Treatment of opioid-induced pain

Abstract

The present invention aims to provide a method for treating pain such as hyperalgesia or allodynia, more specifically, a method for treating opioid-induced pain, such as opioid-induced chronic migraine, opioid-induced hyperalgesia (OIH), and opioid-induced allodynia (OIA), by administering an antibody and / or its antigen-binding fragment having binding specificity to PACAP. The antibody and / or its antigen-binding fragment may include the sequences of the VH, VL, and CDR polypeptides described herein, and the encoding polynucleotides. The antibody and / or its antigen-binding fragment described herein binds to the same linear or conformational epitopes on human PACAP as the anti-PACAP antibody and / or competes for binding to them.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 484,850, filed on 14 February 2023, the contents of which are incorporated in their entirety by reference.

[0002] Disclosure of sequence listings The contents of the electronic sequence listing (1143257o010013.xml; size: 963,036 bytes; and creation date: February 2, 2024) are incorporated herein by reference in their entirety.

[0003] Field of Invention The present invention relates to a method for treating and / or preventing opioid-induced pain, such as opioid-induced chronic migraine, opioid-induced hyperalgesia (OIH), and opioid-induced allodynia (OIA), by administering an antibody and / or its antigen-binding fragment, preferably a humanized or chimeric antibody and / or its antigen-binding fragment, wherein such antibody and / or its antigen-binding fragment specifically binds to pituitary adenylate cyclase-activating polypeptide ("PACAP"). [Background technology]

[0004] Pituitary adenylyl cyclase-activating polypeptide ("PACAP") is a member of the secretin / vasoactive intestinal peptide ("VIP") / growth hormone-releasing hormone ("GHRH") family. PACAP is a multifunctional vasodilator peptide that exists in two α-amidalization-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 27 amino acids at the N-terminus 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 common active form and accounts for up to 90% of PACAP types in mammalian tissues (see Kaiser and Russo, Neuropeptides, 47:451-461, 2013). The sequence of PACAP38 is identical in all mammals, differing from the avian and amphibian orthologues by only one amino acid (see Vaudry et al., Pharmacol. Rev., 52:269-324, 2000). The secretin / VIP / GHRH family includes mammalian peptides histidine methionine ("PHM"), secretin, glucagon, glucagon-like peptide-1 ("GLP1"), glucagon-like peptide-2 ("GLP2"), glucose-dependent insulinotropic polypeptide ("GIP"), and growth hormone-releasing factor ("GRF"). PACAP27 has 68% sequence identity with VIP at the amino acid level (see Vaudry et al., Pharmacol. Rev., 52:269-324, 2000).

[0005] PACAP is widely distributed in the brain and peripheral organs, such as the endocrine system, gonads, sympathetic nerve cells, respiratory system, gastrointestinal tract, cardiovascular system, and genitourinary system (see Schytz et al., Neurotherapeutics, 7:191-196, 2010). In particular, PACAP is expressed throughout the nervous system, including the trigeminal vascular system, trigeminal ganglion, spinal cord, hypothalamus, and pituitary gland. PACAP also plays a role in neurodevelopment, neuroprotection, neuromodulation, neurogenic inflammation, and nociception with multiple effects (see Neuropeptides, 47:451-461, 2013).

[0006] Consistent with its widespread distribution, PACAP exerts multifaceted effects including regulation of neurotransmitter release, vasodilation, bronchodilation, and activation of intestinal motility, increased insulin and histamine secretion, and stimulation of cell proliferation and / or differentiation. PACAP has been shown to act as a hormone, neurohormone, neurotransmitter, and trophic factor in many tissues (Vaudry et al., Pharmacological Rev., 52(2):269-324, 2000).

[0007] The biological effects of PACAP are mediated through three distinct G protein-coupled receptors: PAC1-R, vasoactive intestinal peptide receptor 1 ("VPAC1-R"), and vasoactive intestinal peptide receptor 2 ("VPAC2-R"). These receptors are expressed in a variety of tissues. PAC1-R is particularly abundant in the nervous system (e.g., olfactory bulb, thalamus, hypothalamus, cerebellum, and spinal cord dorsal horn), pituitary gland, and adrenal gland. In contrast, VPAC1-R and VPAC2-R are primarily expressed in the lungs, liver, and testes, but are also detected in other tissues. VPAC1-R expression has been detected in the nervous system (e.g., cerebral cortex and hippocampus), lungs, liver, intestinal smooth muscle cells, megakaryocytes, and platelets. VPAC1-R associates with receptor-associated membrane proteins ("RAMP," specifically RAMP2) (see Christopoulos et al., J. Biol. Chem., 278:3293-3297, 2002). VPAC2-R expression profiles include the nervous system (e.g., thalamus, hippocampus, brainstem, and dorsal root ganglia ("DRG")), cardiovascular system, gastrointestinal system, pancreas, and reproductive system (see Usdin et al., Endocrin., 135:2662-2680, 1994; Sheward et al., Neurosci., 67:409-418, 1995).

[0008] PAC1-R is selective for PACAP38 and PACAP27. In particular, PAC1-R binds to PACAP with 100 to 1000 times higher affinity than VIP, i.e., K for PACAP27 / PACAP38. D While the value of is approximately 0.5 nM, the value of VIP is K D This is approximately 500 nm. Conversely, VPAC1-R and VPAC2-R have equal affinity for PACAP and VIP (K D The concentration is approximately 1 nM (see Schytz et al., 2010). Antibodies that bind to PAC1-R have been developed (see U.S. Patent Application Publication No. 20160251432).

[0009] When activated, all of these receptors can induce the downstream production of cyclic adenosine monophosphate ("cAMP") and / or the activation of phospholipase C ("PLC") and / or the regulation of phospholipase D ("PLD"). In particular, PAC1-R can induce cAMP and Ca 2+ PAC1-R binds to a dual signaling pathway that acts via G s It binds to proteins, which activates adenylyl cyclase to form cAMP, and then activates protein kinase A. PAC1-R is also G q It binds to PLD, thereby activating PLC, which produces inositol phosphate, thereby increasing cytoplasmic calcium release from intracellular calcium stores. There is some evidence regarding the role of PAC1-R in PLD activation (see McCulloch et al., Ann. NYAcad. Sci., 921:175-185, 2000). Modulation of the PACAP signaling pathway has also been reported to result in elevated intracellular sodium levels via the activation of non-selective cation channels (see Roy et al., American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 304(12):R1070-R1084, 2013).

[0010] PACAP is hypothesized to play a role in many diseases and disorders, including but not limited to migraines, headaches, and pain, although such a role for PACAP has not been clinically demonstrated. Migraines are thought to have a neurovascular component. Migraines affect about 10% of the adult population in the United States and are typically accompanied by severe headaches. About 20–30% of migraine sufferers experience aura, which includes focal nervous system phenomena preceding and / or accompanying an event. The role of PACAP in migraine has been supported by several observations: (1) In humans, plasma levels of PACAP during migraine attacks (paroxysmal) are elevated compared to interstitial levels (see Tuka et al., Cephalalgia, 33(13):1085-1095, 2013); (2) In healthy subjects, PACAP38 injection induces headache, and in migraine patients, headache is followed by migraine-like attacks (see Schytz et al., Brain, 132:16-25, 2009; and Amin et al., Brain, 137:779-794, 2014, respectively); (3) PACAP-induced vasodilation may play a role in neurogenic inflammation (Kaiser and See Russo, Neuropeptides, 47:451-461, 2013; and (4) PACAP-induced migraine is associated with photophobia, phonophobia, and nausea and responds to triptans (see Amin et al., Brain, 32:140-149, 2012). PACAP has also been shown to induce vasodilation, photophobia, and 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).

[0011] PACAP and the PACAP receptor have also been suggested to modulate inflammatory and neuropathic pain, and are involved in both nociceptivity and antinociceptivity (see Davis-Taber et al., J. Pain, 9(5):449-56, 2008). PACAP has also been reported to be required for spinal desensitization and induction of neuropathic pain (see Mabuchi et al., J. Neurosci., 24(33):7283-91, 2004). Furthermore, morphine withdrawal-related behaviors have been reported to be modified in PACAP receptor-deficient mice, further suggesting a role for PACAP in morphine withdrawal anxiety responses (see Martin et al., Mol. Brain Res., 110(1):109-18, 2003).

[0012] One effective treatment for pain is the administration of certain narcotics, such as opioids, or non-steroidal anti-inflammatory drugs ("NSAIDs"). However, the administration of these treatments often has adverse effects. NSAIDs can cause renal failure, intestinal bleeding, and liver dysfunction. Narcotics can cause nausea, vomiting, mental dysfunction, and addiction. A further adverse effect of treating migraines or other pain with opioids is the risk of developing opioid-induced pain, such as opioid-induced hyperalgesia (OIH) and opioid-induced allodynia (OIA). Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids. This condition is characterized by a paradoxical response in which patients who have been given opioids for pain treatment may become more sensitive to certain painful stimuli. The type of pain experienced may be the same as the underlying pain initially treated with opioids, or it may be different from the original underlying pain. (See Lee, Pain Physician, 14:145-161, 2011.)

[0013] In LC-MS studies, PACAP, vasoactive intestinal peptide (VIP), and secretogranin (SCG) were identified as common peptides involved in both migraine and opioid-induced hyperalgesia (see Anapindi, Molecular & Cellular Proteomics 18, 2447-2458, 2019). Administration of M65, a PAC1 receptor antagonist, was found to restore chronic migraine and OIH in mouse models.

[0014] Opioid-induced pain, such as opioid-induced chronic migraine, OIH, and OIA, is a common problem for patients who have been administered opioids for the treatment of pain. Current treatment for opioid-induced pain involves gradually reducing the opioid treatment regimen and, in some cases, completely discontinuing opioid treatment. Such reduction or discontinuation of opioid treatment may result in relief of opioid-induced pain, but it may leave the original pain untreated and result in less than optimal pain relief for the patient. Therefore, there is an unmet need for treatment of opioid-induced pain to provide relief from experienced pain and, ideally, enable continuous and optimal pain relief for the patient. [Overview of the Initiative]

[0015] The inventors of this disclosure have, surprisingly, found that administration of anti-PACAP antibodies and / or their antigen-binding fragments to subjects suffering from opioid-induced pain provides pain relief to patients. As demonstrated by the examples of this disclosure, administration of anti-PACAP antibodies and / or their antigen-binding fragments to subjects suffering from opioid-induced pain resulted in complete attenuation of opioid-induced pain, even when tested several days after administration.

[0016] Accordingly, in one embodiment, the present disclosure provides a method for treating, improving and / or preventing pain such as hyperalgesia or allodynia, the method comprising administering an effective amount of an anti-pituitary adenylyl cyclase-activated polypeptide ("PACAP") antibody and / or its antigen-binding fragment to a subject in need thereof. In one embodiment, the pain arises from the subject's exposure to opioids, for example, from opioid-induced pain.

[0017] Accordingly, in one embodiment, the present disclosure provides a method for treating, improving and / or preventing opioid-induced pain, comprising administering an effective amount of the anti-pituitary adenylyl cyclase-activating polypeptide ("PACAP") antibody disclosed herein to a subject in need thereof. In one embodiment, the opioid-induced pain is selected from the group consisting of opioid-induced chronic migraine, opioid-induced hyperalgesia (OIH), and opioid-induced allodynia (OIA).

[0018] In another aspect of the present invention, the present disclosure provides a method for treating, improving and / or preventing medication overuse headache (MOH), comprising administering an effective amount of the anti-PACAP antibody disclosed herein to a subject in need thereof.

[0019] definition Pituitary adenylyl cyclase-activated polypeptide (PACAP): As used herein, unless otherwise specified, PACAP includes any mammalian form of PACAP, and in particular includes the following human (Homo sapiens) PACAP27 and human (Homo sapiens) PACAP38 amino acid sequences: PACAP38:HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK (SEQ ID NO: 1241), the C-terminal lysine is amidated, as are any mutants, splice variants, isoforms, orthologues, homologs, and variants of this sequence. PACAP27:HSDGIFTDSYSRYRKQMAVKKYLAAVL (SEQ ID NO: 1242), the C-terminal leucine is amidated, as are any mutants, splice variants, isoforms, orthologues, homologs, and variants of this sequence.

[0020] In this specification, “photophobia” refers to a condition of abnormal intolerance to the visual perception of light, and is further defined, in some cases, by an abnormal or irrational fear of light, or by the presence of actual physical photosensitivity of the eye. In this invention, photophobia includes, in particular, photophobia associated with migraines and other neurological causes of photophobic behavior that may trigger migraines.

[0021] The term “opioid-induced chronic migraine,” as used herein, refers to a condition in which a patient who has been administered opioids for the treatment of an underlying pain, such as headache or migraine, is experiencing or has developed chronic migraine. Chronic migraine is defined as having headache for at least 15 days per month and at least 8 days with migraine features lasting more than 3 months. The term “migraine” refers to a complex and dysfunctional neurological disorder that can progress between four stages: prodrome, aura, headache, and postdrome. Migraine is defined by the International Headache Society as a headache lasting 4 to 72 hours and characterized by at least two of the following: unilateral localization, pulsating pain, moderate to severe pain intensity, and exacerbation with movement such as walking. In addition, the headache must be accompanied by at least one of the following: nausea and / or vomiting, photophobia, or phonophobia. Migraines can also be accompanied by an aura, which typically occurs before the scheduled time during the premonition or prodrome phase and often involves visual changes, such as scintillating scotoma, which moves across the field of vision. Prodromal symptoms may also be accompanied by other symptoms, such as fatigue, gastrointestinal problems, and mood swings. Migraines often result in prolonged periods of helplessness. Post-attack symptoms are the final stage and occur after an attack, during which the migraine sufferer may feel fatigued or mildly agitated. Chronic migraines can be classified into migraines with aura, migraines without aura, and hemiplegic migraines. Chronic migraine can be a migraine resulting from the administration of opioids to treat headaches and / or pain such as migraines, or an exacerbation of opioid-induced migraine, for example, a migraine exacerbation resulting from exposure to low-dose migraine triggers that do not normally cause a migraine, but the migraine response worsens due to opioid treatment, the number of migraine days increases, and chronic migraine develops.

[0022] As used herein, the term "opioid overuse headache" refers to a condition in which a patient receiving opioids for the treatment of an underlying pain, such as headache or migraine, experiences or develops a headache that is increased in intensity, duration, and / or frequency of recurrence.

[0023] The term "opioid-induced hyperalgesia" (OIH, also known as opioid-induced paraalgesic pain sensitivity) refers to a state of nociceptive sensitization caused by exposure to opioids. This condition is characterized by a paradoxical response in which patients who have been administered opioids to treat their original pain become more sensitive to certain painful stimuli. The type of pain experienced in OIH may be the same as the pain initially treated by the opioid administration, or it may be different from the original pain. In one embodiment, OIH is characterized by radiating pain, pain of a less distinct quality, pain of a less distinct quality, original pain affecting a wider area than initially affected, pain that has increased in intensity without an underlying disease that worsens the original pain, pain that extends from the original pain to other areas of distribution, and / or pain that is different from the original pain and develops without a specific diagnosis.

[0024] As used herein, the term "opioid-induced allodynia" (OIA) refers to a condition in which a patient receiving opioids for the treatment of an underlying pain experiences pain from stimuli that were not previously painful, such as a painful response to stroking the skin with a cotton ball.

[0025] The term "headache" refers to pain in any part of the head. Headaches may occur on one or both sides of the head, be isolated to a specific location, radiate from one point across the head, or have a pinpoint, fixed-in-place quality. Headaches can be sharp, throbbing, or dull. Headaches may appear gradually or suddenly, and they may last from within an hour to several days.

[0026] In this specification, the term “opioid analgesic” refers to all natural or synthetic drugs having morphine-like activity. Synthetic and semi-synthetic opioid analgesics are compounds of five chemical classes: phenanthrene; phenylheptylamine; phenylpiperidine; morphinane; and derivatives of benzomorphan, all of which fall within the scope of this term. Exemplary opioid analgesics include codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanil, sufentanil, meperidine, methadone, nalbuffine, propoxyfene, and pentazocine, or their pharmaceutically acceptable salts.

[0027] The term "medication overuse headache" (MOH) is a secondary disorder caused by the overuse of acute medications, as defined in ICHD-3 8.2. MOH is defined as a headache occurring at intervals of 15 days or more per month in patients with a history of primary headache, and lasting for more than 3 months (10 days or more or 15 days or more per month, depending on the medication) as a result of regular overuse of acute or symptomatic headache medications. Eligibility is diagnosed according to the following criteria: a) headache occurring at intervals of ≥15 days per month in patients with a pre-existing headache disorder, b) regular overuse for >3 months of one or more medications that may be taken for the acute and / or symptomatic treatment of headache, and c) the cause not better explained by another ICHD-3 diagnosis.

[0028] As used herein, “treatment” refers to a method for obtaining a beneficial or desired clinical outcome. For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: improvement in any aspect of opioid-induced pain. For example, in relation to the treatment of headache or migraine, this includes, but is not limited to, reduction in severity, relief of pain intensity and other associated symptoms, reduction in recurrence frequency, improvement in the quality of life of persons suffering from headaches, and reduction in the dosage of other medications required to treat the headache. In the case of migraine, other associated symptoms include, but are not limited to, nausea, vomiting, and sensitivity to light, sound, and / or movement.

[0029] "Prevention," "reducing incidence," or "preventive methods" refer to reducing the likelihood of developing a particular disease, condition, symptom, or disorder (the terms disease, condition, and disorder are used interchangeably throughout this application). These terms are used interchangeably herein. In the present invention, prevention of a given disease may be achieved by prophylactically administering an anti-PACAP antibody and / or its antigen-binding fragment to a subject undergoing opioid treatment, such as a subject undergoing opioid treatment and considered to be at risk of developing opioid-induced pain. The therapeutic methods disclosed herein may also be used to delay the onset of opioid-induced pain, such as "delaying" the onset of migraine or headache, meaning to slow, hinder, slow down, block, stabilize, and / or postpone the progression of a condition or disease. This delay may be of varying lengths depending on the history of the condition or disease and / or the individual being treated. As will be apparent to those skilled in the art, sufficient or substantial delay may effectively encompass prevention in that an individual does not develop opioid-induced pain. A method of “delaying” the onset of symptoms is one that reduces the probability of developing symptoms within a required timeframe and / or reduces the severity of symptoms within a given timeframe compared to not using the method. Such comparisons are typically based on clinical trials using a statistically significant number of subjects.

[0030] "Improving" means reducing or improving one or more symptoms of a condition, e.g., opioid-induced pain, compared to not administering an anti-PACAP antagonist antibody. "Improving" also means reducing the severity of a particular disease, condition, symptom, or disorder (the terms disease, condition, and disorder are used interchangeably throughout this application). Severity reduction includes, for example, reducing the amount of drugs and / or therapies commonly used for a condition by reducing the need for, amount, and / or exposure to drugs or therapies. Severity reduction also includes reducing the duration and / or frequency of a particular condition, symptom, or disorder (e.g., delaying or increasing the time to the next episode of an attack in an individual). The therapeutic methods disclosed herein may also be used to control opioid-induced pain, such as "control of opioid-induced chronic migraine," which means maintaining or reducing the severity or duration of one or more symptoms of a condition, e.g., headache or migraine or the frequency of headache or migraine attacks (compared to pre-treatment levels) in an individual. For example, the duration or severity of headaches, or the frequency of attacks, may be reduced by at least approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% in an individual compared to pre-treatment levels. The reduction in the duration or severity of headaches, or the frequency of attacks, may last for any length of time, such as 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.

[0031] As used herein, the “effective dose” or “effective amount” of a drug, compound, or pharmaceutical composition is an amount sufficient to produce a beneficial or desired result. With respect to prophylactic use, beneficial or desired results include eliminating or reducing the risk of disease, reducing its severity, or delaying the onset of disease, including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the onset of the disease. For therapeutic use, beneficial or desired results include clinical outcomes such as a reduction in the intensity, duration, or frequency of headache attacks, and a reduction in one or more symptoms (biochemical, histological, and / or behavioral) arising from headache (including its complications and intermediate pathological phenotypes presented during the onset of the disease), an improvement in the quality of life of people affected by the disease, a reduction in the dose of other drugs necessary to treat the disease, an enhancement of the effect of another drug, and / or a delay in the progression of the disease in patients. An effective dose may be administered in one or more doses. For the purposes of the present invention, an effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve a preventive, prophylactic, or therapeutic action, either directly or indirectly. As understood in a clinical context, an effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, “effective dose” may be considered in relation to the administration of one or more therapeutic agents, and a single agent may be considered to be given in an effective dose if, in combination with one or more other agents, the desired outcome can or does not occur.

[0032] Target antibody coding sequences include those coded by natural sequences, as well as nucleic acids and their variants whose sequences are not identical to those disclosed for the degeneracy of the gene code. When the translation of a polynucleotide sequence following the gene code results in a polypeptide sequence (i.e., a polynucleotide sequence "codes" a polypeptide sequence), the polynucleotide sequence "corresponds" to the polypeptide sequence, and when two sequences code for the same polypeptide sequence, one polynucleotide sequence "corresponds" to the other polynucleotide sequence.

[0033] Variant polypeptides may include substitutions, additions, or deletions of amino acids ("aa"). Amino acid substitutions may be conservative substitutions or substitutions to exclude non-essential amino acids, e.g., to modify glycosylation sites, or to minimize misfolding due to the substitution or deletion of one or more cysteine ​​residues not required for function. Variants may be designed to retain or enhance the biological activity of specific regions of a protein (e.g., functional domains, catalytic amino acid residues). Variants also include fragments of polypeptides disclosed herein, particularly biologically active fragments and / or fragments corresponding to functional domains. Techniques for in vitro mutagenesis of cloned genes are known. Polypeptides modified using conventional molecular biological methods to improve their resistance to proteolysis, optimize their solubility, or make them more suitable as therapeutic agents are also included in the present invention.

[0034] Chimeric antibodies are obtained from certain antibody-producing cells. L Region and V H The region can be prepared by recombinant means, which involves combining the region with the constant light chain region and constant heavy chain region of another species. Typically, chimeric antibodies utilize a variable region of a rodent or rabbit and a human constant region to produce an antibody that primarily has a human domain. The production of such chimeric antibodies is well known in the art and can be achieved by standard means (for example, as described in U.S. Patent No. 5,624,659, which is incorporated herein by reference in its entirety). It is further intended that the human constant region of the chimeric antibody of the present invention may be selected from IgG1, IgG2, IgG3, and IgG4.

[0035] Humanized antibodies are engineered to contain even more human-like immunoglobulin domains and incorporate only the complementarity-determining regions of animal-derived antibodies. This is achieved by carefully examining the sequences of the hypervariable loops in the variable regions of monoclonal antibodies and adapting them to the structure of human antibody chains. While seemingly complex, the process is actually simple. See, for example, U.S. Patent No. 6,187,287.

[0036] The general structure of antibodies in vertebrates is now well understood. See Edelman, GM, Ann. NYAcad. Sci., 190:5 (1971). An antibody consists of two identical light polypeptide chains ("light chains") with a molecular weight of approximately 23,000 daltons and two identical heavy chains ("heavy chains") with a molecular weight of 53,000 to 70,000. The four chains are linked by disulfide bonds in a "Y-shaped" configuration, where the light chains support the heavy chains starting from the mouth of the "Y-shaped" configuration. The "branched" portion of the "Y-shaped" configuration is called the Fab region, and the stem portion is called the Fc region. The amino acid sequence orientation extends from the N-terminus at the top of the "Y-shaped" configuration to the C-terminus at the bottom of each chain. The N-terminus has a variable region that is specific to the antigen that induced it, and it is approximately 100 amino acids long, with slight variations between the light and heavy chains, as well as from antibody to antibody.

[0037] The variable region is linked in each chain to a constant region that extends the remaining length of the chain and does not vary within a particular class of antibody by the specificity of the antibody (i.e., the antigen that elicits it). There are five known major classes that determine the class of immunoglobulin molecule (IgG, IgM, IgA, IgD, and IgE corresponding to γ, μ, α, δ, or ε (gamma, mu, alpha, delta, or epsilon) heavy chain constant regions). The constant region or class determines the subsequent effector functions of the antibody, including activation of complement (see Kabat, E.A., Structural Concepts in Immunology and Immunochemistry, 2nd Ed., p. 413 - 436, New York, NY: Holt, Rinehart, Winston (1976)), and determines other cellular responses (see Andrews et al., Clinical Immunology, pp. 1 - 18, W.B. Sanders, Philadelphia, PA (1980); Kohl et al., Immunology, 48:187 (1983)), while the variable region determines the antigen to which it reacts. Light chains are classified as either κ (kappa) or λ (lambda). Each heavy chain class can be prepared using either a kappa light chain or a lambda light chain.In the case where an immunoglobulin is produced by either a hybridoma or a B cell, the light and heavy chains are covalently linked to each other, and the "tail" portions of the two heavy chains are linked to each other by covalent disulfide bonds.

[0038] The expression "variable region" or "VR" refers to the domains within each pair of light and heavy chains in an antibody that are directly involved in binding of the antibody to an antigen. Each heavy chain has a variable domain (V H ) at one end, followed by several constant domains. Each light chain has a variable domain (VL) at one end and a constant domain at its other end, the constant domain of the light chain aligns with the first constant domain of the heavy chain, and the light chain variable domain aligns with the variable domain of the heavy chain.

[0039] The terms “complementarity-determining region,” “hypervariable region,” or “CDR” refer to one or more hypervariable or complementarity-determining regions ("CDRs") found in the variable regions of the light or heavy chains of an antibody (see Kabat et al., Sequences of Proteins of Immunological Interest, 4th ed., Bethesda, MD: USDept. of Health and Human Services, Public Health Service, National Institutes of Health (1987)). These terms include hypervariable regions as defined by Kabat et al. (Sequences of Proteins of Immunological Interest, NIH Publication No. 91-3242, Bethesda, MD: USDept. of Health and Human Services, National Institutes of Health (1983)) or hypervariable loops in the three-dimensional structure of an antibody (Chothia and Lesk, J.Mol.Biol., 196:901-917, 1987). The CDRs in each chain are held in close proximity by a framework region ("FR") and, together with the CDR from the other chain, contribute to the formation of the antigen-binding site. Within the CDRs are selective amino acids described as selectivity-determining regions ("SDRs") that represent important contact residues used by the CDR in antibody-antigen interactions. (See Kashmiri et al., Methods, 36(1):25-34, 2005).

[0040] 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 include amino acid residues directly involved in binding (also called the immunodominant component of the epitope) and other amino acid residues not directly involved in binding, such as those effectively blocked by the specific antigen-binding peptide (in other words, the amino acid residues are within the “footprint” of the specific antigen-binding peptide). The term epitope as used herein includes any specific region of PACAP that specifically binds to an anti-PACAP antibody, i.e., both types of amino acid sites in PACAP38 and PACAP27. PACAP may include several different epitopes, but are not limited to, (1) linear peptide antigenic determinants, (2) structural antigenic determinants consisting of one or more discontinuous amino acids located in close proximity to each other in the mature PACAP three-dimensional structure, and (3) post-translational antigenic determinants consisting of molecular structures covalently bound to the PACAP protein, such as a carbohydrate group, in whole or in part. In particular, the term “epitope” includes specific residues in a protein or peptide, such as PACAP, that are involved in the binding of an antibody to the protein or peptide, as determined by known and accepted methods such as alanine scanning techniques. Such methods are illustrated herein.

[0041] The phrase that an antibody (e.g., the first antibody) binds to the same epitope as another antibody (e.g., the second antibody) "substantially" or "at least partially" means that the epitope-binding site for the first antibody contains at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more of the amino acid residues on the antigen that constitute the epitope-binding site of the second antibody. Furthermore, the binding of the first antibody to an epitope that is substantially or partially the same as or overlaps with that of the second antibody means that the first and second antibodies compete for binding to the antigen, as described above. Therefore, the phrase "binding to substantially the same epitope or determinant" as a monoclonal antibody means that one antibody "competes" with that antibody.

[0042] The phrase "bound to the same or overlapping epitopes or determinants" as the antibody of interest means that an antibody "competes" with the antibody of interest for at least one (e.g., at least two, at least three, at least four, at least five) residues on PACAP to which the antibody of interest specifically binds. Identification of one or more antibodies that bind to substantially or essentially the same epitopes as the monoclonal antibodies described herein can be readily determined using alanine scanning. Furthermore, any one of the various immunological screening assays capable of evaluating antibody competition is also available. Many such assays are conventionally performed and well known in the art (see, for example, U.S. Patent No. 5,660,827, issued August 26, 1997, which is specifically incorporated herein by reference). It will be understood that actually determining the epitopes to which the antibodies described herein bind is by no means essential for identifying antibodies that bind to the same, substantially the same, or overlapping epitopes as the monoclonal antibodies described herein.

[0043] The term “Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain. The “Fc region” can be the native Fc region or a variant Fc region. While the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the Fc region of a human IgG heavy chain is typically defined as extending from the amino acid residue at position Cys226 or Pro230 to its carboxyl terminus. The numbering of residues within the Fc region is based on EU index numbering, such as Kabat's. (See Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition, Bethesda, MD: USD ept. of Health and Human Services, Public Health Service, National Institutes of Health, 1991). The Fc region of an immunoglobulin generally contains two constant domains, CH2 and CH3. [Brief explanation of the drawing]

[0044] [Figure 1-1] Figures 1A-1G provide full-length heavy chain polypeptide sequences (sequence numbers 401; 441; 841; 881; 921; 961; 1201; 1281; 1321; 1361; 1401; 1441; 1481; 1521; and 1561, respectively) for antibodies Ab10, Ab20, Ab21, Ab22, Ab23, Ab10.H, Ab21.H6, Ab21.H2, Ab21.H3, and Ab21.H4, aligned by their FR, CDR, and constant regions. [Figure 1-2] Same as above. [Figure 1-3] Same as above. [Figure 1-4] Same as above. [Figure 2-1]Figures 2A-2D provide full-length light chain polypeptide sequences (SEQ ID NOs. 421; 461; 861; 901; 941; 981; 1221; 1301; 1341; 1381; 1421; 1461; 1501; 1541; and 1581, respectively) for antibodies Ab10, Ab20, Ab21, Ab22, Ab23, Ab10.H, Ab21.H6, Ab21.H2, Ab21.H3, and Ab21.H4, aligned by their FR, CDR, and constant regions. [Figure 2-2] Same as above. [Figure 2-3] Same as above. [Figure 3-1] Figures 3A-3S provide polynucleotide sequences (SEQ ID NOs: 411; 451; 851; 891; 931; 971; 1211; 1291; 1331; 1371; 1411; 1451; 1491; 1531; and 1571, respectively) encoding the full-length heavy chains of antibodies Ab10, Ab20, Ab21, Ab22, Ab23, Ab10.H, Ab21.H6, Ab21.H2, Ab21.H3, and Ab21.H4, aligned by their FR, CDR, and constant regions. [Figure 3-2] Same as above. [Figure 3-3] Same as above. [Figure 3-4] Same as above. [Figure 3-5] Same as above. [Figure 3-6] Same as above. [Figure 3-7] Same as above. [Figure 3-8] Same as above. [Figure 3-9] Same as above. [Figure 3-10] Same as above. [Figure 4-1]Figures 4A-4J provide polynucleotide sequences (sequence numbers 431; 471; 871; 911; 951; 991; 1231; 1311; 1351; 1391; 1431; 1471; 1511; 1551; and 1591, respectively) encoding the full-length light chains of Ab10, Ab20, Ab21, Ab22, Ab23, Ab10.H, Ab21.H2, Ab21.H3, and Ab21.H4, aligned by their FR, CDR, and constant regions. [Figure 4-2] Same as above. [Figure 4-3] Same as above. [Figure 4-4] Same as above. [Figure 4-5] Same as above. [Figure 5] This provides polypeptide sequence coordinates for the sequence characteristics of specific antibody heavy chain proteins, including the variable region and CDR of the heavy chain, for antibodies Ab10, Ab20, Ab21, Ab22, Ab23, Ab10.H, Ab21.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, Ab10.H6, Ab21.H2, Ab21.H3, and Ab21.H4. [Figure 6] This provides polypeptide sequence coordinates for the sequence characteristics of specific antibody heavy chain proteins, including the constant region and framework region (FR) of the heavy chain, for antibodies Ab10, Ab20, Ab21, Ab22, Ab23, Ab10.H, Ab21.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, Ab10.H6, Ab21.H2, Ab21.H3, and Ab21.H4. [Figure 7] This provides polypeptide sequence coordinates for the sequence characteristics of specific antibody light chain proteins, including the variable region and CDR of the light chain, for antibodies Ab10, Ab20, Ab21, Ab22, Ab23, Ab10.H, Ab21.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, Ab10.H6, Ab21.H2, Ab21.H3, and Ab21.H4. [Figure 8]This provides polypeptide sequence coordinates for the sequence characteristics of specific antibody light chain proteins, including the constant region and framework region (FR) of the light chain, for antibodies Ab10, Ab20, Ab21, Ab22, Ab23, Ab10.H, Ab21.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, Ab10.H6, Ab21.H2, Ab21.H3, and Ab21.H4. [Figure 9] This provides polynucleotide sequence coordinates for specific antibody heavy chain DNA sequence features, including the variable region and CDR of the heavy chain, for antibodies Ab10, Ab20, Ab21, Ab22, Ab23, Ab10.H, Ab21.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, Ab10.H6, Ab21.H2, Ab21.H3, and Ab21.H4. [Figure 10] This provides polynucleotide sequence coordinates for the sequence characteristics of specific antibody heavy chain DNA, including the constant region and FR, for antibodies Ab10, Ab20, Ab21, Ab22, Ab23, Ab10.H, Ab21.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, Ab10.H6, Ab21.H2, Ab21.H3, and Ab21.H4. [Figure 11] This provides polynucleotide sequence coordinates for specific antibody light chain DNA sequence features, including the variable region and CDR of the light chain, for antibodies Ab10, Ab20, Ab21, Ab22, Ab23, Ab10.H, Ab21.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, Ab10.H6, Ab21.H2, Ab21.H3, and Ab21.H4. [Figure 12] This provides polynucleotide sequence coordinates for the sequence characteristics of specific antibody light chain DNA, including the constant region and FR, for antibodies Ab10, Ab20, Ab21, Ab22, Ab23, Ab10.H, Ab21.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, Ab10.H6, Ab21.H2, Ab21.H3, and Ab21.H4. [Figure 13]A schematic diagram of the experimental setup for the experiment described in Example 1 is shown. Mice were administered opioids or vehicles twice daily on days 1, 2, 3, 4, and 5, and an anti-PACAP antibody was administered on day 3, or M65 or orcegepant was administered on day 5. The mechanical threshold was measured by Von Frey before administration on any of the days 1, 3, 5, and 7, and after drug administration on day 5. [Figure 14] The mechanical thresholds measured pre-administration (baseline) on either day 1, day 3, day 5, and day 7 are shown for mice that did not receive morphine and received no treatment (VEH-VEH, positive control), mice that received morphine but received no treatment (MORPH-VEH, negative control), and mice that received morphine and were treated with hIgG control antibody on day 3 (M-HIgG control), mice treated with anti-PACAP antibody on day 3 (M-Ab10.H), mice treated with orsegepant on day 5 (M-orsegepant), or mice treated with M65 on day 5 (M-M65). The data demonstrate that mice administered morphine developed opioid-induced hyperalgesia, as seen by lower mechanical thresholds. Administration of anti-PACAP antibody provided long-lasting pain relief with a recovery to the positive control's mechanical threshold on day 5. In contrast, long-term pain relief was not observed in mice treated with orsegepant or M65. Two-way repeated measures ANOVA (2-way RM ANOVA), p<0.001, time, treatment, and interaction. N=12 / group (the experiment was conducted 3 times, with 4 mice / group each time). *p<0.01 M-Ab10.H (compared to MORPH-VEH). [Figure 15]The following mechanical thresholds are shown, measured before administration (baseline) and after administration of orsegepant or M65 on day 5 (post-drug), for any of the following mice: mice that did not receive morphine and received no treatment (VEH-VEH, positive control), mice that received morphine but received no treatment (MOR-VEH, negative control), and mice that received morphine and were treated with hIgG control antibody on day 3 (M-HIgG control), mice treated with anti-PACAP antibody on day 3 (M-Ab10.H), mice treated with orsegepant on day 5 (M-orsegepant), or mice treated with M65 on day 5 (M-M65). The subgroups M-orsegepant and M-M65 were administered the respective drug (orsegepant or M65) between the two measurements. The data demonstrate that subgroups VEH-VEH and M-Ab10.H exhibit consistently high mechanical thresholds at both data points, while subgroups MOR-VEH and M-HIgG control exhibit consistently low mechanical thresholds at both data points. Acute administration of M65 was found to produce some pain relief, while acute administration of orsegepant was found not to produce significant pain relief. N=12 / group (the experiment was conducted three times, with 4 mice / group each time). [Figure 16]The following shows the mechanical threshold values ​​measured after administration of orsegepant or M65 on day 5 for mice that did not receive morphine or treatment (VEH-VEH, positive control), mice that received morphine but did not receive treatment (MOR-VEH, negative control), and mice that received morphine and were treated with hIgG control antibody on day 3 (M-HIgG control), mice treated with anti-PACAP antibody on day 3 (M-Ab10.H), mice treated with orsegepant on day 5 (M-orsegepant), or mice treated with M65 on day 5 (M-M65). The subgroups M-orsegepant and M-M65 were administered the respective drugs (orsegepant or M65) 2 hours or 30 minutes before measurement. The data demonstrate that the subgroups VEH-VEH and M-Ab10.H have high mechanical thresholds, while the subgroups MOR-VEH and M-HIgG control have low mechanical thresholds. Acute administration of M65 was found to produce some pain relief, while acute administration of orsegepant was found not to produce significant pain relief. One-way ANOVA with Holm-Sidak post-hoc analysis, p<0.001. N=12 / group (the experiment was conducted 3 times, with 4 mice / group each time). *p<0.05, ***p<0.001 (compared to VEH-VEH control). ###p<0.001 (compared to MORPH-VEH group). [Figure 17] A schematic diagram of the experimental setup for the experiment described in Example 2 is shown. Mice were administered opioids or vehicles once daily on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11, nitroglycerin (NTG) once daily on days 3, 5, 7, 9, and 11, an anti-PACAP antibody on day 10, or M65 or orsegepant on day 12. The mechanical threshold was measured by Von Frey before administration on any of the days 1, 3, 7, 11, 12, and 14, and after drug administration on day 12. [Figure 18]The following shows the mechanical thresholds measured before administration (baseline) on any of the following days: days 1, 3, 7, 11, and 12. These include mice that do not receive morphine and are not treated (VEH-VEH, positive control), mice that receive morphine and NTG but are not treated (MOR / NTG-VEH, negative control), and mice that receive morphine and NTG and are treated with hIgG control antibody on day 10 (MOR / NTG-HIgG control), mice treated with anti-PACAP antibody on day 10 (MOR / NTG-Ab10.H), mice treated with orsegepant on day 12 (MOR / NTG-orsegepant), or mice treated with M65 on day 12 (MOR / NTG-M65). The data demonstrate that mice administered morphine and low doses of NTG develop opioid-induced migraine-associated hyperalgesia, as seen by lower mechanical thresholds on days 7, 11, and 12. Administration of anti-PACAP antibodies provides prolonged pain relief with a recovery to the mechanical threshold of the positive control on day 12. Two-way repeated measures ANOVA (2-way RM ANOVA), p<0.001 for time, treatment, and interaction. N=8(7) / group (the experiment was performed twice, with 4(3) mice / group each time). **p<0.01 Mor / NTG-Ab10.H (compared to MOR / NTG-VEH). [Figure 19]The following mechanical thresholds were measured before administration (baseline) and after administration of orsegepant or M65 on day 12 (post-drug) for any of the following subgroups: mice that did not receive morphine or NTG and received no treatment (VEH-VEH, positive control), mice that received morphine and NTG but received no treatment (MOR-VEH, negative control), mice that received morphine and NTG and were treated with hIgG control antibody on day 10 (MOR / NTG-HIgG control), mice that were treated with anti-PACAP antibody on day 10 (MOR / NTG-Ab10.H), mice that were treated with orsegepant on day 12 (MOR / NTG-orsegepant), or mice that were treated with M65 on day 12 (MOR / NTG-M65). The subgroups MOR / NTG-orsegepant and MOR / NTG-M65 were administered the respective drugs (orsegepant or M65) between the two measurements. The data demonstrate that the subgroups VEH-VEH and MOR / NTG-Ab10.H exhibited consistently high mechanical thresholds at both data points, while the subgroups MOR / NTG-VEH and MOT / NTG-HIgG control exhibited consistently low mechanical thresholds at both data points. Acute administration of M65 was found to produce some pain relief, while acute administration of orsegepant was found not to produce significant pain relief. N=8(7) / group (the experiment was conducted twice, with 4(3) mice / group each time). [Figure 20]The following shows the mechanical thresholds measured after administration of orsegepant or M65 on day 12 for mice that did not receive morphine and NTG and received no treatment (VEH-VEH, positive control), mice that received morphine and NTG but received no treatment (MOR / NTG-VEH, negative control), mice that received morphine and NTG and were treated with hIgG control antibody on day 10 (MOR / NTG-HIgG control), mice that were treated with anti-PACAP antibody on day 10 (MOR / NTG-Ab10.H), mice that were treated with orsegepant on day 12 (MOR / NTG-orsegepant), or mice that were treated with M65 on day 12 (MOR / NTG-M65). Subgroups MOR / NTG-orsegepant and MOR / NTG-M65 were administered the respective drugs (orsegepant or M65) 2 hours or 30 minutes prior to measurement. The data demonstrate that subgroups VEH-VEH and MOR / NTG-Ab10.H have high mechanical thresholds, while subgroups MOR / NTG-VEH and MOR / NTG-HIgG control have low mechanical thresholds. Acute administration of M65 was found to produce some pain relief, while acute administration of orsegepant was found not to produce significant pain relief. One-way ANOVA with Holm-Sidak post-hoc analysis, p<0.001. N=8(7) / group (the experiment was conducted twice, with 4(3) mice / group each time). ***p<0.001 (compared to VEH-VEH control), ###p<0.001 (compared to MOR / NTG-VEH group). [Figure 21]The following mechanical thresholds were measured before administration (baseline) and after administration of orsegepant or M65 on day 12 (post-drug) for any of the following subgroups: mice that did not receive morphine or NTG and received no treatment (VEH-VEH, positive control), mice that received morphine and NTG but received no treatment (MOR-VEH, negative control), mice that received morphine and NTG and were treated with hIgG control antibody on day 10 (MOR / NTG-HIgG control), mice that were treated with anti-PACAP antibody on day 10 (MOR / NTG-Ab10.H), mice that were treated with orsegepant on day 12 (MOR / NTG-orsegepant), or mice that were treated with M65 on day 12 (MOR / NTG-M65). The subgroups MOR / NTG-orsegepant and MOR / NTG-M65 were administered the respective drugs (orsegepant or M65) between the two measurements. The data demonstrate that the subgroups VEH-VEH and MOR / NTG-Ab10.H exhibited consistently high mechanical thresholds at both data points, while the subgroups MOR / NTG-VEH and MOT / NTG-HIgG control exhibited consistently low mechanical thresholds at both data points. Acute administration of M65 was found to produce some pain relief, while acute administration of orsegepant was found not to produce significant pain relief. N=8(7) / group (the experiment was conducted twice, with 4(3) mice / group each time). [Figure 22] This study demonstrates that 20 mg / kg of PACAP antibody attenuates the development of head allodynia in an OIH model. Mice were tested 6 days after injection. One-way ANOVA with Holm-Sidak post-hoc analysis showed p<0.01 (compared to VEH-VEH) and p<0.05 (compared to MORPH-VEH). Mice were also tested on days 1, 2, and 5, and the results showed that mice treated with PACAP antibody already had a reduction by day 2, and the difference compared to VEH-VEH was significant on days 5 and 6. [Figure 23]Ab10.H at 20 mg / kg prevented the development of cranial allodynia associated with the exacerbation of opioid migraine. Brain mechanical baseline was collected in naive mice before morphine (mor) injection (day 1), before matched NTG injection (day 3), before morphine / NTG injection (day 7), 20-22 hours after the last morphine / NTG injection (day 12), and before blood and tissue sampling (day 14). The upper curves in the figure, separated from day 3 onwards, show the curves for the veh / veh group (white circles) and Mor / NTG-Ab10.H PACAP antibody (black circles). The lower curves show Mor / NTG-CTNL, Mor / NTG-orsegepant, Mor / NTG-Vhl, and Mor / NTG-M65. Two-way ANOVA (2-way ANOVA) factors p<0.001 for treatment, time, and interaction. From day 7 to day 14, Ab10H was significantly different from morphine / NTG-Veh or morphine / Veh-CNTL ab. [Figure 24] Pretreatment with PACAP antibody Ab10.H (both at 20 mg / kg) prevented the development of head allodynia. Analysis on day 12. One-way ANOVA with Holm-Sidak post-hoc analysis **p<0.01 (compared to VEH-VEH), p<0.05 (compared to MORPH-VEH). [Modes for carrying out the invention]

[0045] Detailed description of the invention The present invention relates to a method for treating and / or preventing opioid-induced pain, such as opioid-induced chronic migraine, opioid-induced hyperalgesia (OIH), and opioid-induced allodynia (OIA), by administering an antibody and / or its antigen-binding fragment to a subject in need thereof, wherein such antibody and / or its antigen-binding fragment specifically binds to pituitary adenylyl cyclase-activated polypeptide ("PACAP").

[0046] In one embodiment, the present invention relates to a method for treating and / or preventing pain by administering an anti-PACAP antibody and / or its antigen-binding fragment to a subject in need.

[0047] In one embodiment, pain is selected from the group consisting of neuropathic pain, nociceptive pain, inflammatory pain, mixed pain, and visceral pain. In one embodiment, pain is neuropathic pain such as central nervous system pain and / or peripheral nervous system pain. In one embodiment, pain is an exacerbation of neuropathic pain resulting from exposure to the opioid of the subject. In one embodiment, pain is hyperalgesia and / or allodynia. In one embodiment, pain is hyperalgesia and / or allodynia resulting from exposure to the opioid of the subject, such as opioid-induced hyperalgesia and / or opioid-induced allodynia. In one embodiment, pain is migraine resulting from exposure to the opioid of the subject, such as opioid-induced chronic migraine.

[0048] Opioid-induced pain Opioid analgesics are a frequently prescribed type of medication, and their use has increased dramatically, with the number of prescriptions doubling between 1998 and 2010. Furthermore, long-term use of opioids has become more common. Opioid-induced pain is a common problem for patients who have been administered opioids for the treatment of pain. In one embodiment, the present invention relates to the treatment of opioid-induced pain, e.g., opioid-induced chronic migraine, OIH, and / or OIA. In a preferred embodiment, the opioid-induced pain is opioid-induced chronic migraine or opioid-induced hyperalgesia, e.g., opioid-induced hyperalgesia.

[0049] As used herein, the term opioid refers to both naturally occurring opiates and synthetic or semi-synthetic opioids that bind to opioid receptors. The terms opioid and opiate may be used interchangeably herein. Opioids are potent analgesics widely used in clinical practice. Opiates refer to naturally occurring alkaloids extracted from the poppy seed pod (Opium poppy; Papaver somniferum). Semi-synthetic opioids are synthesized from naturally occurring opiates as starting materials and include heroin (diamorphine), oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, buprenorphine, and etorphine. Synthetic opioids are synthetic compounds that bind to opioid receptors, and include methadone, pethidine, fentanyl, alfentanyl, sufentanyl, remifentanil, carfentanil, tramadol, tapentadol, and loperamide.

[0050] In one embodiment, the opioid is an opioid analgesic selected from the group consisting of, for example, codeine, dihydrocodeine, morphine or a morphine derivative or a pharmaceutically acceptable salt thereof, codeine, dihydrocodeine, oxycodone, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanil, sufentanil, meperidine, methadone, nalbuffine, propoxifene, and pentazocine, or a pharmaceutically acceptable salt thereof.

[0051] In one embodiment, pain arises from a subject receiving opioids, such as when opioids are administered as analgesics to treat pre-existing pain. Therefore, in one embodiment, the pain is opioid-induced pain. In one embodiment, pain arises from a subject receiving opioids for the treatment of acute pain, such as cancer-related pain, surgery-related pain, and / or pain resulting from neurodegenerative conditions such as rheumatoid arthritis. Therefore, in one embodiment, the pre-existing pain treated with opioids is acute pain, such as cancer-related pain, surgery-related pain, and / or pain resulting from neurodegenerative conditions such as rheumatoid arthritis.

[0052] In one embodiment, the pain arises from a subject being administered opioids for the treatment of chronic pain such as headache, back pain, migraine, neuropathic pain, and / or fibromyalgia. Thus, in one embodiment, the original pain treated with opioids is chronic pain such as headache, back pain, migraine, neuropathic pain, and / or fibromyalgia.

[0053] Further exemplary underlying pain or conditions for which opioids may be administered include, but are not limited to, generalized pain, chronic pain, inflammatory pain, postoperative incision pain, postoperative pain, trauma-related pain, lower back pain, eye pain, toothache, complex regional pain syndrome, cancer pain (e.g., primary or metastatic bone cancer pain), fracture pain, osteoporotic fracture pain, burn-related pain, gouty joint pain, sickle cell carcinoma pain, temporomandibular joint disorder pain, cirrhosis, hepatitis, neurogenic pain, neuropathic pain, nociceptive pain, visceral pain, trigeminal neuralgia, postherpetic neuralgia, phantom limb pain, fibromyalgia, menstrual pain, ovarian pain, reflex sympathetic dystrophy, osteoarthritis or rheumatoid arthritis pain, lower back pain, diabetic neuropathy, sciatica, and indigestion.

[0054] In one embodiment, the original pain is headache and / or migraine. Therefore, in one embodiment, the subject is administered opioids for the treatment of headaches and / or migraines, such as migraine with or without aura, hemiplegic migraine, cluster headache, migraine-like neuralgia, chronic headache, and tension headache. In one embodiment, the subject is administered opioids for the treatment of migraine. Administration of opioids to a subject for the treatment of migraine may lead to the development of chronic migraine. Routine use of opioids for the treatment of migraine often results in more frequent and severe headaches. Long-term use of opioids for the treatment of migraine may induce a transition from episodic migraine to chronic migraine, and in many cases, the damage cannot be reversed by subsequent detoxification from opioid dependence. Chronic migraine is defined as a type of chronic daily headache (CDH, headache occurring 15 days or more per month for at least 3 months), with at least 8 headache days per month meeting the criteria for migraine without aura or migraine that responds to migraine-specific treatment. Thus, in one embodiment, opioid-induced pain is opioid-induced chronic migraine. In one embodiment, opioid-induced chronic migraine results from the administration of opioids for the treatment of headache and / or pain such as migraine, and results in an exacerbation of opioid-induced migraine such as migraine resulting from exposure to low-dose migraine triggers that do not normally cause migraine, but the migraine response is exacerbated due to opioid treatment, resulting in an increase in the number of days with migraine and chronic migraine episodes.

[0055] The administration of opioids to a subject can also lead to the development of opioid-induced hyperalgesia. Opioid-induced hyperalgesia (OIH), also known as opioid-induced paroxysmal pain sensitivity, is defined as a state of nociceptive sensitization caused by exposure to opioids. This condition is characterized by a paradoxical response in which patients who have been administered opioids to treat their original pain become more sensitive to certain painful stimuli. Thus, in one embodiment, opioid-induced pain is opioid-induced hyperalgesia.

[0056] The type of pain experienced in OIH may be the same as the pain initially treated with opioid administration, or it may be different from the original pain. In one embodiment, OIH is a) Referred pain, b) Pain whose quality is not very clear, c) Pain whose quality is difficult to clearly define, d) The original pain that affects a wider area than the area initially affected, e) Pain that has worsened and increased in intensity without an underlying disease of the original pain, f) Pain extending from the original pain area to other areas of distribution, and / or g) Characterized by pain that is different from the original pain and that develops without a specific diagnosis.

[0057] In one embodiment, pain in OIH arises from one or more of the following: a) Pain in the absence of noxious stimuli (spontaneous pain), b) Increased duration of pain in response to short-term stimuli (progressing pain or paroxysmal pain), c) Decreased pain threshold (allodynia), d) Increased responsiveness to suprathreshold stimuli (hyperalgesia), e) Spread of pain and hyperalgesia to intact tissue (pain and secondary hyperalgesia as mentioned), and / or f) Abnormal sensations (e.g., paresthesia, perceptual abnormalities).

[0058] In one embodiment, OIH is a result of the subject being administered high doses of opioids and / or receiving opioids over a longer period of time. Alternatively, OIH may occur after a single dose of opioids or after only a few doses of opioids. Therefore, in one embodiment, OIH occurs after acute opioid administration or after chronic opioid administration.

[0059] Administration of opioids to a subject may, as an alternative to or in addition to OIH, lead to the development of opioid-induced allodynia (OIA), where the patient, who is being administered opioids to treat the original pain, experiences pain from stimuli that were not previously painful, such as a painful response to stroking the skin with a cotton ball. Therefore, in one embodiment, opioid-induced pain is opioid-induced hyperalgesia and / or opioid-induced allodynia. In one embodiment, opioid-induced pain is opioid-induced allodynia.

[0060] Pain treatment methods In one embodiment, the present invention provides a method for improving, alleviating, treating and / or preventing symptoms of pain, such as hyperalgesia or allodynia. In one embodiment, the present invention provides a method for improving pain, such as hyperalgesia or allodynia, comprising administering an anti-PACAP antibody and / or its antigen-binding fragment as described herein to a subject in need thereof. In one embodiment, the present invention provides a method for alleviating symptoms of pain, such as hyperalgesia or allodynia, comprising administering an anti-PACAP antibody and / or its antigen-binding fragment as described herein to a subject in need thereof.

[0061] In one embodiment, the present invention provides a method for treating pain, such as hyperalgesia or allodynia, comprising administering an anti-PACAP antibody and / or its antigen-binding fragment as described herein to a subject in need thereof.

[0062] In one embodiment, the present invention provides a method for preventing pain, such as hyperalgesia or allodynia, comprising administering an anti-PACAP antibody and / or its antigen-binding fragment as described herein to a subject in need thereof.

[0063] In one embodiment, the present invention provides a method for improving, reducing, treating, and / or preventing symptoms of opioid-induced pain, comprising administering an anti-PACAP antibody and / or its antigen-binding fragment as described herein to a subject in need thereof.

[0064] In one embodiment, the present invention provides a method for improving opioid-induced pain, comprising administering an anti-PACAP antibody and / or its antigen-binding fragment described herein to a subject in need thereof.

[0065] In one embodiment, the present invention provides a method for alleviating symptoms of opioid-induced pain, comprising administering an anti-PACAP antibody and / or its antigen-binding fragment as described herein to a subject in need thereof.

[0066] In one embodiment, the present invention provides a method for treating opioid-induced pain, comprising administering an anti-PACAP antibody and / or its antigen-binding fragment as described herein to a subject in need thereof.

[0067] In one embodiment, the present invention provides a method for preventing opioid-induced pain, comprising administering an anti-PACAP antibody and / or its antigen-binding fragment described herein to a subject in need thereof.

[0068] The present invention further comprises the use of anti-PACAP antibodies and / or their antigen-binding fragments disclosed herein in the manufacture of pharmaceuticals for improving, alleviating, treating, and / or preventing symptoms of opioid-induced pain, such as opioid-induced chronic migraine, OIH, and / or OIA.

[0069] The present invention further comprises anti-PACAP antibodies and / or antigen-binding fragments thereof disclosed herein for use in improving, alleviating, treating, and / or preventing symptoms of opioid-induced pain, such as opioid-induced chronic migraine, OIH, and / or OIA.

[0070] In one embodiment, the method of the present disclosure prevents opioid-induced pain. Opioid-induced pain can be prevented by prophylactically administering an anti-PACAP antibody and / or its antigen-binding fragment to subjects who are about to receive opioid treatment and are at risk of developing opioid-induced pain, such as subjects with a history of opioid-induced pain or a family history of opioid-induced pain. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is administered before opioid administration. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is administered about one or two weeks before opioid administration, or 6, 5, 4, 3, 2, or 1 day before, or 20, 16, 12, 8, 6, 4, 2, or 1 hour before opioid administration.

[0071] In one embodiment, the opioid and the anti-PACAP antibody and / or its antigen-binding fragment are administered simultaneously to provide relief of the original pain while preventing opioid-induced pain. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is administered at the same time as the opioid.

[0072] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is administered after opioid administration. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is administered within approximately 1 hour, 6 hours, 12 hours, 1 day, 2 days, 4 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 8 months, 10 months, or 1 year after opioid administration.

[0073] When a subject suffers from opioid-induced pain, one of the currently applied treatments is to gradually reduce the opioid treatment regimen and, if possible, to completely discontinue opioid treatment. Such reduction or discontinuation of opioid treatment may result in relief of opioid-induced pain, but may leave the original pain untreated and result in pain relief that is less than optimal for the patient. The present invention provides a method for improving, reducing and / or treating the symptoms of opioid-induced pain, comprising administering an anti-PACAP antibody and / or its antigen-binding fragment described herein to a subject in need thereof. In one embodiment, the opioid treatment regimen is gradually reduced or completely discontinued before or concurrently with the administration of the anti-PACAP antibody and / or its antigen-binding fragment. In another embodiment, opioid treatment is continued while the subject is being additionally treated with the anti-PACAP antibody and / or its antigen-binding fragment. In such embodiments, pain relief for the subject being treated is optimal from continuous opioid administration for the treatment of the original pain, while opioid-induced pain is improved, reduced, and / or treated by administration of an anti-PACAP antibody and / or its antigen-binding fragment. In one embodiment, an opioid and an anti-PACAP antibody and / or its antigen-binding fragment are administered concurrently to provide pain relief for the original pain while improving, reducing, and / or treating the symptoms of opioid-induced pain. In one embodiment, the method described herein comprises the administration of an anti-PACAP antibody and / or its antigen-binding fragment and an opioid, the combination of which induces an additive or synergistic effect in improving and / or preventing pain such as hyperalgesia, allodynia or opioid-induced pain, optionally opioid-induced pain, optionally opioid-induced chronic migraine, opioid-induced hyperalgesia (OIH), and opioid-induced allodynia (OIA).

[0074] In one embodiment, opioid-induced pain persists in a subject despite reduction or discontinuation of opioid treatment, as treatment fails when attempts are made to reduce the opioid treatment regimen or to completely discontinue opioid treatment.

[0075] In such embodiments, opioid-induced pain can be treated by administering an anti-PACAP antibody and / or its antigen-binding fragment to the subject. Thus, in one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is administered to a subject who has developed opioid-induced pain and is no longer receiving opioids.

[0076] Treatment methods for medication overuse headache The Disclosure also provides a method for treating or preventing medication overuse headache, for example, associated with the overuse of anti-migraine drugs and / or the overuse of triptans and / or ergots and / or analgesics, comprising administering an effective amount of the PACAP antibody of the present invention to a patient in need. The medication overuse headache may be determined based on the following criteria: (a) headaches occurring for 15 days or more per month in a patient with a pre-existing headache disorder; and (b) overuse of one or more drugs that can be taken for acute and / or symptomatic treatment of headaches for more than three months.

[0077] The aforementioned overuse may include the use of ergot alkaloids (e.g., ergotamine) for 10 days or more per month, the use of triptans for 10 days or more per month, the use of one or more non-opioid analgesics (such as paracetamol (acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic) for 15 days or more per month, the use of one or more concomitant analgesics for 10 days or more per month (as further described below), the use of one or more opioids for 10 days or more per month, or the concomitant use of two or more drug classes for 10 days or more per month (as further described below).

[0078] In the methods of this specification, the triptan may be, but is not limited to, any one of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, alumotriptan, and flubatriptan.

[0079] The aforementioned drug overuse headache may include ergotamine overuse headache, triptan overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, concomitant analgesic overuse headache, drug overuse headache resulting from multiple drug classes that are not individually overused, drug overuse headache resulting from unspecified or unverified overuse of multiple drug classes, or drug overuse headache resulting from other drugs.

[0080] The aforementioned non-opioid analgesic overuse headache may include paracetamol (acetaminophen) overuse headache, nonsteroidal anti-inflammatory drug (NSAID) overuse headache, such as acetylsalicylic acid (aspirin) overuse headache or ibuprofen overuse headache, or another non-opioid analgesic overuse headache.

[0081] The aforementioned ergotamine overuse headache may include headaches occurring in patients with a pre-existing primary headache for 15 days or more per month, and which result from the regular use of ergot alkaloids such as ergotamine for 10 days or more per month for more than three months.

[0082] In the methods of this specification, the ergot alkaloid may include ergotamine, nicergoline, methysergide, or dihydroergotamine.

[0083] The aforementioned triptan overuse headache may include headaches occurring in patients with a pre-existing primary headache for 15 days or more per month and resulting from the regular use of one or more triptans for 10 days or more per month for more than three months.

[0084] The aforementioned non-opioid analgesic overuse headache may include headaches occurring for 15 days or more per month in patients with a pre-existing primary headache condition, and which result from the regular use of opioid analgesics (such as paracetamol (acetaminophen), acetylsalicylic acid (aspirin), ibuprofen, another NSAID, or another non-opioid analgesic) for more than three months, for 15 days or more per month.

[0085] In the methods described herein, the NSAID may include, but is not limited to, ibuprofen, naproxen, or indomethacin. The concomitant analgesic overuse headache may include headaches occurring for 15 days or more per month, or headaches resulting from the regular use of one or more concomitant analgesics for 10 days or more per month for more than three months. With respect to drug overuse headache, the term concomitant analgesic refers to a formulation that combines two or more classes of drugs, each with an analgesic (e.g., paracetamol and codeine) or an adjuvant (e.g., caffeine). Commonly overused concomitant analgesics involve the combination of a non-opioid analgesic with at least one opioid, barbiturate, e.g., butarbital and / or caffeine. In exemplary embodiments, concomitant analgesic overuse headache results from the combination of acetaminophen, aspirin, and caffeine, e.g., EXCEDRIN® or EXCEDRIN MIGRAINE®.

[0086] Other known concomitant analgesics include analgesics used in combination with at least one non-analgesic, such as a vasoconstrictor like pseudoephedrine for sinus-related preparations, or an antihistamine used to treat allergy patients.

[0087] The aforementioned opioid overuse headache may include headaches occurring in patients with a pre-existing primary headache condition for 15 days or more per month, and resulting from the regular use of one or more opioids for 10 days or more per month for more than three months.

[0088] Medication overuse headaches resulting from multiple drug classes that are not individually overused may include headaches occurring in patients with a pre-existing primary headache for 15 days or more per month and occurring as a result of regular use of any combination of ergotamine, triptans, non-opioid analgesics and / or opioids for more than 3 months, with a total of at least 10 days per month of overuse of any single drug or drug class.

[0089] In the methods described herein, the opioid is a mixture of opioid alkaloids such as oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, thebaine, olipavin, paveletam, diacetylmorphine, nicomorphine, dipropanoylmorphine, diacetyldihydromorphine, acetylpropionylmorphine, desomorphine, methyldesorphine, dibenzoylmorphine, ethylmorphine, heterocodeine, buprenorphine, etorphine, hydromorphone, oxymorphone, fentanyl, alphamethylfentanyl, alfentanyl, sufentanyl, remifen Examples of opioid drugs include, but are not limited to, tanyl, carfentanil, omefentanil, pethidine (meperidin), ketobemidone, desmethylprozine or 1-methyl-4-phenyl-4-propionoxypiperidine (MPPP), allylprozine, prozine, 4-piperidinol or 1-phenethyl-4-phenylacetate (PEPAP), trimeperidine (promedol), diphenylpropylamine, propoxyfen, dextropropoxyfen, dextromoramide, vegitramide, pyritramide, and any one or any combination of these opioid drugs.

[0090] The aforementioned drug overuse headaches resulting from the unspecified or unverified overuse of multiple drug classes may include headaches occurring for 15 days or more per month in patients with known primary headaches, and which develop as a result of regular use of any combination of ergotamine, triptans, non-opioid analgesics and / or opioids for at least 10 days per month for more than 3 months, the identity, quantity and / or pattern of use of these drug classes have not been reliably established.

[0091] The aforementioned drug overuse headache caused by other drugs may include headaches occurring in patients with a pre-existing primary headache for 15 days or more per month, and for at least 10 days per month for more than 3 months, resulting from the regular ingestion of one or more drugs other than those mentioned above, taken for the acute or symptomatic treatment of headache.

[0092] Dosage and Administration The methods of this disclosure may include administering an anti-PACAP antibody, or its antigen-binding fragment, in a therapeutically effective dose to a subject in need. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is administered in the form of a pharmaceutical composition. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment disclosed herein, as well as combinations of the antibody and / or its antigen-binding fragment, are administered to a subject in a pharmaceutical formulation.

[0093] "Pharmaceutical composition" or "pharmaceutical" refers to a chemical or biological composition suitable for administration to a target, preferably a mammal, more preferably a human. Such compositions are specifically formulated for administration via one or more of a multitude of routes, including, but not limited to, oral, cutaneous, epidural, inhalation, intra-arterial, intracardiac, intraventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, rectal via enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal. In addition, administration may be carried out by injection, powder, liquid, gel, drop, or other means of administration.

[0094] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is administered to the subject at concentrations between 0.1 mg / ml and 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg / ml (+ / - 10% error).

[0095] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment is administered to the subject at a dose of approximately 0.01 to 100.0 or 200.0 mg / kg of recipient body weight. In a particular embodiment, depending on the type and severity of opioid-induced pain, for example, whether by one or more separate doses or by continuous infusion, approximately 1 μg / kg to 50 mg / kg (e.g., 0.1 to 20 mg / kg) of antibody is the initial candidate dose for administration to the patient. In another embodiment, approximately 1 μg / kg to 15 mg / kg (e.g., 0.1 mg / kg to 10 mg / kg) of antibody is the initial candidate dose for administration to the patient. A typical daily dose may range from approximately 1 μg / kg to 100 mg / kg or more, depending on several factors, e.g., the specific mammal being treated, the clinical condition of the individual patient, the site of drug delivery, the method of administration, the administration schedule, and other factors known to the physician. However, other administration regimens may be useful.

[0096] For example, in addition to the relative doses (mg / kg) discussed herein, the subject anti-PACAP antibody and / or its antigen-binding fragment may be administered to a subject in absolute doses (mg). Thus, in one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment described herein may be administered to a subject in doses ranging from about 1 microgram to about 1000 milligrams, regardless of the route of administration.

[0097] In preferred embodiments of the present invention, the anti-PACAP antibody or its antigen-binding fragment described herein, and combinations thereof, are administered to the recipient at a frequency of once every 26 weeks or less, for example, once every 16 weeks or less, once every 8 weeks or less, once every 4 weeks or less, once every 2 weeks or less, once every week or less, or once a day or less.

[0098] According to a preferred embodiment, the antibody-containing pharmaceutical or pharmaceutical composition is administered peripherally to a subject via one or more routes selected from the following: orally, sublingually, orally, topically, rectally, or by inhalation; percutaneously, subcutaneously, intravenously, intra-arterially, or intramuscularly; intracardiacally; intraosseously, intradermally, intraperitoneally, transmucosally, transvaginally, intravitreally, on the skin, intra-articularly, peri-articularly, or topically.

[0099] subject The subjects to whom the anti-PACAP antibody and / or its antigen-binding fragment is administered may be, for example, any human or non-human animal in need of such treatment, prevention and / or improvement. For example, the subjects may be individuals diagnosed with opioid-induced pain such as opioid-induced chronic migraine, OIH and / or OIA. In one embodiment, the subjects are subjects who have not experienced sufficient pain relief from opioid treatment. In one embodiment, the subjects are subjects who have experienced increased pain after receiving opioid treatment. In one embodiment, the subjects are migraine patients who have not responded well to opioid treatment, for example, migraine patients who have experienced increased migraine pain and / or increased frequency of migraine days. In one embodiment, the subjects are subjects who are considering receiving opioid treatment, for example, subjects who are considering receiving opioid treatment and are considered to be at risk of developing opioid-induced pain, for example, subjects with a history of or family history of opioid-induced pain. In a preferred embodiment, the subjects are human. In one embodiment, the subjects are those who have previously received opioids and are experiencing opioid-induced pain, for example, those who suffer from opioid-induced pain but are no longer being administered opioids.

[0100] PACAP PACAP is a multifunctional vasodilator peptide expressed throughout the central nervous system ("CNS") and periphery. PACAP is a member of the selectin / VIP / GRH family. PACAP exists in two α-amidalized active forms, PACAP38 (SEQ ID NO: 1241) and PACAP27 (SEQ ID NO: 1242). In this specification, the term "PACAP" includes either or both PACAP38 and PACAP27 unless otherwise specified. PACAP is highly conserved across species.

[0101] In humans, PACAP is derived from a 176-amino acid precursor protein (prepro-PACAP), the gene located on chromosome 18p11, and PACAP38 is encoded by exon 5. (See Vaudry et al., Pharmacol. Rev., 61:283-357, 2009). Prepro-PACAP contains a 24-amino acid signaling protein at the N-terminus, a 29-amino acid PACAP-related peptide, and PACAP in the C-terminal domain. The precursor is metabolized by prohormone-converting enzymes to the biologically active PACAP38 and PACAP27.

[0102] VIP (SEQ ID NO: 1243) belongs to the same protein family as PACAP and shares high homology with PACAP; that is, VIP and PACAP27 have 68% sequence homology at the amino acid level, as well as a similar overall secondary structure, namely a long alpha-helical structure at the C-terminus.

[0103] The action of PACAP is mediated via three different G protein-coupled receptors: PAC1-R, VPAC1-R, and VPAC2-R. VPAC1-R can associate with all receptor-related membrane proteins ("RAMP," see Kaiser and Russo, Neuropeptides 47:451-461, 2013). PAC1-R is selective for PACAP, while VPAC1-R and VPAC2-R bind to both VIP and PACAP with high affinity. PAC1-R binds to PACAP with 100 to 1000 times higher affinity than VIP, i.e., its KD for PACAP27 / PACAP38 is approximately 0.5 nM, compared to approximately 500 nM for VIP. Conversely, VPAC1-R and VPAC2-R have equal affinity for both PACAP and VIP (approximately 1 nM KD). (See Schytz et al., 2010). All three receptors are widely expressed in both peripheral tissues and the central nervous system (CNS), with PAC1-R being primarily expressed in the CNS, most abundantly in the olfactory bulb, hypothalamus, hippocampal dentate gyrus, and cerebellar granule cells. (See Hashimoto et al., J.Comp.Neurol., 371:567-577, 1996; and Shioda et al., Neurosci.Res., 28:345-354, 1997).

[0104] Activation of PAC1-R, VPAC1-R, and / or VPAC2-R results in increased adenylyl cyclase activity and, consequently, increased cAMP production. However, PACAP receptors can also mediate their effects via PLC, leading to increased Ca2+ levels and PLD.

[0105] PACAP has a wide range of biological effects, including roles in neurodevelopment, neuroprotection, neuromodulation, neurogenic inflammation, and nociception. PACAP has also been 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 cellular uptake of PACAP is dependent on the expression of GAG proteins, and that PACAP binds to sulfated GAGs. In particular, it has been found that binding of PACAP38 to GAGs can induce receptor-independent cellular uptake of PACAP38. This study further demonstrated that the transition from random coil to α-helix in PACAP38 is essential for GAG-dependent uptake of PACAP38, as mutant PACAP38 that failed to undergo structural transposition was not internalized as efficiently by GAG-containing cell lines as the wild-type form of PACAP38 (Neree et al., FEBS Lett., 588(24):4590-4596, 2014). In follow-up studies, it was found that PACAP's ability to cluster GAGs, i.e., heparin, is directly related to its ability to function as a cell-permeable peptide ("CPP"). This activity is hypothesized to be due to the heparin-binding motif or Cardin-Weintraub motif found in secretin / glucagon / GHRH family members such as PACAP (Neree et al., Int.J.Mol.Sci., 16:27391-27400, 2015). Interestingly, Neree et al. (2015) presented data demonstrating that PACAP38 could cluster sulfated GAGs in vitro. These data suggested that the observed clustering effect is important for GAG-mediated cellular uptake by PACAP38, as other peptides such as glucagon showed higher binding affinity to sulfated GAGs (heparin) but were not internalized by cells as efficiently as PACAP38.Furthermore, in in vitro studies in which cells were exposed to PACAP, increased chondrogenesis, including a cartilage matrix rich in sulfated GAG proteins, has been reported, which is consistent with its putative protective role expressed during various cellular stress responses (Juhasz et al., PLoS ONE, 9(3):e91541, 2014). Using cell types lacking PACAP-specific receptors on their plasma membranes, such as CHO-K1 cells, Doan et al. presented data demonstrating the ability of such cells to participate in receptor-independent cellular uptake of various forms of fluorescently labeled PACAP38 and PACAP27 (Doan et al., Biochem. Biophys. Acta 1823, 940-949, 2012).

[0106] Anti-PACAP antibody having binding activity to PACAP and its antigen-binding fragment. The present invention provides a method for treating and / or preventing opioid-induced pain, such as opioid-induced chronic migraine, opioid-induced hyperalgesia (OIH), and opioid-induced allodynia (OIA), by administering an antibody or antigen-binding fragment thereof that binds to PACAP, including human PACAP.

[0107] Antibodies or antigen-binding fragments thereof that bind to PACAP (anti-PACAP antibodies and their antigen-binding fragments), including those with different CDRs and epitope specificities, can be obtained using methods generally known in the art. Such antibodies and / or their antigen-binding fragments antagonize the biological effects of PACAP in vivo and are therefore useful for the treatment or prevention of PACAP-related conditions, including opioid-induced chronic migraine, opioid-induced hyperalgesia (OIH), and opioid-induced allodynia (OIA).

[0108] In some embodiments, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention interferes with, blocks, reduces, or modulates the interaction between PACAP and its receptors (e.g., PAC1-R, VPAC1-R, and VPAC2-R). In some embodiments, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is "neutralizing," for example, by completely interfering with the specific interaction between PACAP and PAC1-R, VPAC1-R, and / or VPAC2-R. In some embodiments, the antibody or its antigen-binding fragment neutralizes PACAP by remaining bound to PACAP in a position and / or manner that prevents PACAP from specifically binding to PAC1-R, VPAC1-R, and / or VPAC2-R. As used herein, the term "one or more biological effects related to PACAP" refers to any biological effects mediated by, induced by, or otherwise attributed to PACAP, such as binding properties, functional properties, and other biologically significant properties. Non-limiting exemplary biological effects of PACAP include: binding of PACAP to PAC1-R, VPAC1-R, and / or VPAC2-R; activation of PAC1-R, VPAC1-R, and / or VPAC2-R mediated signaling by PACAP; increased PACAP-mediated cAMP production; increased PACAP-mediated PLC activity; increased PACAP-mediated PLD activity; and Ca 2+ Examples include PACAP-mediated increases in levels; as well as PACAP-mediated vasodilation, photophobia, mast cell degranulation, and / or neuronal activation. The subject anti-PACAP antibody and / or its antigen-binding fragment can inhibit one, a combination of, or all of these exemplary PACAP biological activities.

[0109] The anti-PACAP antibodies and / or their antigen-binding fragments of this disclosure are preferably human, humanized, or chimeric anti-PACAP antibodies and / or their antigen-binding fragments that antagonize, inhibit, neutralize, or block at least one biological effect associated with human PACAP. In certain embodiments, the anti-PACAP antibodies and / or their antigen-binding fragments inhibit or neutralize at least one biological effect induced by PACAP, including PACAP27 and / or PACAP38, as described below. In other embodiments, anti-PACAP antibodies and / or their antigen-binding fragments neutralize or inhibit the PACAP activation of at least one of PAC1-R, VPAC1-R, and / or VPAC2-R, neutralize or inhibit the PACAP activation of each of PAC1-R, VPAC1-R, and VPAC2-R, and / or neutralize or inhibit the PACAP activation of PAC1-R, and / or inhibit the binding of PACAP to the cell surface via, for example, the inhibition of PACAP-induced cAMP production by glycosaminoglycans ("GAGs"), and / or reduce PACAP-induced vasodilation, photophobia, mast cell degranulation, and / or neuronal activation when administered to a subject. In further embodiments, an anti-PACAP antibody and / or its antigen-binding fragment can inhibit PACAP binding to at least one of PAC1-R, VPAC1-R, and / or VPAC2-R, or inhibit PACAP binding to each of PAC1-R, VPAC1-R, and / or VPAC2-R, or inhibit PACAP binding to PAC1-R. In other embodiments, an anti-PACAP antibody and / or its antigen-binding fragment inhibits PACAP-induced cAMP production. In some embodiments, the antibody or its antigen-binding fragment according to the present invention can inhibit PACAP-mediated activity (including binding to PAC1R-expressing cells). In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment used in this method binds to PACAP27 and / or PACAP38, blocking the binding of PACAP27 and / or PACAP38 to PAC1-R, VPAC1-R, and / or VPAC2-R.In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment used in this method binds to PACAP27 and / or PACAP38, blocking the binding of PACAP27 and / or PACAP38 to PAC1-R, VPAC1-R, and VPAC2-R, respectively. Preferably, the anti-PACAP antibody and / or its antigen-binding fragment binds to PACAP27 and / or PACAP38, blocking the binding of PACAP27 and / or PACAP38 to PAC1-R.

[0110] In one embodiment, an anti-PACAP antibody and / or its antigen-binding fragment comprises one or more of the following: (a) inhibiting or neutralizing at least one biological effect induced by PACAP; (b) neutralizing or inhibiting PACAP activation of at least one of the PAC1 receptor ("PAC1-R"), vasoactive intestinal peptide receptor type 1 ("VPAC1-R"), and / or vasoactive intestinal peptide receptor type 2 ("VPAC2-R"); (c) neutralizing or inhibiting PACAP activation of each of PAC1-R, VPAC1-R, and VPAC2-R; (d) neutralizing or inhibiting PACAP activation of PAC1-R; and (e) PACAP binding to at least one of PAC1-R, VPAC1-R, and / or VPAC2-R. (f) can inhibit PACAP binding to each of PAC1-R, VPAC1-R, and / or VPAC2-R; (g) can inhibit PACAP binding to PAC1-R expressing cells; (h) can inhibit PACAP binding to the cell surface via, for example, glycosaminoglycans ("GAGs"); (i) does not inhibit PACAP-mediated binding of such antibodies to the cell surface via, for example, GAGs; (j) inhibits PACAP-mediated binding of such antibodies to the cell surface via, for example, GAGs; (k) inhibits PACAP-induced cAMP production; and / or (l) reduces PACAP-induced vasodilation, photophobia, mast cell degranulation, and / or neuronal activation when administered to a subject.

[0111] In further embodiments, anti-PACAP antibodies and / or their antigen-binding fragments, when administered alone or in combination to a subject, e.g., a human, reduce PACAP-induced vasodilation, photophobia, mast cell degranulation, and / or neuronal activation. In relevant embodiments, human or humanized anti-PACAP antibodies and / or their antigen-binding fragments are suitable for treating human subjects having acute, recurrent, or chronic conditions associated with increased vasodilation, photophobia, mast cell degranulation, and / or neuronal activation.

[0112] In preferred embodiments, the anti-PACAP antibody and / or its antigen-binding fragment substantially does not interact with (bind to) VIP. The anti-PACAP antibody and / or its antigen-binding fragment, as included in the present invention, has a binding affinity for PACAP, and the binding affinity includes an anti-PACAP antibody and / or its antigen-binding fragment that specifically binds to PACAP38 and PACAP27 but does not bind to VIP, and / or an antibody or its antigen-binding fragment that specifically binds to PACAP38 but does not bind to PACAP27 or VIP, and / or an antibody and / or its antigen-binding fragment that specifically binds to linear and / or conformational epitopes within PACAP38 and / or PACAP27. Preferably, the anti-PACAP antibody and / or its antigen-binding fragment has no cross-reactivity with VIP, or has minimal cross-reactivity.

[0113] The antibodies of the present invention also include humanized and chimeric forms of the antibodies of this disclosure. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is chimeric, human, or humanized. The chimeric antibody and humanized antibody may contain Fc derived from the constant region of IgG1, IgG2, IgG3, or IgG4. In one embodiment, the chimeric antibody or humanized antibody or fragment or V H Or V LPolypeptides originate from or are derived from one or more rabbit antibodies, such as rabbit antibodies isolated from a population of cloned rabbit B cells. In some embodiments, the antibodies or antigen-binding fragments according to the present invention are humanized, for example, humanized rabbit antibodies against PACAP. More specifically, anti-PACAP antibodies and / or antigen-binding fragments according to the present invention may include human, humanized, and chimeric antibodies and their fragments, as well as scFv, camel antibodies (camelbodies), shark antibodies, nanobodies, novel immunoglobulin antigen receptors ("IgNAR"), fragment antigen-binding ("Fab") fragments, Fab' fragments, MetMab-like antibodies, bispecific antibodies, monovalent antibody fragments, and F(ab')2 fragments. Embodiments described herein further include variants and equivalents that are substantially homologous to the antibodies, antibody fragments, diabodies, SMIP, camel antibodies, nanobodies, IgNAR, polypeptides, variable regions, and CDRs described herein. These may include, for example, conservative substitution mutations (i.e., substitution of one or more amino acids by similar amino acids). For example, conservative substitution refers to substituting an amino acid with another within the same general class, such as substituting one acidic amino acid with another acidic amino acid, one basic amino acid with another basic amino acid, or one neutral amino acid with another neutral amino acid. The intended effects of conservative amino acid substitutions are well known in the art. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may be selected from the group consisting of scFv, camel antibody, nanobody, novel immunoglobulin antigen receptor ("IgNAR"), fragment antigen-binding ("Fab") fragment, Fab' fragment, MetMab-like antibody, monovalent antigen-binding fragment, and F(ab')2 fragment.

[0114] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment substantially or completely lacks N-glycosylation and / or O-glycosylation. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment contains a human constant domain, e.g., an IgG1, IgG2, IgG3, or IgG4 antibody or a fragment thereof. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may contain an Fc region modified to alter (enhance or impair) at least one of effector function, half-life, proteolysis, or glycosylation. For example, the Fc region may contain one or more mutations that alter or eliminate N-glycosylation and / or O-glycosylation.

[0115] In some embodiments, the anti-PACAP antibody and / or its antigen-binding fragment is determined by ELISA, biolayer interferometry ("BLI"), binding equilibrium exclusion (KINEXA®, Sapidyne Instruments, Boise, ID), or SPR, for example, at 25° or 37°C, using a method such as 5 × 10⁻¹⁰. -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 K below M D It binds to PACAP. Preferably, the human, humanized, or chimeric anti-PACAP antibody and / or its antigen-binding fragment is 5 × 10 -11 M, 10 -11 M, 5×10 -12 M, 10 -12 K below M DIt binds to PACAP. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment 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. D It binds to PACAP. Preferably, the anti-PACAP antibody and / or its antigen-binding fragment has a K content of less than about 50 pM, less than about 40 pM, less than about 25 pM, or less than about 1 pM. D It binds to PACAP. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment has a K content of about 10 pM to about 100 pM, about 1 pM to about 100 pM, or about 1 pM to about 10 pM. D In another embodiment, a human, humanized, or chimeric anti-PACAP antibody and / or its antigen-binding fragment is 5 × 10 -4 s -1 , 10 -4 s -1 , 5×10 -5 s -1 , or 10 -5 s -1 The following is the dissociation rate constant (off-rate) (k off ) binds to PACAP.

[0116] In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment does not substantially interact with (bind to) VIP. Preferably, the anti-PACAP antibody and / or its antigen-binding fragment has a stronger affinity for PACAP compared to VIP, i.e., there is some cross-reactivity, but the antibody preferentially binds to PACAP compared to VIP. For example, the affinity of the antibody and / or its antigen-binding fragment for PACAP is at least 10 times, 30 times, 100 times, 300 times, 10000 times, 30000 times, 100000 times, 300000 times, 1000000 times, 3000000 times, 10000000 times, 10000000 times, 30000000 times stronger than the binding of the antibody and / or its antigen-binding fragment to VIP (e.g., the K of the antibody or fragment regarding binding to human PACAP). D This is about K regarding the connection to VIP. D10 times, 30 times, 100 times, 300 times, 1000 times, 30000 times, 100000 times, 300000 times, 1000000 times, 3000000 times, 10000000 times, 30000000 times, 30000000 times (lower).

[0117] In some embodiments, the present invention relates to an isolated antibody or antigen-binding fragment that competes with the antibodies or antigen-binding fragments disclosed herein with respect to binding to PACAP. In one embodiment, the anti-PACAP antibody and / or antigen-binding fragment specifically binds to a linear or conformational epitope and / or Ab10.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, Ab10.H6, Ab21.H, Ab21.H2, Ab21.H3, Ab21.H4, Ab21, Ab22, and Ab23, preferably Ab10.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, Ab10 Anti-PACAP antibodies selected from the group consisting of .H6, Ab21.H, Ab21.H2, Ab21.H3, or Ab21.H4 compete for binding to the same linear or conformational epitopes on human PACAP (specific amino acid sequences of the variable and constant regions of these anti-PACAP antibodies, as well as the nucleic acids encoding such variable and constant regions, and the epitopes to which they bind, as determined by alanine scanning, are disclosed below).

[0118] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment specifically binds to linear or structural epitopes on human PACAP that are the same as or overlap with Ab10.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, or Ab10.H6. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment specifically binds to linear or structural epitopes on human PACAP that are the same as or overlap with Ab10.H or Ab10.H3. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment specifically binds to linear or structural epitopes on human PACAP that are the same as or overlap with Ab10.H. In a preferred embodiment, the anti-PACAP antibody and / or its antigen-binding fragment specifically binds to linear or structural epitopes on human PACAP that are the same as or overlap with Ab10.H3.

[0119] The present invention also includes an anti-PACAP antibody and / or antigen-binding fragment that may contain at least two, at least three, at least four, at least five, or all six complementarity-determining regions ("CDRs") of an anti-PACAP antibody that may contain Ab10.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, or Ab10.H6. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment contains at least two, at least three, at least four, at least five, or all six complementarity-determining regions ("CDRs") of the anti-PACAP antibody Ab10.H or Ab10.H3. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment contains at least two, at least three, at least four, at least five, or all six complementarity-determining regions ("CDRs") of the anti-PACAP antibody Ab10.H. In a preferred embodiment, the anti-PACAP antibody and / or its antigen-binding fragment comprises at least two, at least three, at least four, at least five, or all six complementarity-determining regions ("CDRs") of the anti-PACAP antibody Ab10.H3.

[0120] In one embodiment, an anti-PACAP antibody and / or its antigen-binding fragment specifically binds to the same or overlapping linear or conformational epitopes on human PACAP as Ab21.H, Ab21.H2, Ab21.H3, or Ab21.H4. The present invention also includes an anti-PACAP antibody and / or antigen-binding fragment that may contain at least two, at least three, at least four, at least five, or all six complementarity-determining regions ("CDRs") of an anti-PACAP antibody that may contain Ab21.H, Ab21.H2, Ab21.H3, or Ab21.H4.

[0121] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment specifically binds to a linear or conformational epitope on human PACAP that is identical to or overlaps with Ab22 or Ab23. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment comprises at least two, at least three, at least four, at least five, or all six complementarity-determining regions ("CDRs") of the anti-PACAP antibody selected from Ab22 or Ab23.

[0122] In some embodiments, the present invention provides an anti-PACAP antibody and / or its antigen-binding fragment that comprises at least two complementarity-determining regions ("CDRs") of an anti-PACAP antibody selected from the group consisting of Ab10.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, Ab10.H6, Ab21.H, Ab21.H2, Ab21.H3, Ab21.H4, Ab21, Ab22, and Ab23, preferably Ab10.H or Ab10.H3, or at least three CDRs, or at least four CDRs, or at least five CDRs, or all six CDRs. If all six CDRs are absent, preferably at least V H CDR3 and V LCDR3 is present. In exemplary embodiments, the antibody and / or its antigen-binding fragment is a variable heavy chain ("V") from Ab10.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, Ab10.H6, Ab21.H, Ab21.H2, Ab21.H3, Ab21.H4, Ab21, Ab22, and Ab23, preferably Ab10.H or Ab10.H3. H ") and / or variable light chain ("V L This includes ").

[0123] Furthermore, in some embodiments, the anti-PACAP antibody and / or its antigen-binding fragment may also include sequence variants of any of the disclosed antibodies, which are modified by mutagenesis, such as affinity maturation that alters one or more properties such as binding affinity or immunogenicity.

[0124] In another embodiment, the present invention intends a polypeptide sequence having at least 90% sequence homology to one or more polypeptide sequences of antigen-binding fragments, variable regions, and CDRs described herein. More preferably, the present invention intends a polypeptide sequence having at least 95% sequence homology, more preferably at least 98% sequence homology, and still more preferably at least 99% sequence homology to one or more polypeptide sequences of antigen-binding fragments, variable regions, and CDRs described herein. Methods for determining homology between nucleic acid sequences and amino acid sequences are well known to those skilled in the art.

[0125] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment includes a sequence variant having at least 90% sequence homology to either Ab10.H or Ab10.H3, for example, at least 95% sequence homology to either Ab10.H or Ab10.H3, more preferably at least 98% sequence homology, and still more preferably at least 99% sequence homology. In one embodiment, the sequence variant is distinguished by a conservative substitution mutation (i.e., substitution of one or more amino acids by similar amino acids). For example, a conservative substitution refers to substituting one amino acid with another within the same general class, such as substituting one acidic amino acid with another acidic amino acid, one basic amino acid with another basic amino acid, or one neutral amino acid with another neutral amino acid.

[0126] In some expression systems, the heavy chain may be cleaved at the C-terminus, resulting in the cleavage of C-terminal lysine (Lys,K). An example of such an expression system is the widely used CHO cell line. Therefore, in one embodiment, the anti-PACAP antibody comprises a heavy chain or heavy chain constant region as described herein, where the C-terminal lysing (Lys,K) is cleaved, i.e., C-terminal lysine (Lys,K) is absent.

[0127] The present invention also envisions an anti-PACAP antibody comprising any polypeptide or polynucleotide sequence described herein, substituted with any of the other polynucleotide sequences described herein. For example, but not limited thereto, the present invention envisions an antibody comprising any combination of variable light chain and variable heavy chain sequences described herein, and further envisions an antibody obtained by substituting any of the CDR sequences described herein with any of the other CDR sequences described herein.

[0128] In one embodiment, an anti-PACAP antibody and / or its antigen-binding fragment is linked to one or more functional moieties. The antibody and / or its antigen-binding fragment is post-translationally modified to include an effector moiety such as a chemical linker, a detectable moiety such as a fluorescent dye, enzyme, substrate, bioluminescent substance, or radioactive substance, and a chemiluminescent moiety, or a functional moiety such as streptavidin, avidin, biotin, cytotoxin, cytotoxic agent, and radioactive substance. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is linked directly or indirectly to another moiety such as a detectable label or therapeutic agent.

[0129] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is linked to at least one effector portion, for example, a chemical linker. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is linked to one or more detectable portions, for example, a fluorescent dye, an enzyme, a substrate, a bioluminescent substance, a radioactive substance, a chemiluminescent portion, or a mixture thereof.

[0130] Antibodies and / or their antigen-binding fragments may also be chemically modified to provide further advantages such as increased polypeptide solubility, stability, and circulation time (in vivo half-life), or decreased immunogenicity (see U.S. Patent No. 4,179,337). Chemical moieties for derivatization may be selected from water-soluble polymers, such as polyethylene glycol, ethylene glycol / propylene glycol copolymer, carboxymethylcellulose, dextran, and polyvinyl alcohol. Antibodies and / or their antigen-binding fragments may be modified at random positions within the molecule or at predetermined positions within the molecule, and may contain one, two, three, or more linked chemical moieties. The polymer may have any molecular weight and may be branched or unbranched. For polyethylene glycol, preferred molecular weights are about 1 kDa to about 100 kDa for ease of handling and manufacture (the term "about" indicates that in polyethylene glycol preparations, some molecules are more and somewhat less by weight than the stated molecular weight). Other sizes may be used depending on the desired therapeutic profile (e.g., desired duration of sustained release, effect on biological activity if any, ease of handling, degree or absence of antigenicity, and other known effects of polyethylene glycol on therapeutic proteins or analogs). For example, polyethylene glycol may be available in approximately 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, and 15,000. It may have an average molecular weight of 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000, 25,000, 30,000, 35,000, 40,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, or 100,000 kDa.Branched polyethylene glycol is described, for example, in U.S. Patent No. 5,643,575; Morpurgo et al., Appl. Biochem. Biotechnol., 56:59-72 (1996); Vorobjev et al., Nucleosides and Nucleotides, 18:2745-2750 (1999); and Caliceti et al., Bioconjug. Chem., 10:638-646 (1999), each of which disclosures are incorporated herein by reference. Many coupling methods are available to those skilled in the art (see, for example, European Patent No. 0401384, incorporated herein by reference, disclosing a method for coupling PEG to G-CSF; and Malik et al., Exp. Hematol., 20:1028-1035 (1992) (reporting pegylation of GM-CSF using tresilchloride)). For example, polyethylene glycol can be covalently bonded through amino acid residues via reactive groups such as free amino groups or carboxyl groups. Reactive groups are those to which activated polyethylene glycol molecules can be bonded. Amino acid residues with free amino groups may include lysine residues and N-terminal amino acid residues, while those with free carboxyl groups may include aspartic acid residues, glutamic acid residues, and C-terminal amino acid residues. Sulfhydryl groups can also be used as reactive groups for linking polyethylene glycol molecules. For therapeutic purposes, linking via amino groups, such as N-terminal or lysine groups, is preferred. As suggested above, polyethylene glycol can be linked to proteins via bonding to any of several amino acid residues. For example, polyethylene glycol can be linked to polypeptides via covalent bonding to lysine, histidine, aspartic acid, glutamic acid, or cysteine ​​residues. One or more reaction chemistry methods may be used to link polyethylene glycol to specific amino acid residues (e.g., lysine, histidine, aspartic acid, glutamic acid, or cysteine), or to two or more types of amino acid residues (e.g., lysine, histidine, aspartic acid, glutamic acid, cysteine, and combinations thereof).

[0131] Alternatively, the antibody and / or its antigen-binding fragment may have an increased in vivo half-life through fusion with albumin (but not limited to recombinant human serum albumin or fragments or variants thereof (see, for example, U.S. Patent No. 5,876,969, European Patent No. 0413622, and U.S. Patent No. 5,766,883, the whole of which is incorporated herein by reference)) or other circulating blood proteins, such as transferrin or ferritin. In preferred embodiments, the polypeptide and / or antibody (including fragments or variants thereof) of the present invention is fused with a mature form of human serum albumin (i.e., amino acids 1-585 of human serum albumin shown in Figures 1 and 2 of European Patent No. 0322094, the whole of which is incorporated herein by reference). Polynucleotides encoding the fusion proteins of the present invention are also incorporated herein by reference.

[0132] Regarding detectable parts, further exemplary enzymes include, but are not limited to, horseradish peroxidase, acetylcholinesterase, alkaline phosphatase, beta-galactosidase, and luciferase. Further exemplary fluorescent substances include, but are not limited to, rhodamine, fluorescein, fluorescein isothiocyanate, umbelliferone, dichlorotriazinylamine, phycoerythrin, and dansilchloride. Further exemplary chemiluminescent parts include, but are not limited to, luminol. Further exemplary bioluminescent substances include, but are not limited to, luciferin and aequorin. Further exemplary radioactive substances include, but are not limited to, iodine-125 (125I), carbon-14 (14C), sulfur-35 (35S), tritium (3H), and phosphorus-32 (32P).

[0133] Methods for conjugating antibodies or their antigen-binding fragments to detectable portions are known in the art, such as those described by Hunter et al., Nature, 144:945 (1962); David et al., Biochemistry, 13:1014 (1974); Pain et al., J. Immunol. Meth., 40:219 (1981); and Nygren, J., Histochem. and Cytochem., 30:407 (1982).

[0134] Furthermore, the present invention encompasses compositions suitable for therapeutic and / or prophylactic use, comprising a therapeutically effective amount and / or a prophylactic effective amount of at least one anti-PACAP antibody and / or its antigen-binding fragment described herein. In particular, compositions and dosage forms containing the subject anti-PACAP antibody and / or its antigen-binding fragment for use in treating and / or prophylactically treating opioid-induced pain are provided herein. The compositions may be suitable for subcutaneous, intramuscular, and / or intravenous administration. The compositions may be lyophilized, stabilized, and / or formulated for administration by injection. In some embodiments, the compositions include pharmaceutically acceptable diluents, carriers, solubilizers, emulsifiers, preservatives, or mixtures thereof.

[0135] The present invention envisions one or more isolated nucleic acid sequences encoding the anti-PACAP antibody and / or its antigen-binding fragment described herein, and one or more vectors containing these isolated nucleic acid sequences.

[0136] In addition, the present invention provides a host cell comprising one or more of the above-mentioned isolated nucleic acid sequences or vectors. The host cell is a mammalian, bacterial, fungal, yeast, avian, amphibian, plant, or insect cell, or a CHO cell. In addition, the CHO cell may be selected from one of the following subclones or subcell lines: DP12 (CHO K1 dhfr-) cell line, NS0 cell, CHO-DXB11 (CHO-DUKX), CHO-pro3, CHO-DG44, CHO 1-15, CHO DP-12, Lec2, M1WT3, Lec8, or pgsA-745.Furthermore, the host cell may be a filamentous fungus or yeast selected from, for example, the following genera: Arxiozyma; Ascobotryozyma; Citeromyces; Debaryomyces; Dekkera; Eremothecium; Issatchenkia; Kazachstania; Kluyveromyces; Kodamaea amaea); Lodderomyces; Pachysolen; Pichia; Saccharomyces; Saturnispora; Tetrapisispora; Torulaspora; Williopsis; and Zygosaccharomyces, preferably Pichia, and more preferably Pichia pastris. The host cells may be, for example, 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 cancer ("HELA") cells; canine kidney cells ("MDCK"); buffalo rat liver ("BRL") cells; human lung cells; human liver ("Hep G2") cells; mouse mammary cancer ("MMT") cells; TRI cells; MRC 5 cells; and FS4 cells.In one embodiment, the host cell is a mammalian eukaryotic host cell 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 cancer ("HELA") cells; canine kidney cells ("MDCK"); buffalo rat liver ("BRL") cells; human lung cells; human liver ("Hep G2") cells; mouse mammary cancer ("MMT") cells; TRI cells; MRC 5 cells; and FS4 cells. Preferably, 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., a bacterial cell, or a eukaryotic cell including mammalian, fungal, yeast, avian, or insect cells. In one embodiment, the host cell is a filamentous fungus or a yeast cell. Preferably, the yeast species is of the genus Pichia. Most preferably, the Pichia species is selected from Pichia pastoris, Pichia methanolica, and Hansenula polymorpha (Pichia angusta).

[0137] Exemplary polypeptide sequences of anti-PACAP antibodies The present invention may be carried out using any anti-PACAP antibody. Exemplary anti-PACAP antibodies and / or their antigen-binding fragments according to the present invention, as well as their specific CDRs, are identified in this section. For convenience, each exemplary antibody or its antigen-binding fragment and the corresponding sequence are separately identified by specific naming, namely Ab10, Ab10.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, Ab10.H6, Ab20, Ab21, Ab21.H, Ab21.H2, Ab21.H3, Ab21.H4, Ab22, and Ab23.

[0138] Exemplary anti-PACAP antibodies and / or their antigen-binding fragments suitable for use in the present invention are selected from SEQ ID NOs: 962, 1282, 1322, 1362, 1402, 1442, 1202, 1482, 1522, and 1562. H V has an amino acid sequence that has at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% sequence identity with respect to the chain. H V selected from the chain and / or selected from sequence numbers 982, 1302, 1342, 1382, 1422, 1462, 1222, 1502, 1542, and 1582. L V has an amino acid sequence that has at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% sequence identity with respect to the chain. L The chain and / or all of the at least two, three, four, five, or six CDRs contained therein.

[0139] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is V selected from SEQ ID NOs: 962 or 1322. H V has an amino acid sequence that has at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% sequence identity with respect to the chain. H V selected from the chain and / or sequence number 982 or 1342 L V has an amino acid sequence that has at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% sequence identity with respect to the chain. L The chain and / or all of at least 2, 3, 4, 5, or 6 CDRs contained therein. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is V selected from SEQ ID NO: 962. H V has an amino acid sequence that has at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% sequence identity with respect to the chain. H V selected from the chain and / or sequence number 982 L V has an amino acid sequence that has at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% sequence identity with respect to the chain.L The chain and / or all of at least 2, 3, 4, 5, or 6 CDRs contained therein. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is V selected from SEQ ID NO: 1322. H V has an amino acid sequence that has at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% sequence identity with respect to the chain. H V selected from the chain and / or sequence number 1342 L V has an amino acid sequence that has at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% sequence identity with respect to the chain. L The chain and / or all of the at least two, three, four, five, or six CDRs contained therein.

[0140] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment contains two, three, four, five, or all six complementarity-determining regions ("CDRs") of Ab21.H, Ab21.H2, Ab21.H3, Ab21.H4, Ab22, or Ab23, or contains all six complementarity-determining regions of Ab10.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, or Ab10.H6. In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment is humanized and contains all six CDRs of anti-PACAP antibodies selected from Ab10.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, Ab10.H6, Ab21.H, Ab21.H2, Ab21.H3, Ab21.H4, Ab22, or Ab23.

[0141] In one embodiment, an anti-PACAP antibody and / or its antigen-binding fragment specifically binds to an epitope on the fragment or variant containing human PACAP or a corresponding amino acid residue, and the epitope is i. At least one of human PACAP residues 22, 23, 27, 28, and 31; ii. At least one of human PACAP residues 12, 20, 23, 24, 26, 27, and 28; iii. At least one of human PACAP residues 19, 22, 23, and 27; iv. At least two of the residues from (i), (ii), or (iii); v. At least three of the residues from (i), (ii), or (iii); vi. At least four of the residues from (i), (ii), or (iii); vii. At least five of the residues from (i) or (ii); viii.(ii) at least six of the residues; ix.(ii) at least seven of the residues; and x. At least residues 23, 27, and 28 of human PACAP, and optionally, 1 to 6 additional residues from (i) and / or (ii), may be selected from the group.

[0142] In one embodiment, an anti-PACAP antibody and / or its antigen-binding fragment specifically binds to an epitope on human PACAP (or a fragment or variant thereof containing the corresponding amino acid sequence present in wild-type PACAP 38), but does not specifically bind to human wild-type human PACAP 27. In another embodiment, an anti-PACAP antibody and / or its antigen-binding fragment specifically binds to an epitope on human PACAP or a fragment or variant thereof containing the corresponding amino acid residue, and the epitope consists of one of the residues (i), (ii), or (iii). In yet another embodiment, an anti-PACAP antibody and / or its antigen-binding fragment specifically binds to an epitope on human PACAP (or a fragment or variant thereof containing the corresponding amino acid residue) present in human wild-type PACAP 38 and human wild-type human PACAP 27. The epitope can be identified, for example, by alanine scanning or by another method accepted in the art.

[0143] Antibody Ab10.H In one embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, having a heavy chain sequence comprising the sequence of SEQ ID NO: 961, which consists of the heavy chain variable region of SEQ ID NO: 962 linked to the heavy chain constant region of SEQ ID NO: 970.

[0144] In one embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable heavy chain sequence comprising the sequence described below: EVQLVESGGGLVQPGGSLRLSCAASGIDLNSYYMTWVRQAPGKGLEWIGFIDAGGDAYYASWAKGRFTISRDNSKNTVYLQMNSLRAEDTAVYFCARDLDLWGQGTLVTVSS (Sequence ID 962).

[0145] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, which binds to the same epitope as Ab10.H and contains the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or a constant heavy chain sequence containing the sequence described below. [ka]

[0146] In another embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, comprising a light chain sequence including the sequence of SEQ ID NO: 981, which consists of the light chain variable region of SEQ ID NO: 982 linked to the light chain constant region of SEQ ID NO: 990.

[0147] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable light chain sequence comprising the sequence described below: DAQLTQSPSTLSASVGDRVTITCQSSESVYGNYLAWFQQKPGKAPKFLIYEASKLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGDISEGVAFGGGTKVEIKR (Sequence ID 982).

[0148] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, wherein the antibody binds to the same epitope as Ab10.H and contains a constant light chain sequence comprising the sequence described below: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 990).

[0149] In another embodiment, the present invention includes an antibody and / or antigen-binding fragment having binding specificity to PACAP, comprising one, two, or three polypeptide sequences from SEQ ID NO: 964; SEQ ID NO: 966; and SEQ ID NO: 968, which correspond to the CDR (hypervariable region) of the heavy chain sequence of SEQ ID NO: 961 or contain the variable heavy chain sequence of SEQ ID NO: 962, and / or further comprising one, two, or three polypeptide sequences from SEQ ID NO: 984; SEQ ID NO: 986; and SEQ ID NO: 988, which correspond to the CDR (hypervariable region) of the light chain sequence of SEQ ID NO: 981 or contain the variable light chain of SEQ ID NO: 982, or an antibody or antigen-binding fragment comprising a combination of sequences which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.

[0150] In another embodiment of the present invention, the antibody and antigen-binding fragments of the present invention comprise, or consist of, one or more combinations of the exemplified variable heavy chain and variable light chain sequences, or the above heavy chain and light chain sequences, or sequences that are at least 90% or 95% identical thereto.

[0151] The present invention further envisions a PACAP antibody and / or its antigen-binding fragment comprising one, two, three, or four polypeptide sequences from sequence numbers 963; 965; 967; and 969, corresponding to the FR (constant region) of the heavy chain sequence of sequence number 961 or the variable heavy chain sequence of sequence number 962, and / or one, two, three, or four polypeptide sequences from sequence numbers 983; 985; 987; and 989, corresponding to the FR (constant region) of the light chain sequence of sequence number 981 or the variable light chain sequence of sequence number 982, or a combination thereof, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to them.

[0152] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment or fragment comprises, or instead comprises, one or more combinations of the FR, CDR, variable heavy chain and variable light chain, and the heavy chain and light chain sequences described above, including all of them, or sequences that are at least 90% or 95% identical thereto.

[0153] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 961 or SEQ ID NO: 962, or a polypeptide that is at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 981 or SEQ ID NO: 982, or a polypeptide that is at least 90% or 95% identical thereto.

[0154] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 964; SEQ ID NO: 966; and SEQ ID NO: 968, corresponding to the heavy chain sequence of SEQ ID NO: 961, the variable heavy chain sequence of SEQ ID NO: 962, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0155] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 984; SEQ ID NO: 986; and SEQ ID NO: 988, corresponding to the light chain sequence of SEQ ID NO: 981, the variable light chain sequence of SEQ ID NO: 982, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0156] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 963; SEQ ID NO: 965; SEQ ID NO: 967; and SEQ ID NO: 969, corresponding to the heavy chain sequence of SEQ ID NO: 961, the variable heavy chain sequence of SEQ ID NO: 962, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0157] In a further embodiment of the present invention, the antibody and / or antigen-binding fragment of a subject having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from sequence numbers 983; 985; 987; and 989, corresponding to the light chain sequence of sequence number 981, the variable light chain sequence of sequence number 982, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0158] The present invention also intends an anti-PACAP antibody and / or antigen-binding fragment comprising one or more of the antibody fragments described herein. In one embodiment, the antibody and / or antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 962; the variable light chain region of SEQ ID NO: 982; the complementarity-determining regions of the variable heavy chain region of SEQ ID NO: 964; SEQ ID NO: 966; and SEQ ID NO: 968; and the complementarity-determining regions of the variable light chain region of SEQ ID NO: 984; SEQ ID NO: 986; and SEQ ID NO: 988, or all of sequences that are at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 962; the variable light chain region of SEQ ID NO: 982; the framework regions of the variable heavy chain region of SEQ ID NO: 963; SEQ ID NO: 965; SEQ ID NO: 967; and SEQ ID NO: 969; and the framework regions of the variable light chain region of SEQ ID NO: 983; SEQ ID NO: 985; SEQ ID NO: 987; and SEQ ID NO: 989, or sequences that are at least 90% or 95% identical thereto.

[0159] In another embodiment of the present invention, the PACAP antibody is an antibody or antigen-binding fragment comprising or consisting of SEQ ID NOs. 961 and 981, or SEQ ID NOs. 962 and 982, or instead comprising Ab10.H, or a CDR of Ab10.H, and having at least one of the biological activities described herein, or containing a sequence that competes with Ab10.H for binding to PACAP, preferably being at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab10.H, or an antibody that binds to an epitope on PACAP that is identical to or overlaps with that of Ab10.H.

[0160] In further embodiments of the present invention, the antigen-binding fragment comprises or consists of a Fab fragment having binding specificity to PACAP. With respect to the antibody Ab10.H, the Fab fragment preferably comprises the variable heavy chain sequence of SEQ ID NO: 962 and the variable light chain sequence of SEQ ID NO: 982, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. This embodiment of the present invention further comprises a Fab containing additions, deletions, and variants of SEQ ID NO: 962 and / or SEQ ID NO: 982 that retain binding specificity to PACAP.

[0161] In one embodiment, the Fab fragment may be produced by enzymatic digestion of Ab10.H (e.g., papain). In another embodiment of the present invention, anti-PACAP antibodies such as Ab10.H and the Fab fragment may be produced through expression in mammalian cells such as CHO, NSO, or HEK 293 cells, fungi, insects, or microbial systems, such as yeast cells (e.g., haploid or diploid yeast, e.g., haploid or diploid Pichia). Suitable Pichia species include, but are not limited to, Pichia pastoris.

[0162] In additional embodiments, the present invention further aims to encode an antibody polypeptide having binding specificity to PACAP, comprising the heavy and / or light chain of Ab10.H, as well as one or more combinations of the heavy or light chains described above, including FR, CDR, variable heavy and variable light chain sequences, and all of them, or sequences that are at least 90% or 95% identical thereto.

[0163] In specific embodiments, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody and / or its antigen-binding fragment, comprising (a) a variable heavy chain including a CDR1 sequence consisting of SEQ ID NO: 964; a CDR2 sequence consisting of SEQ ID NO: 966; and a CDR3 sequence consisting of SEQ ID NO: 968; and / or (b) a CDR1 sequence consisting of SEQ ID NO: 984; a CDR2 sequence consisting of SEQ ID NO: 986; and a CDR3 sequence consisting of SEQ ID NO: 988. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 962, and / or (b) a variable light chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 982. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 962, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 982. More specifically, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 961, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 981.

[0164] In another specific embodiment, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, and comprises (a) a variable heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 962, and including a CDR1 sequence consisting of SEQ ID NO: 964; a CDR2 sequence consisting of SEQ ID NO: 966; and a CDR3 sequence consisting of SEQ ID NO: 968; and / or (b) a variable light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 982, and including a CDR1 sequence consisting of SEQ ID NO: 984; a CDR2 sequence consisting of SEQ ID NO: 986; and a CDR3 sequence consisting of SEQ ID NO: 988. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 962, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 982. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 961, and including a CDR1 sequence consisting of SEQ ID NO: 964; a CDR2 sequence consisting of SEQ ID NO: 966; and a CDR3 sequence consisting of SEQ ID NO: 968; and / or (b) a light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 981, and including a CDR1 sequence consisting of SEQ ID NO: 984; a CDR2 sequence consisting of SEQ ID NO: 986; and a CDR3 sequence consisting of SEQ ID NO: 988. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 961, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 981.Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 961, and (b) a light chain having the amino acid sequence of SEQ ID NO: 981.

[0165] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment are a. (i) A variable heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with respect to SEQ ID NO: 962, and including a CDR1 sequence consisting of SEQ ID NO: 964; a CDR2 sequence consisting of SEQ ID NO: 966; and a CDR3 sequence consisting of SEQ ID NO: 968; and / or (ii) A variable light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with respect to SEQ ID NO: 982, and including a CDR1 sequence consisting of SEQ ID NO: 984; a CDR2 sequence consisting of SEQ ID NO: 986; and a CDR3 sequence consisting of SEQ ID NO: 988; b. (i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 962, and / or (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 982; c. (i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 962, and (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 982; d. (i) A heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 961, and including a CDR1 sequence consisting of SEQ ID NO: 964; a CDR2 sequence consisting of SEQ ID NO: 966; and a CDR3 sequence consisting of SEQ ID NO: 968; and / or (ii) A light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 981, and including a CDR1 sequence consisting of SEQ ID NO: 984; a CDR2 sequence consisting of SEQ ID NO: 986; and a CDR3 sequence consisting of SEQ ID NO: 988; e. (i) a heavy chain having the amino acid sequence of SEQ ID NO: 961, and / or (ii) a light chain having the amino acid sequence of SEQ ID NO: 981; and / or f. (i) A heavy chain having the amino acid sequence of SEQ ID NO: 961, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 981.

[0166] Antibody Ab21 In one embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, having a heavy chain sequence comprising the sequence of SEQ ID NO: 841, which consists of the heavy chain variable region of SEQ ID NO: 842 linked to the heavy chain constant region of SEQ ID NO: 850.

[0167] In one embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable heavy chain sequence comprising the sequence described below: QSVEESGGRLVTPGTPLTLTCTVSGIDLSSYYMTWVRQAPGKGLEWVGFIDAGGSAYYATWAKGRFTISKASTTVDLKITSPTTEDTATYFCARDLDLWGPGTLVTVSS (Sequence ID 842).

[0168] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, which binds to the same epitope as Ab21 and contains a polypeptide of SEQ ID NO: 1244, 1245, or 1246, or a constant heavy chain sequence containing the sequence described below. [ka]

[0169] In another embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, comprising a light chain sequence including the sequence of SEQ ID NO: 861, which consists of the light chain variable region of SEQ ID NO: 862 linked to the light chain constant region of SEQ ID NO: 870.

[0170] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable light chain sequence comprising the sequence described below: AAVLTQTPSPVSAAVGGTVSISCKSSESVYGDYLAWFQQKPGQPPKQLIYDASTLASGVPSRFKGSGSGTQFTLTISGVQCDDAATYYCAGGYVSAGVAFGGGTEVVVKR (Sequence ID 862).

[0171] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, wherein the antibody binds to the same epitope as Ab21 and contains a constant light chain sequence comprising the sequence described below: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 870).

[0172] In another embodiment, the present invention includes an antibody and / or antigen-binding fragment having binding specificity to PACAP, comprising one, two, or three polypeptide sequences from SEQ ID NO: 844; SEQ ID NO: 846; and SEQ ID NO: 848, which correspond to the CDR (hypervariable region) of the heavy chain sequence of SEQ ID NO: 841 or contain the variable heavy chain sequence of SEQ ID NO: 842, and / or further comprising one, two, or three polypeptide sequences from SEQ ID NO: 864; SEQ ID NO: 866; and SEQ ID NO: 868, which correspond to the CDR (hypervariable region) of the light chain sequence of SEQ ID NO: 861 or contain the variable light chain of SEQ ID NO: 862, or an antibody or antigen-binding fragment comprising a combination of sequences which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. In another embodiment of the present invention, the antibody and antigen-binding fragments of the present invention comprise, or consist of, one or more combinations of the exemplified variable heavy chain and variable light chain sequences, or the above heavy chain and light chain sequences, or sequences that are at least 90% or 95% identical thereto.

[0173] The present invention further envisions a PACAP antibody and / or its antigen-binding fragment comprising one, two, three, or four polypeptide sequences from sequence numbers 843; 845; 847; and 849, corresponding to the FR (constant region) of the heavy chain sequence of sequence number 841 or the variable heavy chain sequence of sequence number 842, and / or one, two, three, or four polypeptide sequences from sequence numbers 863; 865; 867; and 869, corresponding to the FR (constant region) of the light chain sequence of sequence number 861 or the variable light chain sequence of sequence number 862, or a combination thereof, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to them.

[0174] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment or fragment comprises, or instead comprises, one or more combinations of the FR, CDR, variable heavy chain and variable light chain, and the heavy chain and light chain sequences described above, including all of them, or sequences that are at least 90% or 95% identical thereto.

[0175] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 841 or SEQ ID NO: 842, or a polypeptide that is at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 861 or SEQ ID NO: 862, or a polypeptide that is at least 90% or 95% identical thereto.

[0176] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 844; SEQ ID NO: 846; and SEQ ID NO: 848, corresponding to the heavy chain sequence of SEQ ID NO: 841, the variable heavy chain sequence of SEQ ID NO: 842, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0177] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 864; SEQ ID NO: 866; and SEQ ID NO: 868, corresponding to the light chain sequence of SEQ ID NO: 861, the variable light chain sequence of SEQ ID NO: 862, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0178] In a further embodiment of the present invention, the antibody and / or antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 843; SEQ ID NO: 845; SEQ ID NO: 847; and SEQ ID NO: 849, corresponding to the heavy chain sequence of SEQ ID NO: 841, the variable heavy chain sequence of SEQ ID NO: 842, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0179] In a further embodiment of the present invention, the antibody and / or antigen-binding fragment of a subject having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 863; SEQ ID NO: 865; SEQ ID NO: 867; and SEQ ID NO: 869, corresponding to the light chain sequence of SEQ ID NO: 861, the variable light chain sequence of SEQ ID NO: 862, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0180] The present invention also intends an anti-PACAP antibody and / or antigen-binding fragment comprising one or more of the antibody fragments described herein. In one embodiment, the antibody and / or antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 842; the variable light chain region of SEQ ID NO: 862; the complementarity-determining regions of the variable heavy chain region of SEQ ID NO: 844; SEQ ID NO: 846; and SEQ ID NO: 848; and the complementarity-determining regions of the variable light chain region of SEQ ID NO: 862 (SEQ ID NO: 864; SEQ ID NO: 866; and SEQ ID NO: 868), or sequences that are at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 842; the variable light chain region of SEQ ID NO: 862; the framework regions of the variable heavy chain region of SEQ ID NO: 842 (SEQ ID NO: 843; SEQ ID NO: 845; SEQ ID NO: 847; and SEQ ID NO: 849); and the framework regions of the variable light chain region of SEQ ID NO: 862 (SEQ ID NO: 863; SEQ ID NO: 865; SEQ ID NO: 867; and SEQ ID NO: 869), or sequences that are at least 90% or 95% identical thereto.

[0181] In another embodiment of the present invention, the PACAP antibody is an antibody or antigen-binding fragment comprising SEQ ID NOs. 841 and 861, or SEQ ID NOs. 842 and 862, or Ab21 consisting thereof, or a CDR of Ab21, and having at least one of the biological activities described herein, or containing a sequence that competes with Ab21 for binding to PACAP, preferably being at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab21, or an antibody that binds to an epitope on PACAP that is identical to or overlaps with that of Ab21.

[0182] In further embodiments of the present invention, the antigen-binding fragment comprises or consists of a Fab fragment having binding specificity to PACAP. With respect to antibody Ab21, the Fab fragment preferably comprises the variable heavy chain sequence of SEQ ID NO: 842 and the variable light chain sequence of SEQ ID NO: 862, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. This embodiment of the present invention further comprises a Fab containing additions, deletions, and variants of SEQ ID NO: 842 and / or SEQ ID NO: 862 that retain binding specificity to PACAP.

[0183] In one embodiment, the Fab fragment may be produced by enzymatic digestion of Ab21 (e.g., papain). In another embodiment of the present invention, anti-PACAP antibodies such as Ab21 and the Fab fragment may be produced through expression in mammalian cells such as CHO, NSO, or HEK 293 cells, fungi, insects, or microbial systems, such as yeast cells (e.g., haploid or diploid yeast, e.g., haploid or diploid Pichia). Suitable Pichia species include, but are not limited to, Pichia pastoris.

[0184] In additional embodiments, the present invention further aims to encode an antibody polypeptide having binding specificity to PACAP, comprising the heavy and / or light chain of Ab21, as well as one or more combinations of the heavy or light chains described above, including FR, CDR, variable heavy and variable light chain sequences, and all of them, or sequences that are at least 90% or 95% identical thereto.

[0185] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, comprising (a) a variable heavy chain including a CDR1 sequence consisting of SEQ ID NO: 844; a CDR2 sequence consisting of SEQ ID NO: 846; and a CDR3 sequence consisting of SEQ ID NO: 848; and / or (b) a CDR1 sequence consisting of SEQ ID NO: 864; a CDR2 sequence consisting of SEQ ID NO: 866; and a CDR3 sequence consisting of SEQ ID NO: 868. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 842, and / or (b) a variable light chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 862. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 842, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 862. More specifically, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 841, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 861.

[0186] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment are a. A variable heavy chain containing the CDR1 sequence consisting of SEQ ID NO: 844; the CDR2 sequence consisting of SEQ ID NO: 846; and the CDR3 sequence consisting of SEQ ID NO: 848; and / or b. A variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 864; a CDR2 sequence consisting of SEQ ID NO: 866; and a CDR3 sequence consisting of SEQ ID NO: 868, wherein the antibody is optionally selected as follows: (a)(i) A variable heavy chain containing an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with respect to SEQ ID NO: 842, and / or (ii) A variable light chain containing an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with respect to SEQ ID NO: 862; (b)(i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 842, or (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 862; (c)(i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 842, and (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 862; (d)(i) a heavy chain having the amino acid sequence of SEQ ID NO: 841, and / or (ii) a light chain having the amino acid sequence of SEQ ID NO: 861; or (e) comprising (i) a heavy chain having the amino acid sequence of SEQ ID NO: 841, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 861.

[0187] Antibody Ab21.H In one embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, having a heavy chain sequence comprising the sequence of SEQ ID NO: 1201, which consists of the heavy chain variable region of SEQ ID NO: 1202 linked to the heavy chain constant region of SEQ ID NO: 1210.

[0188] In one embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable heavy chain sequence comprising the sequence described below: EVQLVESGGGLVQPGGSLRLSCAASGIDLSSYYMTWVRQAPGKGLEWIGFIDAGGSAYYATWAKGRFTISRDNSKNTVYLQMNSLRAEDTAVYFCARDLDLWGQGTLVTVSS (Sequence ID 1202).

[0189] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, which binds to the same epitope as Ab21.H and comprises the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or a constant heavy chain sequence comprising the sequence described below. [ka]

[0190] In another embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, comprising a light chain sequence including the sequence of SEQ ID NO: 1221, which consists of the light chain variable region of SEQ ID NO: 1222 linked to the light chain constant region of SEQ ID NO: 1230.

[0191] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable light chain sequence comprising the sequence described below: DAQLTQSPSTLSASVGDRVTITCKSSESVYGDYLAWFQQKPGKAPKQLIYDASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGYVSAGVAFGGGTKVEIKR (Sequence ID 1222).

[0192] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, wherein the antibody binds to the same epitope as Ab21.H and contains a constant light chain sequence comprising the sequence described below: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 1230).

[0193] In another embodiment, the present invention includes an antibody and / or antigen-binding fragment having binding specificity to PACAP, comprising one, two, or three polypeptide sequences from SEQ ID NO: 1204; SEQ ID NO: 1206; and SEQ ID NO: 1208, which correspond to the CDR (hypervariable region) of the heavy chain sequence of SEQ ID NO: 1201 or contain the variable heavy chain sequence of SEQ ID NO: 1202, and / or further comprising one, two, or three polypeptide sequences from SEQ ID NO: 1224; SEQ ID NO: 1226; and SEQ ID NO: 1228, which correspond to the CDR (hypervariable region) of the light chain sequence of SEQ ID NO: 1221 or contain the variable light chain of SEQ ID NO: 1222, or an antibody or antigen-binding fragment comprising a combination of sequences which are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. In another embodiment of the present invention, the antibody and antigen-binding fragments of the present invention comprise, or consist of, one or more combinations of the exemplified variable heavy chain and variable light chain sequences, or the above heavy chain and light chain sequences, or sequences that are at least 90% or 95% identical thereto.

[0194] The present invention further envisions a PACAP antibody and / or an antigen-binding fragment thereof comprising one, two, three, or four polypeptide sequences from sequence numbers 1203; 1205; 1207; and 1209, corresponding to the FR (constant region) of the heavy chain sequence of sequence number 1201 or the variable heavy chain sequence of sequence number 1202, and / or one, two, three, or four polypeptide sequences from sequence numbers 1223; 1225; 1227; and 1229, corresponding to the FR (constant region) of the light chain sequence of sequence number 1221 or the variable light chain sequence of sequence number 1222, or a combination thereof, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to them.

[0195] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment or fragment of the present invention comprises, or alternatively consists of, one or more combinations of FR, CDR, variable heavy chain and variable light chain, and the heavy chain and light chain sequences described above including all of them, or a sequence that is at least 90% or 95% identical thereto.

[0196] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment of the present invention comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 1201, or SEQ ID NO: 1202, or a polypeptide that is at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody and / or its antigen-binding fragment of the present invention comprises, or alternatively consists of, the polypeptide sequence of SEQ ID NO: 1221, or SEQ ID NO: 1222, or a polypeptide that is at least 90% or 95% identical thereto.

[0197] In a further embodiment of the present invention, the antibody and / or its antigen-binding fragment having binding specificity for PACAP comprises, or alternatively consists of, one, two, or three of the polypeptide sequences of SEQ ID NO: 1204; SEQ ID NO: 1206; and SEQ ID NO: 1208, corresponding to the CDR (hypervariable region) of the heavy chain sequence of SEQ ID NO: 1201, or the variable heavy chain sequence of SEQ ID NO: 1202, or a sequence that is at least 90% or 95% identical thereto.

[0198] In a further embodiment of the present invention, the antibody and / or its antigen-binding fragment having binding specificity for PACAP comprises, or alternatively consists of, one, two, or three of the polypeptide sequences of SEQ ID NO: 1224; SEQ ID NO: 1226; and SEQ ID NO: 1228, corresponding to the CDR (hypervariable region) of the light chain sequence of SEQ ID NO: 1221, or the variable light chain sequence of SEQ ID NO: , or a sequence that is at least 90% or 95% identical thereto.

[0199] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 1203; SEQ ID NO: 1205; SEQ ID NO: 1207; and SEQ ID NO: 1209, corresponding to the heavy chain sequence of SEQ ID NO: 1201, the variable heavy chain sequence of SEQ ID NO: 1202, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0200] In a further embodiment of the present invention, the antibody and / or antigen-binding fragment of a subject having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 1223; SEQ ID NO: 1225; SEQ ID NO: 1227; and SEQ ID NO: 1229, corresponding to the light chain sequence of SEQ ID NO: 1221, the variable light chain sequence of SEQ ID NO: 1222, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0201] The present invention also intends an anti-PACAP antibody and / or antigen-binding fragment comprising one or more of the antibody fragments described herein. In one embodiment, the antibody and / or antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 1202; the variable light chain region of SEQ ID NO: 1222; the complementarity-determining regions of the variable heavy chain region of SEQ ID NO: 1204; SEQ ID NO: 1206; and SEQ ID NO: 1208; and the complementarity-determining regions of the variable light chain region of SEQ ID NO: 1224; SEQ ID NO: 1226; and SEQ ID NO: 1228, or all of sequences that are at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more antibody fragments containing all of the following: the variable heavy chain region of SEQ ID NO: 1202; the variable light chain region of SEQ ID NO: 1222; the framework regions of the variable heavy chain region of SEQ ID NO: 1203; SEQ ID NO: 1205; SEQ ID NO: 1207; and SEQ ID NO: 1209; and the framework regions of the variable light chain region of SEQ ID NO: 1223; SEQ ID NO: 1225; SEQ ID NO: 1227; and SEQ ID NO: 1229, or sequences that are at least 90% or 95% identical thereto.

[0202] In another embodiment of the present invention, the PACAP antibody is an antibody or antigen-binding fragment comprising or consisting of SEQ ID NOs. 1201 and SEQ ID NOs. 1221, or SEQ ID NOs. 1202 and SEQ ID NOs. 1222, or Ab21.H, or a CDR of Ab21.H, and having at least one of the biological activities described herein, or containing a sequence that competes with Ab21.H for binding to PACAP, preferably being at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab21.H, or an antibody that binds to an epitope on PACAP that is identical to or overlaps with that of Ab21.H.

[0203] In further embodiments of the present invention, the antigen-binding fragment comprises or consists of a Fab fragment having binding specificity to PACAP. With respect to the antibody Ab21.H, the Fab fragment preferably comprises the variable heavy chain sequence of SEQ ID NO: 1202 and the variable light chain sequence of SEQ ID NO: 1222, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. This embodiment of the present invention further comprises a Fab containing additions, deletions, and variants of SEQ ID NO: 1202 and / or SEQ ID NO: 1222 that retain binding specificity to PACAP.

[0204] In one embodiment, the Fab fragment may be produced by enzymatic digestion of Ab21.H (e.g., papain). In another embodiment of the present invention, anti-PACAP antibodies such as Ab21.H and the Fab fragment may be produced through expression in mammalian cells such as CHO, NSO, or HEK 293 cells, fungi, insects, or microbial systems, such as yeast cells (e.g., haploid or diploid yeast, e.g., haploid or diploid Pichia). Suitable Pichia species include, but are not limited to, Pichia pastoris.

[0205] In additional embodiments, the present invention further aims to encode an antibody polypeptide having binding specificity to PACAP, comprising the heavy and / or light chain of Ab21.H, as well as one or more combinations of the heavy or light chains described above, including FR, CDR, variable heavy and variable light chain sequences, and all of them, or sequences that are at least 90% or 95% identical thereto.

[0206] In specific embodiments, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, comprising (a) a variable heavy chain including a CDR1 sequence consisting of SEQ ID NO: 1204; a CDR2 sequence consisting of SEQ ID NO: 1206; and a CDR3 sequence consisting of SEQ ID NO: 1208; and / or (b) a CDR1 sequence consisting of SEQ ID NO: 1224; a CDR2 sequence consisting of SEQ ID NO: 1226; and a CDR3 sequence consisting of SEQ ID NO: 1228. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with respect to SEQ ID NO: 1202; and / or (b) a variable light chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with respect to SEQ ID NO: 1222. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1202, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 1222. More specifically, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1201, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 1221.

[0207] In another specific embodiment, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, and comprises (a) a variable heavy chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1202, and comprising a CDR1 sequence consisting of SEQ ID NO: 1204; a CDR2 sequence consisting of SEQ ID NO: 1206; and a CDR3 sequence consisting of SEQ ID NO: 1208; and / or (b) a variable light chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1222, and comprising a CDR1 sequence consisting of SEQ ID NO: 1224; a CDR2 sequence consisting of SEQ ID NO: 1226; and a CDR3 sequence consisting of SEQ ID NO: 1228. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1202, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 1222. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1201, and including a CDR1 sequence consisting of SEQ ID NO: 1204; a CDR2 sequence consisting of SEQ ID NO: 1206; and a CDR3 sequence consisting of SEQ ID NO: 1208; and / or (b) a light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1221, and including a CDR1 sequence consisting of SEQ ID NO: 1224; a CDR2 sequence consisting of SEQ ID NO: 1226; and a CDR3 sequence consisting of SEQ ID NO: 1228. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1201, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 1221.Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1201, and (b) a light chain having the amino acid sequence of SEQ ID NO: 1221.

[0208] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment are a. A variable heavy chain containing the CDR1 sequence consisting of SEQ ID NO: 1204; the CDR2 sequence consisting of SEQ ID NO: 1206; and the CDR3 sequence consisting of SEQ ID NO: 1208; and / or b. A variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 1224; a CDR2 sequence consisting of SEQ ID NO: 1226; and a CDR3 sequence consisting of SEQ ID NO: 1228, wherein the antibody is optionally: (a)(i) A variable heavy chain containing an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1202, and / or (ii) A variable light chain containing an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1222; (b)(i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 1202, or (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 1222; (c)(i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 1202, and (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 1222; (d)(i) a heavy chain having the amino acid sequence of SEQ ID NO: 1201, and / or (ii) a light chain having the amino acid sequence of SEQ ID NO: 1221; or (e) comprising (i) a heavy chain having the amino acid sequence of SEQ ID NO: 1201, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 1221.

[0209] Antibody Ab22 In one embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, having a heavy chain sequence comprising the sequence of SEQ ID NO: 881, which consists of the heavy chain variable region of SEQ ID NO: 882 linked to the heavy chain constant region of SEQ ID NO: 890.

[0210] In one embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable heavy chain sequence comprising the sequence described below: QEQLVESGGGLVQPEGSLTLTCTASGFDFSSNAMCWVRQAPGKGLEWIGSIYNADGKNYYAIWAKGRFTISRTSSTTVTLQMTSLTAADTATYFCARDFDLWGQGTLVTVSS (Sequence ID 882).

[0211] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, which binds to the same epitope as Ab22 and contains a polypeptide of SEQ ID NO: 1244, 1245, or 1246, or a constant heavy chain sequence containing the sequence described below. [ka]

[0212] In another embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, comprising a light chain sequence including the sequence of SEQ ID NO: 901, which consists of the light chain variable region of SEQ ID NO: 902 linked to the light chain constant region of SEQ ID NO: 910.

[0213] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable light chain sequence comprising the sequence described below: AAVLTQTPSPVSAAVGGTVTINCQSSQSVYDNDWLAWFQQKPGQPPKLLIYLTSTLASGVPSRFSGSGSGTQFTLTISGVQCDDAATYYCLGGYDEDGDTHVFGGGTEVVVKR (Sequence ID 902).

[0214] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, wherein the antibody binds to the same epitope as Ab22 and contains a constant light chain sequence comprising the sequence described below: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 910).

[0215] In another embodiment, the invention comprises one, two, or three of the polypeptide sequences of SEQ ID NO: 884; SEQ ID NO: 886; and SEQ ID NO: 888, which contain a variable heavy chain sequence of SEQ ID NO: 882 or correspond to the CDR (hypervariable region) of the heavy chain sequence of SEQ ID NO: 881, and / or one, two, or three of the polypeptide sequences of SEQ ID NO: 904; SEQ ID NO: 906; and SEQ ID NO: 908, which contain a variable light chain of SEQ ID NO: 902 or correspond to the CDR (hypervariable region) of the light chain sequence of SEQ ID NO: 901, and further comprises an antibody having binding specificity for PACAP and / or an antigen-binding fragment thereof, or an antibody or antigen-binding fragment containing a combination of sequences that are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. In another embodiment of the invention, the antibodies and antigen-binding fragments of the invention comprise or alternatively consist of one or more combinations of the exemplified variable heavy and variable light chain sequences, or the heavy and light chain sequences described above, or sequences that are at least 90% or 95% identical thereto.

[0216] The invention further contemplates a PACAP antibody and / or an antigen-binding fragment thereof comprising one, two, three, or four of the polypeptide sequences of SEQ ID NO: 883; SEQ ID NO: 885; SEQ ID NO: 887; and SEQ ID NO: 889, which correspond to the FR (constant region) of the heavy chain sequence of SEQ ID NO: 881 or the variable heavy chain sequence of SEQ ID NO: 882, and / or one, two, three, or four of the polypeptide sequences of SEQ ID NO: 903; SEQ ID NO: 905; SEQ ID NO: 907; and SEQ ID NO: 909, which correspond to the FR (constant region) of the light chain sequence of SEQ ID NO: 901 or the variable light chain sequence of SEQ ID NO: 902, or a combination of these polypeptide sequences, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto.

[0217] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment or fragment comprises, or instead comprises, one or more combinations of the FR, CDR, variable heavy chain and variable light chain, and the heavy chain and light chain sequences described above, including all of them, or sequences that are at least 90% or 95% identical thereto.

[0218] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 881 or SEQ ID NO: 882, or a polypeptide that is at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 901 or SEQ ID NO: 902, or a polypeptide that is at least 90% or 95% identical thereto.

[0219] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences from SEQ ID NO: 884; SEQ ID NO: 886; and SEQ ID NO: 888, corresponding to the heavy chain sequence of SEQ ID NO: 881, the variable heavy chain sequence of SEQ ID NO: 882, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0220] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 904; SEQ ID NO: 906; and SEQ ID NO: 908, corresponding to the light chain sequence of SEQ ID NO: 901, the variable light chain sequence of SEQ ID NO: 902, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0221] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 883; SEQ ID NO: 885; SEQ ID NO: 887; and SEQ ID NO: 889, corresponding to the heavy chain sequence of SEQ ID NO: 881, the variable heavy chain sequence of SEQ ID NO: 882, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0222] In a further embodiment of the present invention, the antibody and / or antigen-binding fragment of a subject having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from sequence numbers 903; 905; 907; and 909, corresponding to the light chain sequence of sequence number 901, the variable light chain sequence of sequence number 902, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0223] The present invention also intends an anti-PACAP antibody and / or antigen-binding fragment comprising one or more of the antibody fragments described herein. In one embodiment, the antibody and / or antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 882; the variable light chain region of SEQ ID NO: 902; the complementarity-determining regions of the variable heavy chain region of SEQ ID NO: 882 (SEQ ID NO: 884; SEQ ID NO: 886; and SEQ ID NO: 888); and the complementarity-determining regions of the variable light chain region of SEQ ID NO: 902 (SEQ ID NO: 904; SEQ ID NO: 906; and SEQ ID NO: 908), or sequences that are at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 882; the variable light chain region of SEQ ID NO: 902; the framework regions of the variable heavy chain region of SEQ ID NO: 882 (SEQ ID NO: 883; SEQ ID NO: 885; SEQ ID NO: 887; and SEQ ID NO: 889); and the framework regions of the variable light chain region of SEQ ID NO: 902 (SEQ ID NO: 903; SEQ ID NO: 905; SEQ ID NO: 907; and SEQ ID NO: 909), or sequences that are at least 90% or 95% identical thereto.

[0224] In another embodiment of the present invention, the PACAP antibody is an antibody or antigen-binding fragment comprising SEQ ID NOs. 881 and SEQ ID NOs. 901, or SEQ ID NOs. 882 and SEQ ID NOs. 902, or Ab22 consisting thereof, or a CDR of Ab22, and having at least one of the biological activities described herein, or containing a sequence that competes with Ab22 for binding to PACAP, preferably being at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab22, or an antibody that binds to an epitope on PACAP that is identical to or overlaps with that of Ab22.

[0225] In further embodiments of the present invention, the antigen-binding fragment comprises or consists of a Fab fragment having binding specificity to PACAP. With respect to the antibody Ab22, the Fab fragment preferably comprises the variable heavy chain sequence of SEQ ID NO: 882 and the variable light chain sequence of SEQ ID NO: 902, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. This embodiment of the present invention further comprises a Fab containing additions, deletions, and variants of SEQ ID NO: 882 and / or SEQ ID NO: 902 that retain binding specificity to PACAP.

[0226] In one embodiment, the Fab fragment may be produced by enzymatic digestion of Ab22 (e.g., papain). In another embodiment of the present invention, anti-PACAP antibodies such as Ab22 and the Fab fragment may be produced through expression in mammalian cells such as CHO, NSO, or HEK 293 cells, fungi, insects, or microbial systems, such as yeast cells (e.g., haploid or diploid yeast, e.g., haploid or diploid Pichia). Suitable Pichia species include, but are not limited to, Pichia pastoris.

[0227] In additional embodiments, the present invention further aims to encode an antibody polypeptide having binding specificity to PACAP, comprising the heavy and / or light chain of Ab22, as well as one or more combinations of the heavy or light chains described above, including FR, CDR, variable heavy and variable light chain sequences, and all of them, or sequences that are at least 90% or 95% identical thereto.

[0228] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, comprising (a) a variable heavy chain including a CDR1 sequence consisting of SEQ ID NO: 884; a CDR2 sequence consisting of SEQ ID NO: 886; and a CDR3 sequence consisting of SEQ ID NO: 888; and / or (b) a CDR1 sequence consisting of SEQ ID NO: 904; a CDR2 sequence consisting of SEQ ID NO: 906; and a CDR3 sequence consisting of SEQ ID NO: 908. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 882, and / or (b) a variable light chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 902. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 882, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 902. More specifically, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 881, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 901.

[0229] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment are a. A variable heavy chain containing the CDR1 sequence consisting of SEQ ID NO: 884; the CDR2 sequence consisting of SEQ ID NO: 886; and the CDR3 sequence consisting of SEQ ID NO: 888; and / or b. A variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 904; a CDR2 sequence consisting of SEQ ID NO: 906; and a CDR3 sequence consisting of SEQ ID NO: 908, wherein the antibody is optionally selected (a)(i) A variable heavy chain containing an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with respect to SEQ ID NO: 882, and / or (ii) A variable light chain containing an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with respect to SEQ ID NO: 902; (b)(i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 882, or (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 902; (c)(i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 882, and (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 902; (d)(i) a heavy chain having the amino acid sequence of SEQ ID NO: 881, and / or (ii) a light chain having the amino acid sequence of SEQ ID NO: 901; or (e) comprising (i) a heavy chain having the amino acid sequence of SEQ ID NO: 881, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 901.

[0230] Antibody Ab23 In one embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, having a heavy chain sequence comprising the sequence of SEQ ID NO: 921, which consists of the heavy chain variable region of SEQ ID NO: 922 linked to the heavy chain constant region of SEQ ID NO: 930.

[0231] In one embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable heavy chain sequence comprising the sequence described below: QSVEESGGRLVTPGTPLTLTCTVSGFSLNNYAMSWVRQAPGKGLEWIGIMGVNDITYYASWAKGRFTISKTSTTVDLKMTSLTTEDTATYFCTREIRDDGDSSDKLWGPGTLVTVSS (Sequence ID 922).

[0232] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, which binds to the same epitope as Ab23 and contains the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or a constant heavy chain sequence containing the sequence described below. [ka]

[0233] In another embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, comprising a light chain sequence including the sequence of SEQ ID NO: 941, which consists of the light chain variable region of SEQ ID NO: 942 linked to the light chain constant region of SEQ ID NO: 950.

[0234] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable light chain sequence comprising the sequence described below: AIKMTQTPSSVSAAVGGTVTINCQASEDIYTNLAWYQQKPGQPPNLLIYDASDLASGVPSRFSGSGDGTQFTLTISAVQCEDAATYYCQGVAWSSNTGYGSAFGGGTEVVVKR (Sequence ID 942).

[0235] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, wherein the antibody binds to the same epitope as Ab23 and contains a constant light chain sequence comprising the sequence described below: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 950).

[0236] In another embodiment, the present invention includes an antibody and / or antigen-binding fragment having binding specificity to PACAP, comprising one, two, or three polypeptide sequences from SEQ ID NO: 924; SEQ ID NO: 926; and SEQ ID NO: 928, which correspond to the CDR (hypervariable region) of the heavy chain sequence of SEQ ID NO: 921 or contain the variable heavy chain sequence of SEQ ID NO: 922, and / or further comprising one, two, or three polypeptide sequences from SEQ ID NO: 944; SEQ ID NO: 946; and SEQ ID NO: 948, which correspond to the CDR (hypervariable region) of the light chain sequence of SEQ ID NO: 941 or contain the variable light chain of SEQ ID NO: 942, or an antibody or antigen-binding fragment comprising a combination of sequences which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. In another embodiment of the present invention, the antibody and antigen-binding fragments of the present invention comprise, or consist of, one or more combinations of the exemplified variable heavy chain and variable light chain sequences, or the above heavy chain and light chain sequences, or sequences that are at least 90% or 95% identical thereto.

[0237] The present invention further envisions a PACAP antibody and / or its antigen-binding fragment comprising one, two, three, or four polypeptide sequences from sequence numbers 923; 925; 927; and 929, corresponding to the FR (constant region) of the heavy chain sequence of sequence number 921 or the variable heavy chain sequence of sequence number 922, and / or one, two, three, or four polypeptide sequences from sequence numbers 943; 945; 947; and 949, corresponding to the FR (constant region) of the light chain sequence of sequence number 941 or the variable light chain sequence of sequence number 942, or a combination thereof, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to them.

[0238] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment or fragment comprises, or instead comprises, one or more combinations of the FR, CDR, variable heavy chain and variable light chain, and the heavy chain and light chain sequences described above, including all of them, or sequences that are at least 90% or 95% identical thereto.

[0239] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 921 or SEQ ID NO: 922, or a polypeptide that is at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 941 or SEQ ID NO: 942, or a polypeptide that is at least 90% or 95% identical thereto.

[0240] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 924; SEQ ID NO: 926; and SEQ ID NO: 928, corresponding to the heavy chain sequence of SEQ ID NO: 921, the variable heavy chain sequence of SEQ ID NO: 922, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0241] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 944; SEQ ID NO: 946; and SEQ ID NO: 948, corresponding to the light chain sequence of SEQ ID NO: 941, the variable light chain sequence of SEQ ID NO: 942, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0242] In a further embodiment of the present invention, the antibody and / or antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 923; SEQ ID NO: 925; SEQ ID NO: 927; and SEQ ID NO: 929, corresponding to the heavy chain sequence of SEQ ID NO: 921, the variable heavy chain sequence of SEQ ID NO: 922, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0243] In a further embodiment of the present invention, the antibody and / or antigen-binding fragment of a subject having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 943; SEQ ID NO: 945; SEQ ID NO: 947; and SEQ ID NO: 949, corresponding to the light chain sequence of SEQ ID NO: 941, the variable light chain sequence of SEQ ID NO: 942, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0244] The present invention also intends an anti-PACAP antibody and / or antigen-binding fragment comprising one or more of the antibody fragments described herein. In one embodiment, the antibody and / or antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 922; the variable light chain region of SEQ ID NO: 942; the complementarity-determining regions of the variable heavy chain region of SEQ ID NO: 924; SEQ ID NO: 926; and SEQ ID NO: 928; and the complementarity-determining regions of the variable light chain region of SEQ ID NO: 944; SEQ ID NO: 946; and SEQ ID NO: 948, or all of sequences that are at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 922; the variable light chain region of SEQ ID NO: 942; the framework regions of the variable heavy chain region of SEQ ID NO: 923; SEQ ID NO: 925; SEQ ID NO: 927; and SEQ ID NO: 929; and the framework regions of the variable light chain region of SEQ ID NO: 943; SEQ ID NO: 945; SEQ ID NO: 947; and SEQ ID NO: 949, or sequences that are at least 90% or 95% identical thereto.

[0245] In another embodiment of the present invention, the PACAP antibody is an antibody or antigen-binding fragment comprising SEQ ID NOs. 921 and 941, or SEQ ID NOs. 922 and 942, or Ab23 consisting thereof, or a CDR of Ab23, and having at least one of the biological activities described herein, or comprising a sequence that competes with Ab23 for binding to PACAP, preferably being at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab23, or is an antibody that binds to an epitope on PACAP that is identical to or overlaps with that of Ab23.

[0246] In a further embodiment of the present invention, the antigen-binding fragment comprises or consists of a Fab fragment having binding specificity to PACAP. With respect to antibody Ab23, the Fab fragment preferably comprises the variable heavy chain sequence of SEQ ID NO: 922 and the variable light chain sequence of SEQ ID NO: 942, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. This embodiment of the present invention further comprises a Fab containing additions, deletions, and variants of SEQ ID NO: 922 and / or SEQ ID NO: 942 that retain binding specificity to PACAP.

[0247] In one embodiment, the Fab fragment may be produced by enzymatic digestion of Ab23 (e.g., papain). In another embodiment of the present invention, anti-PACAP antibodies such as Ab23 and the Fab fragment may be produced through expression in mammalian cells such as CHO, NSO, or HEK 293 cells, fungi, insects, or microbial systems, such as yeast cells (e.g., haploid or diploid yeast, e.g., haploid or diploid Pichia). Suitable Pichia species include, but are not limited to, Pichia pastoris.

[0248] In additional embodiments, the present invention further aims to encode an antibody polypeptide having binding specificity to PACAP, comprising the heavy and / or light chain of Ab23, as well as one or more combinations of the heavy or light chains described above, including FR, CDR, variable heavy and variable light chain sequences, and all of them, or sequences that are at least 90% or 95% identical thereto.

[0249] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, comprising (a) a variable heavy chain including a CDR1 sequence consisting of SEQ ID NO: 924; a CDR2 sequence consisting of SEQ ID NO: 926; and a CDR3 sequence consisting of SEQ ID NO: 928; and / or (b) a CDR1 sequence consisting of SEQ ID NO: 944; a CDR2 sequence consisting of SEQ ID NO: 946; and a CDR3 sequence consisting of SEQ ID NO: 948. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 922, and / or (b) a variable light chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 942. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 922, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 942. More specifically, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 921, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 941.

[0250] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment are a. A variable heavy chain containing the CDR1 sequence consisting of SEQ ID NO: 924; the CDR2 sequence consisting of SEQ ID NO: 926; and the CDR3 sequence consisting of SEQ ID NO: 928; and / or b. A variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 944; a CDR2 sequence consisting of SEQ ID NO: 946; and a CDR3 sequence consisting of SEQ ID NO: 948, wherein the antibody is optionally selected as follows: (a)(i) A variable heavy chain containing an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with respect to SEQ ID NO: 922, and / or (ii) A variable light chain containing an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with respect to SEQ ID NO: 942; (b)(i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 922, or (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 942; (c)(i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 922, and (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 942; (d)(i) a heavy chain having the amino acid sequence of SEQ ID NO: 921, and / or (ii) a light chain having the amino acid sequence of SEQ ID NO: 941; or (e) comprising (i) a heavy chain having the amino acid sequence of SEQ ID NO: 921, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 941.

[0251] Antibody Ab10.H2 In one embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, having a heavy chain sequence comprising the sequence of SEQ ID NO: 1281, which consists of the heavy chain variable region of SEQ ID NO: 1282 linked to the heavy chain constant region of SEQ ID NO: 1290.

[0252] In one embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable heavy chain sequence comprising the sequence described below: EVQLVESGGGLVQPGGSLRLSCAASGIDLNSYYMTWVRQAPGKGLEWIGFIDAGGDAYYASWAKGRFTISRDNSKNTVYLQMNSLRAEDTAVYFCARDLDLWGQGTLVTVSS (Sequence ID 1282).

[0253] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, which binds to the same epitope as Ab10.H2 and contains the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or a constant heavy chain sequence containing the sequence described below. [ka]

[0254] In another embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, comprising a light chain sequence including the sequence of SEQ ID NO: 1301, which consists of the light chain variable region of SEQ ID NO: 1302 linked to the light chain constant region of SEQ ID NO: 1310.

[0255] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable light chain sequence comprising the sequence described below: AVLTQSPSTLSASVGDRVTITCQSSESVYGNYLAWFQQKPGKAPKFLIYEASKLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGDISEGVAFGGGTKVEIKR (Sequence ID 1302).

[0256] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, wherein the antibody binds to the same epitope as Ab10.H2 and contains a constant light chain sequence comprising the sequence described below: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 1310).

[0257] In another embodiment, the present invention includes an antibody and / or antigen-binding fragment having binding specificity to PACAP, comprising one, two, or three polypeptide sequences from SEQ ID NO: 1284; SEQ ID NO: 1286; and SEQ ID NO: 1288, which correspond to the CDR (hypervariable region) of the heavy chain sequence of SEQ ID NO: 1281 or contain the variable heavy chain sequence of SEQ ID NO: 1282, and / or further comprising one, two, or three polypeptide sequences from SEQ ID NO: 1304; SEQ ID NO: 1306; and SEQ ID NO: 1308, which correspond to the CDR (hypervariable region) of the light chain sequence of SEQ ID NO: 1301 or contain the variable light chain of SEQ ID NO: 1302, or an antibody or antigen-binding fragment comprising a combination of sequences which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. In another embodiment of the present invention, the antibody and antigen-binding fragments of the present invention comprise, or consist of, one or more combinations of the exemplified variable heavy chain and variable light chain sequences, or the above heavy chain and light chain sequences, or sequences that are at least 90% or 95% identical thereto.

[0258] The present invention further envisions a PACAP antibody and / or its antigen-binding fragment comprising one, two, three, or four polypeptide sequences from sequence numbers 1283; 1285; 1287; and 1289, corresponding to the FR (constant region) of the heavy chain sequence of sequence number 1281 or the variable heavy chain sequence of sequence number 1282, and / or one, two, three, or four polypeptide sequences from sequence numbers 1303; 1305; 1307; and 1309, corresponding to the FR (constant region) of the light chain sequence of sequence number 1301 or the variable light chain sequence of sequence number 1302, or a combination thereof, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to them.

[0259] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment or fragment comprises, or instead comprises, one or more combinations of the FR, CDR, variable heavy chain and variable light chain, and the heavy chain and light chain sequences described above, including all of them, or sequences that are at least 90% or 95% identical thereto.

[0260] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 1281 or SEQ ID NO: 1282, or a polypeptide that is at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 1301 or SEQ ID NO: 1302, or a polypeptide that is at least 90% or 95% identical thereto.

[0261] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences from SEQ ID NO: 1284; SEQ ID NO: 1286; and SEQ ID NO: 1288, corresponding to the heavy chain sequence of SEQ ID NO: 1281, the variable heavy chain sequence of SEQ ID NO: 1282, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0262] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 1304; SEQ ID NO: 1306; and SEQ ID NO: 1308, corresponding to the light chain sequence of SEQ ID NO: 1301, the variable light chain sequence of SEQ ID NO: 1302, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0263] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 1283; SEQ ID NO: 1285; SEQ ID NO: 1287; and SEQ ID NO: 1289, corresponding to the heavy chain sequence of SEQ ID NO: 1281, the variable heavy chain sequence of SEQ ID NO: 1282, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0264] In a further embodiment of the present invention, the antibody and / or antigen-binding fragment of a subject having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 1303; SEQ ID NO: 1305; SEQ ID NO: 1307; and SEQ ID NO: 1309, corresponding to the light chain sequence of SEQ ID NO: 1301, or the variable light chain sequence of SEQ ID NO: 1302, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0265] The present invention also intends an anti-PACAP antibody and / or antigen-binding fragment comprising one or more of the antibody fragments described herein. In one embodiment, the antibody and / or antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 1282; the variable light chain region of SEQ ID NO: 1302; the complementarity-determining regions of the variable heavy chain region of SEQ ID NO: 1284; SEQ ID NO: 1286; and SEQ ID NO: 1288; and the complementarity-determining regions of the variable light chain region of SEQ ID NO: 1304; SEQ ID NO: 1306; and SEQ ID NO: 1308, or all of sequences that are at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 1282; the variable light chain region of SEQ ID NO: 1302; the framework regions of the variable heavy chain region of SEQ ID NO: 1283; SEQ ID NO: 1285; SEQ ID NO: 1287; and SEQ ID NO: 1289; and the framework regions of the variable light chain region of SEQ ID NO: 1303; SEQ ID NO: 1305; SEQ ID NO: 1307; and SEQ ID NO: 1309, or sequences that are at least 90% or 95% identical thereto.

[0266] In another embodiment of the present invention, the PACAP antibody is an antibody or antigen-binding fragment comprising or consisting of SEQ ID NOs. 1281 and SEQ ID NOs. 1301, or SEQ ID NOs. 1282 and SEQ ID NOs. 1302, or Ab10.H2 or a CDR of Ab10.H2, and having at least one of the biological activities described herein, or containing a sequence that competes with Ab10.H2 for binding to PACAP, preferably being at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab10.H2, or an antibody that binds to an epitope on PACAP that is identical to or overlaps with that of Ab10.H2.

[0267] In further embodiments of the present invention, the antigen-binding fragment comprises or consists of a Fab fragment having binding specificity to PACAP. With respect to the antibody Ab10.H2, the Fab fragment preferably comprises the variable heavy chain sequence of SEQ ID NO: 1282 and the variable light chain sequence of SEQ ID NO: 1302, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. This embodiment of the present invention further comprises a Fab containing additions, deletions, and variants of SEQ ID NO: 1282 and / or SEQ ID NO: 1302 that retain binding specificity to PACAP.

[0268] In one embodiment, the Fab fragment may be produced by enzymatic digestion of Ab10.H2 (e.g., papain). In another embodiment of the present invention, anti-PACAP antibodies such as Ab10.H2 and the Fab fragment may be produced through expression in mammalian cells such as CHO, NSO, or HEK 293 cells, fungi, insects, or microbial systems, such as yeast cells (e.g., haploid or diploid yeast, e.g., haploid or diploid Pichia). Suitable Pichia species include, but are not limited to, Pichia pastoris.

[0269] In additional embodiments, the present invention further aims to encode an antibody polypeptide having binding specificity to PACAP, comprising the heavy and / or light chain of Ab10.H2, as well as one or more combinations of the heavy or light chains described above, including FR, CDR, variable heavy and variable light chain sequences, and all of them, or sequences that are at least 90% or 95% identical thereto.

[0270] In specific embodiments, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, comprising (a) a variable heavy chain including a CDR1 sequence consisting of SEQ ID NO: 1284; a CDR2 sequence consisting of SEQ ID NO: 1286; and a CDR3 sequence consisting of SEQ ID NO: 1288; and / or (b) a CDR1 sequence consisting of SEQ ID NO: 1304; a CDR2 sequence consisting of SEQ ID NO: 1306; and a CDR3 sequence consisting of SEQ ID NO: 1308. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with respect to SEQ ID NO: 1282, and / or (b) a variable light chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with respect to SEQ ID NO: 1302. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1282, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 1302. More specifically, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1281, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 1301.

[0271] In another specific embodiment, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, and comprises (a) a variable heavy chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1282, and comprising a CDR1 sequence consisting of SEQ ID NO: 1284; a CDR2 sequence consisting of SEQ ID NO: 1286; and a CDR3 sequence consisting of SEQ ID NO: 1288; and / or (b) a variable light chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1302, and comprising a CDR1 sequence consisting of SEQ ID NO: 1304; a CDR2 sequence consisting of SEQ ID NO: 1306; and a CDR3 sequence consisting of SEQ ID NO: 1308. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1282, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 1302. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1281, and including a CDR1 sequence consisting of SEQ ID NO: 1284; a CDR2 sequence consisting of SEQ ID NO: 1286; and a CDR3 sequence consisting of SEQ ID NO: 1288; and / or (b) a light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1301, and including a CDR1 sequence consisting of SEQ ID NO: 1304; a CDR2 sequence consisting of SEQ ID NO: 1306; and a CDR3 sequence consisting of SEQ ID NO: 1308. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1281, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 1301.Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1281, and (b) a light chain having the amino acid sequence of SEQ ID NO: 1301.

[0272] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment are a. (i) A variable heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1282, and including a CDR1 sequence consisting of SEQ ID NO: 1284; a CDR2 sequence consisting of SEQ ID NO: 1286; and a CDR3 sequence consisting of SEQ ID NO: 1288; and / or (ii) A variable light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1302, and including a CDR1 sequence consisting of SEQ ID NO: 1304; a CDR2 sequence consisting of SEQ ID NO: 1306; and a CDR3 sequence consisting of SEQ ID NO: 1308; b. (i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 1282, and / or (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 1302; c. (i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 1282, and (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 1302; d. (i) A heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1281, and including a CDR1 sequence consisting of SEQ ID NO: 1284; a CDR2 sequence consisting of SEQ ID NO: 1286; and a CDR3 sequence consisting of SEQ ID NO: 1288; and / or (ii) A light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1301, and including a CDR1 sequence consisting of SEQ ID NO: 1304; a CDR2 sequence consisting of SEQ ID NO: 1306; and a CDR3 sequence consisting of SEQ ID NO: 1308; e. (i) a heavy chain having the amino acid sequence of SEQ ID NO: 1281, and / or (ii) a light chain having the amino acid sequence of SEQ ID NO: 1301; and / or f. (i) A heavy chain having the amino acid sequence of SEQ ID NO: 1281, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 1301.

[0273] Antibody Ab10.H3 In one embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, having a heavy chain sequence comprising the sequence of SEQ ID NO: 1321, which consists of the heavy chain variable region of SEQ ID NO: 1322 linked to the heavy chain constant region of SEQ ID NO: 1330.

[0274] In one embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable heavy chain sequence comprising the sequence described below: EVQLVESGGGLVQPGGSLRLSCAASGIDLNSYYMTWVRQAPGKGLEWIGFIDAGGDAYYASWAKGRFTISRDNSKNTVYLQMNSLRAEDTAVYFCARDLDLWGQGTLVTVSS (Sequence ID 1322).

[0275] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, which binds to the same epitope as Ab10.H3 and contains the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or a constant heavy chain sequence containing the sequence described below. [ka]

[0276] In some expression systems, the heavy chain may be cleaved at the C-terminus, resulting in the cleavage of the C-terminal lysine (Lys, K). An example of such an expression system is the widely used CHO cell line. In such systems, the resulting heavy chain constant region sequence will include the following sequence: [ka]

[0277] Therefore, in one embodiment, the anti-PACAP antibody contains a heavy chain comprising the following sequence. [ka]

[0278] In another embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, comprising a light chain sequence including the sequence of SEQ ID NO: 1341, which consists of the light chain variable region of SEQ ID NO: 1342 linked to the light chain constant region of SEQ ID NO: 1350.

[0279] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable light chain sequence comprising the sequence described below: DIQLTQSPSTLSASVGDRVTITCQSSESVYGNYLAWFQQKPGKAPKFLIYEASKLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGDISEGVAFGGGTKVEIKR (Sequence ID 1342).

[0280] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, wherein the antibody binds to the same epitope as Ab10.H3 and contains a constant light chain sequence comprising the sequence described below: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 1350).

[0281] In another embodiment, the present invention includes an antibody and / or antigen-binding fragment having binding specificity to PACAP, comprising one, two, or three polypeptide sequences from SEQ ID NO: 1324; SEQ ID NO: 1326; and SEQ ID NO: 1328, which correspond to the CDR (hypervariable region) of the heavy chain sequence of SEQ ID NO: 1321 or 1604, or which contain the variable heavy chain sequence of SEQ ID NO: 1322, and / or further comprising one, two, or three polypeptide sequences from SEQ ID NO: 1344; SEQ ID NO: 1346; and SEQ ID NO: 1348, which correspond to the CDR (hypervariable region) of the light chain sequence of SEQ ID NO: 1341, or which contain the variable light chain of SEQ ID NO: 1342, or an antibody or antigen-binding fragment comprising a combination of sequences which are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. In another embodiment of the present invention, the antibody and antigen-binding fragments of the present invention comprise, or consist of, one or more combinations of the exemplified variable heavy chain and variable light chain sequences, or the above heavy chain and light chain sequences, or sequences that are at least 90% or 95% identical thereto.

[0282] The present invention further envisions a PACAP antibody and / or its antigen-binding fragment comprising one, two, three, or four polypeptide sequences from sequence numbers 1323; 1325; 1327; and 1329, corresponding to the heavy chain sequence of sequence number 1321 or 1604, or the constant region (FR) of the variable heavy chain sequence of sequence number 1322, and / or one, two, three, or four polypeptide sequences from sequence numbers 1343; 1345; 1347; and 1349, corresponding to the light chain sequence of sequence number 1341, or the constant region (FR) of the variable light chain sequence of sequence number 1342, or a combination thereof, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to them.

[0283] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment or fragment comprises, or instead comprises, one or more combinations of the FR, CDR, variable heavy chain and variable light chain, and the heavy chain and light chain sequences described above, including all of them, or sequences that are at least 90% or 95% identical thereto.

[0284] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 1321, 1604, or SEQ ID NO: 1322, or a polypeptide that is at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 1341 or SEQ ID NO: 1342, or a polypeptide that is at least 90% or 95% identical thereto.

[0285] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 1324; SEQ ID NO: 1326; and SEQ ID NO: 1328, corresponding to the heavy chain sequence of SEQ ID NO: 1321 or 1604, or the variable heavy chain sequence of SEQ ID NO: 1322, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0286] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 1344; SEQ ID NO: 1346; and SEQ ID NO: 1348, corresponding to the light chain sequence of SEQ ID NO: 1341, the variable light chain sequence of SEQ ID NO: 1342, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0287] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 1323; SEQ ID NO: 1325; SEQ ID NO: 1327; and SEQ ID NO: 1329, corresponding to the heavy chain sequence of SEQ ID NO: 1321 or 1604, or the variable heavy chain sequence of SEQ ID NO: 1322, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0288] In a further embodiment of the present invention, an antibody and / or antigen-binding fragment of a subject having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 1343; SEQ ID NO: 1345; SEQ ID NO: 1347; and SEQ ID NO: 1349, corresponding to the light chain sequence of SEQ ID NO: 1341, or the variable light chain sequence of SEQ ID NO: 1342, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0289] The present invention also intends an anti-PACAP antibody and / or antigen-binding fragment comprising one or more of the antibody fragments described herein. In one embodiment, the antibody and / or antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 1322; the variable light chain region of SEQ ID NO: 1342; the complementarity-determining regions of the variable heavy chain region of SEQ ID NO: 1324; SEQ ID NO: 1326; and SEQ ID NO: 1328; and the complementarity-determining regions of the variable light chain region of SEQ ID NO: 1344; SEQ ID NO: 1346; and SEQ ID NO: 1348, or all of sequences that are at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more antibody fragments containing all of the following: the variable heavy chain region of SEQ ID NO: 1322; the variable light chain region of SEQ ID NO: 1342; the framework region of the variable heavy chain region of SEQ ID NO: 1322 (SEQ ID NO: 1323; SEQ ID NO: 1325; SEQ ID NO: 1327; and SEQ ID NO: 1329); and the framework region of the variable light chain region of SEQ ID NO: 1343; SEQ ID NO: 1345; SEQ ID NO: 1347; and SEQ ID NO: 1349, or sequences that are at least 90% or 95% identical thereto.

[0290] In another embodiment of the present invention, the PACAP antibody is an antibody or antigen-binding fragment comprising or containing Ab10.H3 consisting of SEQ ID NO: 1321 or 1604 and SEQ ID NO: 1341, or SEQ ID NO: 1322 and SEQ ID NO: 1342, or instead comprising Ab10.H3 or a CDR of Ab10.H3, and having at least one of the biological activities described herein, or containing a sequence that competes with Ab10.H3 for binding to PACAP, preferably being at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab10.H3, or an antibody that binds to an epitope on PACAP that is identical to or overlaps with that of Ab10.H3.

[0291] In further embodiments of the present invention, the antigen-binding fragment comprises or consists of a Fab fragment having binding specificity to PACAP. With respect to the antibody Ab10.H3, the Fab fragment preferably comprises the variable heavy chain sequence of SEQ ID NO: 1322 and the variable light chain sequence of SEQ ID NO: 1342, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. This embodiment of the present invention further comprises a Fab containing additions, deletions, and variants of SEQ ID NO: 1322 and / or SEQ ID NO: 1342 that retain binding specificity to PACAP.

[0292] In one embodiment, the Fab fragment may be produced by enzymatic digestion of Ab10.H3 (e.g., papain). In another embodiment of the present invention, anti-PACAP antibodies such as Ab10.H3 and the Fab fragment may be produced through expression in mammalian cells such as CHO, NSO, or HEK 293 cells, fungi, insects, or microbial systems, such as yeast cells (e.g., haploid or diploid yeast, e.g., haploid or diploid Pichia). Suitable Pichia species include, but are not limited to, Pichia pastoris.

[0293] In additional embodiments, the present invention further aims to encode an antibody polypeptide having binding specificity to PACAP, comprising the heavy and / or light chain of Ab10.H3, as well as one or more combinations of the heavy or light chains described above, including FR, CDR, variable heavy and variable light chain sequences, and all of them, or sequences that are at least 90% or 95% identical thereto.

[0294] In specific embodiments, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, comprising (a) a variable heavy chain including a CDR1 sequence consisting of SEQ ID NO: 1324; a CDR2 sequence consisting of SEQ ID NO: 1326; and a CDR3 sequence consisting of SEQ ID NO: 1328; and / or (b) a CDR1 sequence consisting of SEQ ID NO: 1344; a CDR2 sequence consisting of SEQ ID NO: 1346; and a CDR3 sequence consisting of SEQ ID NO: 1348. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1322, and / or (b) a variable light chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1342. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1322, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 1342. More specifically, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1321 or 1604, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 1341.

[0295] In another specific embodiment, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, and comprises (a) a variable heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1322, and including a CDR1 sequence consisting of SEQ ID NO: 1324; a CDR2 sequence consisting of SEQ ID NO: 1326; and a CDR3 sequence consisting of SEQ ID NO: 1328; and / or (b) a variable light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1342, and including a CDR1 sequence consisting of SEQ ID NO: 1344; a CDR2 sequence consisting of SEQ ID NO: 1346; and a CDR3 sequence consisting of SEQ ID NO: 1348. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1322, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 1342. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may include (a) a heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1321 or 1604, and comprising a CDR1 sequence consisting of SEQ ID NO: 1324; a CDR2 sequence consisting of SEQ ID NO: 1326; and a CDR3 sequence consisting of SEQ ID NO: 1328; and / or (b) a light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1341, and comprising a CDR1 sequence consisting of SEQ ID NO: 1344; a CDR2 sequence consisting of SEQ ID NO: 1346; and a CDR3 sequence consisting of SEQ ID NO: 1348. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1321 or 1604, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 1341.Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1321 or 1604, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 1341.

[0296] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment are a. (i) A variable heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1322, and including a CDR1 sequence consisting of SEQ ID NO: 1324; a CDR2 sequence consisting of SEQ ID NO: 1326; and a CDR3 sequence consisting of SEQ ID NO: 1328; and / or (ii) A variable light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1342, and including a CDR1 sequence consisting of SEQ ID NO: 1344; a CDR2 sequence consisting of SEQ ID NO: 1346; and a CDR3 sequence consisting of SEQ ID NO: 1348; b. (i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 1322, and / or (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 1342; c. (i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 1322, and (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 1342; d. (i) A heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1321 or 1604, and including a CDR1 sequence consisting of SEQ ID NO: 1324; a CDR2 sequence consisting of SEQ ID NO: 1326; and a CDR3 sequence consisting of SEQ ID NO: 1328; and / or (ii) A light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1341, and including a CDR1 sequence consisting of SEQ ID NO: 1344; a CDR2 sequence consisting of SEQ ID NO: 1346; and a CDR3 sequence consisting of SEQ ID NO: 1348; e. (i) a heavy chain having the amino acid sequence of SEQ ID NO: 1321 or 1604, and / or (ii) a light chain having the amino acid sequence of SEQ ID NO: 1341; and / or f. (i) A heavy chain having the amino acid sequence of SEQ ID NO: 1321 or 1604, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 1341.

[0297] Antibody Ab10.H4 In one embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, having a heavy chain sequence comprising the sequence of SEQ ID NO: 1361, which consists of the heavy chain variable region of SEQ ID NO: 1362 linked to the heavy chain constant region of SEQ ID NO: 1370.

[0298] In one embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable heavy chain sequence comprising the sequence described below: EVQLVESGGGLVQPGGSLRLSCAASGIDLNSYYMTWVRQAPGKGLEWIGFIDAGGDAYYASWAKGRFTISRDNSKNTVYLQMNSLRAEDTAVYFCARDLDLWGQGTLVTVSS (Sequence ID 1362).

[0299] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, which binds to the same epitope as Ab10.H4 and contains a polypeptide of SEQ ID NO: 1244, 1245, or 1246, or a constant heavy chain sequence containing the sequence described below. [ka]

[0300] In another embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, comprising a light chain sequence including the sequence of SEQ ID NO: 1381, which consists of the light chain variable region of SEQ ID NO: 1382 linked to the light chain constant region of SEQ ID NO: 1390.

[0301] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable light chain sequence comprising the sequence described below: DIVLTQSPSTLSASVGDRVTITCQSSESVYGNYLAWFQQKPGKAPKFLIYEASKLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGDISEGVAFGGGTKVEIKR (Sequence ID 1382).

[0302] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, wherein the antibody binds to the same epitope as Ab10.H4 and contains a constant light chain sequence comprising the sequence described below: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 1390).

[0303] In another embodiment, the present invention includes an antibody and / or antigen-binding fragment having binding specificity to PACAP, comprising one, two, or three polypeptide sequences from SEQ ID NO: 1364; SEQ ID NO: 1366; and SEQ ID NO: 1368, which correspond to the CDR (hypervariable region) of the heavy chain sequence of SEQ ID NO: 1361 or contain the variable heavy chain sequence of SEQ ID NO: 1362, and / or further comprising one, two, or three polypeptide sequences from SEQ ID NO: 1384; SEQ ID NO: 1386; and SEQ ID NO: 1388, which correspond to the CDR (hypervariable region) of the light chain sequence of SEQ ID NO: 1381 or contain the variable light chain of SEQ ID NO: 1382, or an antibody or antigen-binding fragment comprising a combination of sequences which are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. In another embodiment of the present invention, the antibody and antigen-binding fragments of the present invention comprise, or consist of, one or more combinations of the exemplified variable heavy chain and variable light chain sequences, or the above heavy chain and light chain sequences, or sequences that are at least 90% or 95% identical thereto.

[0304] The present invention further envisions a PACAP antibody and / or its antigen-binding fragment comprising one, two, three, or four polypeptide sequences from sequence numbers 1363; 1365; 1367; and 1369, corresponding to the FR (constant region) of the heavy chain sequence of sequence number 1361 or the variable heavy chain sequence of sequence number 1362, and / or one, two, three, or four polypeptide sequences from sequence numbers 1383; 1385; 1387; and 1389, corresponding to the FR (constant region) of the light chain sequence of sequence number 1381 or the variable light chain sequence of sequence number 1382, or a combination thereof, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to them.

[0305] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment or fragment comprises, or instead comprises, one or more combinations of the FR, CDR, variable heavy chain and variable light chain, and the heavy chain and light chain sequences described above, including all of them, or sequences that are at least 90% or 95% identical thereto.

[0306] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 1361 or SEQ ID NO: 1362, or a polypeptide that is at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 1381 or SEQ ID NO: 1382, or a polypeptide that is at least 90% or 95% identical thereto.

[0307] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 1364; SEQ ID NO: 1366; and SEQ ID NO: 1368, corresponding to the heavy chain sequence of SEQ ID NO: 1361, the variable heavy chain sequence of SEQ ID NO: 1362, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0308] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 1384; SEQ ID NO: 1386; and SEQ ID NO: 1388, corresponding to the light chain sequence of SEQ ID NO: 1381, the variable light chain sequence of SEQ ID NO: 1382, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0309] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead consists of, one, two, three, or four polypeptide sequences from SEQ ID NO: 1363; SEQ ID NO: 1365; SEQ ID NO: 1367; and SEQ ID NO: 1369, corresponding to the heavy chain sequence of SEQ ID NO: 1361, the variable heavy chain sequence of SEQ ID NO: 1362, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0310] In a further embodiment of the present invention, an antibody and / or antigen-binding fragment of a subject having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 1383; SEQ ID NO: 1385; SEQ ID NO: 1387; and SEQ ID NO: 1389, corresponding to the light chain sequence of SEQ ID NO: 1381, the variable light chain sequence of SEQ ID NO: 1382, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0311] The present invention also intends an anti-PACAP antibody and / or antigen-binding fragment comprising one or more of the antibody fragments described herein. In one embodiment, the antibody and / or antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 1362; the variable light chain region of SEQ ID NO: 1382; the complementarity-determining regions of the variable heavy chain region of SEQ ID NO: 1364; SEQ ID NO: 1366; and SEQ ID NO: 1368; and the complementarity-determining regions of the variable light chain region of SEQ ID NO: 1384; SEQ ID NO: 1386; and SEQ ID NO: 1388, or all of sequences that are at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more antibody fragments containing all of the following: the variable heavy chain region of SEQ ID NO: 1362; the variable light chain region of SEQ ID NO: 1382; the framework region of the variable heavy chain region of SEQ ID NO: 1362 (SEQ ID NO: 1363; SEQ ID NO: 1365; SEQ ID NO: 1367; and SEQ ID NO: 1369); and the framework region of the variable light chain region of SEQ ID NO: 1382 (SEQ ID NO: 1383; SEQ ID NO: 1385; SEQ ID NO: 1387; and SEQ ID NO: 1389), or sequences that are at least 90% or 95% identical thereto.

[0312] In another embodiment of the present invention, the PACAP antibody is an antibody or antigen-binding fragment comprising or consisting of SEQ ID NOs. 1361 and SEQ ID NOs. 1381, or SEQ ID NOs. 1362 and SEQ ID NOs. 1382, or instead comprising Ab10.H4, or a CDR of Ab10.H4, and having at least one of the biological activities described herein, or containing a sequence that competes with Ab10.H4 for binding to PACAP, preferably being at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab10.H4, or an antibody that binds to an epitope on PACAP that is identical to or overlaps with that of Ab10.H4.

[0313] In further embodiments of the present invention, the antigen-binding fragment comprises or consists of a Fab fragment having binding specificity to PACAP. With respect to the antibody Ab10.H4, the Fab fragment preferably comprises the variable heavy chain sequence of SEQ ID NO: 1362 and the variable light chain sequence of SEQ ID NO: 1382, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. This embodiment of the present invention further comprises a Fab containing additions, deletions, and variants of SEQ ID NO: 1362 and / or SEQ ID NO: 1382 that retain binding specificity to PACAP.

[0314] In one embodiment, the Fab fragment may be produced by enzymatic digestion of Ab10.H4 (e.g., papain). In another embodiment of the present invention, anti-PACAP antibodies such as Ab10.H4 and the Fab fragment may be produced through expression in mammalian cells such as CHO, NSO, or HEK 293 cells, fungi, insects, or microbial systems, such as yeast cells (e.g., haploid or diploid yeast, e.g., haploid or diploid Pichia). Suitable Pichia species include, but are not limited to, Pichia pastoris.

[0315] In additional embodiments, the present invention further aims to encode an antibody polypeptide having binding specificity to PACAP, comprising the heavy and / or light chain of Ab10.H4, as well as one or more combinations of the heavy or light chains described above, including FR, CDR, variable heavy and variable light chain sequences, and all of them, or sequences that are at least 90% or 95% identical thereto.

[0316] In specific embodiments, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, comprising (a) a variable heavy chain including a CDR1 sequence consisting of SEQ ID NO: 1364; a CDR2 sequence consisting of SEQ ID NO: 1366; and a CDR3 sequence consisting of SEQ ID NO: 1368; and / or (b) a CDR1 sequence consisting of SEQ ID NO: 1384; a CDR2 sequence consisting of SEQ ID NO: 1386; and a CDR3 sequence consisting of SEQ ID NO: 1388. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1362, and / or (b) a variable light chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1382. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1362, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 1382. More specifically, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1361, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 1381.

[0317] In another specific embodiment, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, and comprises (a) a variable heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1362, and including a CDR1 sequence consisting of SEQ ID NO: 1364; a CDR2 sequence consisting of SEQ ID NO: 1366; and a CDR3 sequence consisting of SEQ ID NO: 1368; and / or (b) a variable light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1382, and including a CDR1 sequence consisting of SEQ ID NO: 1384; a CDR2 sequence consisting of SEQ ID NO: 1386; and a CDR3 sequence consisting of SEQ ID NO: 1388. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1362, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 1382. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1361, and including a CDR1 sequence consisting of SEQ ID NO: 1364; a CDR2 sequence consisting of SEQ ID NO: 1366; and a CDR3 sequence consisting of SEQ ID NO: 1368; and / or (b) a light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1381, and including a CDR1 sequence consisting of SEQ ID NO: 1384; a CDR2 sequence consisting of SEQ ID NO: 1386; and a CDR3 sequence consisting of SEQ ID NO: 1388. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1361, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 1381.Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1361, and (b) a light chain having the amino acid sequence of SEQ ID NO: 1381.

[0318] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment are a. (i) A variable heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1362, and including a CDR1 sequence consisting of SEQ ID NO: 1364; a CDR2 sequence consisting of SEQ ID NO: 1366; and a CDR3 sequence consisting of SEQ ID NO: 1368; and / or (ii) A variable light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1382, and including a CDR1 sequence consisting of SEQ ID NO: 1384; a CDR2 sequence consisting of SEQ ID NO: 1386; and a CDR3 sequence consisting of SEQ ID NO: 1388; b. (i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 1362, and / or (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 1382; c. (i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 1362, and (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 1382; d. (i) A heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1361, and including a CDR1 sequence consisting of SEQ ID NO: 1364; a CDR2 sequence consisting of SEQ ID NO: 1366; and a CDR3 sequence consisting of SEQ ID NO: 1368; and / or (ii) A light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1381, and including a CDR1 sequence consisting of SEQ ID NO: 1384; a CDR2 sequence consisting of SEQ ID NO: 1386; and a CDR3 sequence consisting of SEQ ID NO: 1388; e. (i) a heavy chain having the amino acid sequence of SEQ ID NO: 1361, and / or (ii) a light chain having the amino acid sequence of SEQ ID NO: 1381; and / or f. (i) A heavy chain having the amino acid sequence of SEQ ID NO: 1361, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 1381.

[0319] Antibody Ab10.H5 In one embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, having a heavy chain sequence comprising the sequence of SEQ ID NO: 1401, which consists of the heavy chain variable region of SEQ ID NO: 1402 linked to the heavy chain constant region of SEQ ID NO: 1410.

[0320] In one embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable heavy chain sequence comprising the sequence described below: EVQLVESGGGLVQPGGSLRLSCAASGIDLNSYYMTWVRQAPGKGLEWIGFIDAGGDAYYASWAKGRFTISRDNSKNTVYLQMNSLRAEDTAVYFCARDLDLWGQGTLVTVSS (Sequence ID 1402).

[0321] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, which binds to the same epitope as Ab10.H5 and contains a polypeptide of SEQ ID NO: 1244, 1245, or 1246, or a constant heavy chain sequence containing the sequence described below. [ka]

[0322] In another embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, comprising a light chain sequence including the sequence of SEQ ID NO: 1421, which consists of the light chain variable region of SEQ ID NO: 1422 linked to the light chain constant region of SEQ ID NO: 1430.

[0323] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable light chain sequence comprising the sequence described below: QLTQSPSTLSASVGDRVTITCQSSESVYGNYLAWFQQKPGKAPKFLIYEASKLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGDISEGVAFGGGTKVEIKR (Sequence ID 1422).

[0324] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, wherein the antibody binds to the same epitope as Ab10.H5 and contains a constant light chain sequence comprising the sequence described below: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 1430).

[0325] In another embodiment, the present invention includes an antibody and / or antigen-binding fragment having binding specificity to PACAP, comprising one, two, or three polypeptide sequences from SEQ ID NO: 1404; SEQ ID NO: 1406; and SEQ ID NO: 1408, which correspond to the CDR (hypervariable region) of the heavy chain sequence of SEQ ID NO: 1401 or contain the variable heavy chain sequence of SEQ ID NO: 1402, and / or further comprising one, two, or three polypeptide sequences from SEQ ID NO: 1424; SEQ ID NO: 1426; and SEQ ID NO: 1428, which correspond to the CDR (hypervariable region) of the light chain sequence of SEQ ID NO: 1421 or contain the variable light chain of SEQ ID NO: 1422, or an antibody or antigen-binding fragment comprising a combination of sequences which are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. In another embodiment of the present invention, the antibody and antigen-binding fragments of the present invention comprise, or consist of, one or more combinations of the exemplified variable heavy chain and variable light chain sequences, or the above heavy chain and light chain sequences, or sequences that are at least 90% or 95% identical thereto.

[0326] The present invention further envisions a PACAP antibody and / or its antigen-binding fragment comprising one, two, three, or four polypeptide sequences from sequence numbers 1403; 1405; 1407; and 1409, corresponding to the constant region (FR) of the heavy chain sequence of sequence number 1401 or the variable heavy chain sequence of sequence number 1402, and / or one, two, three, or four polypeptide sequences from sequence numbers 1423; 1425; 1427; and 1429, corresponding to the constant region (FR) of the light chain sequence of sequence number 1421 or the variable light chain sequence of sequence number 1422, or a combination thereof, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to them.

[0327] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment or fragment comprises, or instead comprises, one or more combinations of the FR, CDR, variable heavy chain and variable light chain, and the heavy chain and light chain sequences described above, including all of them, or sequences that are at least 90% or 95% identical thereto.

[0328] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 1401 or SEQ ID NO: 1402, or a polypeptide that is at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 1421 or SEQ ID NO: 1422, or a polypeptide that is at least 90% or 95% identical thereto.

[0329] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 1404; SEQ ID NO: 1406; and SEQ ID NO: 1408, corresponding to the heavy chain sequence of SEQ ID NO: 1401, the variable heavy chain sequence of SEQ ID NO: 1402, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0330] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 1424; SEQ ID NO: 1426; and SEQ ID NO: 1428, corresponding to the light chain sequence of SEQ ID NO: 1421, the variable light chain sequence of SEQ ID NO: 1422, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0331] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 1403; SEQ ID NO: 1405; SEQ ID NO: 1407; and SEQ ID NO: 1409, corresponding to the heavy chain sequence of SEQ ID NO: 1401, the variable heavy chain sequence of SEQ ID NO: 1402, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0332] In a further embodiment of the present invention, the antibody and / or antigen-binding fragment of a subject having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 1423; SEQ ID NO: 1425; SEQ ID NO: 1427; and SEQ ID NO: 1429, corresponding to the light chain sequence of SEQ ID NO: 1421, the variable light chain sequence of SEQ ID NO: 1422, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0333] The present invention also intends an anti-PACAP antibody and / or antigen-binding fragment comprising one or more of the antibody fragments described herein. In one embodiment, the antibody and / or antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 1402; the variable light chain region of SEQ ID NO: 1422; the complementarity-determining regions of the variable heavy chain region of SEQ ID NO: 1404; SEQ ID NO: 1406; and SEQ ID NO: 1408; and the complementarity-determining regions of the variable light chain region of SEQ ID NO: 1424; SEQ ID NO: 1426; and SEQ ID NO: 1428, or all of sequences that are at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more antibody fragments containing all of the following: the variable heavy chain region of SEQ ID NO: 1402; the variable light chain region of SEQ ID NO: 1422; the framework regions of the variable heavy chain region of SEQ ID NO: 1403; SEQ ID NO: 1405; SEQ ID NO: 1407; and SEQ ID NO: 1409; and the framework regions of the variable light chain region of SEQ ID NO: 1423; SEQ ID NO: 1425; SEQ ID NO: 1427; and SEQ ID NO: 1429, or sequences that are at least 90% or 95% identical thereto.

[0334] In another embodiment of the present invention, the PACAP antibody is an antibody or antigen-binding fragment comprising or consisting of SEQ ID NOs: 1401 and 1421, or SEQ ID NOs: 1402 and 1422, or Ab10.H5 or a CDR of Ab10.H5, and having at least one of the biological activities described herein, or containing a sequence that competes with Ab10.H5 for binding to PACAP, preferably being at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab10.H5, or an antibody that binds to an epitope on PACAP that is identical to or overlaps with that of Ab10.H5.

[0335] In further embodiments of the present invention, the antigen-binding fragment comprises or consists of a Fab fragment having binding specificity to PACAP. With respect to the antibody Ab10.H5, the Fab fragment preferably comprises the variable heavy chain sequence of SEQ ID NO: 1402 and the variable light chain sequence of SEQ ID NO: 1422, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. This embodiment of the present invention further comprises a Fab containing additions, deletions, and variants of SEQ ID NO: 1402 and / or SEQ ID NO: 1422 that retain binding specificity to PACAP.

[0336] In one embodiment, the Fab fragment may be produced by enzymatic digestion of Ab10.H5 (e.g., papain). In another embodiment of the present invention, anti-PACAP antibodies such as Ab10.H5 and the Fab fragment may be produced through expression in mammalian cells such as CHO, NSO, or HEK 293 cells, fungi, insects, or microbial systems, such as yeast cells (e.g., haploid or diploid yeast, e.g., haploid or diploid Pichia). Suitable Pichia species include, but are not limited to, Pichia pastoris.

[0337] In additional embodiments, the present invention further aims to encode an antibody polypeptide having binding specificity to PACAP, comprising the heavy and / or light chain of Ab10.H5, as well as one or more combinations of the heavy or light chains described above, including FR, CDR, variable heavy and variable light chain sequences, and all of them, or sequences that are at least 90% or 95% identical thereto.

[0338] In specific embodiments, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, comprising (a) a variable heavy chain including a CDR1 sequence consisting of SEQ ID NO: 1404; a CDR2 sequence consisting of SEQ ID NO: 1406; and a CDR3 sequence consisting of SEQ ID NO: 1408; and / or (b) a CDR1 sequence consisting of SEQ ID NO: 1424; a CDR2 sequence consisting of SEQ ID NO: 1426; and a CDR3 sequence consisting of SEQ ID NO: 1428. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1402; and / or (b) a variable light chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1422. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1402, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 1422. More specifically, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1401, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 1421.

[0339]

[92] In another specific embodiment, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, comprising (a) a variable heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1402, and comprising a CDR1 sequence consisting of SEQ ID NO: 1404; a CDR2 sequence consisting of SEQ ID NO: 1406; and a CDR3 sequence consisting of SEQ ID NO: 1408; and / or (b) a variable light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1422, and comprising a CDR1 sequence consisting of SEQ ID NO: 1424; a CDR2 sequence consisting of SEQ ID NO: 1426; and a CDR3 sequence consisting of SEQ ID NO: 1428. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1402, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 1422. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1401, and including a CDR1 sequence consisting of SEQ ID NO: 1404; a CDR2 sequence consisting of SEQ ID NO: 1406; and a CDR3 sequence consisting of SEQ ID NO: 1408; and / or (b) a light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1421, and including a CDR1 sequence consisting of SEQ ID NO: 1424; a CDR2 sequence consisting of SEQ ID NO: 1426; and a CDR3 sequence consisting of SEQ ID NO: 1428. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1401, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 1421.Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1401, and (b) a light chain having the amino acid sequence of SEQ ID NO: 1421.

[0340] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment are a. (i) A variable heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1402, and including a CDR1 sequence consisting of SEQ ID NO: 1404; a CDR2 sequence consisting of SEQ ID NO: 1406; and a CDR3 sequence consisting of SEQ ID NO: 1408; and / or (ii) A variable light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1422, and including a CDR1 sequence consisting of SEQ ID NO: 1424; a CDR2 sequence consisting of SEQ ID NO: 1426; and a CDR3 sequence consisting of SEQ ID NO: 1428; b. (i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 1402, and / or (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 1422; c. (i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 1402, and (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 1422; d. (i) A heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1401, and including a CDR1 sequence consisting of SEQ ID NO: 1404; a CDR2 sequence consisting of SEQ ID NO: 1406; and a CDR3 sequence consisting of SEQ ID NO: 1408; and / or (ii) A light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1421, and including a CDR1 sequence consisting of SEQ ID NO: 1424; a CDR2 sequence consisting of SEQ ID NO: 1426; and a CDR3 sequence consisting of SEQ ID NO: 1428; e. (i) a heavy chain having the amino acid sequence of SEQ ID NO: 1401, and / or (ii) a light chain having the amino acid sequence of SEQ ID NO: 1421; and / or f. (i) A heavy chain having the amino acid sequence of SEQ ID NO: 1401, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 1421.

[0341] Antibody Ab10.H6 In one embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, having a heavy chain sequence comprising the sequence of SEQ ID NO: 1441, which consists of the heavy chain variable region of SEQ ID NO: 1442 linked to the heavy chain constant region of SEQ ID NO: 1450.

[0342] In one embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable heavy chain sequence comprising the sequence described below: EVQLVESGGGLVQPGGSLRLSCAASGIDLNSYYMTWVRQAPGKGLEWIGFIDAGGDAYYASWAKGRFTISRDNSKNTVYLQMNSLRAEDTAVYFCARDLDLWGQGTLVTVSS (Sequence ID 1442).

[0343] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, which binds to the same epitope as Ab10.H6 and comprises a polypeptide of SEQ ID NO: 1244, 1245, or 1246, or a constant heavy chain sequence comprising the sequence described below. [ka]

[0344] In another embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, comprising a light chain sequence including the sequence of SEQ ID NO: 1461, which consists of the light chain variable region of SEQ ID NO: 1462 linked to the light chain constant region of SEQ ID NO: 1470.

[0345] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable light chain sequence comprising the sequence described below: QVLTQSPSTLSASVGDRVTITCQSSESVYGNYLAWFQQKPGKAPKFLIYEASKLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGDISEGVAFGGGTKVEIKR (Sequence ID 1462).

[0346] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, wherein the antibody binds to the same epitope as Ab10.H6 and contains a constant light chain sequence comprising the sequence described below: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 1470).

[0347] In another embodiment, the present invention includes an antibody and / or antigen-binding fragment having binding specificity to PACAP, comprising one, two, or three polypeptide sequences from SEQ ID NO: 1444; SEQ ID NO: 1446; and SEQ ID NO: 1448, which correspond to the CDR (hypervariable region) of the heavy chain sequence of SEQ ID NO: 1441 or contain the variable heavy chain sequence of SEQ ID NO: 1442, and / or further comprising one, two, or three polypeptide sequences from SEQ ID NO: 1464; SEQ ID NO: 1466; and SEQ ID NO: 1468, which correspond to the CDR (hypervariable region) of the light chain sequence of SEQ ID NO: 1461 or contain the variable light chain of SEQ ID NO: 1462, or an antibody or antigen-binding fragment comprising a combination of sequences which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. In another embodiment of the present invention, the antibody and antigen-binding fragments of the present invention comprise, or consist of, one or more combinations of the exemplified variable heavy chain and variable light chain sequences, or the above heavy chain and light chain sequences, or sequences that are at least 90% or 95% identical thereto.

[0348] The present invention further envisions a PACAP antibody and / or its antigen-binding fragment comprising one, two, three, or four polypeptide sequences from sequence numbers 1443; 1445; 1447; and 1449, corresponding to the FR (steady region) of the heavy chain sequence of sequence number 1441 or the variable heavy chain sequence of sequence number 1442, and / or one, two, three, or four polypeptide sequences from sequence numbers 1463; 1465; 1467; and 1469, corresponding to the FR (steady region) of the light chain sequence of sequence number 1461 or the variable light chain sequence of sequence number 1462, or a combination thereof, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to them.

[0349] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment or fragment comprises, or instead comprises, one or more combinations of the FR, CDR, variable heavy chain and variable light chain, and the heavy chain and light chain sequences described above, including all of them, or sequences that are at least 90% or 95% identical thereto.

[0350] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 1441 or SEQ ID NO: 1442, or a polypeptide that is at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 1461 or SEQ ID NO: 1462, or a polypeptide that is at least 90% or 95% identical thereto.

[0351] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 1444; SEQ ID NO: 1446; and SEQ ID NO: 1448, corresponding to the heavy chain sequence of SEQ ID NO: 1441, the variable heavy chain sequence of SEQ ID NO: 1442, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0352] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 1464; SEQ ID NO: 1466; and SEQ ID NO: 1468, corresponding to the light chain sequence of SEQ ID NO: 1461, the variable light chain sequence of SEQ ID NO: 1462, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0353] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 1443; SEQ ID NO: 1445; SEQ ID NO: 1447; and SEQ ID NO: 1449, corresponding to the heavy chain sequence of SEQ ID NO: 1441, the variable heavy chain sequence of SEQ ID NO: 1442, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0354] In a further embodiment of the present invention, an antibody and / or antigen-binding fragment of a subject having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 1463; SEQ ID NO: 1465; SEQ ID NO: 1467; and SEQ ID NO: 1469, corresponding to the light chain sequence of SEQ ID NO: 1461, or the variable light chain sequence of SEQ ID NO: 1462, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0355] The present invention also envisions an anti-PACAP antibody and / or antigen-binding fragment comprising one or more of the antibody fragments described herein. In one embodiment, the antibody and / or antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 1442; the variable light chain region of SEQ ID NO: 1462; the complementarity-determining regions of the variable heavy chain region of SEQ ID NO: 1444; SEQ ID NO: 1446; and SEQ ID NO: 1448; and the complementarity-determining regions of the variable light chain region of SEQ ID NO: 1464; SEQ ID NO: 1466; and SEQ ID NO: 1468, or all of sequences that are at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more antibody fragments containing all of the following: the variable heavy chain region of SEQ ID NO: 1442; the variable light chain region of SEQ ID NO: 1462; the framework region of the variable heavy chain region of SEQ ID NO: 1443; SEQ ID NO: 1445; SEQ ID NO: 1447; and SEQ ID NO: 1449; and the framework region of the variable light chain region of SEQ ID NO: 1463; SEQ ID NO: 1465; SEQ ID NO: 1467; and SEQ ID NO: 1469, or sequences that are at least 90% or 95% identical thereto.

[0356] In another embodiment of the present invention, the PACAP antibody is an antibody or antigen-binding fragment comprising or consisting of SEQ ID NOs. 1441 and SEQ ID NOs. 1461, or SEQ ID NOs. 1442 and SEQ ID NOs. 1462, or Ab10.H6 or a CDR of Ab10.H6, and having at least one of the biological activities described herein, or containing a sequence that competes with Ab10.H6 for binding to PACAP, preferably being at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab10.H6, or an antibody that binds to an epitope on PACAP that is identical to or overlaps with that of Ab10.H6.

[0357] In further embodiments of the present invention, the antigen-binding fragment comprises or consists of a Fab fragment having binding specificity to PACAP. With respect to the antibody Ab10.H6, the Fab fragment preferably comprises the variable heavy chain sequence of SEQ ID NO: 1442 and the variable light chain sequence of SEQ ID NO: 1462, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. This embodiment of the present invention further comprises a Fab containing additions, deletions, and variants of SEQ ID NO: 1442 and / or SEQ ID NO: 1462 that retain binding specificity to PACAP.

[0358] In one embodiment, the Fab fragment may be produced by enzymatic digestion of Ab10.H6 (e.g., papain). In another embodiment of the present invention, anti-PACAP antibodies such as Ab10.H6 and the Fab fragment may be produced through expression in mammalian cells such as CHO, NSO, or HEK 293 cells, fungi, insects, or microbial systems, such as yeast cells (e.g., haploid or diploid yeast, e.g., haploid or diploid Pichia). Suitable Pichia species include, but are not limited to, Pichia pastoris.

[0359] In additional embodiments, the present invention further aims to encode an antibody polypeptide having binding specificity to PACAP, comprising the heavy and / or light chain of Ab10.H6, as well as one or more combinations of the heavy or light chains described above, including FR, CDR, variable heavy and variable light chain sequences, and all of them, or sequences that are at least 90% or 95% identical thereto.

[0360] In specific embodiments, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, comprising (a) a variable heavy chain including a CDR1 sequence consisting of SEQ ID NO: 1444; a CDR2 sequence consisting of SEQ ID NO: 1446; and a CDR3 sequence consisting of SEQ ID NO: 1448; and / or (b) a CDR1 sequence consisting of SEQ ID NO: 1464; a CDR2 sequence consisting of SEQ ID NO: 1466; and a CDR3 sequence consisting of SEQ ID NO: 1468. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1442, and / or (b) a variable light chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1462. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1442, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 1462. More specifically, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1441, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 1461.

[0361] In another specific embodiment, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, and comprises (a) a variable heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1442, and including a CDR1 sequence consisting of SEQ ID NO: 1444; a CDR2 sequence consisting of SEQ ID NO: 1446; and a CDR3 sequence consisting of SEQ ID NO: 1448; and / or (b) a variable light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1462, and including a CDR1 sequence consisting of SEQ ID NO: 1464; a CDR2 sequence consisting of SEQ ID NO: 1466; and a CDR3 sequence consisting of SEQ ID NO: 1468. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1442, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 1462. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1441, and including a CDR1 sequence consisting of SEQ ID NO: 1444; a CDR2 sequence consisting of SEQ ID NO: 1446; and a CDR3 sequence consisting of SEQ ID NO: 1448; and / or (b) a light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1461, and including a CDR1 sequence consisting of SEQ ID NO: 1464; a CDR2 sequence consisting of SEQ ID NO: 1466; and a CDR3 sequence consisting of SEQ ID NO: 1468. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1441, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 1461.Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1441, and (b) a light chain having the amino acid sequence of SEQ ID NO: 1461.

[0362] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment are a. (i) A variable heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1442, and including a CDR1 sequence consisting of SEQ ID NO: 1444; a CDR2 sequence consisting of SEQ ID NO: 1446; and a CDR3 sequence consisting of SEQ ID NO: 1448; and / or (ii) A variable light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1462, and including a CDR1 sequence consisting of SEQ ID NO: 1464; a CDR2 sequence consisting of SEQ ID NO: 1466; and a CDR3 sequence consisting of SEQ ID NO: 1468; b. (i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 1442, and / or (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 1462; c. (i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 1442, and (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 1462; d. (i) A heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1441, and including a CDR1 sequence consisting of SEQ ID NO: 1444; a CDR2 sequence consisting of SEQ ID NO: 1446; and a CDR3 sequence consisting of SEQ ID NO: 1448; and / or (ii) A light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1461, and including a CDR1 sequence consisting of SEQ ID NO: 1464; a CDR2 sequence consisting of SEQ ID NO: 1466; and a CDR3 sequence consisting of SEQ ID NO: 1468; e. (i) a heavy chain having the amino acid sequence of SEQ ID NO: 1441, and / or (ii) a light chain having the amino acid sequence of SEQ ID NO: 1461; and / or f. (i) A heavy chain having the amino acid sequence of SEQ ID NO: 1441, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 1461.

[0363] Antibody Ab21.H2 In one embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, having a heavy chain sequence comprising the sequence of SEQ ID NO: 1481, which consists of the heavy chain variable region of SEQ ID NO: 1482 linked to the heavy chain constant region of SEQ ID NO: 1490.

[0364] In one embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable heavy chain sequence comprising the sequence described below: EVQLVESGGGLVQPGGSLRLSCAASGIDLSSYYMTWVRQAPGKGLEWIGFIDAGGSAYYATWAKGRFTISRDNSKNTVYLQMNSLRAEDTAVYFCARDLDLWGQGTLVTVSS (Sequence ID 1482).

[0365] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, which binds to the same epitope as Ab21.H2 and contains the polypeptide of SEQ ID NO: 1244, 1245, or 1246, or a constant heavy chain sequence containing the sequence described below. [ka]

[0366] In another embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, comprising a light chain sequence including the sequence of SEQ ID NO: 1501, which consists of the light chain variable region of SEQ ID NO: 1502 linked to the light chain constant region of SEQ ID NO: 1510.

[0367] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable light chain sequence comprising the sequence described below: AVLTQSPSTLSASVGDRVTITCKSSESVYGDYLAWFQQKPGKAPKQLIYDASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGYVSAGVAFGGGTKVEIKR (Sequence ID 1502).

[0368] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, wherein the antibody binds to the same epitope as Ab21.H2 and contains a constant light chain sequence comprising the sequence described below: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 1510).

[0369] In another embodiment, the present invention includes an antibody and / or antigen-binding fragment having binding specificity to PACAP, comprising one, two, or three polypeptide sequences from SEQ ID NO: 1484; SEQ ID NO: 1486; and SEQ ID NO: 1488, which correspond to the CDR (hypervariable region) of the heavy chain sequence of SEQ ID NO: 1481 or contain the variable heavy chain sequence of SEQ ID NO: 1482, and / or further comprising one, two, or three polypeptide sequences from SEQ ID NO: 1504; SEQ ID NO: 1506; and SEQ ID NO: 1508, which correspond to the CDR (hypervariable region) of the light chain sequence of SEQ ID NO: 1501 or contain the variable light chain of SEQ ID NO: 1502, or an antibody or antigen-binding fragment comprising a combination of sequences which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. In another embodiment of the present invention, the antibody and antigen-binding fragments of the present invention comprise, or consist of, one or more combinations of the exemplified variable heavy chain and variable light chain sequences, or the above heavy chain and light chain sequences, or sequences that are at least 90% or 95% identical thereto.

[0370] The present invention further envisions a PACAP antibody and / or its antigen-binding fragment comprising one, two, three, or four polypeptide sequences from sequence numbers 1483; 1485; 1487; and 1489, corresponding to the FR (constant region) of the heavy chain sequence of sequence number 1481 or the variable heavy chain sequence of sequence number 1482, and / or one, two, three, or four polypeptide sequences from sequence numbers 1503; 1505; 1507; and 1509, corresponding to the FR (constant region) of the light chain sequence of sequence number 1501 or the variable light chain sequence of sequence number 1502, or a combination thereof, or sequences that are at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to them.

[0371] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment or fragment comprises, or instead comprises, one or more combinations of the FR, CDR, variable heavy chain and variable light chain, and the heavy chain and light chain sequences described above, including all of them, or sequences that are at least 90% or 95% identical thereto.

[0372] In another embodiment of the present invention, the anti-PACAP antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 1481 or SEQ ID NO: 1482, or a polypeptide that is at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody and / or its antigen-binding fragment comprises, or consists of, the polypeptide sequence of SEQ ID NO: 1501 or SEQ ID NO: 1502, or a polypeptide that is at least 90% or 95% identical thereto.

[0373] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 1484; SEQ ID NO: 1486; and SEQ ID NO: 1488, corresponding to the heavy chain sequence of SEQ ID NO: 1481, the variable heavy chain sequence of SEQ ID NO: 1482, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0374] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, or three polypeptide sequences of SEQ ID NO: 1504; SEQ ID NO: 1506; and SEQ ID NO: 1508, corresponding to the light chain sequence of SEQ ID NO: 1501, the variable light chain sequence of SEQ ID NO: 1502, or a CDR (hypervariable region) of a sequence that is at least 90% or 95% identical thereto.

[0375] In a further embodiment of the present invention, an antibody and / or its antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 1483; SEQ ID NO: 1485; SEQ ID NO: 1487; and SEQ ID NO: 1489, corresponding to the heavy chain sequence of SEQ ID NO: 1481, the variable heavy chain sequence of SEQ ID NO: 1482, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0376] In a further embodiment of the present invention, the antibody and / or antigen-binding fragment of a subject having binding specificity to PACAP comprises, or instead comprises, one, two, three, or four polypeptide sequences from SEQ ID NO: 1503; SEQ ID NO: 1505; SEQ ID NO: 1507; and SEQ ID NO: 1509, corresponding to the light chain sequence of SEQ ID NO: 1501, the variable light chain sequence of SEQ ID NO: 1502, or the constant region (FR) of a sequence that is at least 90% or 95% identical thereto.

[0377] The present invention also intends an anti-PACAP antibody and / or antigen-binding fragment comprising one or more of the antibody fragments described herein. In one embodiment, the antibody and / or antigen-binding fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more of the following antibody fragments: the variable heavy chain region of SEQ ID NO: 1482; the variable light chain region of SEQ ID NO: 1502; the complementarity-determining regions of the variable heavy chain region of SEQ ID NO: 1484; SEQ ID NO: 1486; and SEQ ID NO: 1488; and the complementarity-determining regions of the variable light chain region of SEQ ID NO: 1504; SEQ ID NO: 1506; and SEQ ID NO: 1508, or all of sequences that are at least 90% or 95% identical thereto. In another embodiment of the present invention, the antibody fragment having binding specificity to PACAP comprises, or instead comprises, one, two, three or more antibody fragments containing all of the following: the variable heavy chain region of SEQ ID NO: 1482; the variable light chain region of SEQ ID NO: 1502; the framework region of the variable heavy chain region of SEQ ID NO: 1483; SEQ ID NO: 1485; SEQ ID NO: 1487; and SEQ ID NO: 1489; and the framework region of the variable light chain region of SEQ ID NO: 1503; SEQ ID NO: 1505; SEQ ID NO: 1507; and SEQ ID NO: 1509, or sequences that are at least 90% or 95% identical thereto.

[0378] In another embodiment of the present invention, the PACAP antibody is an antibody or antigen-binding fragment comprising or consisting of SEQ ID NOs. 1481 and SEQ ID NOs. 1501, or SEQ ID NOs. 1482 and SEQ ID NOs. 1502, or Ab21.H2 or a CDR of Ab21.H2, and having at least one of the biological activities described herein, or containing a sequence that competes with Ab21.H2 for binding to PACAP, preferably being at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that of Ab21.H2, or an antibody that binds to an epitope on PACAP that is identical to or overlaps with that of Ab21.H2.

[0379] In further embodiments of the present invention, the antigen-binding fragment comprises or consists of a Fab fragment having binding specificity to PACAP. With respect to the antibody Ab21.H2, the Fab fragment preferably comprises the variable heavy chain sequence of SEQ ID NO: 1482 and the variable light chain sequence of SEQ ID NO: 1502, or sequences that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical thereto. This embodiment of the present invention further comprises a Fab containing additions, deletions, and variants of SEQ ID NO: 1482 and / or SEQ ID NO: 1502 that retain binding specificity to PACAP.

[0380] In one embodiment, the Fab fragment may be produced by enzymatic digestion of Ab21.H2 (e.g., papain). In another embodiment of the present invention, anti-PACAP antibodies such as Ab21.H2 and the Fab fragment may be produced through expression in mammalian cells such as CHO, NSO, or HEK 293 cells, fungi, insects, or microbial systems, such as yeast cells (e.g., haploid or diploid yeast, e.g., haploid or diploid Pichia). Suitable Pichia species include, but are not limited to, Pichia pastoris.

[0381] In additional embodiments, the present invention further aims to encode an antibody polypeptide having binding specificity to PACAP, comprising the heavy and / or light chain of Ab21.H2, as well as one or more combinations of the heavy or light chains described above, including FR, CDR, variable heavy and variable light chain sequences, and all of them, or sequences that are at least 90% or 95% identical thereto.

[0382] In specific embodiments, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, comprising (a) a variable heavy chain including a CDR1 sequence consisting of SEQ ID NO: 1484; a CDR2 sequence consisting of SEQ ID NO: 1486; and a CDR3 sequence consisting of SEQ ID NO: 1488; and / or (b) a CDR1 sequence consisting of SEQ ID NO: 1504; a CDR2 sequence consisting of SEQ ID NO: 1506; and a CDR3 sequence consisting of SEQ ID NO: 1508. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1482, and / or (b) a variable light chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1502. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1482, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 1502. More specifically, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1481, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 1501.

[0383] In another specific embodiment, the anti-PACAP antibody and / or its antigen-binding fragment according to the present invention is preferably a human, humanized, or chimeric anti-PACAP antibody or its antigen-binding fragment, and comprises (a) a variable heavy chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1482, and comprising a CDR1 sequence consisting of SEQ ID NO: 1484; a CDR2 sequence consisting of SEQ ID NO: 1486; and a CDR3 sequence consisting of SEQ ID NO: 1488; and / or (b) a variable light chain including an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1502, and comprising a CDR1 sequence consisting of SEQ ID NO: 1504; a CDR2 sequence consisting of SEQ ID NO: 1506; and a CDR3 sequence consisting of SEQ ID NO: 1508. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1482, and / or (b) a variable light chain having the amino acid sequence of SEQ ID NO: 1502. In another embodiment, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1481, and including a CDR1 sequence consisting of SEQ ID NO: 1484; a CDR2 sequence consisting of SEQ ID NO: 1486; and a CDR3 sequence consisting of SEQ ID NO: 1488; and / or (b) a light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 1501, and including a CDR1 sequence consisting of SEQ ID NO: 1504; a CDR2 sequence consisting of SEQ ID NO: 1506; and a CDR3 sequence consisting of SEQ ID NO: 1508. Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1481, and / or (b) a light chain having the amino acid sequence of SEQ ID NO: 1501.Alternatively, the anti-PACAP antibody and / or its antigen-binding fragment may comprise (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1481, and (b) a light chain having the amino acid sequence of SEQ ID NO: 1501.

[0384] In one embodiment, the anti-PACAP antibody and / or its antigen-binding fragment are a. A variable heavy chain containing the CDR1 sequence consisting of SEQ ID NO: 1484; the CDR2 sequence consisting of SEQ ID NO: 1486; and the CDR3 sequence consisting of SEQ ID NO: 1488; and / or b. A variable light chain comprising a CDR1 sequence consisting of SEQ ID NO: 1504; a CDR2 sequence consisting of SEQ ID NO: 1506; and a CDR3 sequence consisting of SEQ ID NO: 1508, wherein the antibody is optionally selected as follows: (a)(i) A variable heavy chain containing an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1482, and / or (ii) A variable light chain containing an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1502; (b)(i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 1482, or (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 1502; (c)(i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 1482, and (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 1502; (d)(i) a heavy chain having the amino acid sequence of SEQ ID NO: 1481, and / or (ii) a light chain having the amino acid sequence of SEQ ID NO: 1501; or (e) comprising (i) a heavy chain having the amino acid sequence of SEQ ID NO: 1481, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 1501.

[0385] Antibody Ab21.H3 In one embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, having a heavy chain sequence comprising the sequence of SEQ ID NO: 1521, which consists of the heavy chain variable region of SEQ ID NO: 1522 linked to the heavy chain constant region of SEQ ID NO: 1530.

[0386] In one embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable heavy chain sequence comprising the sequence described below: EVQLVESGGGLVQPGGSLRLSCAASGIDLSSYYMTWVRQAPGKGLEWIGFIDAGGSAYYATWAKGRFTISRDNSKNTVYLQMNSLRAEDTAVYFCARDLDLWGQGTLVTVSS (Sequence ID 1522).

[0387] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, which binds to the same epitope as Ab21.H3 and contains a polypeptide of SEQ ID NO: 1244, 1245, or 1246, or a constant heavy chain sequence containing the sequence described below. [ka]

[0388] In another embodiment, the present invention includes an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, comprising a light chain sequence including the sequence of SEQ ID NO: 1541, which consists of the light chain variable region of SEQ ID NO: 1542 linked to the light chain constant region of SEQ ID NO: 1550.

[0389] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP containing a variable light chain sequence comprising the sequence described below: DIQLTQSPSTLSASVGDRVTITCKSSESVYGDYLAWFQQKPGKAPKQLIYDASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGYVSAGVAFGGGTKVEIKR (Sequence ID 1542).

[0390] In another embodiment, the present invention comprises an antibody and / or an antigen-binding fragment thereof having binding specificity to PACAP, wherein the antibody binds to the same epitope as Ab21.H3 and contains a constant light chain sequence comprising the sequence described below: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP...

Claims

1. A method for treating, improving and / or preventing medication overuse headache or pain, such as hyperalgesia, allodynia, or opioid-induced pain, comprising administering an effective amount of anti-pituitary adenylyl cyclase-activated polypeptide (PACAP) antibody to a subject in need thereof.

2. The method according to claim 1, wherein the pain is opioid-induced pain selected from the group consisting of opioid-induced pain, such as opioid-induced migraine, such as opioid-induced chronic or episodic migraine, opioid-induced hyperalgesia (OIH), and opioid-induced allodynia (OIA).

3. The method according to claim 1 or 2, wherein the opioid-induced pain is opioid-induced hyperalgesia (OIH) or opioid-induced allodynia (OIA).

4. The method according to any one of the prior claims, wherein the opioid-induced pain is opioid-induced hyperalgesia (OIH).

5. The method according to claim 1 or 2, wherein the opioid-induced pain is opioid-induced chronic migraine.

6. The method according to any one of the prior claims, wherein the opioid-induced pain results from treatment with an opioid analgesic selected from the group consisting of codeine, dihydrocodeine, morphine or a morphine derivative or a pharmaceutically acceptable salt thereof, codeine, dihydrocodeine, oxycodone, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanil, sufentanil, meperidine, methadone, nalbuffine, propoxifene, and pentazocine, or a pharmaceutically acceptable salt thereof.

7. The method according to any one of the prior claims, wherein the opioid-induced pain arises from treatment with morphine of the subject.

8. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment antagonizes, inhibits, neutralizes, and / or blocks at least one biological effect associated with human PACAP.

9. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment specifically binds to a linear or three-dimensional structural epitope on human PACAP that is the same as or overlaps with Ab10.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, Ab10.H6, Ab21, Ab21.H, Ab21.H2, Ab21.H3, or Ab21.H4.

10. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment specifically binds to a linear or three-dimensional structural epitope on human PACAP that is the same as or overlaps with Ab10.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, or Ab10.H6.

11. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment comprises at least two, at least three, at least four, at least five, or all six complementarity-determining regions ("CDRs") of an anti-PACAP antibody selected from Ab10.H, Ab10.H2, Ab10.H3, Ab10.H4, Ab10.H5, or Ab10.H6.

12. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment specifically binds to a linear or stereochemical epitope on human PACAP that is the same as or overlaps with Ab10.H or Ab10.H3.

13. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment comprises at least two, at least three, at least four, at least five, or all six complementarity-determining regions ("CDRs") of the anti-PACAP antibody Ab10.H or Ab10.H3.

14. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment specifically binds to a linear or stereochemical epitope on human PACAP that is the same as or overlaps with Ab10.H.

15. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment comprises at least two, at least three, at least four, at least five, or all six complementarity-determining regions ("CDRs") of the anti-PACAP antibody Ab10.H.

16. The method according to any one of claims 1 to 13, wherein the anti-PACAP antibody and / or its antigen-binding fragment specifically binds to a linear or three-dimensional epitope on human PACAP that is the same as or overlaps with Ab10.H3.

17. The method according to any one of claims 1 to 13, wherein the anti-PACAP antibody and / or its antigen-binding fragment comprises at least two, at least three, at least four, at least five, or all six complementarity-determining regions ("CDRs") of the anti-PACAP antibody Ab10.H3.

18. The anti-PACAP antibody and / or its antigen-binding fragment, a. (i) A variable heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 962, and including a CDR1 sequence consisting of SEQ ID NO: 964; a CDR2 sequence consisting of SEQ ID NO: 966; and a CDR3 sequence consisting of SEQ ID NO: 968; and / or (ii) A variable light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 982, and including a CDR1 sequence consisting of SEQ ID NO: 984; a CDR2 sequence consisting of SEQ ID NO: 986; and a CDR3 sequence consisting of SEQ ID NO: 988; b. (i) a variable heavy chain having the amino acid sequence of SEQ ID NO: 962, and / or (ii) a variable light chain having the amino acid sequence of SEQ ID NO: 982; c. (i) A variable heavy chain having the amino acid sequence of SEQ ID NO: 962, and (ii) A variable light chain having the amino acid sequence of SEQ ID NO: 982; d. (i) A heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 961, and comprising a CDR1 sequence consisting of SEQ ID NO: 964; a CDR2 sequence consisting of SEQ ID NO: 966; and a CDR3 sequence consisting of SEQ ID NO: 968; and / or (ii) A light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 981, and comprising a CDR1 sequence consisting of SEQ ID NO: 984; a CDR2 sequence consisting of SEQ ID NO: 986; and a CDR3 sequence consisting of SEQ ID NO: 988; e. (i) a heavy chain having the amino acid sequence of SEQ ID NO: 961, and / or (ii) a light chain having the amino acid sequence of SEQ ID NO: 981; and / or f. (i) a heavy chain having the amino acid sequence of SEQ ID NO: 961, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 981, The method according to any one of claims 1 to 15, including the method described in any one of claims 1 to 15.

19. The anti-PACAP antibody and / or its antigen-binding fragment, a. (i) A variable heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1322, and including a CDR1 sequence consisting of SEQ ID NO: 1324; a CDR2 sequence consisting of SEQ ID NO: 1326; and a CDR3 sequence consisting of SEQ ID NO: 1328; and / or (ii) A variable light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1342, and including a CDR1 sequence consisting of SEQ ID NO: 1344; a CDR2 sequence consisting of SEQ ID NO: 1346; and a CDR3 sequence consisting of SEQ ID NO: 1348; b. (i) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1322, and / or (ii) a variable light chain having the amino acid sequence of SEQ ID NO: 1342; c. (i) a variable heavy chain having the amino acid sequence of SEQ ID NO: 1322, and (ii) a variable light chain having the amino acid sequence of SEQ ID NO: 1342; d. (i) A heavy chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1321 or 1604, and comprising a CDR1 sequence consisting of SEQ ID NO: 1324; a CDR2 sequence consisting of SEQ ID NO: 1326; and a CDR3 sequence consisting of SEQ ID NO: 1328; and / or (ii) A light chain comprising an amino acid sequence having at least 80, 85, 90, 95, 96, 97, 98, or 99% sequence identity with SEQ ID NO: 1341, and comprising a CDR1 sequence consisting of SEQ ID NO: 1344; a CDR2 sequence consisting of SEQ ID NO: 1346; and a CDR3 sequence consisting of SEQ ID NO: 1348; e. (i) a heavy chain having the amino acid sequence of SEQ ID NO: 1321 or 1604, and / or (ii) a light chain having the amino acid sequence of SEQ ID NO: 1341; and / or f. (i) a heavy chain having the amino acid sequence of SEQ ID NO: 1321 or 1604, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 1341, The method according to any one of claims 1 to 13 or 16 to 17, including the method described in claim 1 to 13 or 16 to 17.

20. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment is chimeric, human, or humanized.

21. The method according to any one prior claim, wherein the anti-PACAP antibody and / or its antigen-binding fragment is selected from the group consisting of scFv, camel antibody, nanobody, novel immunoglobulin antigen receptor ("IgNAR"), fragment antigen-binding ("Fab") fragment, Fab' fragment, MetMab-like antibody, monovalent antigen-binding fragment, and F(ab')2 fragment.

22. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment substantially or completely lacks N-glycosylation and / or O-glycosylation.

23. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment comprises a human constant domain, and optionally the antibody is an IgG1, IgG2, IgG3, or IgG4 antibody.

24. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment comprises an Fc region modified to alter at least one of effector function, half-life, proteolysis, or glycosylation, and optionally the Fc region contains one or more mutations that alter or eliminate N-glycosylation and / or O-glycosylation, and / or the Fc region comprises the sequence of any one of SEQ ID NOs: 1244, 1245, or 1246.

25. The anti-PACAP antibody and / or its antigen-binding fragment binds to PACAP with a binding affinity (K Ｄ ), determined at 25° or 37°C by, for example, ELISA, biolayer interferometry ("BLI"), KINEXA or surface plasmon resonance, of 5×10 －５ M, 10 －６ M, 5×10 －６ M, 10 －７ M, 5×10 －７ M, 10 －８ M, 5×10 －８ M, 10 －９ M, 5×10 －９ M, 10 －１０ M, 5×10 －１０ M, 10 －１１ M, 5×10 －１１ M, 10 －１２ M, 5×10 －１２ M, 10 －１３ M, or 10 －１３ M or less, according to the method of any one of the preceding claims.​​

26. The anti-PACAP antibody and / or its antigen-binding fragments are 5 × 10 －１０ M, 10 －１０ M, 5 x 10 －１１ M, 10 －１１ M, 5 x 10 －１２ M, or 10 －１２ Binding affinity (K) below M Ｄ The method according to any one of the prior claims, wherein the device is connected to PACAP.

27. The anti-PACAP antibody and / or its antigen-binding fragments are 5 × 10 －４ s －１ , 10 －４ s －１ , 5 x 10 －５ s －１ , or 10 －５ s －１ The following dissociation rate constant (k) ｄ The method according to any one of the prior claims, wherein the device is connected to PACAP.

28. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment is directly or indirectly linked to a detectable label or therapeutic agent.

29. The anti-PACAP antibody and / or its antigen-binding fragment is less than about 100 nM, 40 nM, 50 pM, or 25 pM, or is between about 10 pM and about 100 pM. Ｄ The method according to any one of the prior claims, wherein the device is coupled to PACAP.

30. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment has a stronger affinity for PACAP than for VIP, and / or does not bind to VIP, and optionally the affinity of the antibody or antigen-binding fragment for PACAP is at least 10 times, 30 times, 100 times, 300 times, 1,000 times, 10,000 times, 30,000 times, 1,000,000 times, 300,000 times, 1,000,000 times, 3,000,000 times, 1,000,000 times, 3,000,000 times or more than the affinity of the antibody or antigen-binding fragment for VIP.

31. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment is linked to at least one effector or functional portion and / or one or more detectable portions, such as a fluorescent dye, an enzyme, a substrate, a bioluminescent material, a radioactive material, a chemiluminescent portion, or a mixture thereof.

32. The anti-PACAP antibody and / or its antigen-binding fragment specifically binds to an epitope on the fragment or variant containing human PACAP or a corresponding amino acid residue, and the epitope is a. At least one of human PACAP residues 22, 23, 27, 28, and 31; b. At least one of human PACAP residues 12, 20, 23, 24, 26, 27, and 28; c. At least one of human PACAP residues 19, 22, 23, and 27; d. At least two of the residues from (a), (b), or (c); e. At least three of the residues from (a), (b), or (c); f. At least four of the residues of (a), (b), or (c); g. At least five of the residues in (a) or (b); h. At least six of the residues in (b); i. At least seven of the residues of (b); and j. At least the aforementioned residues 23, 27, and 28 of human PACAP, and optionally one to six of the aforementioned additional residues of (a) and / or (b), A method according to any one of the prior claims, selected from the group consisting of the following.

33. The anti-PACAP antibody and / or its antigen-binding fragment, a. It specifically binds to epitopes on human PACAP (or fragments or variants thereof containing the corresponding amino acid residue present in human wild-type PACAP38), but does not specifically bind to human wild-type human PACAP27; b. Specifically binds to an epitope on a fragment or variant thereof containing human PACAP or a corresponding amino acid residue, wherein the epitope consists of any one of the residues described in (a), (b), or (c) of claim 32; and / or c. Specifically binds to epitopes on human PAC AP (or its fragments or variants containing corresponding amino acid residues) present in human wild-type PACAP38 and human wild-type human PACAP27. The method according to any one of the prior claims.

34. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment does not substantially interact with (bind to) angiotropic intestinal peptide ("VIP").

35. The anti-PACAP antibody and / or its antigen-binding fragment have the following effects: a. Inhibit or neutralize at least one biological effect induced by PACAP; b. Neutralizing or inhibiting the activation of at least one of the following PACAP receptors: PAC1 receptor ("PAC1-R"), vasoactive intestinal peptide receptor type 1 ("VPAC1-R"), and / or vasoactive intestinal peptide receptor type 2 ("VPAC2-R"); c. Neutralize or inhibit the activation of each of the PACAP molecules: PAC1-R, VPAC1-R, and VPAC2-R; d. Neutralizes or inhibits PAC1-R's PACAP activation; e. It can inhibit the binding of PACAP to at least one of PAC1-R, VPAC1-R, and VPAC2-R; f. The binding of PACAP to each of PAC1-R, VPAC1-R, and / or VPAC2-R can be inhibited; g. It can inhibit the binding of PACAP to PAC1-R expressing cells; h. For example, the binding of PACAP to the cell surface can be inhibited via glycosaminoglycans ("GAGs"); i. Does not inhibit the PACAP-mediated binding of such antibodies to the cell surface, for example, via GAG; j. Inhibit the PACAP-mediated binding of such antibodies to the cell surface, for example, via GAG; k. Inhibit PACAP-induced cAMP production; and / or l. When administered to the target population, it reduces PACAP-induced vasodilation, photophobia, mast cell degranulation, and / or neuronal activation. The method according to any one of the claims, comprising or causing one of the following.

36. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment is administered as one or more isolated nucleic acid sequences encoding the anti-PACAP antibody and / or antigen-binding fragment, or as one or more vectors containing the one or more isolated nucleic acid sequences.

37. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment is administered as a host cell comprising one or more isolated nucleic acid sequences or one or more vectors as described in claim 36.

38. a. The host cell is a mammalian, bacterial, fungal, yeast, avian, amphibian, plant, or insect cell, or a CHO cell, and optionally: (a) For example, filamentous fungi or yeasts selected from the following genera: Arxiozyma; Ascobotryozyma; Citeromyces; Debaryomyces; Dekkara; Eremothecium; Issatchenkia; Kazachstania; Kluyveromyces; Kodamaea ; Roderomyces; Pachysolen; Pichia; Saccharomyces; Saturnispora; Tetrapisispora; Torulaspora; Williopsis; and Zygosaccharomyces, preferably Pichia, and more preferably Pichia pastris It is pastoris, Pichia methanolica or Hansenula polymorpha (Pichia angusta); or (b) Mammalian cells, for example, selected from: 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 cancer ("HELA") cells; canine kidney cells ("MDCK"); buffalo rat liver ("BRL") cells; human lung cells; human liver ("Hep G2") cells; mouse mammary cancer ("MMT") cells; TRI cells; MRC 5 cells; and FS4 cells; and / or b. The host cell is a CHO cell selected from one of the following subclones or subcell lines: DP12 (CHO K1 dhfr-) cell line, NS0 cell, CHO-DXB11 (CHO-DUKX), CHO-pro3, CHO-DG44, CHO 1-15, CHO DP-12, Lec2, M1WT3, Lec8, or pgsA-745. The method according to claim 37.

39. The method according to any one of the prior claims, wherein the anti-PACAP antibody and / or its antigen-binding fragment is administered before the administration of an opioid.

40. The method according to claim 39, wherein the anti-PACAP antibody and / or its antigen-binding fragment is administered about one or two weeks before opioid administration, or 6, 5, 4, 3, 2, or 1 day before, or 20, 16, 12, 8, 6, 4, 2, or 1 hour before opioid administration.

41. The method according to any one of claims 1 to 38, wherein the anti-PACAP antibody and / or its antigen-binding fragment is administered after the administration of an opioid.

42. The method according to claim 41, wherein the anti-PACAP antibody and / or its antigen-binding fragment is administered within approximately 1 hour, 6 hours, 12 hours, 1 day, 2 days, 4 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 8 months, 10 months, or 1 year after opioid administration.

43. The method according to any one of claims 1 to 38, wherein the anti-PACAP antibody and / or its antigen-binding fragment is administered simultaneously with the administration of an opioid.

44. The method according to any one of the prior claims, comprising the administration of the anti-PACAP antibody and / or antigen-binding fragment and an opioid, wherein the concomitant administration induces an additive or synergistic effect in improving and / or preventing pain such as hyperalgesia, allodynia or opioid-induced pain, optionally opioid-induced pain, optionally opioid-induced chronic migraine, opioid-induced hyperalgesia (OIH), and opioid-induced allodynia (OIA).

45. The method according to any one of the prior claims, wherein the subject has a history or family history of opioid-induced pain selected from the group consisting of opioid-induced chronic migraine, opioid-induced hyperalgesia (OIH), and opioid-induced allodynia (OIA).

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