Nat. Biotechnol., 22:1393-1398, 2004; and Li et al., mAbs, 2(5):466-477, 2010).
  • common host cell lines employed in mammalian monoclonal antibody manufacturing schemes include, but are not limited to, human embryonic retinoblast cell line PER.C6® (Crucell N.V., Leiden, The Netherlands), NS0 murine myeloma cells (Medical Research Council, London, UK), CV1 monkey kidney cell line, 293 human embryonic kidney cell line, BHK baby hamster kidney cell line, VERO African green monkey kidney cell line, human cervical carcinoma cell line HELA, MDCK canine kidney cells, BRL buffalo rat liver cells, W138 human lung cells, HepG2 human liver cells, MMT mouse mammary tumor cells, TRI cells, MRC5 cells, Fs4 cells, myeloma or lymphoma cells, or Chinese Hamster ( Cricetulus griseus ) Ovary (CHO) cells, and the like.
  • human embryonic retinoblast cell line PER.C6® Crucell N.V., Leiden, The Netherlands
  • NS0 cells are a non-Ig secreting, non-light chain-synthesizing subclone of NS-1 cells that are resistant to azaguanine.
  • CHO-DXB11 CHO-DUKX
  • CHO-pro3, CHO-DG44 CHO 1-15
  • CHO DP-12 CHO DP-12
  • Lec2, M1WT3, Lec8, pgsA-745 and the like, all of which are genetically altered to optimize the cell line for various parameters.
  • Monoclonal antibodies are commonly manufactured using a batch fed method whereby the monoclonal antibody chains are expressed in a mammalian cell line and secreted into the tissue culture medium in a bioreactor. Medium (or feed) is continuously supplied to the bioreactor to maximize recombinant protein expression. Recombinant monoclonal antibody is then purified from the collected media.
  • nucleic acids encoding the antibody or fragment thereof are generally inserted into a replicable vector for further cloning (amplification of the DNA) or for expression.
  • DNA encoding the antibody is readily isolated or synthesized using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to DNAs encoding the heavy and light chains of the antibody).
  • the vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Selection of promoters, terminators, selectable markers, vectors, and other elements is a matter of routine design within the level of ordinary skill in the art. Many such elements are known in the art and are available through commercial suppliers.
  • the antibodies of this invention may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, which is preferably a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide.
  • a heterologous polypeptide which is preferably a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide.
  • the homologous or heterologous signal sequence selected preferably is one that is recognized and processed (i.e., cleaved by a signal peptidase) by the host cell.
  • mammalian signal sequences as well as viral secretory leaders, for example, the herpes simplex gD signal, are available.
  • Such expression vectors and cloning vectors will generally contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells.
  • this sequence is one that enables the vector to replicate independently of the host chromosomal DNA, and includes origins of replication or autonomously replicating sequences.
  • the origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria
  • the 2mu plasmid origin is suitable for yeast
  • various viral origins Simian Virus 40 (“SV40”), polyoma, adenovirus, vesicular stomatitis virus (“VSV”), or bovine papillomavirus (“BPV”) are useful for cloning vectors in mammalian cells.
  • SV40 Sesimian Virus 40
  • VSV vesicular stomatitis virus
  • BMV bovine papillomavirus
  • the origin of replication component is not needed for mammalian expression vectors (the SV40 origin may typically be used only because it contains the early promoter).
  • These vectors will also typically contain a selection gene, also termed a selectable marker.
  • Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli.
  • a selection scheme utilizes a drug to arrest growth of a host cell.
  • Drug selection is generally used to select for cultured mammalian cells into which foreign DNA has been inserted. Such cells are commonly referred to as “transfectants”. Cells that have been cultured in the presence of the selective agent and are able to pass the gene of interest to their progeny are referred to as “stable transfectants.” Examples of such dominant selection use the drugs neomycin, mycophenolic acid, and hygromycin.
  • An exemplary selectable marker is a gene encoding resistance to the antibiotic neomycin. Selection is carried out in the presence of a neomycin-type drug, such as G-418 or the like. Those cells that are successfully transformed with a heterologous gene produce a protein conferring drug resistance and thus survive the selection regimen.
  • Selection systems can also be used to increase the expression level of the gene of interest, a process referred to as “amplification.”
  • Amplification of transfectants typically occurs by culturing the cells in the presence of a low level of the selective agent and then increasing the amount of selective agent to select for cells that produce high levels of the products of the introduced genes.
  • exemplary suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the antibody nucleic acid, such as dihydrofolate reductase (“DHFR”), thymidine kinase, metallothionein-I and -II, preferably primate metallothionein genes, adenosine deaminase, ornithine decarboxylase, etc.
  • DHFR dihydrofolate reductase
  • thymidine kinase thymidine kinase
  • metallothionein-I and -II preferably primate metallothi
  • an amplifiable selectable marker for mammalian cells is dihydrofolate reductase, which confers resistance to methotrexate.
  • Other drug resistance genes e.g. hygromycin resistance, multi-drug resistance, puromycin acetyltransferase
  • MTX methotrexate
  • An appropriate host cell when wild-type DHFR is employed is the Chinese hamster ovary (“CHO”) cell line deficient in DHFR activity.
  • host cells can be selected by cell growth in medium containing a selection agent for the selectable marker such as an aminoglycosidic antibiotic, e.g., kanamycin, neomycin, or G-418. See U.S. Pat. No. 4,965,199.
  • APH aminoglycoside 3′-phosphotransferase
  • These vectors may comprise an enhancer sequence that facilitates transcription of a DNA encoding the antibody.
  • enhancer sequences are known from mammalian genes (for example, globin, elastase, albumin, alpha-fetoprotein, and insulin).
  • a frequently used enhancer is one derived from a eukaryotic cell virus. Examples thereof include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers (See, Yaniv, Nature, 297:17-18, 1982, on enhancing elements for activation of eukaryotic promoters).
  • the enhancer may be spliced into the vector at a position 5′ or 3′ to the antibody-encoding sequence, but is preferably located at a site 5′ from the promoter.
  • Expression and cloning vectors will also generally comprise a promoter that is recognized by the host organism and is operably linked to the antibody nucleic acid.
  • Promoter sequences are known for eukaryotes. Virtually all eukaryotic genes have an AT-rich region located approximately 25 to 30 bases upstream from the site where transcription is initiated. Another sequence found 70 to 80 bases upstream from the start of transcription of many genes is a CNCAAT region where N may be any nucleotide. At the 3′ end of most eukaryotic genes is an AATAAA sequence that may be the signal for addition of the poly A tail to the 3′ end of the coding sequence. All of these sequences are suitably inserted into eukaryotic expression vectors.
  • Antibody transcription from vectors in mammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus, adenovirus (such as Adenovirus 2), BPV, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus, and most preferably SV40, from heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulin promoter, from heat-shock promoters, provided such promoters are compatible with the host cell systems.
  • viruses such as polyoma virus, fowlpox virus, adenovirus (such as Adenovirus 2), BPV, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus, and most preferably SV40
  • heterologous mammalian promoters e.g., the actin promote
  • the early and late promoters of the SV40 virus are conveniently obtained as an SV40 restriction fragment that also contains the SV40 viral origin of replication.
  • the immediate early promoter of the human cytomegalovirus is conveniently obtained as a HindIII E restriction fragment.
  • a system for expressing DNA in mammalian hosts using the BPV as a vector is disclosed in U.S. Pat. No. 4,419,446. A modification of this system is described in U.S. Pat. No. 4,601,978. See also Reyes et al., Nature, 297:598-601 (1982) on expression of human beta-interferon cDNA in mouse cells under the control of a thymidine kinase promoter from herpes simplex virus. Alternatively, the rous sarcoma virus long terminal repeat can be used as the promoter.
  • Strong transcription promoters can be used, such as promoters from SV40, cytomegalovirus, or myeloproliferative sarcoma virus. See, e.g., U.S. Pat. No. 4,956,288 and U.S. Patent Publication No. 20030103986.
  • Other suitable promoters include those from metallothionein genes (U.S. Pat. Nos. 4,579,821 and 4,601,978) and the adenovirus major late promoter.
  • Expression vectors for use in mammalian cells include pZP-1, pZP-9, and pZMP21, which have been deposited with the American Type Culture Collection, 10801 University Boulevard., Manassas, Va. USA under accession numbers 98669, 98668, and PTA-5266, respectively, and derivatives of these vectors.
  • Expression vectors used in eukaryotic host cells will also generally contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from the 5′ and, occasionally 3′, untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding the antibody.
  • One useful transcription termination component is the bovine growth hormone polyadenylation region. See WO 94/11026 and the expression vector disclosed therein.
  • Suitable host cells for cloning or expressing the subject antibodies include prokaryote, yeast, or higher eukaryote cells described above.
  • useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-1 (ATCC No. CRL 1650); and COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, (ATCC No. CRL 1573; Graham et al., J. Gen. Virol., 36:59-72 (1977)); baby hamster kidney cells (BHK, ATCC CCL 10, ATCC No.
  • monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat liver cells (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human liver cells (Hep G2, HB 8065); mouse mammary tumor (MMT 060562, ATCC CCL51); TRI cells (Mather et al., Annals N.Y. Acad.
  • Host cells are transformed with the above-described expression or cloning vectors for antibody production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences as discussed supra.
  • the mammalian host cells used to produce the antibody of this invention may be cultured in a variety of media.
  • Commercially available media such as Ham's F10 (Sigma-Aldrich Corporation, St. Louis, Mo.), Minimal Essential Medium ((“MEM” (Sigma-Aldrich Corporation, St. Louis, Mo.), Roswell Park Memorial Institute-1640 medium (“RPMI-1640”, Sigma-Aldrich Corporation, St. Louis, Mo.), and Dulbecco's Modified Eagle's Medium ((“DMEM” Sigma-Aldrich Corporation, St. Louis, Mo.) are suitable for culturing the host cells.
  • any of these media may be supplemented as necessary with hormones and/or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (such as sodium chloride, calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics (such as Gentamycin drug), trace elements (defined as inorganic compounds usually present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Any other necessary supplements may also be included at appropriate concentrations that would be known to those skilled in the art.
  • the culture conditions such as temperature, pH, and the like, are those previously used with the host cell selected for expression, and will be apparent to the ordinarily skilled artisan. Methods of development and optimization of media and culture conditions are known in the art (See, Gronemeyer et al., Bioengineering, 1(4):188-212, 2014).
  • these cells are cultured (either adherent cells or suspension cultures) most typically in a batch-fed process in a bioreactor (many models are commercially available) that involves continuously feeding the cell culture with medium and feed, optimized for the particular cell line chosen and selected for this purpose.
  • a bioreactor many models are commercially available
  • Perfusion systems are also available in which media and feed are continuously supplied to the culture while the same volume of media is being withdrawn from the bioreactor. (Wurm, 2004).
  • Synthetic media also commercially available, are available for growing cells in a batch-fed culture, avoiding the possibility of contamination from outside sources, such as with the use of animal components, such as bovine serum albumin, etc.
  • animal-component-free hydrolysates are commercially available to help boost cell density, culture viability and productivity. (Li et al., 2010). Many studies have been performed in an effort to optimize cell culture media, including careful attention to head space available in roller bottles, redox potentials during growth and expression phases, presence of reducing agents to maintain disulfide bonds during production, etc.
  • culturing step also typically involves ensuring that the cells growing in culture maintain the transfected recombinant genes by any means known in the art for cell selection.
  • the culturing step is typically followed by a harvesting step, whereby the cells are separated from the medium and a harvested cell culture media is thereby obtained.
  • a harvesting step whereby the cells are separated from the medium and a harvested cell culture media is thereby obtained.
  • various purification steps involving column chromatography and the like, follow culturing to separate the recombinant monoclonal antibody from cell components and cell culture media components.
  • Centrifugation of cell components may be achieved on a large scale by use of continuous disk stack centrifuges followed by clarification using depth and membrane filters. (See, Kelley, 2009). Most often, after clarification, the recombinant protein is further purified by Protein A chromatography due to the high affinity of Protein A for the Fc domain of antibodies, and typically occurs using a low pH/acidification elution step (typically the acidification step is combined with a precautionary virus inactivation step). Flocculation and/or precipitation steps using acidic or cationic polyelectrolytes may also be employed to separate animal cells in suspension cultures from soluble proteins. (Liu et al., 2010).
  • anion- and cation-exchange chromatography hydrophobic interaction chromatograph (“HIC”), hydrophobic charge induction chromatograph (HCIC), hydroxyapatite chromatography using ceramic hydroxyapatite (Ca 5 (PO 4 ) 3 OH) 2 , and combinations of these techniques are typically used to polish the solution of recombinant monoclonal antibody.
  • Final formulation and concentration of the desired monoclonal antibody may be achieved by use of ultracentrifugation techniques. Purification yields are typically 70 to 80%. (Kelley, 2009).
  • the terms “desired protein” or “desired antibody” are used interchangeably and refer generally to a parent antibody specific to a target, i.e., PACAP or a chimeric or humanized antibody or a binding portion thereof derived therefrom as described herein.
  • the term “antibody” is intended to include any polypeptide chain-containing molecular structure with a specific shape that fits to and recognizes an epitope, where one or more non-covalent binding interactions stabilize the complex between the molecular structure and the epitope.
  • the archetypal antibody molecule is the immunoglobulin, and all types of immunoglobulins, IgG, IgM, IgA, IgE, IgD, etc., from all sources, e.g.
  • antibodies useful as starting material according to the invention are considered to be “antibodies.”
  • a preferred source for producing antibodies useful as starting material according to the invention is rabbits. Examples thereof include chimeric antibodies, human antibodies and other non-human mammalian antibodies, humanized antibodies, single chain antibodies (such as scFvs), camelbodies, nanobodies, IgNAR (single-chain antibodies which may be derived from sharks, for example), small-modular immunopharmaceuticals (“SMIPs”), and antibody fragments such as Fabs, Fab′, F(ab′) 2 , and the like (See Streltsov et al., Protein Sci., 14(11):2901-9 (2005); Greenberg et al., Nature, 374(6518):168-73 (1995); Nuttall et al., Mol.
  • antibodies or antigen binding fragments thereof may be produced by genetic engineering.
  • antibody-producing cells are sensitized to the desired antigen or immunogen.
  • the messenger RNA isolated from antibody producing cells is used as a template to make cDNA using PCR amplification.
  • a library of vectors, each containing one heavy chain gene and one light chain gene retaining the initial antigen specificity, is produced by insertion of appropriate sections of the amplified immunoglobulin cDNA into the expression vectors.
  • a combinatorial library is constructed by combining the heavy chain gene library with the light chain gene library. This results in a library of clones that co-express a heavy and light chain (resembling the Fab fragment or antigen binding fragment of an antibody molecule).
  • the vectors that carry these genes are co-transfected into a host cell. When antibody gene synthesis is induced in the transfected host, the heavy and light chain proteins self-assemble to produce active antibodies that can be detected by screening with the antigen or immunogen.
  • Antibody coding sequences of interest include those encoded by native sequences, as well as nucleic acids that, by virtue of the degeneracy of the genetic code, are not identical in sequence to the disclosed nucleic acids, and variants thereof.
  • Variant polypeptides can include amino acid (“aa”) substitutions, additions, or deletions. The amino acid substitutions can be conservative amino acid substitutions or substitutions to eliminate non-essential amino acids, such as to alter a glycosylation site, or to minimize misfolding by substitution or deletion of one or more cysteine residues that are not necessary for function.
  • Variants can be designed so as to retain or have enhanced biological activity of a particular region of the protein (e.g., a functional domain, catalytic amino acid residues, etc.).
  • Variants also include fragments of the polypeptides disclosed herein, particularly biologically active fragments and/or fragments corresponding to functional domains. Techniques for in vitro mutagenesis of cloned genes are known. Also included in the subject invention are polypeptides that have been modified using ordinary molecular biological techniques so as to improve their resistance to proteolytic degradation or to optimize solubility properties or to render them more suitable as a therapeutic agent.
  • Chimeric antibodies may be made by recombinant means by combining the V L and V H regions, obtained from antibody producing cells of one species with the constant light and heavy chain regions from another.
  • chimeric antibodies utilize rodent or rabbit variable regions and human constant regions, in order to produce an antibody with predominantly human domains.
  • the production of such chimeric antibodies is well known in the art, and may be achieved by standard means (as described, e.g., in U.S. Pat. No. 5,624,659, incorporated herein by reference in its entirety).
  • the human constant regions of chimeric antibodies of the invention may be selected from IgG1, IgG2, IgG3, and IgG4 constant regions.
  • Humanized antibodies are engineered to contain even more human-like immunoglobulin domains, and incorporate only the complementarity determining regions of the animal-derived antibody. This is accomplished by carefully examining the sequence of the hyper-variable loops of the variable regions of the monoclonal antibody and fitting them to the structure of the human antibody chains. Although facially complex, the process is straightforward in practice. See, e.g., U.S. Pat. No. 6,187,287, incorporated fully herein by reference.
  • immunoglobulin fragments comprising the epitope binding site (e.g., Fab′, F(ab′) 2 , or other fragments) may be synthesized.
  • “Fragment” or minimal immunoglobulins may be designed utilizing recombinant immunoglobulin techniques.
  • Fv immunoglobulins for use in the present invention may be produced by synthesizing a fused variable light chain region and a variable heavy chain region. Combinations of antibodies are also of interest, e.g. diabodies, which comprise two distinct Fv specificities.
  • small molecule immunopharmaceuticals (“SMIPs”), camelbodies, nanobodies, and IgNAR are encompassed by immunoglobulin fragments.
  • Immunoglobulins and fragments thereof may be modified post-translationally, e.g. to add effector moieties such as chemical linkers, detectable moieties, such as fluorescent dyes, enzymes, toxins, substrates, bioluminescent materials, radioactive materials, chemiluminescent moieties, and the like, or specific binding moieties, such as streptavidin, avidin, or biotin, and the like may be utilized in the methods and compositions of the present invention. Examples of additional effector molecules are provided infra.
  • a “heterologous” region or domain of a DNA construct is an identifiable segment of DNA within a larger DNA molecule that is not found in association with the larger molecule in nature.
  • the DNA flanking the gene usually does not flank the mammalian genomic DNA in the genome of the source organism.
  • Another example of a heterologous region is a construct where the coding sequence itself is not found in nature (e.g., a cDNA where the genomic coding sequence contains introns or synthetic sequences having codons different than the native gene). Allelic variations or naturally-occurring mutational events do not give rise to a heterologous region of DNA as defined herein.
  • a “coding sequence” is an in-frame sequence of codons that correspond to or encode a protein or peptide sequence. Two coding sequences correspond to each other if the sequences or their complementary sequences encode the same amino acid sequences. A coding sequence in association with appropriate regulatory sequences may be transcribed and translated into a polypeptide. A polyadenylation signal and transcription termination sequence will usually be located 3′ to the coding sequence.
  • a “promoter sequence” is a DNA regulatory region capable of initiating transcription of a downstream (3′ direction) coding sequence, and typically contain additional sites for binding of regulatory molecules, e.g., transcription factors, that affect the transcription of the coding sequence.
  • a coding sequence is “under the control” of the promoter sequence or “operatively linked” to the promoter when RNA polymerase binds the promoter sequence in a cell and transcribes the coding sequence into mRNA, which is then in turn translated into the protein encoded by the coding sequence.
  • Antibodies consist of two identical light polypeptide chains of molecular weight approximately 23,000 daltons (the “light chain”), and two identical heavy chains of molecular weight 53,000-70,000 (the “heavy chain”). The four chains are joined by disulfide bonds in a “Y” configuration wherein the light chains bracket the heavy chains starting at the mouth of the “Y” configuration.
  • the “branch” portion of the “Y” configuration is designated the F ab region; the stem portion of the “Y” configuration is designated the F C region.
  • the amino acid sequence orientation runs from the N-terminal end at the top of the “Y” configuration to the C-terminal end at the bottom of each chain.
  • the N-terminal end possesses the variable region having specificity for the antigen that elicited it, and is approximately 100 amino acids in length, there being slight variations between light and heavy chain and from antibody to antibody.
  • variable region is linked in each chain to a constant region that extends the remaining length of the chain and that within a particular class of antibody does not vary with the specificity of the antibody (i.e., the antigen eliciting it).
  • constant regions There are five known major classes of constant regions that determine the class of the immunoglobulin molecule (IgG, IgM, IgA, IgD, and IgE corresponding to ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ (gamma, mu, alpha, delta, or epsilon) heavy chain constant regions).
  • the constant region or class determines subsequent effector function of the antibody, including activation of complement (see Kabat, E.
  • variable region refers to the domains within each pair of light and heavy chains in an antibody that are involved directly in binding the antibody to the antigen.
  • Each heavy chain has at one end a variable domain (V H ) followed by a number of constant domains.
  • Each light chain has a variable domain (V L ) at one end and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.
  • CDR complementarity determining region
  • hypervariable region refers to one or more of the hyper-variable or complementarity determining regions (“CDRs”) found in the variable regions of light or heavy chains of an antibody (See Kabat et al., Sequences of Proteins of Immunological Interest, 4 th ed., Bethesda, Md.: U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health (1987)). These expressions include the hypervariable regions as defined by Kabat et al., ( Sequences of Proteins of Immunological Interest , NIH Publication No. 91-3242, Bethesda, Md.: U.S. Dept.
  • the CDRs in each chain are held in close proximity by framework regions (“FRs”) and, with the CDRs from the other chain, contribute to the formation of the antigen binding site.
  • FRs framework regions
  • select amino acids that have been described as the selectivity determining regions (“SDRs”) that represent the critical contact residues used by the CDR in the antibody-antigen interaction (see Kashmiri et al., Methods, 36(1):25-34 (2005)).
  • an “epitope” or “binding site” is an area or region on an antigen to which an antigen-binding peptide (such as an antibody) specifically binds.
  • a protein epitope may comprise amino acid residues directly involved in the binding (also called immunodominant component of the epitope) and other amino acid residues, which are not directly involved in the binding, such as amino acid residues that are effectively blocked by the specifically antigen binding peptide (in other words, the amino acid residue is within the “footprint” of the specifically antigen binding peptide).
  • the term epitope herein includes both types of amino acid binding sites in any particular region of PACAP, i.e., PACAP38 and PACAP27, that specifically binds to an anti-PACAP antibody.
  • PACAP may comprise a number of different epitopes, which may include, without limitation, (1) linear peptide antigenic determinants, (2) conformational antigenic determinants that consist of one or more non-contiguous amino acids located near each other in a mature PACAP conformation; and (3) post-translational antigenic determinants that consist, either in whole or part, of molecular structures covalently attached to a PACAP protein such as carbohydrate groups.
  • epitopes include the specific residues in a protein or peptide, e.g., PACAP, which are involved in the binding of an antibody to such protein or peptide as determined by known and accepted methods such as alanine scanning techniques. Such methods are exemplified herein.
  • an antibody binds “substantially” or “at least partially” the same epitope as another antibody (e.g., second antibody) means that the epitope binding site for the first antibody comprises at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more of the amino acid residues on the antigen that constitutes the epitope binding site of the second antibody.
  • a first antibody binds substantially or partially the same or overlapping epitope as a second antibody means that the first and second antibodies compete in binding to the antigen, as described above.
  • the term “binds to substantially the same epitope or determinant as” a monoclonal antibody means that an antibody “competes” with the antibody.
  • an antibody of interest binds to the same or overlapping epitope or determinant as” an antibody of interest means that an antibody “competes” with said antibody of interest for at least one, (e.g., at least 2, at least 3, at least 4, at least 5) or all residues on PACAP to which said antibody of interest specifically binds.
  • the identification of one or more antibodies that bind(s) to substantially or essentially the same epitope as the monoclonal antibodies described herein can be readily determined using alanine scanning. Additionally, any one of variety of immunological screening assays in which antibody competition can be assessed. A number of such assays are routinely practiced and well known in the art (see, e.g., U.S. Pat. No. 5,660,827, issued Aug.
  • test antibodies to be examined are obtained from different source animals, or are even of a different Ig isotype
  • a simple competition assay may be employed in which the control antibody is mixed with the test antibody and then applied to a sample containing PACAP. Protocols based upon ELISAs, radioimmunoassays, Western blotting, and the use of BIACORE® (GE Healthcare Life Sciences, Marlborough, Mass.) analysis are suitable for use in such simple competition studies.
  • control anti-PACAP antibody is pre-mixed with varying amounts of the test antibody (e.g., in ratios of about 1:1, 1:2, 1:10, or about 1:100) for a period of time prior to applying to the PACAP38 or PACAP27 antigen sample.
  • control and varying amounts of test antibody can simply be added separately and admixed during exposure to the PACAP38 or PACAP27 antigen sample.
  • bound antibodies can be distinguished from free antibodies (e.g., by using separation or washing techniques to eliminate unbound antibodies) and control antibody from the test antibody (e.g., by using species specific or isotype specific secondary antibodies or by specifically labeling the control antibody with a detectable label) it can be determined if the test antibody reduces the binding of the control antibody to the PACAP38 or PACAP27 antigens, indicating that the test antibody recognizes substantially the same epitope as the control anti-PACAP antibody.
  • the binding of the (labeled) control antibody in the presence of a completely irrelevant antibody (that does not bind PACAP) can serve as the control high value.
  • the control low value can be obtained by incubating the labeled control antibody with the same but unlabeled control antibody, where competition would occur and reduce binding of the labeled antibody.
  • a significant reduction in labeled antibody reactivity in the presence of a test antibody is indicative of a test antibody that recognizes substantially the same epitope, i.e., one that competes with the labeled control antibody.
  • any test antibody that reduces the binding of the control antibody to PACAP38 or PACAP27 by at least about 50%, such as at least about 60%, or more preferably at least about 70% (e.g., about 65-100%), at any ratio of test antibody between about 1:1 or 1:10 and about 1:100 is considered to be an antibody that binds to substantially the same or overlapping epitope or determinant as the control antibody.
  • test antibody will reduce the binding of the control antibody to PACAP38 or PACAP27 antigen preferably at least about 50%, at least about 60%, at least about 80%, or at least about 90% (e.g., about 95%) of the binding of the control antibody observed in the absence of the test antibody.
  • a simple competition assay in which a test antibody is applied at saturating concentration to a surface onto which PACAP38 or PACAP27 is immobilized also may be advantageously employed.
  • the surface in the simple competition assay is preferably a BIACORE® (GE Healthcare Life Sciences, Marlborough, Mass.) chip (or other media suitable for surface plasmon resonance (“SPR”) analysis).
  • SPR surface plasmon resonance
  • a significant reduction in binding to the PACAP38- or PACAP27-containing surface by the control antibody in the presence of a test antibody indicates that the test antibody recognizes substantially the same epitope as the control antibody such that the test antibody “competes” with the control antibody.
  • Any test antibody that reduces the binding of control antibody by at least about 20% or more, at least about 40%, at least about 50%, at least about 70%, or more can be considered to be an antibody that binds to substantially the same epitope or determinant as the control antibody.
  • such test antibody will reduce the binding of the control antibody to PACAP38 or PACAP27 by at least about 50% (e.g., at least about 60%, at least about 70%, or more).
  • control and test antibodies can be reversed; i.e. the control antibody can be first bound to the surface and then the test antibody is brought into contact with the surface thereafter in a competition assay.
  • the “sandwich-style” binding assay exemplified in Example 9 infra is used.
  • the antibody having greater affinity for PACAP38 or PACAP27 antigen is bound to the PACAP38- or PACAP27-containing surface first, as it will be expected that the decrease in binding seen for the second antibody (assuming the antibodies are competing) will be of greater magnitude.
  • assays are provided in e.g., Saunal and Regenmortel, J. Immunol. Methods, 183:33-41 (1995), the disclosure of which is incorporated herein by reference.
  • an antibody binds the same or overlapping epitope(s) on PACAP as another antibody or the epitope bound by a test antibody may in particular be determined using a Western-blot based assay.
  • a library of peptides corresponding to the antigen bound by the antibody, the PACAP protein is made, that comprise overlapping portions of the protein, typically 10-25, 10-20, or 10-15 amino acids long.
  • These different overlapping amino acid peptides encompassing the PACAP sequence are synthesized and covalently bound to a PEPSPOTS' nitrocellulose membrane (JPT Peptide Technologies, Berlin, Germany). Blots are then prepared and probed according to the manufacturer's recommendations.
  • the immunoblot assay detects by fluorometric means what peptides in the library bind to the test antibody and thereby can identify what residues on the antigen, i.e., PACAP, interact with the test antibody.
  • fluorometric means what peptides in the library bind to the test antibody and thereby can identify what residues on the antigen, i.e., PACAP, interact with the test antibody.
  • epitope mapping techniques are known in the art.
  • X-ray co-crystallography of the antigen and antibody; NMR; SPR (e.g., at 25° or 37° C.); array-based oligo-peptide scanning (or “pepscan analysis”); site-directed mutagenesis (e.g., alanine scanning); mutagenesis mapping; hydrogen-deuterium exchange; phage display; and limited proteolysis are all epitope mapping techniques that are well known in the art (See, e.g., Epitope Mapping Protocols: Second Edition, Methods in Molecular Biology , editors Mike Schutkowski and Ulrich Reineke, 2 nd Ed., New York, N.Y.: Humana Press (2009), and Epitope Mapping Protocols, Methods in Molecular Biology , editor Glenn Morris, 1 st Ed., New York, N.Y.: Humana Press (1996), both of which are herein incorporated by referenced in their entirety).
  • test antibodies to be examined are obtained from different source animals, or are even of a different Ig isotype
  • a simple competition assay may be employed in which the control antibody (one of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, or Ab1.H, for example) is mixed with the test antibody and then applied to a sample containing either or both PACAP38 and PACAP27, each of which is known to be bound by Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab1.H.
  • Protocols based upon ELISAs, radioimmunoassays, Western blotting, and BIACORE® (GE Healthcare Life Sciences, Marlborough, Mass.) analysis are suitable for use in such simple competition studies.
  • the method comprises pre-mixing the control antibody with varying amounts of the test antibody (e.g., in ratios of about 1:1, 1:2, 1:10, or about 1:100) for a period of time prior to applying to the PACAP antigen sample.
  • the control and varying amounts of test antibody can be added separately and admixed during exposure to the PACAP antigen sample.
  • the method can be used to determine that the test antibody reduces the binding of the control antibody to the PACAP antigen, indicating that the test antibody recognizes substantially the same epitope as the control antibody (e.g., Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, or Ab1.H).
  • the control antibody e.g., Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, or Ab1.H).
  • the binding of the (labeled) control antibody in the presence of a completely irrelevant antibody can serve as the control high value.
  • the control low value can be obtained by incubating the labeled control antibody with the same but unlabeled control antibody, where competition would occur and reduce binding of the labeled antibody.
  • a significant reduction in labeled antibody reactivity in the presence of a test antibody is indicative of a test antibody that recognizes substantially the same epitope, i.e., one that competes with the labeled control antibody.
  • such test antibody will reduce the binding of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, or Ab1.H to at least one, preferably each, of the PACAP38 and PACAP27 antigens preferably at least about 50%, at least about 60%, at least about 80% or at least about 90% (e.g., about 95%) of the binding of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, or Ab1.H observed in the absence of the test antibody.
  • These methods can be adapted to identify and/or evaluate antibodies that compete with other control antibodies.
  • a simple competition assay in which a test antibody is applied at saturating concentration to a surface onto which either PACAP38 or PACAP27, or both, are immobilized also may be advantageously employed.
  • the surface in the simple competition assay is preferably of a media suitable for OCTET® and/or PROTEON®.
  • the binding of a control antibody e.g., Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, or Ab1.H
  • This binding to the PACAP-containing surface of the control antibody alone is compared with the binding of the control antibody in the presence of a test antibody.
  • a significant reduction in binding to the PACAP-containing surface by the control antibody in the presence of a test antibody indicates that the test antibody recognizes substantially the same epitope as the control antibody such that the test antibody “competes” with the control antibody.
  • Any test antibody that reduces the binding of control antibody such as Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, or Ab1.H
  • control antibody e.g., Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, or Ab1.H
  • Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, or Ab1.H can be considered to be an antibody that binds to substantially the same epitope or
  • such test antibody will reduce the binding of the control antibody (e.g., Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, or Ab1.H) to the PACAP antigen by at least about 50% (e.g., at least about 60%, at least about 70%, or more).
  • control antibody e.g., Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, or Ab1.H
  • control antibody e.g., Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, or Ab1.H
  • the order of control and test antibodies can be reversed; i.e. the control antibody can be first bound to the surface and then the test
  • the antibody having higher affinity for PACAP38 and PACAP27 is bound to the PACAP-containing surface first, as it will be expected that the decrease in binding seen for the second antibody (assuming the antibodies are competing) will be of greater magnitude.
  • assays are provided in, e.g., Saunal and Regenmortel, J. Immunol. Methods, 183:33-41 (1989), the disclosure of which is incorporated herein by reference.
  • an epitope region for an anti-PACAP antibody may be determined by epitope “footprinting” using chemical modification of the exposed amines/carboxyls in the PACAP38 and PACAP27 protein.
  • HXMS hydrogen-deuterium exchange detected by mass spectrometry
  • a hydrogen/deuterium exchange of receptor and ligand protein amide protons, binding, and back exchange occurs, wherein the backbone amide groups participating in protein binding are protected from back exchange and therefore will remain deuterated.
  • Relevant regions can be identified at this point by peptic proteolysis, fast microbore high-performance liquid chromatography separation, and/or electrospray ionization mass spectrometry (See, e.g., Ehring H., Analytical Biochemistry, 267(2):252-259 (1999) and Engen, J. R. & Smith, D. L., Anal.
  • NMR nuclear magnetic resonance epitope mapping
  • the antigen typically is selectively isotopically labeled with 15 N so that only signals corresponding to the antigen and no signals from the antigen binding peptide are seen in the NMR-spectrum.
  • Antigen signals originating from amino acids involved in the interaction with the antigen binding peptide typically will shift position in the spectres of the complex compared to the spectres of the free antigen, and the amino acids involved in the binding can be identified that way, See, e.g., Ernst Schering Res. Found. Workshop , (44):149-67 (2004); Huang et al., J. Mol. Biol., 281(1):61-67 (1998); and Saito and Patterson, Methods, 9(3):516-24 (1996)).
  • Epitope mapping/characterization also can be performed using mass spectrometry (“MS”) methods (See, e.g., Downard, J. Mass Spectrom., 35(4):493-503 (2000) and Kiselar and Downard, Anal. Chem., 71(9):1792-801 (1999)).
  • Protease digestion techniques also can be useful in the context of epitope mapping and identification.
  • Antigenic determinant-relevant regions/sequences can be determined by protease digestion, e.g. by using trypsin in a ratio of about 1:50 to PACAP38 or PACAP27 overnight (“o/n”) digestion at 37° C. and pH 7-8, followed by mass spectrometry (“MS”) analysis for peptide identification.
  • MS mass spectrometry
  • the peptides protected from trypsin cleavage by the anti-PACAP antibody can subsequently be identified by comparison of samples subjected to trypsin digestion and samples incubated with antibody and then subjected to digestion by e.g. trypsin (thereby revealing a footprint for the antibody).
  • chymotrypsin or pepsin can be used in similar epitope characterization methods.
  • enzymatic digestion can provide a quick method for analyzing whether a potential antigenic determinant sequence is within a region of PACAP in the context of a PACAP-binding polypeptide. If the polypeptide is not surface exposed, it is most likely not relevant in terms of immunogenicity/antigenicity (See, e.g., Manca, Ann. Ist. Super. Sanità, 27(1):15-9 (1991) for a discussion of similar techniques).
  • Site-directed mutagenesis is another technique useful for characterization of a binding epitope.
  • site-directed mutagenesis also known as alanine scanning, alanine scanning mutagenesis, alanine scanning mutations, combinatorial alanine scanning, or creation of alanine point mutations, for example
  • each residue within a protein segment is replaced with an alanine residue (or another residue such as valine where alanine is present in the wild-type sequence) through such methodologies as direct peptide or protein synthesis, site-directed mutagenesis, the GENEARTTM Mutagenesis Service (Thermo Fisher Scientific, Waltham, Mass. U.S.A.) or shotgun mutagenesis, for example.
  • a series of single point mutants of the molecule is thereby generated using this technique; the number of mutants generated is equivalent to the number of residues in the molecule, each residue being replaced, one at a time, by a single alanine residue.
  • Alanine is generally used to replace native (wild-type) residues because of its non-bulky, chemically inert, methyl functional group that can mimic the secondary structure preferences that many other amino acids may possess.
  • the effects replacing a native residue with an alanine has on binding affinity of an alanine scanning mutant and its binding partner can be measured using such methods as, but not limited to, SPR binding experiments. If a mutation leads to a significant reduction in binding affinity, it is most likely that the mutated residue is involved in binding.
  • Monoclonal antibodies specific for structural epitopes can be used as a positive control for binding affinity experiments to verify that the alanine-replacement does not influence the overall tertiary structure of the protein (as changes to the overall fold of the protein may indirectly affect binding and thereby produce a false positive result).
  • alanine scanning methods are used to identify the specific epitope or residues of PACAP which specifically interact with the anti-PACAP antibodies disclosed herein.
  • Electron microscopy can also be used for epitope “footprinting”.
  • Wang et al., Nature, 355:275-278 (1992) used coordinated application of cryoelectron microscopy, three-dimensional image reconstruction, and X-ray crystallography to determine the physical footprint of a Fab-fragment on the capsid surface of native cowpea mosaic virus.
  • label-free assay for epitope evaluation include SPR (sold commercially as the BIACORE® system, GE Healthcare Life Sciences, Marlborough, Mass.) and reflectometric interference spectroscopy (“RifS”) (See, e.g., Fagerstam et al., Journal of Molecular Recognition, 3:208-14 (1990); Nice et al., J. Chromatogr., 646:159-168 (1993); Leipert et al., Angew. Chem. Int. Ed., 37:3308-3311 (1998); Kroger et al., Biosensors and Bioelectronics, 17:937-944 (2002)).
  • framework region refers to one or more of the framework regions within the variable regions of the light and heavy chains of an antibody (See Kabat et al., Sequences of Proteins of Immunological Interest, 4 th edition, Bethesda, Md.: U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health (1987)). These expressions include those amino acid sequence regions interposed between the CDRs within the variable regions of the light and heavy chains of an antibody.
  • the term “Fc region” is used to define a C-terminal region of an immunoglobulin heavy chain.
  • the “Fc region” may be a native sequence Fc region or a variant Fc region.
  • the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof.
  • the numbering of the residues in the Fc region is that of the EU index as in Kabat. Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition, Bethesda, Md.: U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health (1991).
  • the Fc region of an immunoglobulin generally comprises two constant domains, CH2 and CH3.
  • Fc receptor and “FcR” describe a receptor that binds to the Fc region of an antibody.
  • the preferred FcR is a native sequence human FcR.
  • a preferred FcR is one that binds an IgG antibody (a gamma receptor) and includes receptors of the Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII subclasses, including allelic variants and alternatively spliced forms of these receptors.
  • Fc ⁇ RII receptors include Fc ⁇ RIIA (an “activating receptor”) and Fc ⁇ RIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof.
  • FcRs are reviewed in Ravetch and Kinet, Ann. Rev. Immunol., 9:457-92 (1991); Capel et al., Immunomethods, 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med., 126:330-41 (1995).
  • FcR also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol., 117:587 (1976); and Kim et al., J. Immunol., 24:249 (1994)), and which primarily functions to modulate and/or extend the half-life of antibodies in circulation.
  • the disclosed anti-PACAP antibodies are aglycosylated, as a result of the expression system and/or sequence, the subject antibodies are expected to bind FcRn receptors, but not to bind (or to minimally bind) Fc ⁇ receptors.
  • a “functional Fc region” possesses at least one effector function of a native sequence Fc region.
  • effector functions include C1q binding; complement dependent cytotoxicity (“CDC”); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (“ADCC”); phagocytosis; down-regulation of cell surface receptors (e.g. B cell receptor (“BCR”)), etc.
  • Such effector functions generally require the Fc region to be combined with a binding domain (e.g. an antibody variable domain) and can be assessed using various assays known in the art for evaluating such antibody effector functions.
  • a “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature.
  • a “variant Fc region” comprises an amino acid sequence that differs from that of a native sequence Fc region by virtue of at least one amino acid modification, yet retains at least one effector function of the native sequence Fc region.
  • the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g. from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide.
  • the variant Fc region herein will preferably possess at least about 80% sequence identity with a native sequence Fc region and/or with an Fc region of a parent polypeptide, and most preferably at least about 90% sequence identity therewith, more preferably at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity therewith.
  • PACAP is a multifunctional vasodilatory peptide with expression throughout the central nervous system (“CNS”) and periphery.
  • PACAP is a member of the secretin/VIP/GRH family.
  • PACAP exists in two ⁇ -amidated active forms, PACAP38 (SEQ ID NO: 1241) and PACAP27 (SEQ ID NO: 1242).
  • PACAP includes either or both of PACAP38 and PACAP27 unless expressly indicated otherwise. PACAP is highly conserved between species.
  • PACAP is derived from a 176 amino acid precursor protein (preproPACAP) and the gene is located on chromosome 18p11, with PACAP38 encoded for by exon 5 (Vaudry et al., Pharmacol. Rev., 61:283-357 (2009)).
  • PreproPACAP contains an N-terminal 24 amino acid signal protein, a 29 amino acid PACAP-related peptide and PACAP in the C-terminal domain.
  • the precursor is metabolized by prohormone convertase enzymes into biologically active PACAP38 and PACAP27.
  • VIP (SEQ ID NO: 1243) belongs to the same protein family as PACAP and shares high homology with PACAP, i.e., VIP and PACAP27 have 68% sequence homology at the amino acid level, as well as similar overall secondary structure, i.e. long alpha-helical structures at the C-terminus.
  • PACAP's actions are mediated via three different G-protein coupled receptors: PAC1-R, VPAC1-R, and VPAC2-R.
  • VPAC1-R can associate with all of the receptor-associated membrane proteins (“RAMPs”, Kaiser & Russo, Neuropeptides 47: 451-461 (2013)).
  • RAMPs receptor-associated membrane proteins
  • PAC1-R is selective for PACAP, whereas VPAC1-R and VPAC2-R bind to both VIP and PACAP with high affinity.
  • PAC1-R binds to PACAP with 100-1000-fold higher affinity than VIP, i.e., K D ⁇ 0.5 nM for PACAP27/PACAP38 vs. K D ⁇ 500 nM for VIP.
  • VPAC1-R and VPAC2-R have equal affinities for PACAP and VIP (K D ⁇ 1 nM) (See Schytz et al. (2010)). All three receptors are widely expressed in both peripheral tissues and in the CNS, with PAC1-R predominantly expressed in the CNS, most abundantly in the olfactory bulb, thalamus, hypothalamus, the dentate gyrus of the hippocampus and in granule cells of the cerebellum (Hashimoto et al., J. Comp. Neurol., 371:567-577 (1996); Shioda et al., Neurosci. Res., 28:345-354 (1997)).
  • Activation of the PAC1-R, VPAC1-R, and/or VPAC2-R results in increased adenylate cyclase activity and, thus, increased cAMP production.
  • PACAP receptors can also mediate their effects through PLC, leading to increased Ca 2+ levels, and PLD.
  • PACAP has a wide range of biological effects, including a role in neurodevelopment, neuroprotection, neuromodulation, neurogenic inflammation, and nociception. PACAP is also reported to interact with glycosaminoglycans (“GAGs”). GAGs are long, unbranched polysaccharides composed of repeating disaccharide units, such as heparin, chondroitin, keratin, and hyaluronic acid. It has been shown that the cellular uptake of PACAP is dependent on the expression of GAG proteins and that PACAP bound to sulfated GAGs. Particularly, it was determined that PACAP38 binding to GAGs was capable of inducing receptor-independent cellular uptake of PACAP38.
  • GAGs glycosaminoglycans
  • the present invention provides exemplary antibodies or antigen binding fragments thereof that bind PACAP, including human PACAP.
  • Other antibodies or antigen binding fragments thereof that bind PACAP including those having different CDRs, and epitopic specificity may be obtained using the disclosure of the present specification, and using methods that are generally known in the art.
  • Such antibodies and antigen binding fragments thereof antagonize the biological effects of PACAP in vivo and therefore are useful in treating or preventing PACAP-related conditions including, for example, headache, migraine, pain, photophobia, hot flush, PTSD, and anxiety disorders.
  • the antibody or antigen binding fragment thereof according to the invention comprises one or more CDRs, a V L chain and/or V H chain of the anti-PACAP antibodies and antigen binding fragments thereof described herein.
  • an anti-PACAP antibody or antigen binding fragment thereof according to the invention will interfere with, block, reduce, or modulate the interaction between PACAP and its receptor(s) (e.g., PAC1-R, VPAC1-R, and VPAC2-R).
  • PACAP e.g., PAC1-R, VPAC1-R, and VPAC2-R
  • an anti-PACAP antibody or antigen binding fragment thereof according to the invention is “neutralizing”, e.g., it totally prevents the specific interaction of PACAP with PAC1-R, VPAC1-R, and/or VPAC2-R.
  • the antibody or antigen binding fragment thereof neutralizes PACAP, e.g., by remaining bound to PACAP in a location and/or manner that prevents PACAP from specifically binding to PAC1-R, VPAC1-R, and/or VPAC2-R.
  • the antibody or antigen binding fragment thereof according to the invention is capable of inhibiting PACAP-mediated activity (including binding to PAC1-R-expressing cells).
  • the antibody or antigen binding fragment thereof according to the invention are humanized, such as humanized rabbit antibodies to PACAP.
  • the anti-PACAP antibodies or antigen binding fragments thereof have a variety of uses.
  • the subject antibodies and fragments can be useful in therapeutic applications, as well as diagnostically in binding assays.
  • the subject anti-PACAP antibodies or antigen binding fragments thereof are useful for affinity purification of PACAP, in particular human PACAP or its ligands and in screening assays to identify other antagonists of PACAP activity.
  • Some of the antibodies or antigen binding fragments thereof are useful for inhibiting binding of PACAP to PAC1-R, VPAC1-R, and/or VPAC2-R, or inhibiting PACAP-mediated activities and/or biological effects.
  • one or more biological effects associated with PACAP refers to any biological effect mediated, induced, or otherwise attributable to PACAP, e.g., binding properties, functional properties, and other properties of biological significance.
  • Non-limiting exemplary biological effects of PACAP include PACAP binding to PAC1-R, VPAC1-R, and/or VPAC2-R; PACAP activating PAC1-R, VPAC1-R, and/or VPAC2-R-mediated signaling; PACAP-mediated increase in cAMP production; PACAP-mediated increase in PLC activity; PACAP-mediated increase in PLD activity; PACAP-mediated increase in Ca 2+ levels; and PACAP-mediated vasodilation, photophobia, mast cell degranulation, and/or neuronal activation.
  • the subject anti-PACAP antibodies are capable of inhibiting one, a combination of, or all of these exemplary PACAP biological activities.
  • the anti-PACAP antibodies and antigen binding fragments thereof provided herein are capable of inhibiting PACAP-induced vasodilation (see Example 7 and Example 8).
  • the anti-PACAP antibody or antigen binding fragment thereof can be used in a variety of therapeutic applications.
  • the anti-PACAP antibody or antigen binding fragment thereof are useful for treating conditions associated with PACAP, such as, but not limited to, migraine (with or without aura), hemiplegic migraines, cluster headaches, migrainous neuralgia, chronic headaches, tension headaches, general headaches, hot flush, photophobia, chronic paroxysmal hemicrania, secondary headaches due to an underlying structural problem in the head or neck, cranial neuralgia, sinus headaches (e.g., headache associated with sinusitis), allergy-induced headaches or migraines, pain, chronic pain, neuroinflammatory or inflammatory pain, post-operative incision pain, post-surgical pain, trauma-related pain, eye pain, tooth pain, complex regional pain syndrome, cancer pain (e.g., primary or metastatic bone cancer pain), fracture pain, osteoporotic fracture pain, pain resulting from burn, gout joint pain, pain associated with sickle cell crises, pain
  • visceral pain i.e., pain associated with the viscera, or the internal organs of the body
  • organs such as e.g., the heart, lungs, reproductive organs, bladder, ureters, the digestive organs, liver, pancreas, spleen, and kidneys.
  • Conditions associated therewith include by way of example pancreatitis, labor, abdominal surgery associated with ileus, cystitis, menstrual period, or dysmenorrhea.
  • kidney pain, epigastric pain, pleural pain, and painful biliary colic, appendicitis pain may all be considered to be visceral pain.
  • Substernal pain or pressure from early myocardial infarction is also visceral.
  • GI disorders that cause visceral pain include functional bowel disorder (“FBD”) and inflammatory bowel disease (“IBD”). Such GI disorders may further include gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (“IBS”) and functional abdominal pain syndrome (“FAPS”), and, with respect to IBD, Crohn's disease, ileitis, and ulcerative colitis.
  • BFD functional bowel disorder
  • IBD inflammatory bowel disease
  • IBS irritable bowel syndrome
  • FAPS functional abdominal pain syndrome
  • the subject anti-PACAP antibodies and antigen binding fragments thereof may be used alone or in association with other active agents or drugs, including other biologics, to treat any subject in which blocking, inhibiting, or neutralizing the in vivo effect of PACAP or blocking or inhibiting the interaction of PACAP and its receptors, PAC1-R, VPAC1-R, and VPAC2-R, is therapeutically desirable.
  • anti-PACAP antibodies and antigen binding fragments thereof according to the invention, and the specific CDRs thereof are identified in this section.
  • each exemplified antibody or antigen binding fragment thereof, and corresponding sequences are separately identified by a specific nomenclature, i.e., Ab1, Ab1.H, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, and Ab19.
  • the anti-PACAP antibodies and antigen binding fragments thereof comprising the invention have binding affinity for PACAP, wherein the binding affinity comprises anti-PACAP antibodies or antigen binding fragments thereof specifically binding to PACAP38 and PACAP27, but not binding VIP, and/or antibodies or antigen binding fragments thereof specifically binding to PACAP38, but not binding to PACAP27 or VIP, and/or antibodies or antigen binding fragments thereof specifically binding to a linear and/or conformational epitope within PACAP38 and/or PACAP27.
  • the epitopes of PACAP38 and/or PACAP27 to which antagonistic anti-PACAP antibodies or antigen binding fragments thereof according to the invention bind will include those which are identified in Example 12 or residues thereof (as determined by use of alanine scanning) and/or other epitopic identification methods.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that possess a heavy chain sequence comprising the sequence of SEQ ID NO: 1 which consists of the heavy chain variable region of SEQ ID NO: 2 linked to the heavy chain constant region of SEQ ID NO: 10.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab1, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 21 which consists of the light chain variable region of SEQ ID NO: 22 linked to the light chain constant region of SEQ ID NO: 30.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab1, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 4; SEQ ID NO: 6; and SEQ ID NO: 8, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 1, or which contain the variable heavy chain sequence of SEQ ID NO: 2, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 24; SEQ ID NO: 26; and SEQ ID NO: 28, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 21, or which contain the variable light chain sequence of SEQ ID NO: 22, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the invention further contemplates anti-PACAP antibodies and antigen-binding fragments comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 3; SEQ ID NO: 5; SEQ ID NO: 7; and SEQ ID NO: 9, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 1, or the variable heavy chain sequence of SEQ ID NO: 2, and/or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 23; SEQ ID NO: 25; SEQ ID NO: 27; and SEQ ID NO: 29, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 21, or the variable light chain sequence of SEQ ID NO: 22, or combinations of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical therewith.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention or fragments comprise, or alternatively consist of, combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 1, or SEQ ID NO: 2, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 21, or SEQ ID NO: 22, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 4; SEQ ID NO: 6; and SEQ ID NO: 8, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 1, or the variable heavy chain sequence of SEQ ID NO: 2, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 24; SEQ ID NO: 26; and SEQ ID NO: 28, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 21, or the variable light chain sequence of SEQ ID NO: 22, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 3; SEQ ID NO: 5; SEQ ID NO: 7; and SEQ ID NO: 9, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 1, or the variable heavy chain sequence of SEQ ID NO: 2, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 23; SEQ ID NO: 25; SEQ ID NO: 27; and SEQ ID NO: 29, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 21, or the variable light chain sequence of SEQ ID NO: 22, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 2; the variable light chain region of SEQ ID NO: 22; the complementarity determining regions (SEQ ID NO: 4; SEQ ID NO: 6; and SEQ ID NO: 8) of the variable heavy chain region of SEQ ID NO: 2; and the complementarity determining regions (SEQ ID NO: 24; SEQ ID NO: 26; and SEQ ID NO: 28) of the variable light chain region of SEQ ID NO: 22, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 2; the variable light chain region of SEQ ID NO: 22; the framework regions (SEQ ID NO: 3; SEQ ID NO: 5; SEQ ID NO: 7; and SEQ ID NO: 9) of the variable heavy chain region of SEQ ID NO: 2; and the framework regions (SEQ ID NO: 23; SEQ ID NO: 25; SEQ ID NO: 27; and SEQ ID NO: 29) of the variable light chain region of SEQ ID NO: 22, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab1, comprising, or alternatively consisting of, SEQ ID NO: 1 and SEQ ID NO: 21, or SEQ ID NO: 2 and SEQ ID NO: 22, or an antibody or antigen-binding fragment comprising the CDRs of Ab1 and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab1 in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab1, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab1.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 2 and the variable light chain sequence of SEQ ID NO: 22, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 2 and/or SEQ ID NO: 22 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab1.
  • anti-PACAP antibodies such as Ab1 and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast strains such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab1.H, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 61 which consists of the light chain variable region of SEQ ID NO: 62 linked to the light chain constant region of SEQ ID NO: 70.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab1.H, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 44; SEQ ID NO: 46; and SEQ ID NO: 48, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 41, or which contain the variable heavy chain sequence of SEQ ID NO: 42, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 64; SEQ ID NO: 66; and SEQ ID NO: 68, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 61, or which contain the variable light chain sequence of SEQ ID NO: 62, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 41, or SEQ ID NO: 42, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 61, or SEQ ID NO: 62, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 64; SEQ ID NO: 66; and SEQ ID NO: 68, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 61, or the variable light chain sequence of SEQ ID NO: 62, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 43; SEQ ID NO: 45; SEQ ID NO: 47; and SEQ ID NO: 49, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 41, or the variable heavy chain sequence of SEQ ID NO: 42, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 63; SEQ ID NO: 65; SEQ ID NO: 67; and SEQ ID NO: 69, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 61, or the variable light chain sequence of SEQ ID NO: 62, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 42; the variable light chain region of SEQ ID NO: 62; the complementarity determining regions (SEQ ID NO: 44; SEQ ID NO: 46; and SEQ ID NO: 48) of the variable heavy chain region of SEQ ID NO: 42; and the complementarity determining regions (SEQ ID NO: 64; SEQ ID NO: 66; and SEQ ID NO: 68) of the variable light chain region of SEQ ID NO: 62, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 42; the variable light chain region of SEQ ID NO: 62; the framework regions (SEQ ID NO: 43; SEQ ID NO: 45; SEQ ID NO: 47; and SEQ ID NO: 49) of the variable heavy chain region of SEQ ID NO: 42; and the framework regions (SEQ ID NO: 63; SEQ ID NO: 65; SEQ ID NO: 67; and SEQ ID NO: 69) of the variable light chain region of SEQ ID NO: 62, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab1.H, comprising, or alternatively consisting of, SEQ ID NO: 41 and SEQ ID NO: 61, or SEQ ID NO: 42 and SEQ ID NO: 62, or an antibody or antigen-binding fragment comprising the CDRs of Ab1.H and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab1.H in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab1.H, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab1.H.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 42 and the variable light chain sequence of SEQ ID NO: 62, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 42 and/or SEQ ID NO: 62 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab1.H.
  • anti-PACAP antibodies such as Ab1.H and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to PACAP, including the heavy and/or light chains of Ab1.H, as well as fragments, variants, and combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab2, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 101 which consists of the light chain variable region of SEQ ID NO: 102 linked to the light chain constant region of SEQ ID NO: 110.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab2, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 84; SEQ ID NO: 86; and SEQ ID NO: 88, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 81, or which contain the variable heavy chain sequence of SEQ ID NO: 82, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 104; SEQ ID NO: 106; and SEQ ID NO: 108, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 101, or which contain the variable light chain sequence of SEQ ID NO: 102, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the invention further contemplates anti-PACAP antibodies and antigen-binding fragments comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 83; SEQ ID NO: 85; SEQ ID NO: 87; and SEQ ID NO: 89, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 81, or the variable heavy chain sequence of SEQ ID NO: 82, and/or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 103; SEQ ID NO: 105; SEQ ID NO: 107; and SEQ ID NO: 109, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 101, or the variable light chain sequence of SEQ ID NO: 102, or combinations of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical therewith.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention or fragments comprise, or alternatively consist of, combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 81, or SEQ ID NO: 82, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 101, or SEQ ID NO: 102, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 84; SEQ ID NO: 86; and SEQ ID NO: 88, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 81, or the variable heavy chain sequence of SEQ ID NO: 82, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 104; SEQ ID NO: 106; and SEQ ID NO: 108, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 101, or the variable light chain sequence of SEQ ID NO: 102, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 83; SEQ ID NO: 85; SEQ ID NO: 87; and SEQ ID NO: 89, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 81, or the variable heavy chain sequence of SEQ ID NO: 82, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 103; SEQ ID NO: 105; SEQ ID NO: 107; and SEQ ID NO: 109, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 101, or the variable light chain sequence of SEQ ID NO: 102, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 82; the variable light chain region of SEQ ID NO: 102; the complementarity determining regions (SEQ ID NO: 84; SEQ ID NO: 86; and SEQ ID NO: 88) of the variable heavy chain region of SEQ ID NO: 82; and the complementarity determining regions (SEQ ID NO: 104; SEQ ID NO: 106; and SEQ ID NO: 108) of the variable light chain region of SEQ ID NO: 102, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 82; the variable light chain region of SEQ ID NO: 102; the framework regions (SEQ ID NO: 83; SEQ ID NO: 85; SEQ ID NO: 87; and SEQ ID NO: 89) of the variable heavy chain region of SEQ ID NO: 82; and the framework regions (SEQ ID NO: 103; SEQ ID NO: 105; SEQ ID NO: 107; and SEQ ID NO: 109) of the variable light chain region of SEQ ID NO: 102, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab2, comprising, or alternatively consisting of, SEQ ID NO: 81 and SEQ ID NO: 101, or SEQ ID NO: 82 and SEQ ID NO: 102, or an antibody or antigen-binding fragment comprising the CDRs of Ab2 and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab2 in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab2, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab2.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 82 and the variable light chain sequence of SEQ ID NO: 102, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 82 and/or SEQ ID NO: 102 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab2.
  • anti-PACAP antibodies such as Ab2 and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast strains such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to PACAP, including the heavy and/or light chains of Ab2, as well as fragments, variants, and combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that possess a heavy chain sequence comprising the sequence of SEQ ID NO: 681 which consists of the heavy chain variable region of SEQ ID NO: 682 linked to the heavy chain constant region of SEQ ID NO: 690.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab3, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 701 which consists of the light chain variable region of SEQ ID NO: 702 linked to the light chain constant region of SEQ ID NO: 710.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab3, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 684; SEQ ID NO: 686; and SEQ ID NO: 688, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 681, or which contain the variable heavy chain sequence of SEQ ID NO: 682, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 704; SEQ ID NO: 706; and SEQ ID NO: 708, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 701, or which contain the variable light chain sequence of SEQ ID NO: 702, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the invention further contemplates anti-PACAP antibodies and antigen-binding fragments comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 683; SEQ ID NO: 685; SEQ ID NO: 687; and SEQ ID NO: 689, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 681, or the variable heavy chain sequence of SEQ ID NO: 682, and/or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 703; SEQ ID NO: 705; SEQ ID NO: 707; and SEQ ID NO: 709, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 701, or the variable light chain sequence of SEQ ID NO: 702, or combinations of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical therewith.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention or fragments comprise, or alternatively consist of, combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 681, or SEQ ID NO: 682, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 701, or SEQ ID NO: 702, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 684; SEQ ID NO: 686; and SEQ ID NO: 688, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 681, or the variable heavy chain sequence of SEQ ID NO: 682, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 704; SEQ ID NO: 706; and SEQ ID NO: 708, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 701, or the variable light chain sequence of SEQ ID NO: 702, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 683; SEQ ID NO: 685; SEQ ID NO: 687; and SEQ ID NO: 689, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 681, or the variable heavy chain sequence of SEQ ID NO: 682, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 703; SEQ ID NO: 705; SEQ ID NO: 707; and SEQ ID NO: 709, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 701, or the variable light chain sequence of SEQ ID NO: 702, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 682; the variable light chain region of SEQ ID NO: 702; the complementarity determining regions (SEQ ID NO: 684; SEQ ID NO: 686; and SEQ ID NO: 688) of the variable heavy chain region of SEQ ID NO: 682; and the complementarity determining regions (SEQ ID NO: 704; SEQ ID NO: 706; and SEQ ID NO: 708) of the variable light chain region of SEQ ID NO: 702, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 682; the variable light chain region of SEQ ID NO: 702; the framework regions (SEQ ID NO: 683; SEQ ID NO: 685; SEQ ID NO: 687; and SEQ ID NO: 689) of the variable heavy chain region of SEQ ID NO: 682; and the framework regions (SEQ ID NO: 703; SEQ ID NO: 705; SEQ ID NO: 707; and SEQ ID NO: 709) of the variable light chain region of SEQ ID NO: 702, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab3, comprising, or alternatively consisting of, SEQ ID NO: 681 and SEQ ID NO: 701, or SEQ ID NO: 682 and SEQ ID NO: 702, or an antibody or antigen-binding fragment comprising the CDRs of Ab3 and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab3 in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab3, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab3.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 682 and the variable light chain sequence of SEQ ID NO: 702, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 682 and/or SEQ ID NO: 702 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab3.
  • anti-PACAP antibodies such as Ab3 and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast strains such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to PACAP, including the heavy and/or light chains of Ab3, as well as fragments, variants, and combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that possess a heavy chain sequence comprising the sequence of SEQ ID NO: 641 which consists of the heavy chain variable region of SEQ ID NO: 642 linked to the heavy chain constant region of SEQ ID NO: 650.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab4, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 661 which consists of the light chain variable region of SEQ ID NO: 662 linked to the light chain constant region of SEQ ID NO: 670.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab4, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 644; SEQ ID NO: 646; and SEQ ID NO: 648, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 641, or which contain the variable heavy chain sequence of SEQ ID NO: 642, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 664; SEQ ID NO: 666; and SEQ ID NO: 668, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 661, or which contain the variable light chain sequence of SEQ ID NO: 662, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the invention further contemplates anti-PACAP antibodies and antigen-binding fragments comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 643; SEQ ID NO: 645; SEQ ID NO: 647; and SEQ ID NO: 649, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 641, or the variable heavy chain sequence of SEQ ID NO: 642, and/or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 663; SEQ ID NO: 665; SEQ ID NO: 667; and SEQ ID NO: 669, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 661, or the variable light chain sequence of SEQ ID NO: 662, or combinations of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical therewith.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention or fragments comprise, or alternatively consist of, combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 641, or SEQ ID NO: 642, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 661, or SEQ ID NO: 662, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 644; SEQ ID NO: 646; and SEQ ID NO: 648, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 641, or the variable heavy chain sequence of SEQ ID NO: 642, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 664; SEQ ID NO: 666; and SEQ ID NO: 668, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 661, or the variable light chain sequence of SEQ ID NO: 662, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 643; SEQ ID NO: 645; SEQ ID NO: 647; and SEQ ID NO: 649, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 641, or the variable heavy chain sequence of SEQ ID NO: 642, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 663; SEQ ID NO: 665; SEQ ID NO: 667; and SEQ ID NO: 669, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 661, or the variable light chain sequence of SEQ ID NO: 662, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 642; the variable light chain region of SEQ ID NO: 662; the complementarity determining regions (SEQ ID NO: 644; SEQ ID NO: 646; and SEQ ID NO: 648) of the variable heavy chain region of SEQ ID NO: 642; and the complementarity determining regions (SEQ ID NO: 664; SEQ ID NO: 666; and SEQ ID NO: 668) of the variable light chain region of SEQ ID NO: 662, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 642; the variable light chain region of SEQ ID NO: 662; the framework regions (SEQ ID NO: 643; SEQ ID NO: 645; SEQ ID NO: 647; and SEQ ID NO: 649) of the variable heavy chain region of SEQ ID NO: 642; and the framework regions (SEQ ID NO: 663; SEQ ID NO: 665; SEQ ID NO: 667; and SEQ ID NO: 669) of the variable light chain region of SEQ ID NO: 662, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab4, comprising, or alternatively consisting of, SEQ ID NO: 641 and SEQ ID NO: 661, or SEQ ID NO: 642 and SEQ ID NO: 662, or an antibody or antigen-binding fragment comprising the CDRs of Ab4 and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab4 in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab4, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab4.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 642 and the variable light chain sequence of SEQ ID NO: 662, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 642 and/or SEQ ID NO: 662 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab4.
  • anti-PACAP antibodies such as Ab4 and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast strains such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to PACAP, including the heavy and/or light chains of Ab4, as well as fragments, variants, and combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that possess a heavy chain sequence comprising the sequence of SEQ ID NO: 481 which consists of the heavy chain variable region of SEQ ID NO: 482 linked to the heavy chain constant region of SEQ ID NO: 490.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab5, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 501 which consists of the light chain variable region of SEQ ID NO: 502 linked to the light chain constant region of SEQ ID NO: 510.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab5, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 484; SEQ ID NO: 486; and SEQ ID NO: 488, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 481, or which contain the variable heavy chain sequence of SEQ ID NO: 482, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 504; SEQ ID NO: 506; and SEQ ID NO: 508, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 501, or which contain the variable light chain sequence of SEQ ID NO: 502, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the invention further contemplates anti-PACAP antibodies and antigen-binding fragments comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 483; SEQ ID NO: 485; SEQ ID NO: 487; and SEQ ID NO: 489, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 481, or the variable heavy chain sequence of SEQ ID NO: 482, and/or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 503; SEQ ID NO: 505; SEQ ID NO: 507; and SEQ ID NO: 509, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 501, or the variable light chain sequence of SEQ ID NO: 502, or combinations of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical therewith.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention or fragments comprise, or alternatively consist of, combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 481, or SEQ ID NO: 482, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 501, or SEQ ID NO: 502, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 484; SEQ ID NO: 486; and SEQ ID NO: 488, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 481, or the variable heavy chain sequence of SEQ ID NO: 482, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 504; SEQ ID NO: 506; and SEQ ID NO: 508, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 501, or the variable light chain sequence of SEQ ID NO: 502, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 483; SEQ ID NO: 485; SEQ ID NO: 487; and SEQ ID NO: 489, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 481, or the variable heavy chain sequence of SEQ ID NO: 482, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 503; SEQ ID NO: 505; SEQ ID NO: 507; and SEQ ID NO: 509, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 501, or the variable light chain sequence of SEQ ID NO: 502, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 482; the variable light chain region of SEQ ID NO: 502; the complementarity determining regions (SEQ ID NO: 484; SEQ ID NO: 486; and SEQ ID NO: 488) of the variable heavy chain region of SEQ ID NO: 482; and the complementarity determining regions (SEQ ID NO: 504; SEQ ID NO: 506; and SEQ ID NO: 508) of the variable light chain region of SEQ ID NO: 502, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 482; the variable light chain region of SEQ ID NO: 502; the framework regions (SEQ ID NO: 483; SEQ ID NO: 485; SEQ ID NO: 487; and SEQ ID NO: 489) of the variable heavy chain region of SEQ ID NO: 482; and the framework regions (SEQ ID NO: 503; SEQ ID NO: 505; SEQ ID NO: 507; and SEQ ID NO: 509) of the variable light chain region of SEQ ID NO: 502, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab5, comprising, or alternatively consisting of, SEQ ID NO: 481 and SEQ ID NO: 501, or SEQ ID NO: 482 and SEQ ID NO: 502, or an antibody or antigen-binding fragment comprising the CDRs of Ab5 and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab5 in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab5, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab5.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 482 and the variable light chain sequence of SEQ ID NO: 502, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 482 and/or SEQ ID NO: 502 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab5.
  • anti-PACAP antibodies such as Ab5 and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast strains such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to PACAP, including the heavy and/or light chains of Ab5, as well as fragments, variants, and combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that possess a heavy chain sequence comprising the sequence of SEQ ID NO: 721 which consists of the heavy chain variable region of SEQ ID NO: 722 linked to the heavy chain constant region of SEQ ID NO: 730.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab6, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 741 which consists of the light chain variable region of SEQ ID NO: 742 linked to the light chain constant region of SEQ ID NO: 750.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab6, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 724; SEQ ID NO: 726; and SEQ ID NO: 728, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 721, or which contain the variable heavy chain sequence of SEQ ID NO: 722, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 744; SEQ ID NO: 746; and SEQ ID NO: 748, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 741, or which contain the variable light chain sequence of SEQ ID NO: 742, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the invention further contemplates anti-PACAP antibodies and antigen-binding fragments comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 723; SEQ ID NO: 725; SEQ ID NO: 727; and SEQ ID NO: 729, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 721, or the variable heavy chain sequence of SEQ ID NO: 722, and/or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 743; SEQ ID NO: 745; SEQ ID NO: 747; and SEQ ID NO: 749, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 741, or the variable light chain sequence of SEQ ID NO: 742, or combinations of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical therewith.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention or fragments comprise, or alternatively consist of, combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 721, or SEQ ID NO: 722, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 741, or SEQ ID NO: 742, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 724; SEQ ID NO: 726; and SEQ ID NO: 728, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 721, or the variable heavy chain sequence of SEQ ID NO: 722, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 744; SEQ ID NO: 746; and SEQ ID NO: 748, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 741, or the variable light chain sequence of SEQ ID NO: 742, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 723; SEQ ID NO: 725; SEQ ID NO: 727; and SEQ ID NO: 729, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 721, or the variable heavy chain sequence of SEQ ID NO: 722, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 743; SEQ ID NO: 745; SEQ ID NO: 747; and SEQ ID NO: 749, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 741, or the variable light chain sequence of SEQ ID NO: 742, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 722; the variable light chain region of SEQ ID NO: 742; the complementarity determining regions (SEQ ID NO: 724; SEQ ID NO: 726; and SEQ ID NO: 728) of the variable heavy chain region of SEQ ID NO: 722; and the complementarity determining regions (SEQ ID NO: 744; SEQ ID NO: 746; and SEQ ID NO: 748) of the variable light chain region of SEQ ID NO: 742, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 722; the variable light chain region of SEQ ID NO: 742; the framework regions (SEQ ID NO: 723; SEQ ID NO: 725; SEQ ID NO: 727; and SEQ ID NO: 729) of the variable heavy chain region of SEQ ID NO: 722; and the framework regions (SEQ ID NO: 743; SEQ ID NO: 745; SEQ ID NO: 747; and SEQ ID NO: 749) of the variable light chain region of SEQ ID NO: 742, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab6, comprising, or alternatively consisting of, SEQ ID NO: 721 and SEQ ID NO: 741, or SEQ ID NO: 722 and SEQ ID NO: 742, or an antibody or antigen-binding fragment comprising the CDRs of Ab6 and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab6 in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab6, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab6.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 722 and the variable light chain sequence of SEQ ID NO: 742, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 722 and/or SEQ ID NO: 742 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab6.
  • anti-PACAP antibodies such as Ab6 and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to PACAP, including the heavy and/or light chains of Ab6, as well as fragments, variants, and combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that possess a heavy chain sequence comprising the sequence of SEQ ID NO: 521 which consists of the heavy chain variable region of SEQ ID NO: 522 linked to the heavy chain constant region of SEQ ID NO: 530.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab7, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 541 which consists of the light chain variable region of SEQ ID NO: 542 linked to the light chain constant region of SEQ ID NO: 550.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab7, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 524; SEQ ID NO: 526; and SEQ ID NO: 528, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 521, or which contain the variable heavy chain sequence of SEQ ID NO: 522, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 544; SEQ ID NO: 546; and SEQ ID NO: 548, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 541, or which contain the variable light chain sequence of SEQ ID NO: 542, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the invention further contemplates anti-PACAP antibodies and antigen-binding fragments comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 523; SEQ ID NO: 525; SEQ ID NO: 527; and SEQ ID NO: 529, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 521, or the variable heavy chain sequence of SEQ ID NO: 522, and/or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 543; SEQ ID NO: 545; SEQ ID NO: 547; and SEQ ID NO: 549, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 541, or the variable light chain sequence of SEQ ID NO: 542, or combinations of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical therewith.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention or fragments comprise, or alternatively consist of, combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 521, or SEQ ID NO: 522, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 541, or SEQ ID NO: 542, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 524; SEQ ID NO: 526; and SEQ ID NO: 528, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 521, or the variable heavy chain sequence of SEQ ID NO: 522, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 544; SEQ ID NO: 546; and SEQ ID NO: 548, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 541, or the variable light chain sequence of SEQ ID NO: 542, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 523; SEQ ID NO: 525; SEQ ID NO: 527; and SEQ ID NO: 529, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 521, or the variable heavy chain sequence of SEQ ID NO: 522, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 543; SEQ ID NO: 545; SEQ ID NO: 547; and SEQ ID NO: 549, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 541, or the variable light chain sequence of SEQ ID NO: 542, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 522; the variable light chain region of SEQ ID NO: 542; the complementarity determining regions (SEQ ID NO: 524; SEQ ID NO: 526; and SEQ ID NO: 528) of the variable heavy chain region of SEQ ID NO: 522; and the complementarity determining regions (SEQ ID NO: 544; SEQ ID NO: 546; and SEQ ID NO: 548) of the variable light chain region of SEQ ID NO: 542, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 522; the variable light chain region of SEQ ID NO: 542; the framework regions (SEQ ID NO: 523; SEQ ID NO: 525; SEQ ID NO: 527; and SEQ ID NO: 529) of the variable heavy chain region of SEQ ID NO: 522; and the framework regions (SEQ ID NO: 543; SEQ ID NO: 545; SEQ ID NO: 547; and SEQ ID NO: 549) of the variable light chain region of SEQ ID NO: 542, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab7, comprising, or alternatively consisting of, SEQ ID NO: 521 and SEQ ID NO: 541, or SEQ ID NO: 522 and SEQ ID NO: 542, or an antibody or antigen-binding fragment comprising the CDRs of Ab7 and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab7 in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab7, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab7.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 522 and the variable light chain sequence of SEQ ID NO: 542, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 522 and/or SEQ ID NO: 542 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab7.
  • anti-PACAP antibodies such as Ab7 and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to PACAP, including the heavy and/or light chains of Ab7, as well as fragments, variants, and combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that possess a heavy chain sequence comprising the sequence of SEQ ID NO: 761 which consists of the heavy chain variable region of SEQ ID NO: 762 linked to the heavy chain constant region of SEQ ID NO: 770.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab8, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 781 which consists of the light chain variable region of SEQ ID NO: 782 linked to the light chain constant region of SEQ ID NO: 790.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab8, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 764; SEQ ID NO: 766; and SEQ ID NO: 768, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 761, or which contain the variable heavy chain sequence of SEQ ID NO: 762, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 784; SEQ ID NO: 786; and SEQ ID NO: 788, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 781, or which contain the variable light chain sequence of SEQ ID NO: 782, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the invention further contemplates anti-PACAP antibodies and antigen-binding fragments comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 763; SEQ ID NO: 765; SEQ ID NO: 767; and SEQ ID NO: 769, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 761, or the variable heavy chain sequence of SEQ ID NO: 762, and/or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 783; SEQ ID NO: 785; SEQ ID NO: 787; and SEQ ID NO: 789, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 781, or the variable light chain sequence of SEQ ID NO: 782, or combinations of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical therewith.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention or fragments comprise, or alternatively consist of, combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 761, or SEQ ID NO: 762, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 781, or SEQ ID NO: 782, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 764; SEQ ID NO: 766; and SEQ ID NO: 768, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 761, or the variable heavy chain sequence of SEQ ID NO: 762, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 784; SEQ ID NO: 786; and SEQ ID NO: 788, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 781, or the variable light chain sequence of SEQ ID NO: 782, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 763; SEQ ID NO: 765; SEQ ID NO: 767; and SEQ ID NO: 769, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 761, or the variable heavy chain sequence of SEQ ID NO: 762, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 783; SEQ ID NO: 785; SEQ ID NO: 787; and SEQ ID NO: 789, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 781, or the variable light chain sequence of SEQ ID NO: 782, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 762; the variable light chain region of SEQ ID NO: 782; the complementarity determining regions (SEQ ID NO: 764; SEQ ID NO: 766; and SEQ ID NO: 768) of the variable heavy chain region of SEQ ID NO: 762; and the complementarity determining regions (SEQ ID NO: 784; SEQ ID NO: 786; and SEQ ID NO: 788) of the variable light chain region of SEQ ID NO: 782, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 762; the variable light chain region of SEQ ID NO: 782; the framework regions (SEQ ID NO: 763; SEQ ID NO: 765; SEQ ID NO: 767; and SEQ ID NO: 769) of the variable heavy chain region of SEQ ID NO: 762; and the framework regions (SEQ ID NO: 783; SEQ ID NO: 785; SEQ ID NO: 787; and SEQ ID NO: 789) of the variable light chain region of SEQ ID NO: 782, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab8, comprising, or alternatively consisting of, SEQ ID NO: 761 and SEQ ID NO: 781, or SEQ ID NO: 762 and SEQ ID NO: 782, or an antibody or antigen-binding fragment comprising the CDRs of Ab8 and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab8 in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab8, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab8.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 762 and the variable light chain sequence of SEQ ID NO: 782, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 762 and/or SEQ ID NO: 782 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab8.
  • anti-PACAP antibodies such as Ab8 and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to PACAP, including the heavy and/or light chains of Ab8, as well as fragments, variants, and combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab9, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 821 which consists of the light chain variable region of SEQ ID NO: 822 linked to the light chain constant region of SEQ ID NO: 830.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab9, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 804; SEQ ID NO: 806; and SEQ ID NO: 808, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 801, or which contain the variable heavy chain sequence of SEQ ID NO: 802, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 824; SEQ ID NO: 826; and SEQ ID NO: 828, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 821, or which contain the variable light chain sequence of SEQ ID NO: 822, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the invention further contemplates anti-PACAP antibodies and antigen-binding fragments comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 803; SEQ ID NO: 805; SEQ ID NO: 807; and SEQ ID NO: 809, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 801, or the variable heavy chain sequence of SEQ ID NO: 802, and/or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 823; SEQ ID NO: 825; SEQ ID NO: 827; and SEQ ID NO: 829, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 821, or the variable light chain sequence of SEQ ID NO: 822, or combinations of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical therewith.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention or fragments comprise, or alternatively consist of, combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 801, or SEQ ID NO: 802, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 821, or SEQ ID NO: 822, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 824; SEQ ID NO: 826; and SEQ ID NO: 828, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 821, or the variable light chain sequence of SEQ ID NO: 822, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 803; SEQ ID NO: 805; SEQ ID NO: 807; and SEQ ID NO: 809, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 801, or the variable heavy chain sequence of SEQ ID NO: 802, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 823; SEQ ID NO: 825; SEQ ID NO: 827; and SEQ ID NO: 829, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 821, or the variable light chain sequence of SEQ ID NO: 822, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 802; the variable light chain region of SEQ ID NO: 822; the complementarity determining regions (SEQ ID NO: 804; SEQ ID NO: 806; and SEQ ID NO: 808) of the variable heavy chain region of SEQ ID NO: 802; and the complementarity determining regions (SEQ ID NO: 824; SEQ ID NO: 826; and SEQ ID NO: 828) of the variable light chain region of SEQ ID NO: 822, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 802; the variable light chain region of SEQ ID NO: 822; the framework regions (SEQ ID NO: 803; SEQ ID NO: 805; SEQ ID NO: 807; and SEQ ID NO: 809) of the variable heavy chain region of SEQ ID NO: 802; and the framework regions (SEQ ID NO: 823; SEQ ID NO: 825; SEQ ID NO: 827; and SEQ ID NO: 829) of the variable light chain region of SEQ ID NO: 822, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab9, comprising, or alternatively consisting of, SEQ ID NO: 801 and SEQ ID NO: 821, or SEQ ID NO: 802 and SEQ ID NO: 822, or an antibody or antigen-binding fragment comprising the CDRs of Ab9 and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab9 in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab9, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab9.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 802 and the variable light chain sequence of SEQ ID NO: 822, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 802 and/or SEQ ID NO: 822 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab9.
  • anti-PACAP antibodies such as Ab9 and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast strains such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to PACAP, including the heavy and/or light chains of Ab9, as well as fragments, variants, and combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that possess a heavy chain sequence comprising the sequence of SEQ ID NO: 561 which consists of the heavy chain variable region of SEQ ID NO: 562 linked to the heavy chain constant region of SEQ ID NO: 570.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab11, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 581 which consists of the light chain variable region of SEQ ID NO: 582 linked to the light chain constant region of SEQ ID NO: 590.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab11, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 564; SEQ ID NO: 566; and SEQ ID NO: 568, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 561, or which contain the variable heavy chain sequence of SEQ ID NO: 562, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 584; SEQ ID NO: 586; and SEQ ID NO: 588, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 581, or which contain the variable light chain sequence of SEQ ID NO: 582, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the invention further contemplates anti-PACAP antibodies and antigen-binding fragments comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 563; SEQ ID NO: 565; SEQ ID NO: 567; and SEQ ID NO: 569, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 561, or the variable heavy chain sequence of SEQ ID NO: 562, and/or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 583; SEQ ID NO: 585; SEQ ID NO: 587; and SEQ ID NO: 589, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 581, or the variable light chain sequence of SEQ ID NO: 582, or combinations of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical therewith.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 561, or SEQ ID NO: 562, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 581, or SEQ ID NO: 582, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 564; SEQ ID NO: 566; and SEQ ID NO: 568, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 561, or the variable heavy chain sequence of SEQ ID NO: 562, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 584; SEQ ID NO: 586; and SEQ ID NO: 588, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 581, or the variable light chain sequence of SEQ ID NO: 582, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 583; SEQ ID NO: 585; SEQ ID NO: 587; and SEQ ID NO: 589, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 581, or the variable light chain sequence of SEQ ID NO: 582, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 562; the variable light chain region of SEQ ID NO: 582; the complementarity determining regions (SEQ ID NO: 564; SEQ ID NO: 566; and SEQ ID NO: 568) of the variable heavy chain region of SEQ ID NO: 562; and the complementarity determining regions (SEQ ID NO: 584; SEQ ID NO: 586; and SEQ ID NO: 588) of the variable light chain region of SEQ ID NO: 582, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 562; the variable light chain region of SEQ ID NO: 582; the framework regions (SEQ ID NO: 563; SEQ ID NO: 565; SEQ ID NO: 567; and SEQ ID NO: 569) of the variable heavy chain region of SEQ ID NO: 562; and the framework regions (SEQ ID NO: 583; SEQ ID NO: 585; SEQ ID NO: 587; and SEQ ID NO: 589) of the variable light chain region of SEQ ID NO: 582, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab11, comprising, or alternatively consisting of, SEQ ID NO: 561 and SEQ ID NO: 581, or SEQ ID NO: 562 and SEQ ID NO: 582, or an antibody or antigen-binding fragment comprising the CDRs of Ab11 and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab11 in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab11, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab11.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 562 and the variable light chain sequence of SEQ ID NO: 582, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 562 and/or SEQ ID NO: 582 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab11.
  • anti-PACAP antibodies such as Ab11 and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast strains such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to PACAP, including the heavy and/or light chains of Ab11, as well as fragments, variants, and combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that possess a heavy chain sequence comprising the sequence of SEQ ID NO: 601 which consists of the heavy chain variable region of SEQ ID NO: 602 linked to the heavy chain constant region of SEQ ID NO: 610.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab12, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 621 which consists of the light chain variable region of SEQ ID NO: 622 linked to the light chain constant region of SEQ ID NO: 630.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab12, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 604; SEQ ID NO: 606; and SEQ ID NO: 608, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 601, or which contain the variable heavy chain sequence of SEQ ID NO: 602, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 624; SEQ ID NO: 626; and SEQ ID NO: 628, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 621, or which contain the variable light chain sequence of SEQ ID NO: 622, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the invention further contemplates anti-PACAP antibodies and antigen-binding fragments comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 603; SEQ ID NO: 605; SEQ ID NO: 607; and SEQ ID NO: 609, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 601, or the variable heavy chain sequence of SEQ ID NO: 602, and/or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 623; SEQ ID NO: 625; SEQ ID NO: 627; and SEQ ID NO: 629, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 621, or the variable light chain sequence of SEQ ID NO: 622, or combinations of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical therewith.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention or fragments comprise, or alternatively consist of, combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 601, or SEQ ID NO: 602, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 621, or SEQ ID NO: 622, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 604; SEQ ID NO: 606; and SEQ ID NO: 608, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 601, or the variable heavy chain sequence of SEQ ID NO: 602, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 624; SEQ ID NO: 626; and SEQ ID NO: 628, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 621, or the variable light chain sequence of SEQ ID NO: 622, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 603; SEQ ID NO: 605; SEQ ID NO: 607; and SEQ ID NO: 609, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 601, or the variable heavy chain sequence of SEQ ID NO: 602, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 623; SEQ ID NO: 625; SEQ ID NO: 627; and SEQ ID NO: 629, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 621, or the variable light chain sequence of SEQ ID NO: 622, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 602; the variable light chain region of SEQ ID NO: 622; the complementarity determining regions (SEQ ID NO: 604; SEQ ID NO: 606; and SEQ ID NO: 608) of the variable heavy chain region of SEQ ID NO: 602; and the complementarity determining regions (SEQ ID NO: 624; SEQ ID NO: 626; and SEQ ID NO: 628) of the variable light chain region of SEQ ID NO: 622, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 602; the variable light chain region of SEQ ID NO: 622; the framework regions (SEQ ID NO: 603; SEQ ID NO: 605; SEQ ID NO: 607; and SEQ ID NO: 609) of the variable heavy chain region of SEQ ID NO: 602; and the framework regions (SEQ ID NO: 623; SEQ ID NO: 625; SEQ ID NO: 627; and SEQ ID NO: 629) of the variable light chain region of SEQ ID NO: 622, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab12, comprising, or alternatively consisting of, SEQ ID NO: 601 and SEQ ID NO: 621, or SEQ ID NO: 602 and SEQ ID NO: 622, or an antibody or antigen-binding fragment comprising the CDRs of Ab12 and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab12 in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab12, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab12.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 602 and the variable light chain sequence of SEQ ID NO: 622, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 602 and/or SEQ ID NO: 622 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab12.
  • anti-PACAP antibodies such as Ab12 and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast strains such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to PACAP, including the heavy and/or light chains of Ab12, as well as fragments, variants, and combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that possess a heavy chain sequence comprising the sequence of SEQ ID NO: 121 which consists of the heavy chain variable region of SEQ ID NO: 122 linked to the heavy chain constant region of SEQ ID NO: 130.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab13, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 141 which consists of the light chain variable region of SEQ ID NO: 142 linked to the light chain constant region of SEQ ID NO: 150.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab13, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 124; SEQ ID NO: 126; and SEQ ID NO: 128, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 121, or which contain the variable heavy chain sequence of SEQ ID NO: 122, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 144; SEQ ID NO: 146; and SEQ ID NO: 148, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 141, or which contain the variable light chain sequence of SEQ ID NO: 142, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the invention further contemplates anti-PACAP antibodies and antigen-binding fragments comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 123; SEQ ID NO: 125; SEQ ID NO: 127; and SEQ ID NO: 129, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 121, or the variable heavy chain sequence of SEQ ID NO: 122, and/or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 143; SEQ ID NO: 145; SEQ ID NO: 147; and SEQ ID NO: 149, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 141, or the variable light chain sequence of SEQ ID NO: 142, or combinations of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical therewith.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention or fragments comprise, or alternatively consist of, combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 121, or SEQ ID NO: 122, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 141, or SEQ ID NO: 142, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 124; SEQ ID NO: 126; and SEQ ID NO: 128, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 121, or the variable heavy chain sequence of SEQ ID NO: 122, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 144; SEQ ID NO: 146; and SEQ ID NO: 148, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 141, or the variable light chain sequence of SEQ ID NO: 142, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 123; SEQ ID NO: 125; SEQ ID NO: 127; and SEQ ID NO: 129, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 121, or the variable heavy chain sequence of SEQ ID NO: 122, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 143; SEQ ID NO: 145; SEQ ID NO: 147; and SEQ ID NO: 149, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 141, or the variable light chain sequence of SEQ ID NO: 142, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 122; the variable light chain region of SEQ ID NO: 142; the complementarity determining regions (SEQ ID NO: 124; SEQ ID NO: 126; and SEQ ID NO: 128) of the variable heavy chain region of SEQ ID NO: 122; and the complementarity determining regions (SEQ ID NO: 144; SEQ ID NO: 146; and SEQ ID NO: 148) of the variable light chain region of SEQ ID NO: 142, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 122; the variable light chain region of SEQ ID NO: 142; the framework regions (SEQ ID NO: 123; SEQ ID NO: 125; SEQ ID NO: 127; and SEQ ID NO: 129) of the variable heavy chain region of SEQ ID NO: 122; and the framework regions (SEQ ID NO: 143; SEQ ID NO: 145; SEQ ID NO: 147; and SEQ ID NO: 149) of the variable light chain region of SEQ ID NO: 142, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab13, comprising, or alternatively consisting of, SEQ ID NO: 121 and SEQ ID NO: 141, or SEQ ID NO: 122 and SEQ ID NO: 142, or an antibody or antigen-binding fragment comprising the CDRs of Ab13 and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab13 in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab13, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab13.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 122 and the variable light chain sequence of SEQ ID NO: 142, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 122 and/or SEQ ID NO: 142 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab13.
  • anti-PACAP antibodies such as Ab13 and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to PACAP, including the heavy and/or light chains of Ab13, as well as fragments, variants, and combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that possess a heavy chain sequence comprising the sequence of SEQ ID NO: 161 which consists of the heavy chain variable region of SEQ ID NO: 162 linked to the heavy chain constant region of SEQ ID NO: 170.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab14, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 181 which consists of the light chain variable region of SEQ ID NO: 182 linked to the light chain constant region of SEQ ID NO: 190.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab14, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 164; SEQ ID NO: 166; and SEQ ID NO: 168, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 161, or which contain the variable heavy chain sequence of SEQ ID NO: 162, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 184; SEQ ID NO: 186; and SEQ ID NO: 188, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 181, or which contain the variable light chain sequence of SEQ ID NO: 182, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the invention further contemplates anti-PACAP antibodies and antigen-binding fragments comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 163; SEQ ID NO: 165; SEQ ID NO: 167; and SEQ ID NO: 169, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 161, or the variable heavy chain sequence of SEQ ID NO: 162, and/or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 183; SEQ ID NO: 185; SEQ ID NO: 187; and SEQ ID NO: 189, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 181, or the variable light chain sequence of SEQ ID NO: 182, or combinations of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical therewith.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention or fragments comprise, or alternatively consist of, combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 161, or SEQ ID NO: 162, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 181, or SEQ ID NO: 182, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 164; SEQ ID NO: 166; and SEQ ID NO: 168, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 161, or the variable heavy chain sequence of SEQ ID NO: 162, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 184; SEQ ID NO: 186; and SEQ ID NO: 188, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 181, or the variable light chain sequence of SEQ ID NO: 182, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 163; SEQ ID NO: 165; SEQ ID NO: 167; and SEQ ID NO: 169, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 161, or the variable heavy chain sequence of SEQ ID NO: 162, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 183; SEQ ID NO: 185; SEQ ID NO: 187; and SEQ ID NO: 189, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 181, or the variable light chain sequence of SEQ ID NO: 182, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 162; the variable light chain region of SEQ ID NO: 182; the complementarity determining regions (SEQ ID NO: 164; SEQ ID NO: 166; and SEQ ID NO: 168) of the variable heavy chain region of SEQ ID NO: 162; and the complementarity determining regions (SEQ ID NO: 184; SEQ ID NO: 186; and SEQ ID NO: 188) of the variable light chain region of SEQ ID NO: 182, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 162; the variable light chain region of SEQ ID NO: 182; the framework regions (SEQ ID NO: 163; SEQ ID NO: 165; SEQ ID NO: 167; and SEQ ID NO: 169) of the variable heavy chain region of SEQ ID NO: 162; and the framework regions (SEQ ID NO: 183; SEQ ID NO: 185; SEQ ID NO: 187; and SEQ ID NO: 189) of the variable light chain region of SEQ ID NO: 182, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab14, comprising, or alternatively consisting of, SEQ ID NO: 161 and SEQ ID NO: 181, or SEQ ID NO: 162 and SEQ ID NO: 182, or an antibody or antigen-binding fragment comprising the CDRs of Ab14 and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab14 in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab14, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab14.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 162 and the variable light chain sequence of SEQ ID NO: 182, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 162 and/or SEQ ID NO: 182 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab14.
  • anti-PACAP antibodies such as Ab14 and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to PACAP, including the heavy and/or light chains of Ab14, as well as fragments, variants, and combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that possess a heavy chain sequence comprising the sequence of SEQ ID NO: 201 which consists of the heavy chain variable region of SEQ ID NO: 202 linked to the heavy chain constant region of SEQ ID NO: 210.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab15, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 221 which consists of the light chain variable region of SEQ ID NO: 222 linked to the light chain constant region of SEQ ID NO: 230.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab15, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 201, or which contain the variable heavy chain sequence of SEQ ID NO: 202, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 221, or which contain the variable light chain sequence of SEQ ID NO: 222, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the invention further contemplates anti-PACAP antibodies and antigen-binding fragments comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 203; SEQ ID NO: 205; SEQ ID NO: 207; and SEQ ID NO: 209, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 201, or the variable heavy chain sequence of SEQ ID NO: 202, and/or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 223; SEQ ID NO: 225; SEQ ID NO: 227; and SEQ ID NO: 229, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 221, or the variable light chain sequence of SEQ ID NO: 222, or combinations of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical therewith.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention or fragments comprise, or alternatively consist of, combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 201, or SEQ ID NO: 202, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 221, or SEQ ID NO: 222, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 201, or the variable heavy chain sequence of SEQ ID NO: 202, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 221, or the variable light chain sequence of SEQ ID NO: 222, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 203; SEQ ID NO: 205; SEQ ID NO: 207; and SEQ ID NO: 209, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 201, or the variable heavy chain sequence of SEQ ID NO: 202, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 223; SEQ ID NO: 225; SEQ ID NO: 227; and SEQ ID NO: 229, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 221, or the variable light chain sequence of SEQ ID NO: 222, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 202; the variable light chain region of SEQ ID NO: 222; the complementarity determining regions (SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208) of the variable heavy chain region of SEQ ID NO: 202; and the complementarity determining regions (SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228) of the variable light chain region of SEQ ID NO: 222, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 202; the variable light chain region of SEQ ID NO: 222; the framework regions (SEQ ID NO: 203; SEQ ID NO: 205; SEQ ID NO: 207; and SEQ ID NO: 209) of the variable heavy chain region of SEQ ID NO: 202; and the framework regions (SEQ ID NO: 223; SEQ ID NO: 225; SEQ ID NO: 227; and SEQ ID NO: 229) of the variable light chain region of SEQ ID NO: 222, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab15, comprising, or alternatively consisting of, SEQ ID NO: 201 and SEQ ID NO: 221, or SEQ ID NO: 202 and SEQ ID NO: 222, or an antibody or antigen-binding fragment comprising the CDRs of Ab15 and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab15 in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab15, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab15.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 202 and the variable light chain sequence of SEQ ID NO: 222, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 202 and/or SEQ ID NO: 222 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab15.
  • anti-PACAP antibodies such as Ab15 and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to PACAP, including the heavy and/or light chains of Ab15, as well as fragments, variants, and combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that possess a heavy chain sequence comprising the sequence of SEQ ID NO: 241 which consists of the heavy chain variable region of SEQ ID NO: 242 linked to the heavy chain constant region of SEQ ID NO: 250.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab16, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 261 which consists of the light chain variable region of SEQ ID NO: 262 linked to the light chain constant region of SEQ ID NO: 270.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP, that bind the same epitope as Ab16, and that contain a constant light chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain one, two, or three of the polypeptide sequences of SEQ ID NO: 244; SEQ ID NO: 246; and SEQ ID NO: 248, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 241, or which contain the variable heavy chain sequence of SEQ ID NO: 242, and/or which further contain one, two, or three of the polypeptide sequences of SEQ ID NO: 264; SEQ ID NO: 266; and SEQ ID NO: 268, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 261, or which contain the variable light chain sequence of SEQ ID NO: 262, or antibodies or antigen-binding fragments containing combinations of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the antibodies of the invention and antigen-binding fragments comprise, or alternatively consist of, combinations of one or more of the exemplified variable heavy chain and variable light chain sequences, or the heavy chain and light chain sequences set forth above, or sequences that are at least 90% or 95% identical thereto.
  • the invention further contemplates anti-PACAP antibodies and antigen-binding fragments comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 243; SEQ ID NO: 245; SEQ ID NO: 247; and SEQ ID NO: 249, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 241, or the variable heavy chain sequence of SEQ ID NO: 242, and/or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 263; SEQ ID NO: 265; SEQ ID NO: 267; and SEQ ID NO: 269, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 261, or the variable light chain sequence of SEQ ID NO: 262, or combinations of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical therewith.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention or fragments comprise, or alternatively consist of, combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 241, or SEQ ID NO: 242, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 261, or SEQ ID NO: 262, or polypeptides that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 244; SEQ ID NO: 246; and SEQ ID NO: 248, which correspond to the CDRs (hypervariable regions) of the heavy chain sequence of SEQ ID NO: 241, or the variable heavy chain sequence of SEQ ID NO: 242, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, or three of the polypeptide sequences of SEQ ID NO: 264; SEQ ID NO: 266; and SEQ ID NO: 268, which correspond to the CDRs (hypervariable regions) of the light chain sequence of SEQ ID NO: 261, or the variable light chain sequence of SEQ ID NO: 262, or sequences that are at least 90% or 95% identical thereto.
  • the antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 243; SEQ ID NO: 245; SEQ ID NO: 247; and SEQ ID NO: 249, which correspond to the FRs (constant regions) of the heavy chain sequence of SEQ ID NO: 241, or the variable heavy chain sequence of SEQ ID NO: 242, or sequences that are at least 90% or 95% identical thereto.
  • the subject antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or four of the polypeptide sequences of SEQ ID NO: 263; SEQ ID NO: 265; SEQ ID NO: 267; and SEQ ID NO: 269, which correspond to the FRs (constant regions) of the light chain sequence of SEQ ID NO: 261, or the variable light chain sequence of SEQ ID NO: 262, or sequences that are at least 90% or 95% identical thereto.
  • antibodies and antigen-binding fragments having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 242; the variable light chain region of SEQ ID NO: 262; the complementarity determining regions (SEQ ID NO: 244; SEQ ID NO: 246; and SEQ ID NO: 248) of the variable heavy chain region of SEQ ID NO: 242; and the complementarity determining regions (SEQ ID NO: 264; SEQ ID NO: 266; and SEQ ID NO: 268) of the variable light chain region of SEQ ID NO: 262, or sequences that are at least 90% or 95% identical thereto.
  • fragments of the antibodies having binding specificity to PACAP comprise, or alternatively consist of, one, two, three, or more, including all of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 242; the variable light chain region of SEQ ID NO: 262; the framework regions (SEQ ID NO: 243; SEQ ID NO: 245; SEQ ID NO: 247; and SEQ ID NO: 249) of the variable heavy chain region of SEQ ID NO: 242; and the framework regions (SEQ ID NO: 263; SEQ ID NO: 265; SEQ ID NO: 267; and SEQ ID NO: 269) of the variable light chain region of SEQ ID NO: 262, or sequences that are at least 90% or 95% identical thereto.
  • the anti-PACAP antibody is Ab16, comprising, or alternatively consisting of, SEQ ID NO: 241 and SEQ ID NO: 261, or SEQ ID NO: 242 and SEQ ID NO: 262, or an antibody or antigen-binding fragment comprising the CDRs of Ab16 and having at least one of the biological activities set forth herein, or is an anti-PACAP antibody that competes with Ab16 in binding PACAP, preferably one containing sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab16, or an antibody that binds to the same or overlapping epitope(s) on PACAP as Ab16.
  • antigen-binding fragments comprise, or alternatively consist of, Fab fragments having binding specificity for PACAP.
  • the Fab fragment preferably includes the variable heavy chain sequence of SEQ ID NO: 242 and the variable light chain sequence of SEQ ID NO: 262, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • This embodiment of the invention further includes Fabs containing additions, deletions, and variants of SEQ ID NO: 242 and/or SEQ ID NO: 262 that retain the binding specificity for PACAP.
  • Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab16.
  • anti-PACAP antibodies such as Ab16 and Fab fragments may be produced via expression in mammalian cells, such as CHO, NSO, or HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (for example haploid or diploid yeast, such as haploid or diploid Pichia ) and other yeast strains.
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • yeast cells for example haploid or diploid yeast, such as haploid or diploid Pichia
  • Suitable Pichia species include, but are not limited to, Pichia pastoris.
  • the invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to PACAP, including the heavy and/or light chains of Ab16, as well as fragments, variants, and combinations of one or more of the FRs, CDRs, the variable heavy chain and variable light chain sequences, and the heavy chain and light chain sequences set forth above, including all of them, or sequences that are at least 90% or 95% identical thereto.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that possess a heavy chain sequence comprising the sequence of SEQ ID NO: 281 which consists of the heavy chain variable region of SEQ ID NO: 282 linked to the heavy chain constant region of SEQ ID NO: 290.
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a variable heavy chain sequence comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that bind the same epitope as Ab17, and that contain a constant heavy chain sequence comprising the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or comprising the sequence set forth below:
  • the invention includes antibodies and antigen-binding fragments having binding specificity to PACAP that contain a light chain sequence comprising the sequence of SEQ ID NO: 301 which consists of the light chain variable region of SEQ ID NO: 302 linked to the light chain constant region of SEQ ID NO: 310.

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US20160376363A1 (en) 2015-04-16 2016-12-29 Alder Biopharmaceuticals, Inc. Use of anti-pacap antibodies and antigen binding fragments thereof for treatment, prevention, or inhibition of photophobia
US11993648B2 (en) 2015-04-16 2024-05-28 H. Lundbeck A/S Screening method for identifying anti-PACAP antibodies or antibody fragments suitable for use in treating or preventing PACAP-associated photophobia or light aversion
US10981985B2 (en) 2015-04-16 2021-04-20 H. Lundbeck A/S Anti-PACAP antibodies
US10844116B2 (en) 2015-04-16 2020-11-24 The University Of Iowa Research Foundation Use of anti-pacap antibodies and antigen binding fragments thereof for treatment, prevention, or inhibition of photophobia
US10899834B2 (en) 2015-04-16 2021-01-26 H. Lundbeck A/S Anti-PACAP antibodies
US10981984B2 (en) 2015-04-16 2021-04-20 H. Lundbeck A/S Methods of determining whether anti-PACAP antibodies inhibit PACAP-associated photophobia or light aversion
US10968268B2 (en) 2016-04-15 2021-04-06 H. Lundbeck A/S Humanized anti-PACAP antibodies
US10954285B2 (en) 2016-04-15 2021-03-23 H. Lundbeck A/S Humanized anti-PACAP antibodies
US10975135B2 (en) 2016-04-15 2021-04-13 H. Lundbeck A/S Humanized anti-PACAP antibodies
US10913783B2 (en) 2016-04-15 2021-02-09 H. Lundbeck A/S Humanized anti-PACAP antibodies and uses thereof
US20190233498A1 (en) * 2016-04-15 2019-08-01 Alder Biopharmaceuticals, Inc. Anti-pacap antibodies and uses thereof
US11352409B2 (en) * 2016-04-15 2022-06-07 H. Lundbeck A/S Anti-PACAP antibodies and uses thereof
US11938185B2 (en) 2016-04-15 2024-03-26 H. Lundbeck A/S Treatment of headache, migraine and/or photophobia conditions using humanized anti-PACAP antibodies
US10202435B2 (en) * 2016-04-15 2019-02-12 Alder Biopharmaceuticals, Inc. Anti-PACAP antibodies and uses thereof
JP2021024831A (ja) * 2019-08-07 2021-02-22 国立大学法人 大分大学 アミロイドβタンパク質オリゴマーと結合するヒト化抗体
JP7370569B2 (ja) 2019-08-07 2023-10-30 国立大学法人 大分大学 アミロイドβタンパク質オリゴマーと結合するヒト化抗体

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