Pharmaceutical composition

Abstract

This pharmaceutical composition is for treating or preventing anti-neutrophil cytoplasmic antibody-associated vasculitis, and contains an anti-IL-33 antibody as an active ingredient. The pharmaceutical composition according to another embodiment is for reducing the need for surgery in endometriosis patients or adenomyosis uteri patients, and contains an IL-33 antagonist as an active ingredient. The pharmaceutical composition according to another embodiment is for treating or preventing endometriosis or adenomyosis uteri, contains an anti-IL-33 antibody as an active ingredient, is administered once every 2 to 8 weeks, and is administered so that the blood trough level of the anti-IL-33 antibody is 6.7 μg / mL or more.

Description

Pharmaceutical Composition

[0001] The present disclosure relates to pharmaceutical compositions.

[0002] Interleukin-33 (IL-33) is a cytokine belonging to the interleukin-1 family that is thought to play a role in inflammatory conditions. IL-33 is constitutively expressed in the nuclei of epithelial cells and vascular endothelial cells. It is released upon cell destruction following tissue injury due to infection or physical or chemical stress, where it functions as an alarmin. IL-33 expression is also thought to increase in response to stimuli such as lipopolysaccharide, leading to secretion. Extracellularly released IL-33 can activate intracellular signaling by binding to the IL-33 receptor expressed on the cell surface. IL-33 receptors are expressed in various immune system cells and epithelial cells, and IL-33-induced intracellular signaling occurs in these cells.

[0003] Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic small-vessel vasculitis characterized by serum antineutrophil cytoplasmic antibodies (ANCA). It includes three clinical manifestations: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic polyangiitis (EGPA). Patients with AAV exhibit symptoms ranging in severity and scope from painless rhinitis and rash to fulminant renal failure and life-threatening acute pulmonary hemorrhage, reflecting organ damage. Treatment for AAV involves the use of high-dose steroids and immunosuppressants, resulting in toxicities such as infections, other adverse events, and increased mortality (Non-Patent Document 1).

[0004] It has been reported that IL-33 plays an important role in the pathogenesis of AAV, suggesting an interaction between neutrophils, neutrophil extracellular traps (NETs), and B cells (Non-Patent Document 2). It has also been reported that serum IL-33 concentrations are higher in AAV patients compared to healthy adults, particularly in patients with active AAV (Non-Patent Document 3). However, there have been no detailed reports on the role of IL-33 in AAV patients. Even in Non-Patent Document 3, the clinical efficacy of anti-IL-33 antibodies and the like administered to humans for the treatment of AAV has not been verified. In addition, the appropriate dose and administration method that can achieve high therapeutic efficacy and high safety when anti-IL-33 antibodies and the like are administered to humans for the treatment of AAV are unclear.

[0005] On the other hand, there are many reports showing the association between NETs and AAV (Non-Patent Documents 6 and 7). Based on this, it is thought that suppression of NETs formation via IL-33 inhibition by anti-IL-33 antibodies is effective in ameliorating the pathological condition of AAV.

[0006] Endometriosis, a benign, non-cancerous disease in which endometrial tissue grows ectopically, i.e., away from the uterine cavity, affects approximately 10% of all women of reproductive age, and 25-50% of infertile women suffer from endometriosis.

[0007] There are various theories about the cause of endometriosis, but one of the causes is thought to be that endometrial cells travel on menstrual blood to reach other tissues, causing endometrial tissue to develop and proliferate ectopically.

[0008] Adenomyosis is a disease in which lesions similar to endometrium are found in the myometrium (Non-Patent Document 4). Although it shares histological similarities with endometriosis, it is treated as a separate disease due to its different pathogenesis and clinical manifestations. The peak age of onset is in the 40s, and symptoms include dysmenorrhea, lower abdominal pain, lower back pain, infertility, and menorrhagia. The typical clinical symptom is menstrual pain, and many patients complain of pain so severe it interferes with daily life. Patients with adenomyosis may also have endometriosis or uterine fibroids.

[0009] Treatments for endometriosis and adenomyosis include surgical therapy and drug therapy, but these are both symptomatic treatments and no fundamental cure exists. Choosing surgical therapy based on symptoms can result in mental and physical strain, as well as financial issues. For this reason, reducing the need for surgery is desirable for patients. Furthermore, patients with endometriosis and adenomyosis may experience impacts on their daily lives, particularly in terms of work and housework, such as reduced motivation to work and continuous working hours. Therefore, reducing these impacts is also desirable for patients.

[0010] Furthermore, when surgical treatment is selected, a complete cure cannot be achieved due to fertility preservation, and postoperative drug therapy is often used in combination to prevent recurrence. Drugs that can be used in drug therapy include low-dose birth control pills, gonadotropin-releasing hormone (GnRH) agonists such as Leuprorelin, androgen-releasing hormones such as danazol, and progesterone hormones such as dienogest. However, all of these drugs have side effects due to their effects on hormone balance. For example, dienogest is known to increase embryonic mortality when administered to pregnant rats. For this reason, the use of these drugs by pregnant women is contraindicated. Furthermore, many drugs are associated with symptoms of pseudomenopause or pseudopregnancy, resulting in menopausal-like side effects such as infertility, hot flashes, and osteoporosis. Therefore, the development of a highly safe preventive or therapeutic agent for endometriosis or adenomyosis that does not affect pregnancy is anticipated.

[0011] Mbarik et al. have reported that by analyzing the serum and ascites of endometriosis patients, IL-33, which increases with the progression of the disease (stage) in ascites of endometriosis, can be used as a surrogate marker (Non-Patent Document 5). According to the report by Mbarik et al., the concentration of soluble IL-33 receptor (sST2), which functions as an IL-33 antagonist, in ascites is about 100-fold higher than that of IL-33, and similarly to IL-33, it increases with the progression of endometriosis. Therefore, it remains unclear whether IL-33, whose expression is increased in endometriosis, is a cause or a result of the disease, and how it functions in the pathology.

[0012] It has been reported that an IL-33 antagonist can be used to treat localized fibrosis (Patent Document 1). Although Patent Document 1 mentions endometriosis as a type of localized fibrosis, the examples do not examine the therapeutic effect on endometriosis. Patent Document 1 merely lists localized fibrosis as one type of fibrosis, and does not identify the role of IL-33 in endometriosis or other conditions. It has also been reported that an IL-33 antagonist can be used to treat endometriosis or adenomyosis (Patent Document 2). Patent Document 2 describes that an IL-33 antagonist can be administered by continuous infusion or bolus injection at intervals of once a day, once a week, or once a month, or 1 to 7 times a year, and discloses a dose of at least 0.05 μg / kg body weight, but does not disclose any examples of administration to humans.

[0013] Thus, the clinical efficacy of anti-IL-33 antibodies and the like when administered to humans for the treatment of endometriosis or adenomyosis has not been verified in either Patent Documents 1 or 2, or Non-Patent Documents 4 or 5. In addition, the appropriate dose and administration method that can achieve high therapeutic efficacy and high safety when anti-IL-33 antibodies and the like are administered to humans for the treatment of endometriosis or adenomyosis are not clear.

[0014] International Publication No. WO 2016 / 140921 International Publication No. WO 2019 / 045075

[0015] Ann Rheum Dis. 2010;69(6):1036-43. Theranostics. 2020;10(26):12189-203. Rheumatol Int. 2019;39(11):1907-117. Best Pract Res Clin Obstet Gynaecol. 2006;l 20:511-21. Immunolo. Lett. 2015, Vol. 166, p1. Front. Immunol. 2016, 7: 256. Int. Immunopharmacol. 2023, 116:109843.

[0016] The present disclosure provides pharmaceutical compositions for treating or preventing antineutrophil cytoplasmic antibody-associated vasculitis.

[0017] The present disclosure also provides pharmaceutical compositions for reducing the need for surgery in patients with endometriosis or adenomyosis.

[0018] The present disclosure also provides a pharmaceutical composition for reducing the impact of endometriosis or adenomyosis on the daily life of patients with endometriosis or adenomyosis.

[0019] The present disclosure also provides a pharmaceutical composition for treating or preventing endometriosis or adenomyosis.

[0020] The present disclosure includes the following embodiments.

[0021] A pharmaceutical composition according to a first embodiment of the present disclosure is a pharmaceutical composition for treating or preventing anti-neutrophil cytoplasmic antibody-associated vasculitis, and contains an anti-IL-33 antibody as an active ingredient.

[0022] The pharmaceutical composition according to embodiment 2-1 of the present disclosure is a pharmaceutical composition for reducing the need for surgery in patients with endometriosis or adenomyosis, and contains an IL-33 antagonist as an active ingredient.

[0023] The pharmaceutical composition according to embodiment 2-2 of the present disclosure is a pharmaceutical composition for reducing the impact of endometriosis or adenomyosis on daily life in patients with endometriosis or adenomyosis, and contains an IL-33 antagonist as an active ingredient.

[0024] A pharmaceutical composition according to a third embodiment of the present disclosure is a pharmaceutical composition for treating or preventing endometriosis or adenomyosis, which contains an anti-IL-33 antibody as an active ingredient and is administered once every 2 to 8 weeks so that the blood trough level of the anti-IL-33 antibody is 6.7 μg / mL or more.

[0025] According to the first embodiment, a pharmaceutical composition for treating or preventing anti-neutrophil cytoplasmic antibody-associated vasculitis can be provided.

[0026] Furthermore, according to the above-mentioned embodiment 2-1, it is possible to provide a pharmaceutical composition for reducing the need for surgery in patients with endometriosis or adenomyosis.

[0027] Furthermore, according to the above-mentioned embodiment 2-2, it is possible to provide a pharmaceutical composition for reducing the impact of endometriosis or adenomyosis on the daily life of endometriosis or adenomyosis patients.

[0028] Furthermore, according to the third embodiment, a pharmaceutical composition for treating or preventing endometriosis or adenomyosis can be provided.

[0029] FIG. 1-1 is a graph showing that IL-33 is expressed at the tracheal lesion site of MPA and GPA patients with AAV in Example 1-1. FIG. 1-2 is a graph showing that IL-33 activates vascular endothelial cells and promotes neutrophil nettosis in the presence of ANCA, and that nettosis is inhibited by an anti-IL-33 antibody in Example 1-1. FIG. 2-1 is a graph showing details of the clinical trial design in Example 1-2. FIG. 2-2 is a graph showing details of the follow-up survey for adverse events in Example 1-2. FIG. 3-1 shows the results of the HRPQ for work in Example 2-1. (A) is a graph showing the percentage (%) of patients who answered YES to the question, "During the last week, were you unable to work at the scheduled time due to illness / treatment?" and (B) is a graph showing the difference from the baseline for the response to the question, "During the past week, to what extent did illness / treatment affect your work performance?" Figure 3-2 shows the results for the household chores section of the HRPQ in Example 2-1. (A) is a graph showing the percentage (%) of patients who answered YES to the question, "During the last week, was there a time when you were unable to complete your scheduled housework due to illness / treatment?" (B) is a graph showing the difference from the baseline for the response to the question, "To what extent did illness / treatment affect the outcome of your housework during the past week?" Figure 3-3 is a graph showing the time course of serum concentrations of human anti-IL-33 antibodies administered intravenously in a single dose to healthy subjects in five dose groups in Example 2-3. Figure 3-4 is a diagram showing the protocol for subcutaneous or intravenous administration of human anti-IL-33 antibodies to healthy subjects in Example 2-4. Figure 3-5 is a graph showing the time course of serum concentration of a human anti-IL-33 antibody when administered subcutaneously or intravenously in a single dose to healthy subjects in Example 2-4. Figure 3-6 is a graph showing the rate of reduction in the modified B&B scale score for nonmenstrual pelvic pain, the primary endpoint, in Example 2-5.Figure 3-7 is a schematic diagram of the population pharmacokinetic analysis model used to simulate the time course of serum concentration of a human anti-IL-33 antibody when administered subcutaneously in Example 2-6. Figure 3-8 is a graph showing the simulation results, using the analytical model shown in Figure 3-7, of the time course of serum concentration of a human anti-IL-33 antibody when administered subcutaneously once every four weeks at a dose of 60 mg, 200 mg, or 600 mg. Figure 3-9 is a graph showing the simulation results, using the analytical model shown in Figure 3-7, of the time course of serum concentration of a human anti-IL-33 antibody when administered subcutaneously once every two weeks at a dose of 60 mg, 200 mg, or 600 mg. Figure 3-10 is a graph showing the simulation results, using the analytical model shown in Figure 3-7, of the time course of serum concentration of a human anti-IL-33 antibody when administered subcutaneously once every six weeks at a dose of 60 mg, 200 mg, or 600 mg. Figure 3-11 is a graph showing the results of a simulation, using the analytical model shown in Figure 3-7, of the time course of serum concentration of a human anti-IL-33 antibody when administered subcutaneously once every 8 weeks at a dose of 60 mg, 200 mg, or 600 mg.

[0030] To facilitate understanding of this disclosure, the following describes terms used in this disclosure.

[0031] In this specification, the expression "A to B" or the like representing a numerical range is synonymous with "A or more, B or less." Furthermore, in this specification, the expression "A to B, preferably a to b" or the like representing a numerical range is synonymous with "A or more, B or less," "A or more, b or less," "a or more, B or less," and "a or more, b or less."

[0032] [IL-33] IL-33 is a cytokine belonging to the IL-1 family, and human IL-33 consists of 270 amino acids as shown in the amino acid sequence of SEQ ID NO: 48, as disclosed in, for example, WO 2019 / 045075. IL-33 has a chromatin-binding domain on the N-terminal side and an IL-1-like cytokine domain with a molecular weight of 18 kDa and 12 β-strands on the C-terminal side, and further has cathepsin G cleavage sites at positions 95 and 109, an elastase cleavage site at position 99, and a caspase cleavage site at position 178.

[0033] It is believed that during the process of cell necrosis, IL-33 is cleaved by enzymes such as elastase, cathepsin G, or proteinase 3 derived from lysosomes or the like to produce mature (active) fragments, which then function as cytokines. Examples of mature (active) fragments include IL-33 (residues 95 to 270) (IL-33 represented by the amino acid sequence from positions 95 to 270 from the N-terminus of the amino acid sequence represented by SEQ ID NO:48 will be referred to as "IL-33 (residues 95 to 270)"; the same notation will be used hereinafter), IL-33 (residues 99 to 270), IL-33 (residues 109 to 270), IL-33 (residues 112 to 270), etc.

[0034] On the other hand, when cell death is apoptosis, IL-33 is thought to be cleaved at position 178 by caspases activated during the apoptosis process, resulting in an inactive fragment. Examples of inactive fragments include IL-33 (residues 179 to 270).

[0035] When IL-33 is released extracellularly as a cytokine, it binds to the IL-33 receptor and initiates intracellular signal transduction in cells expressing the IL-33 receptor. Signal transduction induced by IL-33 includes, for example, the NF-κB pathway and the MAPKKs pathway, and ultimately induces the production of various cytokines, chemokines, and inflammatory mediators.

[0036] Examples of cytokines induced by IL-33 include TNF-α, IL-1β, interferon (IFN)-γ, IL-6, IL-8, etc. Examples of chemokines induced by IL-33 include CXCL2, CCL2, etc. Examples of inflammatory mediators induced by IL-33 include PGD2, LTB4, etc.

[0037] Cytokines, chemokines, and inflammatory mediators induced by IL-33 are involved in immune cell migration, cytokine production, and degranulation, thereby inducing inflammation. In the present disclosure, IL-33 may be full-length IL-33, an active fragment thereof, or a derivative or mutant thereof, as long as it acts by binding to the IL-33 receptor described below. Furthermore, the IL-33 of the present disclosure may be human IL-33 or IL-33 derived from other organisms. The IL-33 of the present disclosure is preferably human IL-33.

[0038] The IL-33 receptor to which IL-33 binds is composed of a heterodimer of ST2 and IL-1RAcP (IL-1 receptor accessory protein). In the IL-33 receptor, the site that specifically recognizes and binds to IL-33 is present in the extracellular domain of ST2. The IL-33 receptor is expressed in, for example, immune system cells (Th2 cells, mast cells, eosinophils, basophils, macrophages, dendritic cells, NK cells, NKT cells, group 2 innate lymphocytes (natural helper cells), nuocytes, Ih2 (innate helper type 2) cells, etc.), epithelial cells, etc.

[0039] [IL-33 Antagonist] The term "antagonist" refers to a general term for a substance that acts directly on a target, or its ligand or receptor, or its gene (including mRNA produced from the gene by transcription) and has the effect of directly neutralizing the function of the target. Antagonists also include substances that act indirectly on a target and have the effect of indirectly neutralizing the function of the target. For example, antagonists include substances that neutralize the function of a substance that interacts with a target, or that indirectly neutralize the function of a target by suppressing gene expression of the target. Examples of IL-33 antagonists include anti-IL-33 antibodies, anti-IL-33 receptor antibodies, and soluble IL-33 receptors. For example, anti-IL-33 antibodies can bind to the target IL-33 and thereby prevent the association between IL-33 and the IL-33 receptor.

[0040] [IL-33 Receptor] The ST2 gene, which encodes a subunit of the IL-33 receptor, encodes a transmembrane (ST2L) protein, but also encodes a secreted protein lacking the transmembrane and intracellular domains through alternative splicing. The full-length amino acid sequence of human ST2L is represented by SEQ ID NO:49. Among these, ST2L associates with another IL-33 receptor subunit, for example, IL-1RAcP, to form an IL-33 receptor (heterodimer), which activates the intracellular signal transduction pathway when IL-33 binds to the extracellular domain of ST2L. Therefore, ST2L is sometimes simply referred to as the IL-33 receptor.

[0041] [Soluble IL-33 Receptor] The soluble IL-33 receptor is a protein consisting of a part or all of the extracellular domain of the ST2L protein (residues 19 to 328 of the amino acid sequence represented by SEQ ID NO: 49). The soluble IL-33 receptor of the present disclosure can be one that functions as an IL-33 antagonist by binding to IL-33.

[0042] The soluble IL-33 receptor may be optionally modified to improve pharmacokinetics, for example, by binding polyethylene glycol or an antibody constant region. In particular, a soluble IL-33 receptor bound to an antibody constant region may be referred to as sST2-Fc. sST2-Fc can form a dimer, similar to an antibody.

[0043] The constant region of the antibody that can bind may be a constant region derived from any organism, but a human antibody constant region is preferred from the viewpoint of ensuring low antigenicity. As sST2-Fc, human sST2-Fc (for example, a fusion protein of the extracellular region of human ST2L protein and the constant region of human IgG antibody (SEQ ID NO: 50)) is preferred.

[0044] Soluble IL-33 receptors such as sST2-Fc can be produced using an in vitro production system that uses a vector containing a nucleic acid encoding the soluble IL-33 receptor. Examples of in vitro production systems include those that use eukaryotic cells, such as animal cells, plant cells, or fungal cells, and those that use prokaryotic cells, such as bacterial cells such as Escherichia coli and Bacillus subtilis. Examples of animal cells that can be used include commonly used mammalian cells, such as CHO, COS, myeloma, BHK, HeLa, Vero, 293, NS0, Namalwa, and YB2 / 0, as well as insect cells. The protein produced in this manner can be further purified to isolate the soluble IL-33 receptor.

[0045] [Antibody] The term "antibody" is used in the broadest sense and includes various antibodies, such as monoclonal antibodies and polyclonal antibodies, with or without additional functional molecules attached, as well as fragments thereof, so long as they exhibit the desired specific binding properties. The antibody in the present disclosure may be an antibody derived from any animal, such as a mouse antibody, human antibody, rat antibody, rabbit antibody, goat antibody, or camel antibody.

[0046] [Monoclonal Antibodies] Monoclonal antibodies are antibodies from an antibody population consisting of only a single clone (single molecular species) in the designed amino acid sequence. Monoclonal antibodies include chimeric antibodies, humanized antibodies, human antibodies, multispecific antibodies, artificial antibodies, functionally modified antibodies thereof, conjugated antibodies thereof, and fragments thereof. These may be used for purposes such as reducing heterologous antigenicity to the subject or adding additional functions. Monoclonal antibodies can be produced using any known method, such as the hybridoma method, phage display method, or genetic engineering method.

[0047] [Chimeric Antibody] A chimeric antibody is an antibody in which the light chain, the heavy chain, or both are composed of a variable region of a non-human immunoglobulin and a constant region of a human immunoglobulin.

[0048] [Humanized Antibody] A humanized antibody is an antibody that comprises a variable region consisting of a complementarity-determining region of a non-human immunoglobulin and a framework region derived from a human immunoglobulin, and a constant region derived from a human immunoglobulin.

[0049] [Human antibody] A human antibody refers to an antibody in which both the light chain and the heavy chain are derived from human immunoglobulin. Depending on the difference in the heavy chain constant region, human antibodies include IgG (including IgG1, IgG2, IgG3, and IgG4) having a γ heavy chain, IgM having a μ heavy chain, IgA (including IgA1 and IgA2) having an α heavy chain, IgD having a δ heavy chain, or IgE having an ε heavy chain. In principle, the light chain includes either a κ chain or a λ chain.

[0050] [Framework Region] The framework region refers to the portion of the variable region of an immunoglobulin molecule other than the complementarity determining region. There are four framework regions (framework region 1, framework region 2, framework region 3, and framework region 4) in each of the light chain and heavy chain. In the present disclosure, the framework regions of an immunoglobulin molecule are determined according to the Kabat numbering system (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, US Department of Health and Human Services, NIH, USA).

[0051] [Multispecific antibodies] Multispecific antibodies are antibodies that have two or more independent antigen recognition sites with two or more different antigen specificities and can be asymmetric. Examples of multispecific antibodies include bispecific antibodies with two antigen specificities and trispecific antibodies with three antigen specificities.

[0052] [Artificial Antibodies] Artificial antibodies are, for example, protein scaffolds that do not have the structure of immunoglobulin but have the same functions as immunoglobulin. Protein scaffolds include the Kunitz domain of human serine protease inhibitors, the extracellular domain of human fibronectin, ankyrin, lipocalin, etc., and by modifying the sequence of the target binding site on the scaffold, it is possible to generate a protein scaffold that binds to an epitope (Clifford Mintz et al., BioProcess International, 2013, Vol. 11(2), pp. 40-48).

[0053] [Functionally modified antibodies] Functionally modified antibodies refer to antibodies whose functions other than the antigen-binding function, such as cell-killing function and complement activation function, have been adjusted by modifying the amino acids or sugar chains, mainly in the constant region of the immunoglobulin, as well as antibodies whose blood half-life, etc. have been adjusted.

[0054] [Conjugated antibody] A conjugated antibody is an antibody to which a functional molecule other than an antibody, such as a non-peptide polymer such as polyethylene glycol (PEG), a radioactive substance, a toxin, a low molecular weight compound, a cytokine, albumin, or an enzyme, is chemically or genetically bound.

[0055] [Fragment] A fragment is a protein containing a portion of an antibody and capable of binding to an antigen. Examples of antibody fragments include Fab fragments, Fv fragments, F(ab')2 fragments, Fab' fragments, and scFv. Furthermore, these antibody fragments may be chemically or genetically bound to functional molecules other than antibodies, such as non-peptide polymers such as polyethylene glycol (PEG), radioactive substances, toxins, low-molecular-weight compounds, cytokines, albumin, and enzymes.

[0056] [Human Monoclonal Antibody] A human monoclonal antibody refers to a monoclonal antibody having variable and constant regions derived from human germline immunoglobulin sequences. In the present disclosure, the variable regions of a human monoclonal antibody may be recombinant with part or all of the variable regions of another human monoclonal antibody. In such recombinants, recombination may occur at the boundaries between the framework regions and the complementarity-determining regions (CDRs) to avoid affecting the binding ability of the antibody. Furthermore, in the present disclosure, each of framework regions 1 to 4 may be recombinant with each of framework regions 1 to 4 of another human monoclonal antibody to avoid increasing immunogenicity. Furthermore, in the present disclosure, the human monoclonal antibody may be a mutant of a human monoclonal antibody. Furthermore, in order to reduce immunogenicity while maintaining or improving antigen binding, a human monoclonal antibody containing a complementarity-determining region amino acid sequence with a mutation in the CDR of the human monoclonal antibody and a germline framework region amino acid sequence without a mutation in the framework region is preferred. The human monoclonal antibodies of the present disclosure also include monoclonal antibodies derived from transgenic mice into which human antibody genes have been introduced, and antibodies derived from a human antibody gene library.

[0057] Neutralization refers to the ability to inhibit the function of any of its targets. Inhibition of the function (biological activity) of IL-33 includes, for example, inhibition of the production of IL-33-induced cytokines such as IL-6. Indicators of the biological activity of IL-33 can be assessed by one or more of several in vitro or in vivo assays known in the art.

[0058] [Complementarity-Determining Region] A complementarity-determining region refers to a region of the variable region of an immunoglobulin molecule that forms an antigen-binding site, and refers to a portion where there is particularly large variation in amino acid sequence between immunoglobulin molecules. A complementarity-determining region is also called a hypervariable region. There are three complementarity-determining regions (complementarity-determining region 1, complementarity-determining region 2, and complementarity-determining region 3) in each of the light chain and heavy chain. In the present disclosure, the complementarity-determining regions of an immunoglobulin molecule are determined according to the Kabat numbering system.

[0059] Percent (%) Identity of an Amino Acid Sequence: Percent (%) identity of an amino acid sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a specific reference polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity, and excluding any conservative substitutions from being considered part of the sequence identity. Alignment for purposes of determining percent identity can be achieved by a variety of methods within the skill of one in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximum alignment over the full length of the sequences being compared. For example, percent identity can be obtained by using the sequence comparison computer program BLAST in pairwise alignments.

[0060] In situations where BLAST is used for amino acid sequence comparison, the percent identity of a given amino acid sequence A with a given amino acid sequence B is calculated as follows: 100 times the fraction X / Y

[0061] where X is the number of amino acid residues scored as identical by the program alignment of A and B using the sequence alignment program BLAST, and Y is the total number of amino acid residues in B. It is understood that if the length of amino acid sequence A is different from the length of amino acid sequence B, the % identity of A to B will differ from the % identity of B to A.

[0062] [Variable region] The variable region refers to the portion of a monoclonal antibody other than the constant region. The variable region is involved in binding to an antigen and determines the antibody specificity, which varies depending on the antigen. The variable region includes a heavy chain variable region and a light chain variable region.

[0063] [Aptamer] An aptamer is a nucleic acid molecule that specifically binds to a specific substance, and in the present disclosure refers to a molecule that binds to IL-33, an IL-33 receptor, etc., and functions as an IL-33 antagonist. The aptamer in the present disclosure may include an artificial nucleic acid molecule in addition to a natural nucleic acid molecule.

[0064] [Antisense] Antisense refers to an antisense nucleic acid (RNA or DNA) that can hybridize to target gene RNA and has the function of suppressing gene expression. In the present disclosure, "antisense" refers to a molecule that functions as an IL-33 antagonist, binding to the mRNA of IL-33 or IL-33 receptor to suppress gene expression. In the present disclosure, antisense may include artificial nucleic acid molecules in addition to natural nucleic acid molecules.

[0065] [Anti-neutrophil cytoplasmic antibody-associated vasculitis] Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic vasculitis of small vessels characterized by serum anti-neutrophil cytoplasmic antibodies (ANCA), and is classified into microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). AAV is a systemic disease that causes vasculitis in multiple organs, including the kidneys, lungs, skin, and nervous system. The kidneys are particularly susceptible to damage caused by AAV, particularly MPA. AAV-induced organ damage exclusively in the kidneys is called renal-limited vasculitis (RLV). The pharmaceutical composition of the present disclosure is preferably applicable to RLV caused by AAV, in addition to AAV.

[0066] In the present disclosure, AAV refers to a diagnosis of MPA, GPA, or EGPA based on the 2022 ACR / EULAR Classification Criteria (see "Arthritis & Rheumatology, Vol. 74, No. 3, March 2022, pp. 386-392.", "Arthritis & Rheumatology, Vol. 74, No. 3, March 2022, pp. 393-399.", and "Arthritis & Rheumatology, Vol. 74, No. 3, March 2022, pp. 400-406.").

[0067] Endometriosis is a benign, non-cancerous disease characterized by the ectopic growth of endometrial tissue at sites distant from the uterine cavity, i.e., ectopically. These distant sites include the ovaries, abdominal cavity, peritoneum, Douglas's pouch, sigmoid colon, rectum, uterosacral ligament, vagina, vulva, bladder, abdominal wall, and navel. Ectopic endometrial tissue may form adhesions with various organs. Endometrial hematomas in the ovaries are sometimes called chocolate cysts.

[0068] For the definitive diagnosis of endometriosis, laparoscopy is used to directly observe ectopic endometrial tissue. For the classification of the clinical progression stage of endometriosis, the Re-ASRM classification is used, which is scored according to the location of the lesion, whether it is superficial or deep, and the degree of adhesion to various organs, and is considered to fall into one of stages 1 to 4. For the follow-up observation of endometriosis, the Beecham classification is used, which is considered to fall into one of stages 1 to 4 depending on the progression of the disease.

[0069] Examples of endometriosis include superficial endometriosis and deep endometriosis.

[0070] Adenomyosis is a disease in which endometrial tissue is found within the myometrium of the uterus. Based on MRI findings, adenomyosis is classified into partial adenomyosis, which is limited to a portion of the uterus, and circumferential adenomyosis, which extends throughout the uterus (Bergeron et al., Best Pract Res Clin Obstet Gynaecol. 2006;1 20:511-21).

[0071] Hereinafter, embodiments of the present disclosure will be described. Note that the following embodiments are examples for explaining the present disclosure, and the present disclosure is not limited to these embodiments. Furthermore, the examples of the embodiments in the present disclosure can be mutually incorporated.

[0072] The pharmaceutical composition according to the first embodiment of the present disclosure is a pharmaceutical composition for treating or preventing antineutrophil cytoplasmic antibody-associated vasculitis.

[0073] Furthermore, the pharmaceutical composition according to embodiment 2-1 of the present disclosure is a pharmaceutical composition for reducing the need for surgery in patients with endometriosis or adenomyosis.

[0074] Furthermore, the pharmaceutical composition according to embodiment 2-2 of the present disclosure is a pharmaceutical composition for reducing the impact of endometriosis or adenomyosis on the daily life of endometriosis or adenomyosis patients.

[0075] Furthermore, the pharmaceutical composition according to the third embodiment of the present disclosure is a pharmaceutical composition for treating or preventing endometriosis or adenomyosis.

[0076] In the present disclosure, "treatment or prevention" may be referred to as "treatment, etc." Furthermore, in the present disclosure, "treatment" includes "improvement."

[0077] <First embodiment: Pharmaceutical composition for treating or preventing anti-neutrophil cytoplasmic antibody-associated vasculitis> As described above, the pharmaceutical composition according to the first embodiment of the present disclosure is a pharmaceutical composition for treating or preventing anti-neutrophil cytoplasmic antibody-associated vasculitis.

[0078] As shown in the Examples below, when IL-33 expression in the lungs of MPA and GPA patients with AAV was examined by immunohistochemical staining, expression was observed in airway epithelial cells, alveoli, and vascular endothelial cells of AAV patients, with enhanced expression observed at inflammatory sites ( Figure 1-1 ). Next, to investigate the involvement of IL-33 in AAV patients, the expression of downstream molecules of the IL-33 signaling pathway was examined in the plasma of AAV patients. As a result, significant changes in the expression of several downstream molecules of IL-33 were confirmed compared to healthy controls. Among these, we focused on IL-6 and IL-8, which are representative downstream molecules of IL-33, and performed a correlation analysis with the symptoms of AAV patients. As a result, both IL-6 and IL-8 were highly correlated with Birmingham Vasculitis Activity Score (BVAS), ANCA antibody titer, C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR) level, and IgG level, suggesting that IL-6 and IL-8 may be useful biomarkers for AAV, and suggesting the involvement of IL-33, an upstream molecule, in AAV. Furthermore, as shown in the Examples below, stimulation of human umbilical vein endothelial cells (HUVECs) with IL-33 promoted the induction of neutrophil nephrosis induced by ANCA stimulation compared to unstimulated cells, suggesting that IL-33 is involved in the pathogenesis of AAV by inducing the activation of vascular endothelial cells (Figures 1-2).

[0079] As used herein, "neutrophil netosis" refers to programmed cell death specific to neutrophils. Neutrophils undergoing netosis form extracellular net-like structures called neutrophil extracellular traps (NETs). In AAV, ANCA stimulation induces neutrophil netosis, and the neutrophils attack vascular endothelial cells and die.

[0080] From the above, the inventors discovered that IL-33 plays an important role in the pathogenesis of AAV, and that among IL-33 downstream molecules, IL-6 and IL-8 are useful biomarkers for AAV, and have completed the pharmaceutical composition according to the first embodiment of the present disclosure.

[0081] That is, the pharmaceutical composition of the first embodiment contains an anti-IL-33 antibody as an active ingredient. The pharmaceutical composition of the first embodiment can be applied to a subject by appropriately combining, for example, the following compositions, subjects, administration conditions, etc.

[0082] The subjects to which the pharmaceutical composition of the first embodiment is administered are as follows.

[0083] When the pharmaceutical composition of the first embodiment is used to treat antineutrophil cytoplasmic antibody-associated vasculitis, the subject is preferably a subject suffering from antineutrophil cytoplasmic antibody-associated vasculitis, and more preferably a subject who has been definitively diagnosed as suffering from antineutrophil cytoplasmic antibody-associated vasculitis. A definitive diagnosis means a diagnosis in which a doctor has confirmed that the subject has antineutrophil cytoplasmic antibody-associated vasculitis.

[0084] When the pharmaceutical composition of the first embodiment is used to prevent antineutrophil cytoplasmic antibody-associated vasculitis, the recipient is preferably one who is likely to suffer from antineutrophil cytoplasmic antibody-associated vasculitis, and more preferably one who has been diagnosed as being likely to suffer from antineutrophil cytoplasmic antibody-associated vasculitis.

[0085] The subject of administration is a human or a mammal other than a human, preferably a human. A human suffering from antineutrophil cytoplasmic antibody-associated vasculitis may be referred to as a "patient."

[0086] When the subject is a human, the subject may be an adult human or a non-adult human, for example, 18 years of age or older.

[0087] When the subject of administration is a mammal other than a human, the subject may be of an age corresponding to the age of an adult human, or may be of an age corresponding to the age of a non-adult human. The age of a human and the age of a mammal other than a human can be converted as appropriate.

[0088] The pharmaceutical composition of the first embodiment contains an anti-IL-33 antibody as an active ingredient.

[0089] The anti-IL-33 antibody may be a monoclonal antibody, a polyclonal antibody, or a fragment thereof. Furthermore, the anti-IL-33 antibody may be an antibody derived from any animal, such as a mouse antibody, a human antibody, a rat antibody, a rabbit antibody, a goat antibody, or a camel antibody.

[0090] The anti-IL-33 antibody is preferably a monoclonal antibody, more preferably a chimeric monoclonal antibody, a humanized monoclonal antibody, or a human monoclonal antibody, and even more preferably a human monoclonal antibody.

[0091] Examples of human anti-IL-33 monoclonal antibodies include A10-1C04, A23-1A05, A25-2C02, A25-3H04, A26-1F02, etc. The amino acid sequences of the heavy chains and light chains contained in these human anti-IL-33 monoclonal antibodies are represented by SEQ ID NOs: 1 and 2 (A10-1C04), SEQ ID NOs: 3 and 4 (A23-1A05), SEQ ID NOs: 5 and 6 (A25-2C02), SEQ ID NOs: 7 and 8 (A25-3H04), and SEQ ID NOs: 9 and 10 (A26-1F02), respectively.

[0092] When an antibody containing a constant region is used, the constant region is preferably a constant region of a human antibody, more preferably a constant region of human IgG1.

[0093] For details of these monoclonal antibodies, see, for example, WO 2015 / 099175 and WO 2020 / 054871.

[0094] Other known anti-IL-33 antibodies include, for example, etokimab (also known as ANB-020), REGN-3500 (also known as SAR-440340), MEDI-3506, PF-06817024, and CBP-233.

[0095] The amino acid sequences of the heavy and light chains contained in A10-1C04 ​​may be those in which one or more amino acids have been substituted, deleted, inserted, or added in the amino acid sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2, respectively, as long as A10-1C04 ​​has an IL-33 antagonistic activity.

[0096] The number of residues is an integer selected from 2 to "the value obtained by multiplying the number of amino acid residues in the amino acid sequence by 0.2, with any decimal point being rounded down."

[0097] However, if the obtained value (rounded down to the nearest decimal point) is 0, it is determined that one or more amino acids are not substituted, deleted, inserted, or added in the amino acid sequence.

[0098] Furthermore, when the obtained value (rounded down to the nearest decimal point) is 1, it means that one amino acid may be substituted, deleted, inserted or added in the amino acid sequence.

[0099] Therefore, for example, the plurality is an integer selected from 2 to 89 for the amino acid sequence represented by SEQ ID NO: 1. For the amino acid sequence represented by SEQ ID NO: 2, the plurality is an integer selected from 2 to 43.

[0100] This also applies to other human anti-IL-33 monoclonal antibodies. That is, for example, in the case of A23-1A05, the amino acid sequences of the heavy chain and light chain contained in A23-1A05 may be those in which one to several amino acids have been substituted, deleted, inserted, or added in the amino acid sequences shown in SEQ ID NO: 3 and SEQ ID NO: 4, respectively, as long as A23-1A05 has an IL-33 antagonistic activity. The "several" is as defined above.

[0101] Furthermore, as long as A10-1C04 ​​has an IL-33 antagonistic activity, the amino acid sequences of the heavy and light chains contained in A10-1C04 ​​may be amino acid sequences that have a predetermined percentage identity with the amino acid sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2, respectively. The predetermined percentage identity means identity of 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more.

[0102] This also applies to other human anti-IL-33 monoclonal antibodies. That is, for example, in the case of A23-1A05, the amino acid sequences of the heavy chain and light chain contained in A23-1A05 may be amino acid sequences that have a predetermined % identity with the amino acid sequences shown in SEQ ID NO: 3 and SEQ ID NO: 4, respectively, as long as A23-1A05 has an IL-33 antagonistic activity. The predetermined % identity is the same as described above.

[0103] Among these, preferably, the human anti-IL-33 monoclonal antibody comprises: a heavy chain consisting of an amino acid sequence that has 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more identity to the amino acid sequence set forth in SEQ ID NO: 1; and a light chain consisting of an amino acid sequence that has 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more identity to the amino acid sequence set forth in SEQ ID NO: 2. Use of this human anti-IL-33 monoclonal antibody enables more effective treatment of AAV, etc.

[0104] The human anti-IL-33 monoclonal antibody may be an antibody whose complementarity-determining region has the amino acid sequence shown in (a1) to (e1) below. For details of these monoclonal antibodies, see, for example, the contents of WO 2020 / 054871.

[0105] Hereinafter, the first, second and third complementarity determining regions of the heavy chain will be referred to as H1, H2 and H3, respectively, and the first, second and third complementarity determining regions of the light chain will be referred to as L1, L2 and L3, respectively.

[0106] (a1) A10-1C04: SEQ ID NO: 11 (H1), SEQ ID NO: 12 (H2), SEQ ID NO: 13 (H3), SEQ ID NO: 14 (L1), SEQ ID NO: 15 (L2), and SEQ ID NO: 16 (L3) (b1) A23-1A05: SEQ ID NO: 17 (H1), SEQ ID NO: 18 (H2), SEQ ID NO: 19 (H3), SEQ ID NO: 20 (L1), SEQ ID NO: 21 (L2), and SEQ ID NO: 22 (L3) (c1) A25-2C02: SEQ ID NO: 17 (H1), SEQ ID NO: 23 (H2), SEQ ID NO: 24 (H3), SEQ ID NO: 25 (L1), SEQ ID NO: 26 (L2), and SEQ ID NO: 27 (L3) (d1) A25-3H04: SEQ ID NO: 28 (H1), SEQ ID NO: 29 (H2), SEQ ID NO: 30 (H3), SEQ ID NO: 25 (L1), SEQ ID NO: 31 (L2), and SEQ ID NO: 32 (L3) (e1) A26-1F02: SEQ ID NO: 17 (H1), SEQ ID NO: 33 (H2), SEQ ID NO: 34 (H3), SEQ ID NO: 35 (L1), SEQ ID NO: 36 (L2), and SEQ ID NO: 37 (L3)

[0107] Among these, preferably, the human anti-IL-33 monoclonal antibody comprises: H1 consisting of the amino acid sequence represented by SEQ ID NO: 11; H2 consisting of the amino acid sequence represented by SEQ ID NO: 12; H3 consisting of the amino acid sequence represented by SEQ ID NO: 13; L1 consisting of the amino acid sequence represented by SEQ ID NO: 14; L2 consisting of the amino acid sequence represented by SEQ ID NO: 15; and L3 consisting of the amino acid sequence represented by SEQ ID NO: 16. Use of this human anti-IL-33 monoclonal antibody enables more effective treatment of AAV.

[0108] The amino acid sequences of H1, H2, H3, L1, L2, and L3 contained in A10-1C04 ​​may be those in which one to several amino acids have been substituted, deleted, inserted, or added in the amino acid sequences represented by SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16, respectively, as long as A10-1C04 ​​has an IL-33 antagonistic activity. The "several" is as defined above.

[0109] The same applies to other human anti-IL-33 monoclonal antibodies. That is, for example, in the case of A23-1A05, the amino acid sequences of H1, H2, H3, L1, L2, and L3 contained in A23-1A05 may be those in which one to several amino acids have been substituted, deleted, inserted, or added in the amino acid sequences represented by SEQ ID NOs: 17, 18, 19, 20, 21, and 22, respectively, as long as A23-1A05 has an IL-33 antagonistic activity. The "several" is as defined above.

[0110] Furthermore, the amino acid sequences of H1, H2, H3, L1, L2, and L3 contained in A10-1C04 ​​may be amino acid sequences that have a predetermined % identity with the amino acid sequences represented by SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16, respectively, so long as A10-1C04 ​​has an IL-33 antagonistic activity. The predetermined % identity is as described above.

[0111] The same applies to other human anti-IL-33 monoclonal antibodies. That is, for example, in the case of A23-1A05, the amino acid sequences of H1, H2, H3, L1, L2, and L3 contained in A23-1A05 may be amino acid sequences that have a specified % identity with the amino acid sequences represented by SEQ ID NOs: 17, 18, 19, 20, 21, and 22, respectively, as long as A23-1A05 has an IL-33 antagonistic activity. The specified % identity is as described above.

[0112] The human anti-IL-33 monoclonal antibody may be an antibody whose heavy chain variable region and light chain variable region have the amino acid sequences shown in (a2) to (e2) below. For details of these monoclonal antibodies, see, for example, the contents of WO 2020 / 054871.

[0113] (a2) A10-1C04: SEQ ID NO: 38 (heavy chain variable region) and SEQ ID NO: 39 (light chain variable region) (b2) A23-1A05: SEQ ID NO: 40 (heavy chain variable region) and SEQ ID NO: 41 (light chain variable region) (c2) A25-2C02: SEQ ID NO: 42 (heavy chain variable region) and SEQ ID NO: 43 (light chain variable region) (d2) A25-3H04: SEQ ID NO: 44 (heavy chain variable region) and SEQ ID NO: 45 (light chain variable region) (e2) A26-1F02: SEQ ID NO: 46 (heavy chain variable region) and SEQ ID NO: 47 (light chain variable region)

[0114] The amino acid sequences of the heavy chain variable region and light chain variable region contained in A10-1C04 ​​may be those of the amino acid sequences represented by SEQ ID NO: 38 and SEQ ID NO: 39, respectively, in which one to more amino acids have been substituted, deleted, inserted, or added, as long as A10-1C04 ​​has an IL-33 antagonistic activity. The "multiple" here refers to the same as above. In this case, it is preferred that the heavy chain variable region comprises H1 consisting of the amino acid sequence represented by SEQ ID NO: 11, H2 consisting of the amino acid sequence represented by SEQ ID NO: 12, and H3 consisting of the amino acid sequence represented by SEQ ID NO: 13, and the light chain variable region comprises L1 consisting of the amino acid sequence represented by SEQ ID NO: 14, L2 consisting of the amino acid sequence represented by SEQ ID NO: 15, and L3 consisting of the amino acid sequence represented by SEQ ID NO: 16, and that the one to more amino acid substitutions, deletions, insertions, or additions have been made in amino acid sequences other than those of H1, H2, H3, L1, L2, and L3.

[0115] This also applies to other human anti-IL-33 monoclonal antibodies. That is, for example, in the case of A23-1A05, the amino acid sequences of the heavy chain variable region and the light chain variable region contained in A23-1A05 may be those in which one to several amino acids have been substituted, deleted, inserted, or added in the amino acid sequences shown in SEQ ID NO: 40 and SEQ ID NO: 41, respectively, as long as A23-1A05 has an IL-33 antagonistic activity. The "several" is as defined above. In this case, it is preferable that the heavy chain variable region comprises H1 consisting of the amino acid sequence represented by SEQ ID NO: 17, H2 consisting of the amino acid sequence represented by SEQ ID NO: 18, and H3 consisting of the amino acid sequence represented by SEQ ID NO: 19, and the light chain variable region comprises L1 consisting of the amino acid sequence represented by SEQ ID NO: 20, L2 consisting of the amino acid sequence represented by SEQ ID NO: 21, and L3 consisting of the amino acid sequence represented by SEQ ID NO: 22, and that the substitution, deletion, insertion, or addition of one to several amino acids is made in an amino acid sequence other than the amino acid sequences of H1, H2, H3, L1, L2, and L3.

[0116] Furthermore, the amino acid sequences of the heavy chain variable region and the light chain variable region contained in A10-1C04 ​​may be amino acid sequences that have a predetermined % identity with the amino acid sequences represented by SEQ ID NO: 38 and SEQ ID NO: 39, respectively, as long as A10-1C04 ​​has an IL-33 antagonistic activity. The predetermined % identity is the same as described above. In this case, it is preferable that the heavy chain variable region includes H1 consisting of the amino acid sequence represented by SEQ ID NO: 11, H2 consisting of the amino acid sequence represented by SEQ ID NO: 12, and H3 consisting of the amino acid sequence represented by SEQ ID NO: 13, and the light chain variable region includes L1 consisting of the amino acid sequence represented by SEQ ID NO: 14, L2 consisting of the amino acid sequence represented by SEQ ID NO: 15, and L3 consisting of the amino acid sequence represented by SEQ ID NO: 16, and that the predetermined % identity is achieved by substitution, deletion, insertion, or addition of one to several amino acids in an amino acid sequence other than the amino acid sequences of H1, H2, H3, L1, L2, and L3.

[0117] This also applies to other human anti-IL-33 monoclonal antibodies. That is, for example, in the case of A23-1A05, the amino acid sequences of the heavy chain variable region and the light chain variable region contained in A23-1A05 may have a predetermined identity with the amino acid sequences shown in SEQ ID NO: 40 and SEQ ID NO: 41, respectively, as long as A23-1A05 has an IL-33 antagonistic activity. The predetermined identity is the same as described above. In this case, it is preferable that the heavy chain variable region comprises H1 consisting of the amino acid sequence represented by SEQ ID NO: 17, H2 consisting of the amino acid sequence represented by SEQ ID NO: 18, and H3 consisting of the amino acid sequence represented by SEQ ID NO: 19, and the light chain variable region comprises L1 consisting of the amino acid sequence represented by SEQ ID NO: 20, L2 consisting of the amino acid sequence represented by SEQ ID NO: 21, and L3 consisting of the amino acid sequence represented by SEQ ID NO: 22, and that the substitution, deletion, insertion, or addition of one to several amino acids has been made in an amino acid sequence other than the amino acid sequences of H1, H2, H3, L1, L2, and L3, resulting in a predetermined % identity.

[0118] Among these, preferably, the human anti-IL-33 monoclonal antibody comprises: a heavy chain variable region consisting of an amino acid sequence that is 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more identical to the amino acid sequence set forth in SEQ ID NO: 38; and a light chain variable region consisting of an amino acid sequence that is 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more identical to the amino acid sequence set forth in SEQ ID NO: 39. Use of this human anti-IL-33 monoclonal antibody enables more effective treatment of AAV, etc.

[0119] Preferred amino acid sequences of the framework regions of anti-IL-33 antibodies include the following: that is, the amino acid sequence of light chain framework region 1 is residues 1 to 22 of the amino acid sequence represented by SEQ ID NO:51, the amino acid sequence of light chain framework region 2 is residues 36 to 50 of the amino acid sequence represented by SEQ ID NO:51, the amino acid sequence of light chain framework region 3 is residues 58 to 89 of the amino acid sequence represented by SEQ ID NO:51, and the amino acid sequence of light chain framework region 4 is residues 3 to 12 of the amino acid sequence represented by SEQ ID NO:52, and the amino acid sequence of heavy chain framework region 1 is residues 1 to 30 of the amino acid sequence represented by SEQ ID NO:53 or residues 1 to 30 of the amino acid sequence represented by SEQ ID NO:54, the amino acid sequence of heavy chain framework region 2 is residues 36 to 49 of the amino acid sequence represented by SEQ ID NO:53 or residues 36 to 49 of the amino acid sequence represented by SEQ ID NO:54, the amino acid sequence of heavy chain framework region 3 is residues 67 to 98 of the amino acid sequence represented by SEQ ID NO:53 or residues 67 to 98 of the amino acid sequence represented by SEQ ID NO:54, and The amino acid sequence of framework region 4 of the heavy chain is residues 5 to 15 of the amino acid sequence shown in SEQ ID NO:55.

[0120] More preferred amino acid sequences of the framework regions of the anti-IL-33 antibody include the following: the amino acid sequence of light chain framework region 1 is residues 1 to 22 of the amino acid sequence set forth in SEQ ID NO:51, the amino acid sequence of light chain framework region 2 is residues 36 to 50 of the amino acid sequence set forth in SEQ ID NO:51, the amino acid sequence of light chain framework region 3 is residues 58 to 89 of the amino acid sequence set forth in SEQ ID NO:51, and the amino acid sequence of light chain framework region 4 is residues 3 to 12 of the amino acid sequence set forth in SEQ ID NO:52; and the amino acid sequence of heavy chain framework region 1 is residues 1 to 30 of the amino acid sequence set forth in SEQ ID NO:53, the amino acid sequence of heavy chain framework region 2 is residues 36 to 49 of the amino acid sequence set forth in SEQ ID NO:53, the amino acid sequence of heavy chain framework region 3 is residues 67 to 98 of the amino acid sequence set forth in SEQ ID NO:54, and the amino acid sequence of heavy chain framework region 4 is residues 5 to 15 of the amino acid sequence set forth in SEQ ID NO:55.

[0121] The amino acid sequence of framework region 1 of the light chain contained in the anti-IL-33 antibody may be one in which one to several amino acids have been substituted, deleted, inserted, or added in the amino acid sequence represented by residues 1 to 22 of the amino acid sequence represented by SEQ ID NO: 51, as long as the anti-IL-33 antibody has an IL-33 antagonistic activity. The "several" is as defined above.

[0122] This also applies to other framework regions. That is, for example, in the case of framework region 2 of the light chain contained in an anti-IL-33 antibody, the amino acid sequence of framework region 2 of the light chain may be one in which one to several amino acids have been substituted, deleted, inserted, or added in the amino acid sequence represented by residues 36 to 50 of the amino acid sequence represented by SEQ ID NO: 51, as long as the anti-IL-33 antibody has an IL-33 antagonistic activity. The "several" is as defined above.

[0123] Furthermore, the amino acid sequence of framework region 1 of the light chain contained in the anti-IL-33 antibody may be an amino acid sequence that has a predetermined identity with the amino acid sequence represented by residues 1 to 22 of the amino acid sequence represented by SEQ ID NO: 51, as long as the anti-IL-33 antibody has an IL-33 antagonistic activity. The predetermined identity is the same as described above.

[0124] This also applies to other framework regions. That is, for example, in the case of framework region 2 of the light chain contained in an anti-IL-33 antibody, the amino acid sequence of framework region 2 of the light chain may be an amino acid sequence that has a predetermined identity with the amino acid sequence represented by residues 36 to 50 of the amino acid sequence represented by SEQ ID NO: 51, as long as the anti-IL-33 antibody has an IL-33 antagonist activity. The predetermined identity is the same as described above.

[0125] The pharmaceutical composition of the first embodiment may contain only one type of anti-IL-33 antibody, or may contain two or more types of anti-IL-33 antibodies.

[0126] Conditions for administering the pharmaceutical composition of the first embodiment to a subject include the administration route, the number of administrations, the administration interval, the single dose, etc. Any of the administration conditions can be appropriately selected in consideration of, for example, the symptoms and age of the subject, as well as whether the desired effect is exerted and safety is ensured (for example, avoiding unwanted side effects).

[0127] The route of administration of the pharmaceutical composition of the first embodiment may be parenteral or oral, with parenteral being preferred. That is, the pharmaceutical composition of the first embodiment may be administered parenterally or orally, with parenteral administration being preferred.

[0128] Examples of parenteral administration include intravenous administration, intraarterial administration, subcutaneous administration, topical administration, intraperitoneal administration, intramuscular administration, nasal administration, ophthalmic administration, transdermal administration, transmucosal administration, intrathecal administration, rectal administration, and intravaginal administration.

[0129] Among parenteral administrations, from the viewpoint of achieving both sustained supply of the anti-IL-33 antibody to the body of the administration subject and sustained desired effects associated with the administration, intravenous administration, intraarterial administration, subcutaneous administration, or intramuscular administration is preferred, and from the viewpoint of convenience for the administration subject, intravenous administration or subcutaneous administration is more preferred.

[0130] Furthermore, when the administration route is subcutaneous administration, for example, the burden of administration on the administration subject by an administering person other than the administration subject himself / herself can be significantly reduced. Furthermore, when the administration subject is a human, it is highly convenient in that the administration can be performed by the administration subject himself / herself, and the burden of administration on the administration subject himself / herself can also be significantly reduced.

[0131] The pharmaceutical composition of the first embodiment may be administered to a subject once (i.e., one treatment, etc.) or multiple times (i.e., multiple treatments at intervals, etc.).

[0132] In the case of multiple administrations, the interval between administrations can be, for example, several months (e.g., any period between 1 month and 18 months, any period between 1 month and 12 months, etc.), several weeks (e.g., any period between 1 week and 78 weeks, any period between 1 week and 52 weeks, any period between 2 and 8 weeks, 2 weeks, 4 weeks, 6 weeks, 8 weeks, etc.), several days (e.g., any period between 1 day and 6 days, etc.), or several hours (e.g., any period between 1 hour and 24 hours, etc.).

[0133] That is, for example, administration can be performed once every few months, once every few weeks, once every few days, or once every few hours. Among these, administration is preferably performed once every 2 to 8 weeks, more preferably once every 4 weeks. By maintaining the administration interval as described above, AAV can be treated more effectively.

[0134] The administration intervals may be constant or may vary. If the administration intervals vary, the administration intervals may be gradually shortened or gradually lengthened.

[0135] Furthermore, the lower limit of the number of administrations is, for example, 1, 2, 3, 4, 5, 6, 7, or 8 times, and the upper limit is, for example, 78, 66, 54, 8, or 5 times. It may be within a range of any compatible combination thereof. Specifically, it may be 1 to 78 times, 2 to 78 times, 2 to 66 times, 2 to 54 times, 3 to 8 times, 6 to 8 times, or 3 to 5 times, or the respective upper limit or lower limit itself. Among these, the number of administrations is preferably 3 to 8 times, and more preferably 6 to 8 times. By having the number of administrations within the above range, AAV can be more effectively treated, etc.

[0136] Therefore, for example, when the drug is administered once every four weeks, the total number of administrations may have a lower limit of, for example, two times, and an upper limit of, for example, 20 times, 17 times, 14 times, etc. It may also be any range of a consistent combination thereof. Specifically, it may be 2 to 20 times, 2 to 17 times, 2 to 14 times, or the respective upper limit or lower limit itself.

[0137] The single dose of the pharmaceutical composition of the first embodiment can be selected as appropriate and can be increased or decreased as appropriate.

[0138] In the first embodiment, "one administration" includes, for example, both an embodiment in which the entire dose is administered literally in one procedure, and an embodiment in which the entire dose is administered by performing multiple administration procedures within an extremely short period of time that can be considered as one administration. The latter embodiment includes, for example, an embodiment in which the desired dose is administered within a few minutes using multiple vials.

[0139] The pharmaceutical composition of the first embodiment may or may not be administered rapidly, depending on the route of administration, and may or may not be administered continuously by infusion or the like.

[0140] A single dose of the pharmaceutical composition of the first embodiment can be selected so that the anti-IL-33 antibody reaches a predetermined blood trough level or higher in a subject, from the viewpoint of achieving the desired effect and ensuring safety. The predetermined blood trough level can be determined as appropriate by a person skilled in the art. The "blood trough level" may also be referred to as "trough blood concentration level," "trough serum concentration level," "trough blood concentration," etc.

[0141] The predetermined blood trough value is, for example, the IL-6 production inhibitory concentration IC shown in the Examples below. ９０ Alternatively, for example, the IL-8 production inhibitory concentration IC ９０ Taking into consideration the above, an example of the predetermined blood trough level is 6.7 μg / mL. Furthermore, from the viewpoint of ensuring that the effect is reliably exerted while taking into consideration individual differences and the like, examples of the predetermined blood trough level include 15.0 μg / mL, 17.5 μg / mL, 18.3 μg / mL, etc. Among these, the predetermined blood trough level is preferably 3.8 μg / mL from the viewpoint of inhibiting at least IL-6 production, and more preferably 6.7 μg / mL, even more preferably 15.0 μg / mL, and particularly preferably 18.3 μg / mL from the viewpoint of inhibiting the production of IL-6 and IL-8. When the blood trough level of the anti-IL-33 antibody in the subject to be administered is equal to or higher than the above value, AAV can be more effectively treated, etc.

[0142] When the pharmaceutical composition of the first embodiment is administered to a subject so that the anti-IL-33 antibody reaches a predetermined blood trough level or higher in the subject, the administration interval of the pharmaceutical composition of the first embodiment can be, for example, any period between 1 month and 12 months, any period between 1 week and 52 weeks, any period between 2 and 8 weeks, 2 weeks, 4 weeks, 6 weeks, 8 weeks, etc. That is, the pharmaceutical composition can be administered, for example, once every period between 1 month and 12 months, any period between 1 week and 52 weeks, any period between 2 and 8 weeks, every 2 weeks, every 4 weeks, every 6 weeks, or every 8 weeks.

[0143] The single dose of the pharmaceutical composition of the first embodiment may be set as a single dose of the anti-IL-33 antibody, for example, per body weight (kg) of the subject to be administered, or may be set as a dose per individual subject to be administered.

[0144] When the single dose of the pharmaceutical composition of the first embodiment is determined as the dose per body weight (kg) of the subject to be administered, the lower limit of the single dose of the anti-IL-33 antibody is, for example, 0.05 μg / kg, 1 μg / kg, 10 μg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.6 mg / kg, 6 mg / kg, etc., and the upper limit is, for example, 50 mg / kg, 25 mg / kg, 20 mg / kg, 10 mg / kg, 8 mg / kg, 6 mg / kg, etc. Any compatible combination of these ranges may also be used.

[0145] Specific examples include 0.05 μg / kg to 50 mg / kg, 1 μg / kg to 25 mg / kg, 10 μg / kg to 20 mg / kg, 0.1 mg / kg to 10 mg / kg, 0.2 mg / kg to 8 mg / kg, 0.3 mg / kg to 6 mg / kg, 0.6 mg / kg to 6 mg / kg, 6 mg / kg to 10 mg / kg, and the respective upper limits and lower limits.

[0146] When the single dose of the pharmaceutical composition of the first embodiment is set as the dose per individual subject, the lower limit of the single dose of the anti-IL-33 antibody is, for example, 50 mg, 60 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, etc., and the upper limit is, for example, 2000 mg, 1900 mg, 1800 mg, 1700 mg, 1600 mg, 1500 mg, 1400 mg, 1300 mg, 1200 mg, 1100 mg, 1000 mg, 950 mg, 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650 mg, 600 mg, 300 mg, 250 mg, 200 mg, 70 mg, etc. Any compatible combination of these ranges may also be used.

[0147] Specifically, for example, 50 mg to 2000 mg, 50 mg to 1000 mg, 700 mg to 2000 mg, 700 mg to 1900 mg, 600 mg to 1800 mg, 600 mg to 1700 mg, 500 mg to 1600 mg, 500 mg to 1500 mg, 400 mg to 1400 mg, 400 mg to 1300 mg, 300 mg to 1200 mg, 300 mg to 1100 mg, 400 mg to 1100 mg, 250 mg to 1000 mg, 250 mg g to 950 mg, 200 mg to 900 mg, 200 mg to 850 mg, 200 mg to 600 mg, 150 mg to 800 mg, 150 mg to 750 mg, 60 mg to 700 mg, 100 mg to 700 mg, 100 mg to 650 mg, 60 mg to 600 mg, 100 mg to 300 mg, 60 mg to 300 mg, 50 mg to 250 mg, 50 mg to 200 mg, 50 mg to 70 mg, and also the respective upper limits and the respective lower limits.

[0148] When the administration route of the pharmaceutical composition of the first embodiment is intravenous administration, the single dose of the pharmaceutical composition of the first embodiment can be set as the single dose of the anti-IL-33 antibody, for example, per body weight (kg) of the subject to be administered.

[0149] In this case, the lower limit is, for example, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.6 mg / kg, 6 mg / kg, etc., and the upper limit is, for example, 10 mg / kg, 8 mg / kg, 6 mg / kg, etc. Any non-consistent combination thereof may also be used.

[0150] Specifically, for example, 0.1 mg / kg to 10 mg / kg, 0.2 mg / kg to 10 mg / kg, 0.3 mg / kg to 10 mg / kg, 0.6 mg / kg to 10 mg / kg, 0.1 mg / kg to 8 mg / kg, 0.2 mg / kg to 8 mg / kg, 0.3 mg / kg to 8 mg / kg, 0.6 mg / kg to 8 mg / kg, 0.1 mg / kg to 6 mg / kg, 0.2 mg / kg to 6 mg / kg, 0.3 mg / kg to 6 mg / kg, 0.6 mg / kg to 6 mg / kg, 6 mg / kg to 10 mg / kg, and the respective upper and lower limits thereof are included. Among these, 0.1 mg / kg to 10 mg / kg is preferred, 6 mg / kg to 10 mg / kg is more preferred, and 6 mg / kg is even more preferred. By setting the single dose as described above, AAV can be more effectively treated, etc.

[0151] When the route of administration of the pharmaceutical composition of the first embodiment is intravenous administration, examples of the administration interval of the pharmaceutical composition of the first embodiment include any period between 1 month and 12 months, any period between 1 week and 52 weeks, any period between 2 and 8 weeks, 2 weeks, 4 weeks, 6 weeks, 8 weeks, etc. That is, for example, the composition can be administered once every period between 1 month and 12 months, every period between 1 week and 52 weeks, every period between 2 and 8 weeks, every 2 weeks, every 4 weeks, every 6 weeks, or every 8 weeks.

[0152] When the route of administration of the pharmaceutical composition of the first embodiment is intravenous administration, the pharmaceutical composition of the first embodiment may or may not be administered rapidly, and may or may not be administered continuously by infusion or the like.

[0153] When the route of administration of the pharmaceutical composition of the first embodiment is subcutaneous administration, the single dose of the pharmaceutical composition of the first embodiment can be set as the single dose of the anti-IL-33 antibody, for example, as the dose per individual subject to be administered.

[0154] In this case, the lower limit is, for example, 50 mg, 60 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 700 mg, etc., and the upper limit is, for example, 2000 mg, 1900 mg, 1800 mg, 1700 mg, 1600 mg, 1500 mg, 1400 mg, 1300 mg, 1200 mg, 1100 mg, 1000 mg, 950 mg, 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650 mg, 600 mg, 300 mg, etc. Ranges may also be any non-consistent combination thereof.

[0155] Specifically, for example, 50 mg to 2000 mg, 50 mg to 1000 mg, 50 mg to 1900 mg, 50 mg to 1800 mg, 60 mg to 1700 mg, 60 mg to 1600 mg, 60 mg to 1500 mg, 100 mg to 1400 mg, 100 mg to 1300 mg, 100 mg to 1200 mg, 150 mg to 1100 mg, 150 mg to 1000 mg, 200 mg to 600 mg g, 200 mg to 950 mg, 200 mg to 900 mg, 250 mg to 850 mg, 250 mg to 800 mg, 300 mg to 750 mg, 60 mg to 700 mg, 300 mg to 700 mg, 400 mg to 1100 mg, 500 mg to 650 mg, 500 mg to 600 mg, 100 mg to 300 mg, 700 mg to 1900 mg, or the respective upper and lower limits. Of these, 50 mg to 2000 mg is preferred. A single dose as described above allows for more effective treatment of AAV.

[0156] When the route of administration of the pharmaceutical composition of the first embodiment is subcutaneous administration, examples of the administration interval of the pharmaceutical composition of the first embodiment include any period between 1 month and 12 months, any period between 1 week and 52 weeks, any period between 2 and 8 weeks, 2 weeks, 4 weeks, 6 weeks, 8 weeks, etc. That is, for example, the composition can be administered once every period between 1 month and 12 months, every period between 1 week and 52 weeks, every period between 2 and 8 weeks, every 2 weeks, every 4 weeks, every 6 weeks, or every 8 weeks.

[0157] When the route of administration of the pharmaceutical composition of the first embodiment is subcutaneous administration, the pharmaceutical composition of the first embodiment may or may not be administered by bolus administration.

[0158] When the pharmaceutical composition of the first embodiment is administered subcutaneously, the anti-IL-33 antibody concentration in the subject reaches or exceeds the predetermined blood trough level under the following administration conditions.

[0159] When administered once every two weeks, the dose is 100 mg to 300 mg; when administered once every four weeks, the dose is 200 mg to 600 mg; when administered once every six weeks, the dose is 400 mg to 1100 mg; and when administered once every eight weeks, the dose is 700 mg to 1900 mg.

[0160] From the viewpoint of further exerting the desired effect, the anti-IL-33 antibody contained in the pharmaceutical composition of the first embodiment is preferably A10-1C04.

[0161] When the anti-IL-33 antibody contained in the pharmaceutical composition of the first embodiment is A10-1C04 ​​and the route of administration is intravenous administration, the single dose of the pharmaceutical composition of the first embodiment can be set as the single dose of the anti-IL-33 antibody, for example, per body weight (kg) of the subject to be administered.

[0162] In this case, the lower limit is, for example, 0.1 mg / kg, 0.6 mg / kg, 6 mg / kg, etc., and the upper limit is, for example, 10 mg / kg, 6 mg / kg, etc. Any non-consistent combination thereof may also be used.

[0163] Specific examples include 0.1 mg / kg to 10 mg / kg, 0.6 mg / kg to 6 mg / kg, 6 mg / kg to 10 mg / kg, and the respective upper limits and lower limits.

[0164] When the anti-IL-33 antibody contained in the pharmaceutical composition of the first embodiment is A10-1C04 ​​and the route of administration is intravenous administration, the administration interval of the pharmaceutical composition of the first embodiment can be, for example, any period between 2 and 8 weeks, 4 weeks, etc. That is, for example, the composition can be administered once every any period between 2 and 8 weeks, or once every 4 weeks.

[0165] When the anti-IL-33 antibody contained in the pharmaceutical composition of the first embodiment is A10-1C04 ​​and the administration route is intravenous administration, the pharmaceutical composition of the first embodiment may or may not be administered by rapid administration, or may or may not be administered by continuous administration such as by infusion.

[0166] When the anti-IL-33 antibody contained in the pharmaceutical composition of the first embodiment is A10-1C04 ​​and the route of administration is subcutaneous administration, the single dose of the pharmaceutical composition of the first embodiment can be set as the single dose of the anti-IL-33 antibody, for example, as the dose per individual subject to be administered.

[0167] In this case, the lower limit is, for example, 50 mg, 60 mg, 150 mg, 200 mg, 500 mg, 600 mg, etc., and the upper limit is, for example, 2000 mg, 1500 mg, 1200 mg, 1000 mg, 700 mg, 600 mg, 250 mg, 200 mg, 70 mg, etc. Any non-consistent combination of these ranges may also be used.

[0168] Specifically, the ranges are 50 mg to 2000 mg, 50 mg to 1000 mg, 600 mg to 2000 mg, 600 mg to 1500 mg, 600 mg to 1200 mg, 600 mg to 1000 mg, 60 mg to 700 mg, 500 mg to 700 mg, 200 mg to 600 mg, 150 mg to 250 mg, 60 mg to 200 mg, 50 mg to 70 mg, and the respective upper limits and lower limits.

[0169] When the anti-IL-33 antibody contained in the pharmaceutical composition of the first embodiment is A10-1C04 ​​and the route of administration is subcutaneous administration, the administration interval of the pharmaceutical composition of the first embodiment can be, for example, any period between 2 and 8 weeks, 4 weeks, etc. That is, for example, the composition can be administered once every any period between 2 and 8 weeks, or once every 4 weeks.

[0170] When the anti-IL-33 antibody contained in the pharmaceutical composition of the first embodiment is A10-1C04 ​​and the administration route is subcutaneous administration, the pharmaceutical composition of the first embodiment may or may not be administered by bolus administration.

[0171] The content of the anti-IL-33 antibody contained in the pharmaceutical composition of the first embodiment may have a lower limit of, for example, 1 mg / mL, 5 mg / mL, 10 mg / mL, 125 mg / mL, etc., and an upper limit of, for example, 200 mg / mL, 175 mg / mL, 150 mg / mL, 15 mg / mL, etc. Any compatible combination of these ranges may also be used.

[0172] Specifically, for example, 1 mg / mL to 200 mg / mL, 5 mg / mL to 175 mg / mL, 5 mg / mL to 150 mg / mL, 10 mg / mL to 150 mg / mL, 125 mg / mL to 175 mg / mL, 5 mg / mL to 15 mg / mL, each upper limit itself, each lower limit itself, etc.

[0173] When the anti-IL-33 antibody contained in the pharmaceutical composition of the first embodiment is A10-1C04 ​​and the route of administration is subcutaneous administration, the content of A10-1C04 ​​in the pharmaceutical composition of the first embodiment, i.e., the concentration, is preferably 125 mg / mL to 175 mg / mL, from the viewpoints of reducing excessive resistance during administration and minimizing the amount of administration solution to enhance convenience for the administering person and the recipient.

[0174] When the anti-IL-33 antibody contained in the pharmaceutical composition of the first embodiment is A10-1C04 ​​and the route of administration is intravenous administration, from the same viewpoint, the content, i.e., concentration, of A10-1C04 ​​in the pharmaceutical composition of the first embodiment has a lower limit of, for example, 125 mg / mL, 150 mg / mL, etc., and an upper limit of, for example, 175 mg / mL, 150 mg / mL, etc. It may also be within a range of any compatible combination thereof. Specifically, for example, the range may be 125 mg / mL to 175 mg / mL, 125 mg / mL to 150 mg / mL, 150 mg / mL to 175 mg / mL, or the respective upper limits or lower limits themselves. It is preferably 125 mg / mL to 175 mg / mL, more preferably 150 mg / mL.

[0175] The dosage form of the pharmaceutical composition of the first embodiment is preferably a dosage form suitable for parenteral administration when the route of administration of the pharmaceutical composition of the first embodiment is parenteral administration, and is preferably a dosage form suitable for oral administration when the route of administration is oral administration.

[0176] When the administration route of the pharmaceutical composition of the first embodiment is parenteral administration, from the viewpoint of high convenience, it is preferably in the form of a liquid or solid at 1 atmosphere and 20° C., such as an injection, an infusion preparation, or a powder that dissolves when used. When the pharmaceutical composition of the first embodiment is for intravenous or subcutaneous administration, it is preferably in the form of a liquid when used.

[0177] The pharmaceutical composition of the first embodiment may consist solely of an anti-IL-33 antibody, or may further contain, in addition to the anti-IL-33 antibody, other active ingredients, formulation additives (which may be pharmaceutically acceptable carriers), and the like.

[0178] Examples of other active ingredients include the above-mentioned IL-33 antagonists other than anti-IL-33 antibodies, as well as anti-inflammatory drugs, immunosuppressants, etc. One or more other active ingredients can be used.

[0179] Examples of pharmaceutical additives include various salts, diluents such as water, excipients, stabilizers, preservatives, soothing agents, emulsifiers, buffers, surfactants, osmotic pressure adjusters, etc. One or more pharmaceutical additives can be used.

[0180] In addition, the pharmaceutical composition of the first embodiment may further contain, for example, the components described in WO 2020 / 054871. One or more of such components can be used.

[0181] In the following description, when the pharmaceutical composition of the first embodiment is a liquid, it is preferably prepared as described below. When the pharmaceutical composition of the first embodiment is a solid, it is preferably prepared so that it becomes the following embodiment when dissolved or dispersed in a liquid such as water.

[0182] From the viewpoint of long-term storage stability, the pharmaceutical composition of the first embodiment preferably has a salt concentration within a predetermined range or less. Specifically, the lower the salt concentration, the more preferable it is, and the salt concentration may be, for example, 30 mmol / L or less, 10 mmol / L or less, 5 mmol / L or less, etc. Furthermore, the pharmaceutical composition may be salt-free, and may have a salt concentration of 0 or more.

[0183] Examples of salts include alkali metal salts such as sodium chloride and calcium sulfate; salts of alkaline earth metals and inorganic acids; and organic salts.

[0184] The pharmaceutical composition of the first embodiment preferably contains a buffering agent from the viewpoints of long-term storage stability and reducing irritation upon administration.

[0185] Examples of the buffer include organic acid salts such as gluconate, citrate, succinate, acetate, etc.; inorganic acid salts such as phosphate; amino acids; trishydroxymethylaminomethane, etc. One or more types of buffer can be used.

[0186] When the buffer is a salt, examples of the counter ion include alkali metal ions such as sodium and potassium ions.

[0187] When the buffering agent is an amino acid, examples include natural amino acids such as histidine, glycine, and arginine.

[0188] The content of the buffer in the pharmaceutical composition of the first embodiment may have a lower limit of, for example, 1 mmol / L, 3 mmol / L, 5 mmol / L, 8 mmol / L, 9 mmol / L, or 10 mmol / L, and an upper limit of, for example, 150 mmol / L, 100 mmol / L, 30 mmol / L, 20 mmol / L, 15 mmol / L, 12 mmol / L, 11 mmol / L, or 10 mmol / L. The content may also be within a range of any compatible combination thereof. Specific examples of the content may include 1 to 150 mmol / L, 3 to 100 mmol / L, 5 to 30 mmol / L, 5 to 20 mmol / L, 5 to 15 mmol / L, 8 to 12 mmol / L, 9 to 11 mmol / L, 10 to 20 mmol / L, or 1 to 10 mmol / L.

[0189] The buffer preferably contains histidine, and is preferably histidine. In either case, the lower limit of the histidine content in the pharmaceutical composition of the first embodiment is, for example, 5 mmol / L, 8 mmol / L, or 9 mmol / L, and the upper limit is, for example, 20 mmol / L, 15 mmol / L, 12 mmol / L, or 11 mmol / L. The content may be within a range of any compatible combination thereof. Specifically, the content is preferably 5 to 20 mmol / L, more preferably 5 to 15 mmol / L, even more preferably 8 to 12 mmol / L, and particularly preferably 9 to 11 mmol / L.

[0190] In the pharmaceutical composition of the first embodiment, from the viewpoint of reducing irritation upon administration, the pH at 20°C may have a lower limit of, for example, 4.0, 5.0, 5.5, 5.7, 5.8, 5.9, or 6.0, and an upper limit of, for example, 8.0, 7.0, 6.5, 6.3, 6.2, 6.1, or 6.0. Specifically, the pH may be 4.0 to 8.0, 5.0 to 7.0, 5.5 to 6.5, 5.7 to 6.3, 5.8 to 6.2, 5.9 to 6.1, or 6.0 to 8.0. A consistent combination thereof may also be used. To achieve such a range, for example, a buffer may be used in the above-described content range. In particular, the pH at 0°C may have a lower limit of, for example, 5.5, 5.7, or 5.8, and an upper limit of, for example, 6.5, 6.3, 6.2, or 6.1. A consistent combination thereof may also be used. Specifically, it is preferably 5.5 to 6.5, more preferably 5.7 to 6.3, even more preferably 5.8 to 6.2, and particularly preferably 5.9 to 6.1.

[0191] The pharmaceutical composition of the first embodiment preferably contains a surfactant from the viewpoint of improving ease of handling during administration.

[0192] Examples of surfactants include nonionic surfactants, ionic surfactants, zwitterionic surfactants, etc. One or more surfactants may be used.

[0193] Examples of nonionic surfactants include polyoxyethylene alkyl ethers (such as poloxamer 188) and polyoxyethylene sorbitan fatty acid esters (such as polysorbate 20, 40, 60, or 80).

[0194] Examples of ionic surfactants include C １０ ~C １８ Alkyl sulfate, polyoxyethylene sodium alkyl sulfate, C １ ~C １８ Examples thereof include alkyl sulfosuccinate salts.

[0195] Examples of zwitterionic surfactants include soybean phospholipids, egg yolk phospholipids, phosphatidylcholine, phosphatidylethanolamine, serine phospholipids, inositol phospholipids, and phosphatidic acid.

[0196] The surfactant content in the pharmaceutical composition of the first embodiment may have a lower limit of, for example, 0.001% (w / v), 0.005% (w / v), 0.01% (w / v), or 0.02% (w / v), and an upper limit of, for example, 0.1% (w / v), 0.05% (w / v), 0.03% (w / v), or 0.02% (w / v). The surfactant content may also be within a range of any compatible combination thereof. Specifically, the surfactant content may be, for example, 0.001% (w / v) to 0.1% (w / v), 0.005% (w / v) to 0.05% (w / v), 0.01% (w / v) to 0.03% (w / v), or 0.02% (w / v) to 0.05% (w / v).

[0197] The surfactant preferably comprises a nonionic surfactant, and is preferably a nonionic surfactant. The surfactant more preferably comprises polysorbate 80, and is more preferably polysorbate 80. In either case, the content of the surfactant in the pharmaceutical composition of the first embodiment is preferably 0.01% (w / v) to 0.03% (w / v).

[0198] The pharmaceutical composition of the first embodiment preferably contains an osmotic pressure adjuster from the viewpoints of suppressing unintended formation of aggregates and reducing irritation during administration. Examples of osmotic pressure adjusters include polyhydric alcohols having two or more hydroxyl groups in their structure, specifically glycerin, propylene glycol, polyethylene glycol (PEG), etc. Other examples include sugars, specifically D-sorbitol, sucrose, trehalose, mannitol, etc. One or more osmotic pressure adjusters can be used.

[0199] The lower limit of the content of the osmotic pressure adjuster in the pharmaceutical composition of the first embodiment is, for example, 50 mmol / L, 165 mmol / L, i.e., 3% (w / v), 175 mmol / L, 190 mmol / L, 200 mmol / L, etc., and the upper limit is, for example, 300 mmol / L, 275 mmol / L, i.e., 5% (w / v), 250 mmol / L, 230 mmol / L, 210 mmol / L, 200 mmol / L, etc. Any compatible combination of these ranges may also be used.

[0200] Specifically, for example, the concentration can be 50 mmol / L to 300 mmol / L, 165 mmol / L to 275 mmol / L, that is, 3% (w / v) to 5% (w / v), 175 mmol / L to 250 mmol / L, 190 mmol / L to 230 mmol / L, 200 mmol / L to 210 mmol / L, 190 mmol / L to 200 mmol / L, etc.

[0201] The osmotic pressure adjuster preferably contains D-sorbitol, and is preferably D-sorbitol. In either case, the lower limit of the D-sorbitol content in the pharmaceutical composition of the first embodiment is, for example, 165 mmol / L, 190 mmol / L, etc., and the upper limit is, for example, 275 mmol / L, 230 mmol / L, 210 mmol / L, etc. The D-sorbitol content may be within a range of any compatible combination thereof. Specifically, the range is preferably 165 mmol / L to 275 mmol / L, more preferably 190 mmol / L to 230 mmol / L, and even more preferably 190 mmol / L to 210 mmol / L.

[0202] In another embodiment of the present disclosure, there is provided:

[0203] That is, in another embodiment of the present disclosure, there is provided a method for treating, etc., anti-neutrophil cytoplasmic antibody-associated vasculitis, comprising administering a therapeutically effective amount of an anti-IL-33 antibody to a subject in need of such treatment, etc., for anti-neutrophil cytoplasmic antibody-associated vasculitis.

[0204] In another embodiment of the present disclosure, there is provided a method for treating, etc., anti-neutrophil cytoplasmic antibody-associated vasculitis, comprising administering a therapeutically effective amount of a pharmaceutical composition containing an anti-IL-33 antibody as an active ingredient to a subject in need of such treatment, etc., for anti-neutrophil cytoplasmic antibody-associated vasculitis.

[0205] In another embodiment of the present disclosure, there is provided use of an anti-IL-33 antibody for producing a pharmaceutical composition for treating anti-neutrophil cytoplasmic antibody-associated vasculitis, etc.

[0206] In another embodiment of the present disclosure, an anti-IL-33 antibody is provided for use in the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis, etc.

[0207] In another embodiment of the present disclosure, a pharmaceutical composition comprising an anti-IL-33 antibody is provided for use in the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis, etc.

[0208] <Second embodiment: Pharmaceutical composition for reducing the need for surgery in patients with endometriosis or adenomyosis; and pharmaceutical composition for reducing the impact of endometriosis or adenomyosis on the daily lives of patients with endometriosis or adenomyosis> As described above, the pharmaceutical composition according to embodiment 2-1 of the present disclosure is a pharmaceutical composition for reducing the need for surgery in patients with endometriosis or adenomyosis.

[0209] Furthermore, the pharmaceutical composition according to embodiment 2-2 of the present disclosure is a pharmaceutical composition for reducing the impact of endometriosis or adenomyosis on the daily life of endometriosis or adenomyosis patients.

[0210] [Embodiment 2-1: Pharmaceutical composition for reducing the need for surgery in patients with endometriosis or adenomyosis] The pharmaceutical composition of Embodiment 2-1 contains an IL-33 antagonist as an active ingredient. The pharmaceutical composition of Embodiment 2-1 can be administered to patients by appropriately combining, for example, the following compositions, patients, administration conditions, etc.

[0211] In the present disclosure, the "need for surgery" may be, for example, a doctor's judgment or recognition that surgery must be performed on a patient, or a patient's own judgment or recognition that surgery must be performed, or both.

[0212] According to the pharmaceutical composition of embodiment 2-1, for example, in cases where a physician judges or recognizes that surgery must be performed on a patient, or where the patient himself judges or recognizes that surgery must be performed, or in both of these cases where surgery is difficult due to physical and mental strain, cost, or the like, the need for surgery for the patient can be reduced by administering an IL-33 antagonist to the patient as an active ingredient.

[0213] The "need for surgery" can be rephrased as, for example, the "possibility of surgery." The "possibility of surgery" may mean, for example, that a doctor will perform surgery on a patient in the future, or that the patient himself will undergo surgery in the future, or it may be both.

[0214] The operation may be, for example, a surgical operation such as resection.

[0215] The "need for surgery" is preferably assessed by one or more selected from the group consisting of PSIQ and SSIQ.

[0216] PSIQ is an abbreviation for Physician Surgery Intention Question. This interview allows for a score to be generated to evaluate the likelihood that a doctor will recommend surgery for an endometriosis-related disease (including endometriosis and adenomyosis; the same applies below) to a patient if current symptoms persist. The relatively higher the score, the more likely the doctor will recommend surgery to the patient, and the relatively lower the score, the less likely the doctor will recommend surgery to the patient. The PSIQ is a known interview method. The questions and scoring criteria in the PSIQ can be set arbitrarily by, for example, a doctor, a diagnostic institution, etc., and specific examples include the questions and criteria in the examples described below.

[0217] SSIQ is an abbreviation for Subject Surgery Intention Question. This interview can evaluate a patient's willingness to undergo surgery for endometriosis-related disease if their current symptoms persist by scoring them. It can be assessed that the higher the score, the more willing the patient is to undergo surgery, and the lower the score, the less willing the patient is to undergo surgery. Furthermore, since the SSIQ is a patient interview, the score indirectly serves as an indicator of the likelihood that a doctor will recommend surgery for endometriosis-related disease to a patient if their current symptoms persist. It can also be assessed that the higher the score, the more likely the doctor will recommend surgery to the patient, and the lower the score, the less likely the doctor will recommend surgery to the patient. The SSIQ is a well-known interview method. The questions and scoring criteria in the SSIQ can be arbitrarily set by, for example, a doctor, a diagnostic institution, etc., and specific examples include the questions and criteria in the Examples described below.

[0218] The subject to which the pharmaceutical composition of the 2-1 embodiment is administered is a patient with endometriosis or adenomyosis, i.e., a female human who is an endometriosis patient or an adenomyosis patient, and is preferably a patient who has been definitively diagnosed as suffering from endometriosis or adenomyosis. A definitive diagnosis means a diagnosis in which a doctor has confirmed that the patient has endometriosis or adenomyosis, and is made, for example, by directly confirming uterine lesions using an endoscope such as a laparoscope, as described above.

[0219] The patient may be an adult female human or a non-adult female human, for example, an adult may be 18 years of age or older.

[0220] The pharmaceutical composition of embodiment 2-1 contains an IL-33 antagonist as an active ingredient. Details of the IL-33 antagonist are as described above. That is, examples of the IL-33 antagonist include an anti-IL-33 antibody, an anti-IL-33 receptor antibody, and a soluble IL-33 receptor.

[0221] Details of the anti-IL-33 antibody are as described above.

[0222] An anti-IL-33 receptor antibody is an antibody that can bind to the IL-33 receptor and neutralize the action of IL-33.

[0223] The anti-IL-33 receptor antibody may be a monoclonal antibody, a polyclonal antibody, or a fragment thereof. Furthermore, the anti-IL-33 receptor antibody may be derived from any animal, such as a mouse antibody, human antibody, rat antibody, rabbit antibody, goat antibody, or camel antibody.

[0224] The anti-IL-33 receptor antibody is preferably a monoclonal antibody, more preferably a chimeric monoclonal antibody, a humanized monoclonal antibody, or a human monoclonal antibody.

[0225] Examples of human anti-IL-33 receptor antibodies include RG-6149 (also referred to as AMG-282, MSTT1041A, or RO-7187807), GSK-3772847 (also referred to as CNTO-7160), and LY-3375880.

[0226] The details of the soluble IL-33 receptor are as described above, and it is a protein consisting of all or part of the extracellular domain of the ST2L protein (residues 19 to 328 of the amino acid sequence represented by SEQ ID NO: 49). As the soluble IL-33 receptor of the present disclosure, one that functions as an IL-33 antagonist by binding to IL-33 can be used.

[0227] The amino acid sequence of a part or the whole of the extracellular domain of the ST2L protein may be a part or the whole of the amino acid sequence from residue 19 to residue 328 of the amino acid sequence represented by SEQ ID NO: 49, in which one to several amino acids have been substituted, deleted, inserted, or added. The "several" is the same as above. For example, in the case of the entire amino acid sequence of the extracellular domain of the ST2L protein, the number of amino acids is an integer selected from 2 to 62.

[0228] Furthermore, a part or all of the amino acid sequence of the extracellular domain of the ST2L protein may be an amino acid sequence that has a predetermined identity with a part or all of the amino acid sequence from residue 19 to residue 328 of the amino acid sequence represented by SEQ ID NO: 49. The predetermined identity is the same as described above.

[0229] Furthermore, the soluble IL-33 receptor may be, for example, sST2-Fc as described above, and human sST2-Fc (for example, a fusion protein of the extracellular domain of human ST2L protein and the constant domain of human IgG antibody (SEQ ID NO: 50)) is preferred.

[0230] The amino acid sequence of human sST2-Fc may be one in which one to several amino acids have been substituted, deleted, inserted, or added in the amino acid sequence of SEQ ID NO: 50, so long as it has an IL-33 antagonistic activity. The "several" refers to an integer selected from 2 to 109. It is also preferable that the dimer-forming ability be maintained.

[0231] Furthermore, the amino acid sequence of human sST2-Fc may have a predetermined identity with the amino acid sequence shown in SEQ ID NO: 50, so long as it has an IL-33 antagonistic activity. The predetermined identity is the same as described above. Furthermore, it is preferable that the ability to form a dimer is maintained.

[0232] The pharmaceutical composition of embodiment 2-1 may contain only one type of IL-33 antagonist, or may contain two or more types.

[0233] Regarding the conditions for administering the pharmaceutical composition of the second embodiment to a subject, the "anti-IL-33 antibody" of the first embodiment is referred to as the "IL-33 antagonist."

[0234] Furthermore, with regard to the content of the IL-33 antagonist contained in the pharmaceutical composition of the second embodiment, the "content of the anti-IL-33 antibody" of the first embodiment is referred to as the "content of the IL-33 antagonist."

[0235] In addition, the dosage form of the pharmaceutical composition of the second-first embodiment is the same as that of the first embodiment.

[0236] The pharmaceutical composition of the second-first embodiment may consist solely of an IL-33 antagonist, or may further contain, in addition to an IL-33 antagonist, other active ingredients, formulation additives (which may be pharmaceutically acceptable carriers), etc. The contents of the first embodiment are incorporated herein by reference.

[0237] A preferred aspect of the second-first embodiment is the same as that of the first embodiment, but this preferred aspect can more effectively reduce the need for surgery for patients with endometriosis or adenomyosis.

[0238] In another embodiment of the present disclosure, the following is provided:

[0239] That is, in another embodiment of the present disclosure, there is provided a method for reducing the need for surgery in a patient with endometriosis or adenomyosis, comprising administering a mitigatingly effective amount of an IL-33 antagonist to the patient with endometriosis or adenomyosis in need of such reduction.

[0240] Furthermore, in another embodiment of the present disclosure, there is provided a method for reducing the need for surgery in a patient with endometriosis or adenomyosis, comprising administering a mitigatingly effective amount of a pharmaceutical composition containing an IL-33 antagonist as an active ingredient to the patient with endometriosis or adenomyosis in need of such reduction.

[0241] In another embodiment of the present disclosure, there is provided a use of an IL-33 antagonist for the manufacture of a pharmaceutical composition for reducing the need for surgery in patients with endometriosis or adenomyosis.

[0242] Also, in another embodiment of the present disclosure, there is provided an IL-33 antagonist for use in reducing the need for surgery in patients with endometriosis or adenomyosis.

[0243] Also, in another embodiment of the present disclosure, there is provided a pharmaceutical composition comprising an IL-33 antagonist for use in reducing the need for surgery in patients with endometriosis or adenomyosis.

[0244] [Embodiment 2-2: Pharmaceutical composition for reducing the impact of endometriosis or adenomyosis on daily life in patients with endometriosis or adenomyosis] The pharmaceutical composition of Embodiment 2-2 contains an IL-33 antagonist as an active ingredient. The pharmaceutical composition of Embodiment 2-2 can be administered to patients by appropriately combining, for example, the following compositions, patients, administration conditions, etc.

[0245] In the present disclosure, "reducing the impact on daily life" can be rephrased as, for example, "suppressing the impact on daily life" or "reducing the impact on daily life."

[0246] The "impact on daily life" is preferably one or more selected from the group consisting of work and housework.

[0247] "Work" means, for example, work at a workplace.

[0248] "Housework" refers to, for example, everyday work within the home, and specific examples include cooking, cleaning, tidying up, gardening, repairs, etc.

[0249] "Impact on daily life" may be, for example, a decrease in motivation to work, a reduction in continuous working hours, etc.

[0250] In the present disclosure, the "impact on daily life" can be quantitatively evaluated, for example, by the HRPQ. That is, the "impact on daily life" may be evaluated, for example, by the HRPQ. Therefore, for example, the pharmaceutical composition of Embodiment 2-2 can be administered to a patient who is determined to have "impact on daily life" as a result of the HRPQ. Furthermore, the determination that the administration of the pharmaceutical composition of Embodiment 2-2 has "reduced the impact on daily life" or "eliminated the impact on daily life" can also be based on the results of the HRPQ.

[0251] HRPQ is an abbreviation for Health Related Productivity Questionnaire. This questionnaire, for example, consists of 7 to 9 questions, and can be used to evaluate the impact of endometriosis-related disease on the daily life of patients with endometriosis-related disease by scoring it. It can be evaluated that the relatively higher the score, the greater the impact on daily life, and the relatively lower the score, the less the impact on daily life.

[0252] The HRPQ is a known medical interview method. The questions and the criteria for scoring in the HRPQ can be arbitrarily set by, for example, a doctor or a diagnostic institution. Specific examples include the questions and the criteria in the Examples described below.

[0253] The pharmaceutical composition of the second-2 embodiment may contain only one type of IL-33 antagonist, or may contain two or more types of IL-33 antagonist.

[0254] The contents of Embodiment 2-1 are incorporated by reference with regard to the recipient of the pharmaceutical composition of Embodiment 2-2, the IL-33 antagonist contained in the pharmaceutical composition of Embodiment 2-2, the conditions for administering the pharmaceutical composition of Embodiment 2-2 to the recipient, the content of the IL-33 antagonist contained in the pharmaceutical composition of Embodiment 2-2, and the dosage form of the pharmaceutical composition of Embodiment 2-2.

[0255] The pharmaceutical composition of the second embodiment may consist solely of an IL-33 antagonist, or may further contain, in addition to the IL-33 antagonist, other active ingredients, formulation additives (which may be pharmaceutically acceptable carriers), etc. The contents of the second embodiment are incorporated by reference.

[0256] A preferred aspect of the second-second embodiment is the same as that of the first embodiment, but this preferred aspect can more effectively reduce the impact of endometriosis or adenomyosis on the daily lives of endometriosis or adenomyosis patients.

[0257] In another embodiment of the present disclosure, the following is provided:

[0258] That is, in another embodiment of the present disclosure, there is provided a method for reducing the impact of endometriosis or adenomyosis on daily life in a patient with endometriosis or adenomyosis in need of such reduction, comprising administering an alleviatingly effective amount of an IL-33 antagonist to the patient with endometriosis or adenomyosis in need of such reduction.

[0259] Furthermore, in another embodiment of the present disclosure, there is provided a method for reducing the impact of endometriosis or adenomyosis on daily life in a patient with endometriosis or adenomyosis in need of reduction in the impact of endometriosis or adenomyosis on daily life, comprising administering an effective amount of a pharmaceutical composition containing an IL-33 antagonist as an active ingredient to the patient with endometriosis or adenomyosis in need of reduction in the impact of endometriosis or adenomyosis on daily life.

[0260] In another embodiment of the present disclosure, there is provided use of an IL-33 antagonist for producing a pharmaceutical composition for reducing the impact of endometriosis or adenomyosis on daily life in a patient with endometriosis or adenomyosis.

[0261] In another embodiment of the present disclosure, there is provided an IL-33 antagonist for use in reducing the impact of endometriosis or adenomyosis on daily life in patients with endometriosis or adenomyosis.

[0262] In another embodiment of the present disclosure, there is provided a pharmaceutical composition comprising an IL-33 antagonist for use in reducing the impact of endometriosis or adenomyosis on daily life in patients with endometriosis or adenomyosis.

[0263] <Third embodiment: Pharmaceutical composition for treating or preventing endometriosis or adenomyosis> As described above, the pharmaceutical composition according to the third embodiment of the present disclosure is a pharmaceutical composition for treating or preventing endometriosis or adenomyosis.

[0264] The pharmaceutical composition of the third embodiment contains an anti-IL-33 antibody as an active ingredient. The pharmaceutical composition of the third embodiment can be applied to a subject by appropriately combining, for example, the following compositions, subjects, administration conditions, etc.

[0265] The subjects to which the pharmaceutical composition of the third embodiment is administered are as follows.

[0266] When the pharmaceutical composition of the third embodiment is used to treat endometriosis or adenomyosis, the recipient is preferably a recipient suffering from endometriosis or adenomyosis, and more preferably a recipient who has been definitively diagnosed as suffering from endometriosis or adenomyosis. A definitive diagnosis means a diagnosis in which a doctor has confirmed that the recipient has endometriosis or adenomyosis, and is performed, for example, by directly confirming uterine lesions using an endoscope such as a laparoscope, as described above.

[0267] When the pharmaceutical composition of the third embodiment is used to prevent endometriosis or adenomyosis, it is preferable that the recipient is someone who is likely to suffer from endometriosis or adenomyosis, and it is more preferable that the recipient is someone who has been diagnosed as being likely to suffer from endometriosis or adenomyosis.

[0268] The subject of administration is a female human or a female mammal other than a female human, preferably a female human. A female human suffering from endometriosis or adenomyosis may be referred to as a "patient."

[0269] When the subject is a female human, the subject may be an adult female human or a non-adult female human. An adult may be, for example, 18 years of age or older.

[0270] When the subject of administration is a female mammal other than a female human, the subject may be of an age corresponding to the age of an adult female human, or may be of an age corresponding to the age of a non-adult female human. The age of a female human and the age of a female mammal other than a female human can be converted appropriately.

[0271] The pharmaceutical composition of the third embodiment is preferably used to relieve pain associated with endometriosis or adenomyosis in a recipient suffering from endometriosis or adenomyosis, i.e., pain perceived by a recipient suffering from endometriosis or adenomyosis, and more preferably used to relieve pain associated with endometriosis in a recipient suffering from endometriosis.

[0272] "Relieving pain" may mean that pain is still perceived but the intensity of the perceived pain is reduced, or that pain is no longer perceived.

[0273] Examples of pain include menstrual pain, i.e., pain associated with dysmenorrhea such as pain occurring in the uterus during or before or after menstruation; pain occurring in areas other than the uterus due to menstruation, such as lower back pain, lower abdominal pain, pelvic pain, and pain during defecation; non-menstrual pelvic pain; and dyspareunia, i.e., pain occurring due to uterine movement during sexual intercourse.

[0274] The pain may be one or more of the above pains.

[0275] The degree of pain perception, i.e., the increase, alleviation, or disappearance of pain, can be evaluated, for example, by the Biberoglu and Behrman scale (B&B scale) (Biberoglu KO, Behrman SJ, Am J Obstet Gynecol., 139:645 (1981)), which scores the quality of life associated with pain. This scale can evaluate subjective symptoms such as menstrual pain, non-menstrual pelvic pain, and pain during sexual intercourse. The B&B scale may be a modified version of the B&B scale.

[0276] Other scales for assessing the degree of pain perception include the Composite Pelvic Signs and Symptoms Score (CPSS). The CPSSS can assess menstrual pain, nonmenstrual pelvic pain, and dyspareunia. The CPSSS assesses, for example, five items: subjective symptoms, specifically, three types of pain (menstrual pain, nonmenstrual pelvic pain, and dyspareunia in the past 28 days), and physical examination findings by a physician, specifically, two types (pelvic tenderness upon palpation and pelvic induration). Each item is scored on a scale of "0: none, 1: mild, 2: moderate, 3: severe." In this case, the total score of the CPSSS ranges from a minimum of 0 to a maximum of 15, with a lower total score indicating fewer signs and symptoms of endometriosis, such as pain.

[0277] Preferably, the pain is moderate pain or severe pain.

[0278] "Moderate pain" refers to, for example, a total score of 6 or more in an evaluation based on the CPSSS, and a score of 2 for both menstrual pain and non-menstrual pelvic pain.

[0279] "Severe pain" refers to, for example, a total score of 6 or more in an evaluation based on the CPSSS, and a score of 3 for both menstrual pain and non-menstrual pelvic pain.

[0280] Another method for evaluating whether the pharmaceutical composition of the third embodiment relieves pain caused by endometriosis or adenomyosis can be, for example, by evaluating whether the frequency or amount of analgesic administration decreases before and after administration of the pharmaceutical composition. Examples of analgesics include non-steroidal anti-inflammatory analgesics.

[0281] Unlike commonly used hormone regulators, the pharmaceutical composition of the third embodiment alleviates menopausal disorder-like side effects (e.g., infertility, hot flashes, osteoporosis, disorders related to quality of life (e.g., depression, etc.)), and is extremely unlikely to cause fetal toxicity during pregnancy.

[0282] The contents of the first embodiment are incorporated by reference with regard to the anti-IL-33 antibody contained in the pharmaceutical composition of the third embodiment, the conditions for administering the pharmaceutical composition of the third embodiment to a subject, the content of the anti-IL-33 antibody contained in the pharmaceutical composition of the third embodiment, and the dosage form of the pharmaceutical composition of the third embodiment.

[0283] The pharmaceutical composition of the third embodiment may consist solely of an anti-IL-33 antibody, or may further contain, in addition to the anti-IL-33 antibody, other active ingredients, formulation additives (which may be pharmaceutically acceptable carriers), etc. The contents of the first embodiment are incorporated herein by reference.

[0284] As a preferred aspect of the third embodiment, the preferred aspect of the first embodiment is cited, and this preferred aspect makes it possible to more effectively treat endometriosis or adenomyosis.

[0285] <Additional Notes> The pharmaceutical composition according to the first embodiment of the present disclosure also includes the following embodiments: (1-1) A pharmaceutical composition for treating or preventing anti-neutrophil cytoplasmic antibody-associated vasculitis, comprising an anti-IL-33 antibody as an active ingredient. (1-2) The pharmaceutical composition according to item (1-1), wherein the anti-IL-33 antibody comprises: a heavy chain first complementarity-determining region H1 consisting of the amino acid sequence represented by SEQ ID NO: 11; a heavy chain second complementarity-determining region H2 consisting of the amino acid sequence represented by SEQ ID NO: 12; a heavy chain third complementarity-determining region H3 consisting of the amino acid sequence represented by SEQ ID NO: 13; a light chain first complementarity-determining region L1 consisting of the amino acid sequence represented by SEQ ID NO: 14; a light chain second complementarity-determining region L2 consisting of the amino acid sequence represented by SEQ ID NO: 15; and a light chain third complementarity-determining region L3 consisting of the amino acid sequence represented by SEQ ID NO: 16.

[0286] (1-3) The pharmaceutical composition according to item (1-1) or (1-2), wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of an amino acid sequence having 80% or more identity to the amino acid sequence shown in SEQ ID NO: 38; and a light chain variable region consisting of an amino acid sequence having 80% or more identity to the amino acid sequence shown in SEQ ID NO: 39. (1-3-1) The pharmaceutical composition according to any of items (1-1) to (1-3), wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of an amino acid sequence having 90% or more identity to the amino acid sequence shown in SEQ ID NO: 38; and a light chain variable region consisting of an amino acid sequence having 90% or more identity to the amino acid sequence shown in SEQ ID NO: 39. (1-3-2) The pharmaceutical composition according to any of items (1-1) to (1-3-1), wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of an amino acid sequence having 95% or more identity to the amino acid sequence shown in SEQ ID NO: 38; and a light chain variable region consisting of an amino acid sequence having 95% or more identity to the amino acid sequence shown in SEQ ID NO: 39. (1-3-3) The pharmaceutical composition according to any of items (1-1) to (1-3-2), wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of an amino acid sequence having 99% or more identity to the amino acid sequence shown in SEQ ID NO: 38; and a light chain variable region consisting of an amino acid sequence having 99% or more identity to the amino acid sequence shown in SEQ ID NO: 39. (1-3-4) The pharmaceutical composition according to any of items (1-1) to (1-3-3), wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 38; and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 39.

[0287] (1-4) The pharmaceutical composition according to any of items (1-1) to (1-3-4), wherein the anti-IL-33 antibody comprises: a heavy chain consisting of an amino acid sequence having 80% or more identity with the amino acid sequence shown in SEQ ID NO: 1; and a light chain consisting of an amino acid sequence having 80% or more identity with the amino acid sequence shown in SEQ ID NO: 2. (1-4-1) The pharmaceutical composition according to any of items (1-1) to (1-4), wherein the anti-IL-33 antibody comprises: a heavy chain consisting of an amino acid sequence having 90% or more identity with the amino acid sequence shown in SEQ ID NO: 1; and a light chain consisting of an amino acid sequence having 90% or more identity with the amino acid sequence shown in SEQ ID NO: 2. (1-4-2) The pharmaceutical composition according to any of items (1-1) to (1-4-1), wherein the anti-IL-33 antibody comprises: a heavy chain consisting of an amino acid sequence having 95% or more identity with the amino acid sequence shown in SEQ ID NO: 1; and a light chain consisting of an amino acid sequence having 95% or more identity with the amino acid sequence shown in SEQ ID NO: 2. (1-4-3) The pharmaceutical composition according to any one of items (1-1) to (1-4-2), wherein the anti-IL-33 antibody comprises a heavy chain consisting of an amino acid sequence having 99% or more identity to the amino acid sequence shown in SEQ ID NO: 1, and a light chain consisting of an amino acid sequence having 99% or more identity to the amino acid sequence shown in SEQ ID NO: 2. (1-4-4) The pharmaceutical composition according to any one of items (1-1) to (1-4-3), wherein the anti-IL-33 antibody comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1, and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[0288] (1-5-0) The pharmaceutical composition according to any one of items (1-1) to (1-4-4), wherein the anti-IL-33 antibody is administered to achieve a blood trough level of 3.8 μg / mL or more. (1-5) The pharmaceutical composition according to any one of items (1-1) to (1-4-4) and (1-5-0), wherein the anti-IL-33 antibody is administered to achieve a blood trough level of 6.7 μg / mL or more. (1-6) The pharmaceutical composition according to any one of items (1-1) to (1-5), wherein the anti-IL-33 antibody is administered to achieve a blood trough level of 15.0 μg / mL or more. (1-6-1) The pharmaceutical composition according to any one of items (1-1) to (1-6), wherein the anti-IL-33 antibody is administered to achieve a blood trough level of 18.3 μg / mL or more. (1-7) The pharmaceutical composition according to any one of items (1-1) to (1-6-1), which is for intravenous or subcutaneous administration. (1-8) The pharmaceutical composition according to item (1-7), which is for intravenous administration and wherein the dose of the anti-IL-33 antibody is 0.1 mg / kg to 10 mg / kg of body weight. (1-9) The pharmaceutical composition according to item (1-7) or (1-8), which is for intravenous administration and wherein the dose is 6 mg / kg to 10 mg / kg of body weight. (1-10) The pharmaceutical composition according to any one of items (1-7) to (1-9), which is for intravenous administration and wherein the dose is 6 mg / kg of body weight. (1-11) The pharmaceutical composition according to item (1-7), which is for subcutaneous administration and wherein the dose of the anti-IL-33 antibody is 50 mg / dose to 2000 mg / dose. (1-12) The pharmaceutical composition according to any one of items (1-7) to (1-11), which is administered once every 2 to 8 weeks. (1-13) The pharmaceutical composition according to any one of items (1-7) to (1-12), which is administered every 4 weeks. (1-14) The pharmaceutical composition according to any one of items (1-7) to (1-13), which is administered 3 to 8 times. (1-15) The pharmaceutical composition according to any one of items (1-7) to (1-14), which is administered 6 to 8 times.

[0289] (1-16) A method for treating, etc., antineutrophil cytoplasmic antibody-associated vasculitis, comprising administering a therapeutically effective amount of an anti-IL-33 antibody to a subject in need of treatment, etc. for antineutrophil cytoplasmic antibody-associated vasculitis. (1-17) A method for treating, etc., antineutrophil cytoplasmic antibody-associated vasculitis, comprising administering a therapeutically effective amount of the pharmaceutical composition according to any of items (1-7) to (1-15) to a subject in need of treatment, etc. for antineutrophil cytoplasmic antibody-associated vasculitis.

[0290] (1-18) Use of an anti-IL-33 antibody for producing a pharmaceutical composition for treating anti-neutrophil cytoplasmic antibody-associated vasculitis. (1-18-1) Use of an anti-IL-33 antibody for producing a pharmaceutical composition for treating anti-neutrophil cytoplasmic antibody-associated vasculitis, wherein the pharmaceutical composition is the pharmaceutical composition according to any one of items (1-7) to (1-15).

[0291] (1-19) An anti-IL-33 antibody for use in treating antineutrophil cytoplasmic antibody-associated vasculitis.

[0292] (1-20) A pharmaceutical composition comprising an anti-IL-33 antibody for use in the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis. (1-20-1) A pharmaceutical composition comprising an anti-IL-33 antibody for use in the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis, the pharmaceutical composition being the pharmaceutical composition according to any one of items (1-7) to (1-15).

[0293] The pharmaceutical composition according to the second embodiment of the present disclosure also includes the following embodiments: (2-1) A pharmaceutical composition for reducing the need for surgery in a patient with endometriosis or adenomyosis, the pharmaceutical composition comprising an IL-33 antagonist as an active ingredient. (2-2) The pharmaceutical composition according to item (2-1), wherein the need for surgery is assessed by one or more selected from the group consisting of PSIQ and SSIQ.

[0294] (2-3) A pharmaceutical composition for reducing the impact of endometriosis or adenomyosis on daily life in an endometriosis or adenomyosis patient, the pharmaceutical composition comprising an IL-33 antagonist as an active ingredient. (2-4) The pharmaceutical composition according to item (2-3), wherein the impact on daily life is one or more selected from the group consisting of work and housework. (2-5) The pharmaceutical composition according to item (2-3) or (2-4), wherein the impact on daily life is assessed by HRPQ.

[0295] (2-6) The pharmaceutical composition according to any one of items (2-1) to (2-5), wherein the IL-33 antagonist is one or more selected from the group consisting of an anti-IL-33 antibody, an anti-IL-33 receptor antibody, and a soluble IL-33 receptor. (2-7) The pharmaceutical composition according to item (2-6), wherein the anti-IL-33 antibody comprises: a heavy chain first complementarity-determining region H1 consisting of the amino acid sequence set forth in SEQ ID NO: 11; a heavy chain second complementarity-determining region H2 consisting of the amino acid sequence set forth in SEQ ID NO: 12; a heavy chain third complementarity-determining region H3 consisting of the amino acid sequence set forth in SEQ ID NO: 13; a light chain first complementarity-determining region L1 consisting of the amino acid sequence set forth in SEQ ID NO: 14; a light chain second complementarity-determining region L2 consisting of the amino acid sequence set forth in SEQ ID NO: 15; and a light chain third complementarity-determining region L3 consisting of the amino acid sequence set forth in SEQ ID NO: 16.

[0296] (2-8) The pharmaceutical composition according to item (2-6) or (2-7), wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of an amino acid sequence having 80% or more identity to the amino acid sequence shown in SEQ ID NO: 38; and a light chain variable region consisting of an amino acid sequence having 80% or more identity to the amino acid sequence shown in SEQ ID NO: 39. (2-8-1) The pharmaceutical composition according to any of items (2-6) to (2-8), wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of an amino acid sequence having 90% or more identity to the amino acid sequence shown in SEQ ID NO: 38; and a light chain variable region consisting of an amino acid sequence having 90% or more identity to the amino acid sequence shown in SEQ ID NO: 39. (2-8-2) The pharmaceutical composition according to any of items (2-6) to (2-8-1), wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of an amino acid sequence having 95% or more identity to the amino acid sequence shown in SEQ ID NO: 38; and a light chain variable region consisting of an amino acid sequence having 95% or more identity to the amino acid sequence shown in SEQ ID NO: 39. (2-8-3) The pharmaceutical composition according to any of items (2-6) to (2-8-2), wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of an amino acid sequence having 99% or more identity to the amino acid sequence shown in SEQ ID NO: 38; and a light chain variable region consisting of an amino acid sequence having 99% or more identity to the amino acid sequence shown in SEQ ID NO: 39. (2-8-4) The pharmaceutical composition according to any of items (2-6) to (2-8-3), wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 38; and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 39.

[0297] (2-9) The pharmaceutical composition according to any of items (2-6) to (2-8-4), wherein the anti-IL-33 antibody comprises: a heavy chain consisting of an amino acid sequence having 80% or more identity with the amino acid sequence shown in SEQ ID NO: 1; and a light chain consisting of an amino acid sequence having 80% or more identity with the amino acid sequence shown in SEQ ID NO: 2. (2-9-1) The pharmaceutical composition according to any of items (2-6) to (2-9), wherein the anti-IL-33 antibody comprises: a heavy chain consisting of an amino acid sequence having 90% or more identity with the amino acid sequence shown in SEQ ID NO: 1; and a light chain consisting of an amino acid sequence having 90% or more identity with the amino acid sequence shown in SEQ ID NO: 2. (2-9-2) The pharmaceutical composition according to any of items (2-6) to (2-9-1), wherein the anti-IL-33 antibody comprises: a heavy chain consisting of an amino acid sequence having 95% or more identity with the amino acid sequence shown in SEQ ID NO: 1; and a light chain consisting of an amino acid sequence having 95% or more identity with the amino acid sequence shown in SEQ ID NO: 2. (2-9-3) The pharmaceutical composition according to any one of items (2-6) to (2-9-2), wherein the anti-IL-33 antibody comprises a heavy chain consisting of an amino acid sequence having 99% or more identity to the amino acid sequence shown in SEQ ID NO: 1, and a light chain consisting of an amino acid sequence having 99% or more identity to the amino acid sequence shown in SEQ ID NO: 2. (2-9-4) The pharmaceutical composition according to any one of items (2-6) to (2-9-3), wherein the anti-IL-33 antibody comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1, and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[0298] (2-10) The pharmaceutical composition according to any one of items (2-1) to (2-9-4), which is for subcutaneous administration or intravenous administration. (2-11) The pharmaceutical composition according to any one of items (2-1) to (2-10), which is for intravenous administration and wherein the dose of the IL-33 antagonist is 0.1 mg / kg body weight to 10 mg / kg body weight. (2-12) The pharmaceutical composition according to any one of items (2-1) to (2-11), wherein the administration interval is 4 weeks. (2-13) The pharmaceutical composition according to any one of items (2-1) to (2-12), wherein the number of administrations is 3 to 5 times. (2-14) The pharmaceutical composition according to any one of items (2-1) to (2-13), wherein the number of administrations is 4 times. (2-15) The pharmaceutical composition according to items (2-1) to (2-11), wherein the number of administrations is once every 2 to 8 weeks. (2-16) The pharmaceutical composition according to item (2-15), which is administered once every 2 weeks, 4 weeks, 6 weeks, or 8 weeks.

[0299] (2-17) The pharmaceutical composition according to any one of items (2-1) to (2-10), which is for subcutaneous administration and wherein the dose of the anti-IL-33 antagonist is 50 mg / dose to 2000 mg / dose. (2-18) The pharmaceutical composition according to item (2-17), wherein the dose of the anti-IL-33 antagonist is 50 mg / dose to 1000 mg / dose. (2-19) The pharmaceutical composition according to item (2-17) or (2-18), wherein the dose of the anti-IL-33 antagonist is 60 mg / dose to 700 mg / dose. (2-20) The pharmaceutical composition according to any one of items (2-17) to (2-19), which is administered once every 2 to 8 weeks. (2-21) The pharmaceutical composition according to item (2-20), which is administered once every 2 weeks, 4 weeks, 6 weeks, or 8 weeks. (2-22) The pharmaceutical composition according to item (2-21), which is administered once every four weeks. (2-23) The pharmaceutical composition according to item (2-22), wherein the dose of the anti-IL-33 antagonist is 200 mg / dose to 600 mg / dose. (2-24) The pharmaceutical composition according to item (2-21), which is administered once every two weeks. (2-25) The pharmaceutical composition according to item (2-24), wherein the dose of the anti-IL-33 antagonist is 100 mg / dose to 300 mg / dose. (2-26) The pharmaceutical composition according to item (2-21), which is administered once every six weeks. (2-27) The pharmaceutical composition according to item (2-26), wherein the dose of the anti-IL-33 antagonist is 400 mg / dose to 1100 mg / dose. (2-28) The pharmaceutical composition according to item (2-21), which is administered once every 8 weeks. (2-29) The pharmaceutical composition according to item (2-28), wherein the dose of the anti-IL-33 antagonist is 700 mg / dose to 1900 mg / dose.

[0300] (2-30) The pharmaceutical composition according to any one of items (2-1) to (2-9-4), which is administered once every 2 to 8 weeks so that the blood trough level of the anti-IL-33 antagonist is 6.7 μg / mL or more. (2-31) The pharmaceutical composition according to item (2-30), which is administered so that the blood trough level of the anti-IL-33 antagonist is 15.0 μg / mL or more, preferably 17.5 μg / mL or more, and more preferably 18.3 μg / mL or more. (2-32) The pharmaceutical composition according to item (2-30) or (2-31), which is for intravenous or subcutaneous administration. (2-33) The pharmaceutical composition according to item (2-32), (a) for subcutaneous administration, wherein the dose of the anti-IL-33 antagonist is 50 mg / dose to 2000 mg / dose, preferably 50 mg / dose to 1000 mg / dose, and more preferably 60 mg / dose to 700 mg / dose, or (b) for intravenous administration, wherein the dose of the anti-IL-33 antagonist is 0.1 mg / kg body weight to 10 mg / kg body weight, and preferably 0.6 mg / kg body weight to 6 mg / kg body weight. (2-34) The pharmaceutical composition according to item (2-33), which is administered once every 2 weeks, 4 weeks, 6 weeks, or 8 weeks. (2-35) The pharmaceutical composition according to item (2-34), which is administered once every 4 weeks. (2-36) The pharmaceutical composition according to item (2-35), which is for subcutaneous administration and wherein the dose of the anti-IL-33 antagonist is 200 mg / dose to 600 mg / dose. (2-37) The pharmaceutical composition according to item (2-34), which is administered once every two weeks. (2-38) The pharmaceutical composition according to item (2-37), which is for subcutaneous administration and wherein the dose of the anti-IL-33 antagonist is 100 mg / dose to 300 mg / dose. (2-39) The pharmaceutical composition according to item (2-34), which is administered once every six weeks. (2-40) The pharmaceutical composition according to item (2-39), which is for subcutaneous administration and wherein the dose of the anti-IL-33 antagonist is 400 mg / dose to 1100 mg / dose. (2-41) The pharmaceutical composition according to item (2-34), which is administered once every eight weeks. (2-42) The pharmaceutical composition according to item (2-41), which is for subcutaneous administration and the dose of the anti-IL-33 antagonist is 700 mg / dose to 1900 mg / dose.

[0301] (2-43) A method for reducing the need for surgery in a patient with endometriosis or adenomyosis, comprising administering a reducing-effective amount of an IL-33 antagonist to the patient with endometriosis or adenomyosis in need of such reduction. (2-44) A method for reducing the need for surgery in a patient with endometriosis or adenomyosis, comprising administering a reducing-effective amount of a pharmaceutical composition containing an IL-33 antagonist as an active ingredient to the patient with endometriosis or adenomyosis in need of such reduction. (2-45) The method according to item (2-43) or (2-44), wherein the need for surgery is assessed by one or more selected from the group consisting of PSIQ and SSIQ. (2-46) The method according to item (2-44) or (2-45), wherein the pharmaceutical composition is the pharmaceutical composition according to any of items (2-1) to (2-42).

[0302] (2-47) Use of an IL-33 antagonist for producing a pharmaceutical composition for reducing the need for surgery in patients with endometriosis or adenomyosis. (2-47-1) Use of an IL-33 antagonist for producing a pharmaceutical composition for reducing the need for surgery in patients with endometriosis or adenomyosis, wherein the pharmaceutical composition is the pharmaceutical composition according to any of items (2-1) to (2-42).

[0303] (2-48) An IL-33 antagonist for use in reducing the need for surgery in patients with endometriosis or adenomyosis. (2-49) A pharmaceutical composition comprising an IL-33 antagonist for use in reducing the need for surgery in patients with endometriosis or adenomyosis. (2-49-1) A pharmaceutical composition comprising an IL-33 antagonist for use in reducing the need for surgery in patients with endometriosis or adenomyosis, the pharmaceutical composition being the pharmaceutical composition according to any of items (2-1) to (2-42).

[0304] (2-50) A method for reducing the impact of endometriosis or adenomyosis on daily life in an endometriosis patient or adenomyosis patient in need of reduction of the impact of endometriosis or adenomyosis on daily life, comprising administering an effective amount of an IL-33 antagonist to the endometriosis patient or adenomyosis patient in need of reduction of the impact of endometriosis or adenomyosis on daily life. (2-51) A method for reducing the impact of endometriosis or adenomyosis on daily life in an endometriosis patient or adenomyosis patient in need of reduction of the impact of endometriosis or adenomyosis on daily life, comprising administering an effective amount of a pharmaceutical composition containing an IL-33 antagonist as an active ingredient. (2-52) The method according to item (2-50) or (2-51), wherein the impact on daily life is one or more selected from the group consisting of work and housework. (2-53) The method according to any one of items (2-50) to (2-52), wherein the impact on daily life is assessed by HRPQ. (2-54) The method according to any one of items (2-51) to (2-53), wherein the pharmaceutical composition is the pharmaceutical composition according to any one of items (2-1) to (2-42). (2-55) Use of an IL-33 antagonist for producing a pharmaceutical composition for reducing the impact of endometriosis or adenomyosis on daily life in an endometriosis or adenomyosis patient. (2-55-1) Use of an IL-33 antagonist for producing a pharmaceutical composition for reducing the impact of endometriosis or adenomyosis on daily life in an endometriosis or adenomyosis patient, wherein the pharmaceutical composition is the pharmaceutical composition according to any one of items (2-1) to (2-42). (2-56) An IL-33 antagonist for use in reducing the impact of endometriosis or adenomyosis on daily life in patients with endometriosis or adenomyosis. (2-57) A pharmaceutical composition comprising an IL-33 antagonist for use in reducing the impact of endometriosis or adenomyosis on daily life in patients with endometriosis or adenomyosis.(2-57-1) A pharmaceutical composition comprising an IL-33 antagonist for use in reducing the impact of endometriosis or adenomyosis on daily life in patients with endometriosis or adenomyosis, the pharmaceutical composition being the pharmaceutical composition according to any one of items (2-1) to (2-42).

[0305] The pharmaceutical composition according to the third embodiment of the present disclosure also includes the following embodiments. (3-1) A pharmaceutical composition for treating or preventing endometriosis or adenomyosis, comprising an anti-IL-33 antibody as an active ingredient, which is administered once every 2 to 8 weeks so that the blood trough level of the anti-IL-33 antibody is 6.7 μg / mL or higher. (3-1-1) A pharmaceutical composition for treating endometriosis or adenomyosis, comprising an anti-IL-33 antibody as an active ingredient, which is administered once every 2 to 8 weeks so that the blood trough level of the anti-IL-33 antibody is 6.7 μg / mL or higher. (3-1-2) The pharmaceutical composition according to item (3-1) or (3-1-1), wherein the pharmaceutical composition is administered once every 2 weeks, 4 weeks, 6 weeks, or 8 weeks. (3-2) The pharmaceutical composition according to any one of items (3-1) to (3-1-2), wherein the composition is administered so that the blood trough level of the anti-IL-33 antibody is 15.0 μg / mL or more, preferably 17.5 μg / mL or more, and more preferably 18.3 μg / mL or more.

[0306] (3-3) The pharmaceutical composition according to any one of Items (3-1) to (3-2), which is for intravenous or subcutaneous administration. (3-3-1) (a) The pharmaceutical composition according to Item (3-3), which is for subcutaneous administration and wherein the dose of the anti-IL-33 antibody is 50 mg / injection to 2000 mg / injection, preferably 50 mg / injection to 1000 mg / injection, and more preferably 60 mg / injection to 700 mg / injection, or (b) The pharmaceutical composition according to Item (3-3), which is for intravenous administration and wherein the dose of the anti-IL-33 antibody is 0.1 mg / kg body weight to 10 mg / kg body weight, and preferably 0.6 mg / kg body weight to 6 mg / kg body weight. (3-3-2) The pharmaceutical composition according to any one of Items (3-1) to (3-3), which is administered once every four weeks. (3-3-3) The pharmaceutical composition according to item (3-3-2), which is for subcutaneous administration and wherein the dose of the anti-IL-33 antibody is 200 mg / dose to 600 mg / dose. (3-3-4) The pharmaceutical composition according to any one of items (3-1) to (3-3), which is administered once every two weeks. (3-3-5) The pharmaceutical composition according to item (3-3-4), which is for subcutaneous administration and wherein the dose of the anti-IL-33 antibody is 100 mg / dose to 300 mg / dose. (3-3-6) The pharmaceutical composition according to any one of items (3-1) to (3-3), which is administered once every six weeks. (3-3-7) The pharmaceutical composition according to item (3-3-6), which is for subcutaneous administration and wherein the dose of the anti-IL-33 antibody is 400 mg / dose to 1100 mg / dose. (3-3-8) The pharmaceutical composition according to any one of items (3-1) to (3-3), which is administered once every 8 weeks. (3-3-9) The pharmaceutical composition according to item (3-3-8), which is for subcutaneous administration and in which the dose of the anti-IL-33 antibody is 700 mg / dose to 1900 mg / dose.

[0307] (3-4) A pharmaceutical composition for treating or preventing endometriosis or adenomyosis, comprising an anti-IL-33 antibody as an active ingredient, for intravenous administration, wherein the dose of the anti-IL-33 antibody is 0.1 mg / kg to 10 mg / kg of body weight. (3-5) A pharmaceutical composition for treating or preventing endometriosis or adenomyosis, comprising an anti-IL-33 antibody as an active ingredient, for subcutaneous administration, wherein the dose of the anti-IL-33 antibody is 50 mg to 2000 mg / dose. (3-6) The pharmaceutical composition according to item (3-5), wherein the dose is 50 mg to 1000 mg / dose. (3-7) The pharmaceutical composition according to item (3-5) or (3-6), wherein the dose of the anti-IL-33 antibody is 60 mg to 700 mg / dose. (3-8) The pharmaceutical composition according to any one of items (3-4) to (3-7), which is administered once every 2 to 8 weeks. (3-8-1) The pharmaceutical composition according to item (3-8), which is administered once every 2 weeks, 4 weeks, 6 weeks, or 8 weeks. (3-8-2) The pharmaceutical composition according to item (3-8-1), which is administered once every 4 weeks. (3-8-3) The pharmaceutical composition according to item (3-8-2), wherein the dose of the anti-IL-33 antibody is 200 mg / dose to 600 mg / dose. (3-8-4) The pharmaceutical composition according to item (3-8-1), which is administered once every 2 weeks. (3-8-5) The pharmaceutical composition according to item (3-8-4), wherein the dose of the anti-IL-33 antibody is 100 mg / dose to 300 mg / dose. (3-8-6) The pharmaceutical composition according to item (3-8-1), which is administered once every 6 weeks. (3-8-7) The pharmaceutical composition according to item (3-8-6), wherein the dose of the anti-IL-33 antibody is 400 mg / dose to 1100 mg / dose. (3-8-8) The pharmaceutical composition according to item (3-8-1), which is administered once every 8 weeks. (3-8-9) The pharmaceutical composition according to item (3-8-8), wherein the dose of the anti-IL-33 antibody is 700 mg / dose to 1900 mg / dose. (3-9) The pharmaceutical composition according to any of items (3-1) to (3-8-9), which is used for alleviating pain associated with endometriosis or adenomyosis. (3-10) The pharmaceutical composition according to item (3-9), wherein the endometriosis or adenomyosis is endometriosis, and the pain is moderate or severe.(3-11) The pharmaceutical composition according to item (3-9) or (3-10), wherein the pain is one or more selected from the group consisting of menstrual pain, non-menstrual pelvic pain, and dyspareunia.

[0308] (3-12) The pharmaceutical composition according to any of items (3-1) to (3-11), wherein the anti-IL-33 antibody comprises: a heavy chain first complementarity determining region H1 consisting of the amino acid sequence represented by SEQ ID NO: 11; a heavy chain second complementarity determining region H2 consisting of the amino acid sequence represented by SEQ ID NO: 12; a heavy chain third complementarity determining region H3 consisting of the amino acid sequence represented by SEQ ID NO: 13; a light chain first complementarity determining region L1 consisting of the amino acid sequence represented by SEQ ID NO: 14; a light chain second complementarity determining region L2 consisting of the amino acid sequence represented by SEQ ID NO: 15; and a light chain third complementarity determining region L3 consisting of the amino acid sequence represented by SEQ ID NO: 16.

[0309] (3-13) The pharmaceutical composition according to any of items (3-1) to (3-12), wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of an amino acid sequence having 80% or more identity to the amino acid sequence shown in SEQ ID NO: 38; and a light chain variable region consisting of an amino acid sequence having 80% or more identity to the amino acid sequence shown in SEQ ID NO: 39. (3-13-1) The pharmaceutical composition according to any of items (3-1) to (3-13), wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of an amino acid sequence having 90% or more identity to the amino acid sequence shown in SEQ ID NO: 38; and a light chain variable region consisting of an amino acid sequence having 90% or more identity to the amino acid sequence shown in SEQ ID NO: 39. (3-13-2) The pharmaceutical composition according to any one of items (3-1) to (3-13-1), wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of an amino acid sequence having 95% or more identity to the amino acid sequence shown in SEQ ID NO: 38; and a light chain variable region consisting of an amino acid sequence having 95% or more identity to the amino acid sequence shown in SEQ ID NO: 39. (3-13-3) The pharmaceutical composition according to any one of items (3-1) to (3-13-2), wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of an amino acid sequence having 99% or more identity to the amino acid sequence shown in SEQ ID NO: 38; and a light chain variable region consisting of an amino acid sequence having 99% or more identity to the amino acid sequence shown in SEQ ID NO: 39. (3-13-4) The pharmaceutical composition according to any one of Items (3-1) to (3-13-3), wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 38; and a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 39.

[0310] (3-14) The pharmaceutical composition according to any of items (3-1) to (3-13-4), wherein the anti-IL-33 antibody comprises: a heavy chain consisting of an amino acid sequence having 80% or more identity with the amino acid sequence shown in SEQ ID NO: 1; and a light chain consisting of an amino acid sequence having 80% or more identity with the amino acid sequence shown in SEQ ID NO: 2. (3-14-1) The pharmaceutical composition according to any of items (3-1) to (3-14), wherein the anti-IL-33 antibody comprises: a heavy chain consisting of an amino acid sequence having 90% or more identity with the amino acid sequence shown in SEQ ID NO: 1; and a light chain consisting of an amino acid sequence having 90% or more identity with the amino acid sequence shown in SEQ ID NO: 2. (3-14-2) The pharmaceutical composition according to any of items (3-1) to (3-14-1), wherein the anti-IL-33 antibody comprises: a heavy chain consisting of an amino acid sequence having 95% or more identity with the amino acid sequence shown in SEQ ID NO: 1; and a light chain consisting of an amino acid sequence having 95% or more identity with the amino acid sequence shown in SEQ ID NO: 2. (3-14-3) The pharmaceutical composition according to any one of items (3-1) to (3-14-2), wherein the anti-IL-33 antibody comprises a heavy chain consisting of an amino acid sequence having 99% or more identity to the amino acid sequence shown in SEQ ID NO: 1, and a light chain consisting of an amino acid sequence having 99% or more identity to the amino acid sequence shown in SEQ ID NO: 2. (3-14-4) The pharmaceutical composition according to any one of items (3-1) to (3-14-3), wherein the anti-IL-33 antibody comprises a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1, and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[0311] (3-15) The pharmaceutical composition according to any one of items (3-1) to (3-14-4), further comprising one or more selected from the group consisting of a buffering agent, a surfactant, and an osmotic pressure adjusting agent.

[0312] A method for treating endometriosis or adenomyosis, comprising administering a therapeutically effective amount of a pharmaceutical composition containing an anti-IL-33 antibody as an active ingredient to a subject in need of treatment, etc., of endometriosis or adenomyosis, wherein the pharmaceutical composition is the pharmaceutical composition described in any of Items (3-1) to (3-15). Use of an anti-IL-33 antibody for producing a pharmaceutical composition for treating, etc. endometriosis or adenomyosis, wherein the pharmaceutical composition is the pharmaceutical composition described in any of Items (3-1) to (3-15). A pharmaceutical composition comprising an anti-IL-33 antibody for use in the treatment, etc., of endometriosis or adenomyosis, wherein the pharmaceutical composition is the pharmaceutical composition described in any of Items (3-1) to (3-15).

[0313] The present disclosure will be specifically described below using examples, but all examples are merely illustrative and should not be construed as limiting.

[0314] 1. Examples of Pharmaceutical Compositions for Treating or Preventing Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Example 1-1 Because the details of the role of IL-33 in the pathology of AAV are unknown, to investigate the expression of IL-33 in lesions in AAV patients, immunohistochemical staining with an IL-33 antibody was performed on tracheal tissues from two GPA patients and five MPA patients. Representative stained images are shown in Figure 1-1. IL-33 staining images were observed in mucosal epithelium, alveoli, and vascular endothelial cells in both GPA and MPA patients. This was particularly evident in areas of epithelial cell proliferation and areas of increased inflammation. These results demonstrate that IL-33 expression is observed in lesions in AAV patients.

[0315] To investigate the role of IL-33 in AAV pathogenesis, we established a coculture system of HUVEC cells and human neutrophils. HUVEC cells were seeded in 96-well plates. The following day, 100 ng / mL of IL-33 and a control antibody (human IgG1 isotype) or an anti-IL-33 antibody (A10-1C04) were added, and the cells were cultured again overnight. Neutrophils were isolated from human peripheral blood and suspended in medium containing SYTOX Green. The HUVEC cell-seeded plates were washed twice with PBS, and neutrophils were seeded onto the plates together with an anti-myeloproteinase antibody (ANCA) or a control antibody (mouse IgG1 κ isotype). 20 hours after stimulation, dead cells fluorescent with SYTOX Green were observed using an in cell analyzer. Neutrophils were activated by ANCA and induced netosis, but co-culture with HUVEC cells inhibited netosis. Meanwhile, prior stimulation of HUVEC cells with IL-33 enhanced netosis, whereas netosis was suppressed in the presence of anti-IL-33 antibodies (Figures 1-2). This effect was observed both in the presence and absence of ANCA, suggesting that it may underlie AAV pathology. This may represent the AAV pathology in which B cells are depleted by Rituxan and relapse occurs despite a reduction in ANCA titers. These results suggest that one role of IL-33 in AAV pathology is its promotion of neutrophil activation and netosis via vascular endothelial cell activation, suggesting the possibility that anti-IL-33 antibodies may inhibit neutrophil activation and netosis. These results suggest that administration of anti-IL-33 antibodies may be able to suppress or reverse AAV pathology.

[0316] [Example 1-2] Considering that AAV is a disease that can lead to serious outcomes such as death in severe patients, this clinical trial targets AAV patients with non-severe active disease and / or AAV patients for whom it is difficult to reduce or discontinue steroids. This clinical trial is a Phase Ib, open-label, uncontrolled study aimed at exploratory investigation of the efficacy, safety, pharmacokinetics, and mechanism of action of a single dose of 10 mg / kg of a human anti-IL-33 antibody (A10-1C04) administered on the first day of administration, followed by a single dose of 6 mg / kg of the human anti-IL-33 antibody administered five times at four-week intervals from Week 4 to Week 20 (a total of six doses).

[0317] (Preparation of human anti-IL-33 antibody) A human anti-IL-33 antibody (A10-1C04) was prepared by the method described in WO 2015 / 099175. The human anti-IL-33 antibody (A10-1C04) had a heavy chain first complementarity-determining region H1 consisting of the amino acid sequence represented by SEQ ID NO: 11, a heavy chain second complementarity-determining region H2 consisting of the amino acid sequence represented by SEQ ID NO: 12, a heavy chain third complementarity-determining region H3 consisting of the amino acid sequence represented by SEQ ID NO: 13, a light chain first complementarity-determining region L1 consisting of the amino acid sequence represented by SEQ ID NO: 14, a light chain second complementarity-determining region L2 consisting of the amino acid sequence represented by SEQ ID NO: 15, and a light chain third complementarity-determining region L3 consisting of the amino acid sequence represented by SEQ ID NO: 16, a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 38, a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 39, a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2. The affinity of the human anti-IL-33 antibody for human IL-33 (residues 112 to 270) (ATGen, ILC0701) was measured by KinExA and found to be Kd = 100.3 pM.

[0318] Furthermore, when interleukin 6 (IL-6) and IL-8 production in the presence of human IL-33 was evaluated in vitro using HUVEC cells, the inhibitory concentrations for IL-6 and IL-8 production in the presence of the human anti-IL-33 antibody were IC ９０ The IC50 values ​​were 3.8 μg / mL (geometric mean value) and 6.7 μg / mL (geometric mean value) at the respective concentrations. ９０It was thought that the presence of IL-6 and IL-8 at this concentration would reduce the amounts of IL-6 and IL-8 produced by stimulation with IL-33, thereby achieving the desired therapeutic effect. Therefore, this concentration (6.7 μg / mL) can be used as the standard for the serum trough concentration at which the drug's efficacy, such as a decrease in BVAS and CRP, as described below, is achieved.

[0319] (Preparation of Pharmaceutical Composition) The human anti-IL-33 antibody is suspended in a solvent to prepare a pharmaceutical composition having the following composition as an intravenous injection.

[0320] (Composition of intravenous injection) 150 mg / mL human anti-IL-33 antibody 10 mmol / L histidine (pH 6.0) 220 mmol / L D-sorbitol (4.0% (w / v)) 0.02% (w / v) Polysorbate 80

[0321] (Subjects) The subjects are AAV patients with active disease (including those who have failed rituximab treatment) and / or AAV patients for whom it is difficult to reduce or discontinue steroids.

[0322] (Rituximab treatment failure cases) Among AAV patients with active disease, patients who meet the following criteria are defined as rituximab treatment failure cases: - Patients who are in need of new remission induction therapy because remission induction therapy with rituximab is insufficient - Patients who relapse during remission maintenance therapy with rituximab and need remission induction therapy

[0323] (Inclusion criteria) Patients who meet all of the following inclusion criteria and have the ability to give consent are eligible for the study. (1) Patients who are 18 years of age or older on the day of consent acquisition. (2) Patients who have met the 2022 ACR / EULAR Classification Criteria (Arthritis & Rheumatology, Vol. 74, No. 3, March 2022, pp. 386-392, Arthritis & Rheumatology, Vol. 74, No. 3, March 2022, pp. 393-399, and Arthritis & Rheumatology, Vol. 74, No. 3, March 2022) by the day of consent acquisition. 2022, pp. 400-406. (3) Patients who have been diagnosed with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), or eosinophilic granulomatosis with polyangiitis (EGPA) based on the results of the clinical trial. (1) Patients who meet all of the following criteria I) to III) at the time of screening and who are judged by the principal (sub)investigator to have active disease. If measurements or tests are performed multiple times during the screening period, the results from the latest day will be used to confirm that the criteria are met. I) Elevated C-reactive protein (CRP) due to active AAV is defined as CRP of 0.2 mg / dL or higher II) Birmingham Vasculitis Activity Score (BVAS) of 1 or higher III) One or more of the following findings a) to e) are present. However, c) is only applicable to patients with EGPA. a) FDG-PET / CT (fluorine-18-2-deoxy-D-glucose positron emission tomography and computed tomography) images show grade 2 or higher (FDG accumulation equivalent to that in the liver) and findings judged by a radiologist to indicate inflammation b) Forced vital capacity (FVC) (mL) below the lower limit of normal based on the "New reference values ​​for spirometry in Japanese people using the LMS method" (Japanese Respiratory Society Pulmonary Physiology Specialist Committee, 2014) and KL-6 is 500 U / mL or higher c) Asthma or a history of asthma and eosinophil count is 1000 / μL or higher d) eGFR is 60 mL / min / 1.73m ２e) Hearing loss due to active AAV and an air conduction hearing threshold (average of measurements at 0.25, 0.5, 1, 2, and 4 kHz) of at least one ear of 30 dB or higher. 2) Patients who meet both I) and II) below and for whom it is difficult to reduce or discontinue steroids. I) A worsening of the primary disease due to steroid reduction or discontinuation within 6 months prior to the start of screening has been observed, and the steroid dose thereafter exceeds the steroid dose at the time of worsening. However, patients who meet only 2) of the selection criterion (3) are limited to those who, after starting administration of the investigational drug, the investigator (sub-investigator) determines that they can attempt to reduce or discontinue the steroid dose to the dose at the time of worsening by 16 weeks. II) There has been no new administration or increase in the dose of azathioprine or avacopan since the time of worsening of the primary disease in I).

[0324] (Exclusion Criteria) Patients who meet any one of the following exclusion criteria will be excluded from the study. (1) Patients who are judged by the investigator (sub-investigator) to have symptoms caused by AAV that are life-threatening or lead to vital organ dysfunction. (2) Patients with autoimmune diseases or vasculitis other than AAV, such as systemic lupus erythematosus, IgA vasculitis, rheumatoid vasculitis, Sjogren's syndrome, antiglomerular basement membrane nephritis, cryoglobulinemic vasculitis, idiopathic inflammatory myopathy, and systemic sclerosis. (3) Patients who have shown a tendency for improvement in the activity of their primary disease during remission maintenance treatment from 12 weeks prior to the start of screening to the start of study drug administration, and who are judged by the investigator (sub-investigator) to have the possibility of spontaneous improvement without a change in treatment. (4) Patients who have received rituximab or biological agents with immunosuppressive effects (TNF inhibitors, etc.) from 12 weeks prior to the start of screening to the start of study drug administration. (5) Patients who received mepolizumab from 8 weeks before the start of screening to the start of investigational drug administration. (6) Patients who received cyclophosphamide, methotrexate, mycophenolate mofetil, plasma exchange therapy, or other immunosuppressive therapy from 4 weeks before the start of screening to the start of investigational drug administration. (7) Patients who received a live vaccine from 4 weeks before the start of administration to the start of investigational drug administration. (8) Patients who received steroids exceeding 20 mg / day prednisolone equivalent (see prednisolone conversion table (Table 1)) from 4 weeks before the start of screening to the start of investigational drug administration, or who have started new steroid administration or increased their steroid dose. However, limited to patients who have failed rituximab treatment, new administration and increased doses may be started up to the day before the start of investigational drug administration, up to the dose used in the most recent remission induction treatment (doses exceeding 20 mg / day prednisolone equivalent are permitted). (9) Patients who have started new administration of azathioprine or whose dose has increased or decreased between 4 weeks before the start of screening and the start of administration of the investigational drug. (10) Patients who have started new administration of avacopan or whose dose has increased or decreased between 4 weeks before the start of screening and the start of administration of the investigational drug.

[0325] (11) Patients with a concurrent or past infection with hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). However, patients who are negative for hepatitis B virus surface (HBs) antigen, HBs antibody, and hepatitis B virus core (HBc) antibody at the time of screening will not be excluded. Also, patients with a history of hepatitis C will not be excluded if they maintain a negative HCV-RNA test for 12 weeks or more after completing hepatitis C treatment. (12) Patients with a concurrent active systemic infection on the screening assessment date or the start date of investigational drug administration. (13) Patients with a history of malignant tumors within 5 years prior to the start date of screening. However, this does not include patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or cervical intraepithelial neoplasia who have completed treatment (including therapy for the purpose of treating cancer other than anticancer drugs) without recurrence for 1 year or more. (14) Patients who have previously experienced anaphylaxis or clinically significant allergic symptoms due to administration of an antibody preparation. (15) Patients who have previously received an anti-IL-33 antibody, including this investigational drug. (16) Patients with serious concurrent diseases (see Grade 3 in the "Classification Criteria for Severity of Adverse Reactions to Drugs, etc."; see Notification No. 80 of the Director of the Safety Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, dated June 29, 1992 (https: / / www.mhlw.go.jp / shingi / 2005 / 10 / dl / s1006-4f2.pdf)). (17) Men and women of childbearing potential (excluding postmenopausal women who have been amenorrhea for at least one year and women who have undergone surgical hysterectomy or bilateral oophorectomy) who do not agree to use the methods of contraception specified in the "Lifestyle Guidance" described below from the date of consent until 12 weeks after the end of investigational drug administration. (18) Female patients who are pregnant, breastfeeding, or may be pregnant. (19) Patients who have participated in other clinical trials and received the investigational drug within 12 weeks or within 5 half-lives of the other investigational drug, whichever is longer, prior to obtaining consent. (20) Patients who are otherwise deemed ineligible for this clinical trial by the investigator (sub-investigator).

[0326]

[0327] (Lifestyle Guidance) The investigator (sub-investigator) or clinical trial collaborator will provide lifestyle guidance to the subject, paying attention to the following points. (1) Receive medical examinations and tests on the designated days. If you are unable to attend the hospital on the designated days, be sure to contact the investigator (sub-investigator) or clinical trial collaborator and follow their instructions. (2) Carry your clinical trial participation card and present it when visiting another hospital or department. If you are using medication prescribed by a doctor other than the one in charge of this clinical trial or medication purchased from a pharmacy, be sure to inform the investigator (sub-investigator) or clinical trial collaborator. In addition, if you are using new medication during the clinical trial, be sure to inform the investigator (sub-investigator) or clinical trial collaborator before use. (3) If you feel any abnormalities in your body, regardless of the severity, immediately contact the investigator (sub-investigator) or clinical trial collaborator and follow their instructions. (4) The investigator (sub-investigator) or clinical trial collaborator will instruct the subject not to change their lifestyle (daily activities and exercise), as a general rule. (5) The investigator (sub-investigator) or clinical trial collaborator must instruct the subject to use a reliable contraceptive method, either 1) or 2) below, from the date of informed consent until 12 weeks after the end of administration of the investigational drug. This does not include postmenopausal women who have been amenorrhea for at least one year, or women who have undergone surgical hysterectomy or bilateral oophorectomy. 1) Abstain from sexual intercourse. 2) Use two effective contraceptive methods approved or certified in Japan. In addition to male condoms, the combined use of oral contraceptives and intrauterine devices (including intrauterine systems) is recommended.

[0328] (Phase and type of clinical trial) Phase of clinical trial: Phase Ib Type of clinical trial: Exploratory study

[0329] (Clinical trial design) Details are shown in Figure 2-1. Clinical trial period: The period from the date of consent acquisition to the end of the treatment period. Screening period: The period from the start of screening to the day before the start of administration (first administration of the investigational drug), for a maximum of 4 weeks. Treatment period: The period from the start of administration (first administration of the investigational drug) to the end of the treatment period (the final evaluation date 24 weeks into the treatment period or 4 weeks after the last administration before discontinuing the treatment period).

[0330] Dosage and administration method: On the first day of administration, 10 mg per kg of body weight on the day of administration is administered intravenously over 1 hour to 1 hour and 30 minutes. At weeks 4, 8, 12, 16, and 20, 6 mg of the human anti-IL-33 antibody per kg of body weight on the day of administration is administered intravenously over 45 (±5) minutes. Body weight is calculated to one decimal place. For administration, an appropriate amount of the human anti-IL-33 antibody is diluted in 250 mL of physiological saline.

[0331] (Administration period) The treatment period will be 24 weeks, with the drug administered six times in total at four-week intervals from the start of administration until the 20th week.

[0332] (Methods and criteria for evaluating efficacy) (1) Change from baseline in BVAS at each evaluation time point (2) Proportion of subjects achieving BVAS = 0 at each evaluation time point (3) Change from baseline in VDI (Vasculitis Damage Index) at each evaluation time point (4) Patient Global Impression of Change (PGIC) at each evaluation time point (5) CGIC (Clinical Global Impression of Change) at each evaluation time point (6) Change from baseline in FDG-PET / CT findings at 24 weeks of treatment (7) Change from baseline in chest CT findings at each evaluation time point (8) Change from baseline in head and neck CT / MRI (Magnetic resonance imaging) findings at each evaluation time point (9) Change from baseline in respiratory function test {FVC (mL)} at each evaluation time point. (10) Change from baseline in hearing threshold by pure tone audiometry at each evaluation time point. (11) Changes in biomarkers (BM) {eGFR, urinary protein / creatinine ratio (first morning urine), eosinophil count, serum KL-6, CRP and ANCA-titer (MPO-ANCA, PR3-ANCA)} at each evaluation time point. (12) Changes in steroid dosage. (13) Changes from baseline in SF-36 at each evaluation time point. (14) Changes from baseline in EQ-5D-5L at each evaluation time point.

[0333] (Safety evaluation methods and criteria) (1) Adverse events and side effects (see "Adverse events" below for details) (2) Body weight (3) Vital signs (4) Standard 12-lead electrocardiogram at rest (5) General clinical tests

[0334] (Adverse Events) An adverse event is a clinically undesirable or unintended sign (including clinically significant abnormalities in test values), symptom, or disease observed during the treatment period after administration of the investigational drug, regardless of whether or not it has a causal relationship with the investigational drug. However, if the degree or severity of an adverse event worsens, it will be considered a new adverse event.

[0335] (1) Symptoms or Diseases The investigator (sub-investigator) will confirm the presence or absence of adverse events through interviews and physical examinations.

[0336] (2) Objective findings If the principal investigator (sub-investigator) judges that the abnormality is clinically significant (*), it will be treated as an adverse event. (*) "Clinically significant abnormalities" are determined based on the following criteria: - When there is a relationship with clinical signs or clinical symptoms However, if these symptoms and signs are separately reported as adverse events, the abnormalities in the clinical test and other test results do not need to be treated as adverse events. - When medical or surgical treatment is performed for the abnormalities in the clinical test and other test results - When the administration method of the investigational drug is changed (dose change, drug suspension, discontinuation, etc.) due to the abnormalities in the clinical test and other test results - When the principal investigator (sub-investigator) judges that the abnormality is clinically significant for other reasons

[0337] (3) Evaluation and criteria for adverse events 1) Date of onset The date on which symptoms were observed or the date on which abnormalities in clinical tests were observed.

[0338] 2) Severity The severity of adverse events will be classified according to the following criteria: 1. Mild: No impact on the subject's daily life 2. Moderate: The event causes some disruption to the subject's daily life 3. Severe: The event causes the subject to be unable to carry out their daily life

[0339] 3) Severity The severity of adverse events will be classified as follows: 1. Not serious: Anything other than 2 2. Serious: Any of the following a) to f) a) resulting in death b) being life-threatening c) requiring hospitalization for treatment or prolonged hospitalization d) resulting in permanent or significant disability or incapacity e) resulting in congenital anomalies or birth defects f) any other event or reaction that is deemed to be a medically significant condition

[0340] 4) Causal relationship with the investigational drug The principal investigator (sub-investigator) will evaluate whether there is a "reasonable possibility" that the investigational drug caused the adverse event in question. The evaluation will be made taking into consideration causes other than the investigational drug, such as the natural course of the underlying disease, complications, etc., concomitant therapy, other risk factors, and the temporal relationship between the administration of the investigational drug and the occurrence of the event (recurrence after re-administration, disappearance after discontinuation of administration, etc.). Adverse events that are evaluated as having a "reasonable possibility" of a causal relationship with the investigational drug will be considered side effects of the investigational drug in question. 1. Reasonable possibility 2. No reasonable possibility

[0341] 5) Outcome The outcome of adverse events is classified into the following six stages: 1. Recovered 2. Relieved 3. Not recovered 4. Recovered but with sequelae 5. Death 6. Unknown

[0342] 6) Date of outcome Dates of outcome will be classified according to the following criteria. Recovered: The date of recovery. However, if the date of recovery cannot be specified, it will be the date on which the outcome was confirmed or determined. Relieved: The date on which improvement was confirmed or determined. Not recovered: The date on which no recovery was confirmed or determined. Recovered but with sequelae: The date on which sequelae were confirmed or determined. Died: The date of death. However, if the date of death cannot be specified, it will be the date on which death was confirmed or determined. Unknown: If the outcome was unknown because the subject died for reasons other than the adverse event, it will be the date on which it was confirmed or determined. Others will be the date on which it was confirmed or determined.

[0343] 7) Follow-up Details are shown in Figure 2-2. - The period "1" after the end of administration will be 4 weeks, during which the presence or absence of adverse events will be investigated. For subjects who discontinue administration, the presence or absence of adverse events will be investigated for 4 weeks from the date of the last administration of the investigational drug. - The period "2" after the end of the treatment period will be 28 days, during which adverse events that occurred during the treatment period will be followed up. - The progress of adverse events followed up during the period "2" after the end of the treatment period will be recorded in the case report form. - If an adverse event has improved or has not resolved, the outcome date on the case report form will be the last observation date during the period "2" after the end of the treatment period. - For adverse events that have improved or have not resolved at the end of "2" after the end of the treatment period, the subsequent progress ("3") will be investigated. - If there is a valid reason to discontinue the survey midway during the survey after the end of the evaluation period (after the end of "1"), the follow-up will be terminated.

[0344] (4) Items to be recorded in the case report form If an adverse event is observed, the principal (sub) investigator shall record the name of the adverse event (*), the date of onset, degree, severity, causal relationship with the investigational drug, if any treatment was administered, the details of the treatment (drug name, therapy, etc.), outcome, and the date of outcome in the case report form. (*) The "name of the adverse event" shall follow the following standards: - In principle, the diagnosis name shall be used. - If the diagnosis name is unclear, the symptom name shall be used. - If multiple symptoms are observed and can be expressed with a single diagnosis name, that diagnosis name shall be used. - Surgical procedures, etc. shall not be considered adverse events, but if a disease or symptom requiring surgical procedures, etc. is confirmed, it shall be considered an adverse event.

[0345] (Pharmacokinetics) At the following evaluation times, blood samples will be taken to measure the serum concentration of the anti-IL-33 antibody, and measurements will be taken at a drug concentration measurement facility. The acceptable range for blood sampling 1.5 hours after the start of administration is within ±10 minutes of the set time. Samples will be collected by a clinical testing facility and sent to the drug concentration measurement facility. The principal investigator (sub-investigator) or clinical trial collaborator will record the date and time of blood collection in the case report form. Samples will be collected, labeled, processed, stored, and transported in accordance with the procedure manual.

[0346] (1) Evaluation time points - Day of administration start, 20 weeks: before administration of the investigational drug and 1.5 hours after the start of administration - 1, 4, 8, 12, 16 weeks: before administration of the investigational drug - 24 weeks - Discontinued subjects: at the time of discontinuation (2) Number of blood samples taken: 10 times (3) Volume of blood sampled: 2 mL, total: 20 mL

[0347] (Pharmacodynamics) BM measurements (PD markers: serum IL-33, IL-6, and IL-8, exploratory PD markers: urinary MCP-1 / creatinine ratio, urinary sCD163 / creatinine ratio, serum cystatin C, serum SP-D, erythrocyte sedimentation rate (ESR), and white blood cell differential) will be performed.

[0348] (Other Evaluation Items) (1) Human anti-IL-33 antibodies (ADA and NAb) (2) BM measurement (whole blood gene expression analysis and plasma protein multiplex analysis)

[0349] (Statistical Analysis) (1) Efficacy The proportion of subjects meeting the following treatment success criteria (*) at 24 weeks will be calculated. The proportion of subjects achieving BVAS = 0 and their 95% confidence intervals (Wilson confidence intervals) will be calculated for each evaluation time point. For each other evaluation item, summary statistics (number of subjects, mean, standard deviation, median, minimum, and maximum) of the measured values ​​and changes from baseline for each evaluation time point will be shown.

[0350] (*) Criteria for treatment success Treatment success is defined as when both conditions 1 and 2 below are met. Condition 1: The subject meets either (A) or (B) below. (A) In subjects who meet the criteria for "Selection Criteria (3) 1) Patients judged to have active disease," all of the following (a) to (c) must be met. (a) The total score of the BVAS is 0. (b) Improvement in disease activity findings that meet one or more of the following 1) to 5) is recognized. However, 3) is only applicable to EGPA subjects. 1) In FDG-PET / CT images, baseline findings of Grade 2 or higher (FDG accumulation equivalent to that of the liver) and judged by a radiologist to be indicative of inflammation must improve to Grade 1 or lower (FDG accumulation less than that of the liver). 2) In subjects with a baseline FVC (mL) below the lower limit of normal calculated using the "New Reference Values ​​for Spirometry in Japanese People Using the LMS Method" (Japanese Respiratory Society Pulmonary Physiology Specialist Committee, 2014) 1) and a baseline KL-6 of 500 U / mL or more, the change in FVC (mL) increases by 6% or more from baseline, or the change in KL-6 decreases by 15% or more from baseline. 3) In subjects with a history of or comorbid asthma and a baseline eosinophil count of 1000 / μL or more, the eosinophil count decreases to 450 / μL or less. 4) The baseline eGFR is 60 mL / min / 1.73 m ２In subjects with a baseline eGFR of less than 0.2 g / gCr and a baseline first morning urine protein / creatinine ratio of more than 0.2 g / gCr, both of the following are met: - No worsening of eGFR (definition of eGFR worsening: a worsening of GFR category 44 with a decrease of 25% or more from baseline in eGFR). - A decrease of 50% or more from baseline in the first morning urine protein / creatinine ratio and less than 3.5 g / gCr. 5) In subjects with active AAV-related hearing loss and a baseline air conduction hearing threshold (average of measurements at 0.25, 0.5, 1, 2, and 4 kHz) of 30 dB or more, the air conduction hearing threshold decreases by 10 dB or more from baseline. (c) An improvement in BM is observed that meets either 1) or 2) below. 1) In subjects with a baseline CRP of 0.2 mg / dL or more, the CRP decreases to 0.14 mg / dL or less. 2) In subjects whose baseline ANCA titer is equal to or exceeds the positive reference value (MPO-ANCA: 5.1 IU / mL, PR3-ANCA: 3.1 IU / mL), the ANCA titer will decrease to below the positive reference value. (B) In subjects who meet the "selection criterion (3) 2) Patients for whom it is difficult to reduce or discontinue steroids," the steroid dose will be reduced by 16 weeks of the treatment period to the dose used when the primary disease worsens due to steroid reduction or discontinuation observed within 6 months prior to the start of screening, and the steroid dose will be maintained until 24 weeks of the treatment period.

[0351] Condition 2: Subjects who meet the "selection criterion (3) 1) patients judged to have active disease" must meet (A) and (B), and subjects who meet the "selection criterion (3) 2) patients for whom it is difficult to reduce or discontinue steroids" must meet all of (A) to (C). (A) No worsening of CGIC. (B) The steroid dose has not been increased since the start of administration of the investigational drug. (C) The total BVAS score has not worsened by 1 point or more from the baseline value.

[0352] (2) Safety The incidence of adverse events and side effects will be calculated. The measured values ​​of general clinical tests and vital signs, as well as the changes from baseline, will be presented as summary statistics for each evaluation point.

[0353] (3) Pharmacokinetics and immunogenicity Summary statistics of serum MT-2990 concentrations will be calculated for each evaluation time point. Details of the analysis and other items to be considered will be described in the statistical analysis plan.

[0354] (4) Others Summary statistics of the measured values ​​at each evaluation time point and the change from baseline for PD markers and exploratory PD markers (excluding urinary MCP-1 / creatinine ratio and urinary sCD163 / creatinine ratio) are shown.

[0355] (5) Confidence intervals The confidence intervals are two-sided, and unless otherwise specified, the confidence coefficient is 95%.

[0356] Administration of anti-IL-33 antibodies at the above dosage regimen is expected to have a therapeutic effect on AAV patients.

[0357] 2. Examples of a pharmaceutical composition for reducing the need for surgery in patients with endometriosis or adenomyosis, and a pharmaceutical composition for reducing the impact of endometriosis or adenomyosis on daily life in patients with endometriosis or adenomyosis In the following explanation and the drawings referenced as appropriate, "IV" represents intravenous administration, "SC" represents subcutaneous administration, "Q2W" represents administration once every two weeks, "Q4W" represents administration once every four weeks, "Q6W" represents administration once every six weeks, and "Q8W" represents administration once every eight weeks.

[0358] Example 2-1 (1) IL-33 Antagonist A human anti-IL-33 antibody (A10-1C04) was produced as an IL-33 antagonist by the method described in WO 2015 / 099175. The antibody has a heavy chain first complementarity-determining region H1 consisting of the amino acid sequence represented by SEQ ID NO: 11, a heavy chain second complementarity-determining region H2 consisting of the amino acid sequence represented by SEQ ID NO: 12, a heavy chain third complementarity-determining region H3 consisting of the amino acid sequence represented by SEQ ID NO: 13, a light chain first complementarity-determining region L1 consisting of the amino acid sequence represented by SEQ ID NO: 14, a light chain second complementarity-determining region L2 consisting of the amino acid sequence represented by SEQ ID NO: 15, and a light chain third complementarity-determining region L3 consisting of the amino acid sequence represented by SEQ ID NO: 16, a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 38, a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 39, a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2. The affinity of the human anti-IL-33 antibody for human IL-33 (residues 112 to 270) (ATGen, ILC0701) was measured by KinExA and found to be Kd = 100.3 pM.

[0359] (2) Intravenous Injection The human anti-IL-33 antibody was suspended in a solvent to prepare an intravenous injection (intravenous injection) having the following composition: 0.9% saline was used as a placebo.

[0360] (Composition of intravenous injection) 10 mg / mL human anti-IL-33 antibody 10 mmol / L histidine (pH 6.0) 200 mmol / L sorbitol 0.02% Polysorbate 80

[0361] (3) Administration plan Seventy-six endometriosis patients aged 18 to 49 who had been definitively diagnosed by endoscopy, etc. were the subjects of administration. The patients were randomly divided into two groups: one group (n = 37) was an antibody administration group (anti-IL-33 antibody) that received the intravenous injection containing the human anti-IL-33 antibody, and the other group (n = 39) was a placebo administration group (Placebo) that received the placebo.

[0362] The human anti-IL-33 antibody was mixed with 0.9% saline to give a single dose of 6 mg / kg, and the intravenous injection (250 ml / injection) was administered intravenously to the antibody-administered group, while the placebo-administered group received 250 ml of the placebo intravenously.

[0363] The intervals between administration of the intravenous injection or the placebo to each patient were four, with the first administration being on Day 1 (week 1), followed by administration on Day 29 (week 4), Day 57 (week 8), and Day 85 (week 12).

[0364] (4) PSIQ and SSIQ Before the start of administration on Day 1 (Day 0, Baseline) and on Day 113 (16th week), the physician who diagnosed each patient interviewed them about PSIQ, and the physician also interviewed each patient about SSIQ.

[0365] The PSIQ evaluation results are expressed as a score from 0 to 10, with a relatively higher score indicating a higher likelihood that the doctor will recommend surgery to the patient, and a relatively lower score indicating a lower likelihood that the doctor will recommend surgery to the patient.

[0366] The SSIQ evaluation results are also expressed as a score from 0 to 10, and it can be evaluated that the higher the score, the more motivated the patient is to choose surgery, and the lower the score, the less motivated the patient is to choose surgery.

[0367] Based on the interview results before the start of administration (Baseline) and on Day 113 (Week 16), the mean values ​​for the antibody-administered group and the placebo-administered group were calculated for each of the PSIQ and SSIQ. Furthermore, for each patient, the change in score on Day 113 (Week 16) based on the score before the start of administration (Baseline) was calculated, and the mean change in score was calculated for each of the antibody-administered group and the placebo-administered group. These calculations were performed using analysis software (SAS (registered trademark) 9.4, SAS). The results are shown in Table 2-1.

[0368]

[0369] As shown in Table 2-1, the PSIQ in the placebo group was −0.9 (mean) from before the start of administration (Baseline) to Week 16, whereas in the antibody group it was −1.2 (mean).

[0370] As shown in Table 2-1, the SSIQ in the placebo group was −1.8 (mean) from before the start of administration (Baseline) to Week 16, whereas in the antibody group it was nearly double that, at −3.4 (mean).

[0371] Thus, it was found that administration of an intravenous injection containing a human anti-IL-33 antibody reduced the likelihood of doctors recommending surgery to patients, as assessed by the PSIQ, and reduced the patients' own willingness to choose surgery, as assessed by the SSIQ.

[0372] (5) HRPQ Each patient was interviewed using the HRPQ before the start of administration on Day 1 (week 0), and on Day 29 (week 4), Day 57 (week 8), Day 85 (week 12), and Day 113 (week 16).

[0373] The HRPQ is a questionnaire that expresses the evaluation results of work-related items and household chores-related items as scores, with relatively higher scores indicating higher impacts and relatively lower scores indicating lower impacts.

[0374] Based on the interview results at each time point, the mean values ​​for the antibody-administered group and the placebo-administered group were calculated for each item on the HRPQ. Furthermore, for each patient, the change in score at each time point relative to the baseline score before the start of administration (baseline) was calculated, and the mean change in score was calculated for each of the antibody-administered group and the placebo-administered group. These calculations were performed using analysis software (SAS (registered trademark) 9.4, SAS). The results are shown in Tables 2-2 and 2-3 and Figures 3-1 and 3-2.

[0375]

[0376]

[0377] Figure 3-1 shows the results for the work section of the HRPQ, where (A) is a graph showing the percentage (%) of patients who answered YES to the question, "Last week, were you unable to work at your scheduled time due to illness / treatment?" and (B) is a graph showing the difference from the Baseline regarding the response to the question, "During your work hours in the past week, to what extent did illness / treatment affect your work performance?"

[0378] Furthermore, Figure 3-2 shows the results for Household chores from the HRPQ, where (A) is a graph showing the percentage (%) of patients who answered YES to the question, "Last week, was there a time when you were unable to do your housework for the scheduled time due to illness / treatment?" and (B) is a graph showing the difference from the baseline regarding the answer to the question, "During the past week, how much of an impact did illness / treatment have on the outcome of your housework?"

[0379] In Table 2-2, questionnaire item 3 (Last week, due to illness / treatment, were you unable to work at the scheduled time? (Yes (%))) indicates the percentage (%) of patients who answered YES to the question, "Last week, due to illness / treatment, were you unable to work at the scheduled time?" out of the total number of patients interviewed. In Table 2-3, questionnaire item 6 (Last week, due to illness / treatment, were you unable to do housework at the scheduled time? (Yes (%))) indicates the percentage (%) of patients who answered YES to the question, "Last week, due to illness / treatment, were you unable to do housework at the scheduled time?" out of the total number of patients interviewed.

[0380] In Tables 2-2 and 2-3, the results in which the antibody administration group was able to reduce the effects more than the placebo administration group are circled in bold.

[0381] Specifically, Table 2-2 shows the results for questionnaire items 3 and 4 in the antibody administration group at weeks 4, 8, 12, and 16, and the results for questionnaire item 4 of the change from baseline in the antibody administration group at weeks 4, 8, 12, and 16.

[0382] Table 2-3 shows the results for questionnaire items 6 and 7 in the antibody administration group at weeks 8, 12, and 16, and the results for questionnaire item 7 in the antibody administration group at weeks 8, 12, and 16, showing the change from baseline.

[0383] As shown in Tables 2-2 and 2-3 and Figures 3-1 and 3-2, a decrease in scores over time was confirmed for both work and housework items following administration. Thus, HRPQ assessment demonstrated that administration of an intravenous injection containing a human anti-IL-33 antibody can reduce the impact on daily life, including work and housework.

[0384] The PSIQ, SSIQ, and HRPQ protocols are described below.

[0385] (PSIQ protocol) The PSIQ is used to rate on a scale of 0 to 10 the likelihood that a doctor would recommend surgery for endometriosis-related disease to a patient if current symptoms persist. Item 1: "If current symptoms persist in treating this patient's endometriosis, how likely is it that you (the doctor) would recommend laparoscopic surgery?" Score 0: Not likely Score 10: Very likely

[0386] (SSIQ protocol) The SSIQ assesses the patient's willingness to undergo surgery for endometriosis-related diseases on a scale of 0 to 10 if their current symptoms persist. Item 1: "If your current symptoms persist, how likely is it that you (the patient) would consider laparoscopic surgery to treat your endometriosis?" Score 0: Not likely Score 10: Very likely

[0387] (HRPQ Protocol) These questions address how the illness and its treatment have affected the ability to remain in the workforce and to carry out daily activities at work and at home.

[0388] Item 1. "What is your current employment status?" a: Full-time employment → Go to item 2. b: Part-time employment → Go to item 2. c: Not employed → Go to item 5.

[0389] Item 2. "How many hours did you plan to work last week?" [ ] Hours If 0 hours or not employed, proceed to item 5.

[0390] Item 3. "Last week, were you unable to work the scheduled hours due to illness / treatment?" a: Yes → Due to illness / treatment, I was unable to work for [b] hours. c: No → Due to illness / treatment, I was not unable to work the scheduled hours.

[0391] Item 4. "During the past week's work hours, to what extent did illness / treatment affect your work performance?" [ ] % 0%: It had no effect on what you accomplished 100%: It had an effect on what you accomplished

[0392] Item 5. "How many hours of housework (cooking, cleaning, gardening, repairs, etc.) did you plan to do last week?" [ ] hours

[0393] Item 6: "Last week, were you unable to do the scheduled hours of housework due to illness / treatment?" a: Yes → Because of illness / treatment, I was unable to do housework for [b] hours. c: No → Because of illness / treatment, I was not unable to do the scheduled hours of housework.

[0394] Item 7. "During the past week, how much did your illness / treatment affect your housework performance during the time you were performing it?" [ ] % 0%: Did not affect your performance 100%: Did affect your performance

[0395] <2. Examples of pharmaceutical compositions for reducing the need for surgery in patients with endometriosis or adenomyosis, and pharmaceutical compositions for reducing the impact of endometriosis or adenomyosis on the daily lives of patients with endometriosis or adenomyosis; and 3. Examples of pharmaceutical compositions for treating or preventing endometriosis or adenomyosis> [Example 2-2] A pharmaceutical composition containing an anti-IL-33 antibody was prepared by the following method.

[0396] (1) Preparation of Anti-IL-33 Antibody A human anti-IL-33 antibody (A10-1C04) was prepared in the same manner as in Example 2-1.

[0397] Furthermore, when IL-6 and IL-8 production in the presence of human IL-33 was evaluated in vitro using HUVEC cells, the inhibitory concentrations for IL-6 and IL-8 production in the presence of the human anti-IL-33 antibody were IC ９０ The IC50 values ​​were 3.8 μg / mL (geometric mean value) and 6.7 μg / mL (geometric mean value) at the respective concentrations. ９０ It was thought that the presence of IL-6 and IL-8 at this concentration would reduce the amounts of IL-6 and IL-8 produced by stimulation with IL-33, thereby achieving the desired therapeutic effect. Therefore, this concentration (6.7 μg / mL) can be used as the standard serum trough concentration at which the effects of reducing the need for surgery and the impact on daily life are achieved.

[0398] (2) Preparation of Pharmaceutical Compositions The human anti-IL-33 antibody was suspended in a solvent to prepare pharmaceutical compositions having the following compositions as subcutaneous or intravenous injections. 0.9% physiological saline was used as a placebo for the intravenous injections used in Examples 2-3 and 2-5 described below.

[0399] (Composition of subcutaneous injection) 150 mg / mL human anti-IL-33 antibody 10 mmol / L histidine (pH 6.0) 220 mmol / L D-sorbitol (4.0% (w / v)) 0.02% (w / v) Polysorbate 80

[0400] (Composition of intravenous injection) 10 mg / mL human anti-IL-33 antibody 10 mmol / L histidine (pH 6.0) 200 mmol / L D-sorbitol (3.6% (w / v)) 0.02% (w / v) Polysorbate 80

[0401] [Example 2-3] A phase 1 clinical trial was conducted to evaluate the safety, tolerability, and pharmacokinetics of the human anti-IL-33 antibody when administered intravenously to healthy subjects, based on the following method: This study was a single ascending dose, randomized, double-blind, placebo-controlled study.

[0402] The subjects were 40 healthy male subjects. The arithmetic mean age of this group was 29.8 years, and the arithmetic mean weight was 80.1 kg (minimum 64.5 kg to maximum 97.4 kg).

[0403] The dose of the human anti-IL-33 antibody was set to five dose groups: 0.1, 0.3, 1, 3, or 10 mg / kg. Eight subjects were assigned to each dose group, and the eight subjects in each dose group were randomly assigned to an antibody-administered group (6 subjects) and a placebo group (2 subjects). Under these conditions, the intravenous injection was administered to each subject in a single dose over approximately one hour to achieve the prescribed dose. Subjects receiving placebo received a single dose of 250 mL over approximately one hour. Serum samples were collected before administration (pre-dose), and at 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours after administration, as well as 8, 15, 29, 57, and 85 days after administration, to measure the antibody level.

[0404] The results of the serum antibody concentrations in the antibody-administered groups are shown in FIG. 3-3.

[0405] Maximum serum concentration (C ｍａｘ ) indicates the time (T ｍａｘ The median mean mean time to death (MTD) was similar across dose groups, ranging from 1500 to 2000 hours.

[0406] Average half-life (arithmetic mean t １／２ ) was 617 hours in the 0.1 mg / kg dose group and ranged from 404.1 hours to 460.3 hours in the other dose groups.

[0407] Furthermore, Dose-C ｍａｘ In both the dose-AUC relationship and the dose-AUC relationship, dose proportionality was confirmed between 0.1 mg / kg and 10 mg / kg.

[0408] Furthermore, the human anti-IL-33 antibody was safe and well tolerated in all subjects, and all adverse events that occurred were mild. Therefore, it was found that a pharmaceutical composition containing the human anti-IL-33 antibody is highly tolerable and safe.

[0409] Based on these results, a simulation of serum concentration trends following repeated administration once every four weeks estimated that the repeated dose (intravenous injection) that would yield an AUC equivalent to that of a single 10 mg / kg dose would be 7.2 mg / kg. Therefore, it was estimated that intravenous administration once every four weeks at doses up to 7.2 mg / kg would ensure the same tolerability and safety as a single 10 mg / kg intravenous administration.

[0410] [Examples 2-4] A phase 1 clinical trial was conducted to evaluate the safety, tolerability, and absolute bioavailability of the human anti-IL-33 antibody when administered subcutaneously or intravenously to healthy subjects, based on the following method: This study was an open-label, single-dose, open-label study.

[0411] The subcutaneous administration group consisted of 12 healthy subjects (6 men and 6 women). The arithmetic mean age and arithmetic mean weight were 39.4 years and 73.81 kg, respectively. Separately, the intravenous administration group consisted of 12 healthy subjects (7 men and 5 women). The arithmetic mean age and arithmetic mean weight were 31.6 years and 72.94 kg, respectively.

[0412] The administration protocol is shown in Figures 3-4. In the subcutaneous administration group, four subjects (two men and two women) underwent screening (for a maximum of 28 days), hospital isolation (for a total of nine days, from the day before administration to eight days after administration), and follow-up (for 11 weeks). On the second day of the hospital isolation period, the subcutaneous injection was rapidly administered in a single dose in two 2 mL vials to a total dose of 600 mg. The presence or absence of injection site reactions was then evaluated up to 48 hours after administration. If the four subjects were deemed tolerable, the remaining eight subjects (four men and four women) in the subcutaneous administration group were further administered the same administration protocol as above.

[0413] In the intravenous administration group, a total of 12 subjects received a single dose of the intravenous injection over approximately 1 hour using the same administration protocol as above, with a dose of 600 mg. Serum samples were collected before administration (0 hr) and at predetermined time points after administration to measure the antibody levels.

[0414] The results of the time course of antibody serum concentration in the antibody-administered groups are shown in Figure 3-5. The bioavailability of the human anti-IL-33 antibody following a single subcutaneous administration of 600 mg was 57.26%, based on the geometric mean ratio of AUC(0-∞) (subcutaneous administration / intravenous administration).

[0415] The elimination pattern was similar in both groups, with the mean half-life (arithmetic mean t １／２ ) was 365.7 hours, and the mean half-life (arithmetic mean t １／２ ) was 338.8 hours.

[0416] Furthermore, the human anti-IL-33 antibody was safe and well-tolerated at a dose of 600 mg, and the incidence of adverse events associated with administration of the human anti-IL-33 antibody was low, and all of the events were mild, in both subcutaneous and intravenous administration. Furthermore, one injection site reaction was reported in the subcutaneous administration group, but it was mild. Therefore, it was found that the pharmaceutical composition containing the human anti-IL-33 antibody is highly tolerable and safe, in both subcutaneous and intravenous administration.

[0417] [Example 2-5] A phase 2 clinical trial was conducted to evaluate the efficacy and safety of the human anti-IL-33 antibody according to the following method: This trial was a randomized, double-blind, placebo-controlled trial.

[0418] (1) Administration Plan Seventy-six female endometriosis patients aged 18 to 49 years who had been definitively diagnosed by endoscopy or other methods were treated with the drug. The arithmetic mean age was 32.7 years, and the arithmetic mean weight was 76.5 kg (weight range: 50.35 kg to 109.40 kg). The patients were randomly divided into two groups: one group (n = 37) was the treatment group (A10-1C04) administered with the intravenous injection containing the human anti-IL-33 antibody, and the other group (n = 39) was the placebo group (Placebo) administered with the placebo. All 76 patients had a total score of 6 or higher in the CPSSS evaluation, and both menstrual pain and nonmenstrual pelvic pain scores of 2 or higher in the subjective symptoms. That is, all 76 patients were patients with moderate or severe pain.

[0419] The intravenous injection was administered intravenously over about 1 hour to the treatment group so that the human anti-IL-33 antibody was administered at a dose of 6 mg / kg (250 mL / administration), and the placebo was administered intravenously over about 1 hour to the placebo group so that the placebo was administered at a dose of 250 mL / administration.

[0420] The intravenous injection or the placebo was administered to each patient four times at intervals, with the first administration being on Day 1 (week 1), followed by administration on Day 29 (week 4), Day 57 (week 8), and Day 85 (week 12, end of treatment).

[0421] (2) Change in pain based on the modified B&B scale from baseline to week 16 (evaluation of efficacy) As the primary endpoint, subjects were asked to select one of the following items regarding the degree of pain over the past 24 hours for non-menstrual pelvic pain and to rate it at the same time every day. As secondary endpoints, subjects were asked to rate the degree of pain over the past 24 hours for menstrual pain and dyspareunia using the same method as above. All of these ratings were obtained up to day 113 (week 16) using an electronic diary of endometriosis-associated pain.

[0422] <Evaluation items for non-menstrual pelvic pain and menstrual pain> None (0 points): No discomfort. Mild (1 point): Mild discomfort, but able to easily do normal activities. Moderate (2 points): Moderate discomfort or pain. Could not do most of the things I usually do. Severe (3 points): Severe pain. Could not do most of the things I usually do.

[0423] <Evaluation items for dyspareunia> - Not applicable (excluded from evaluation): There was no sexual intercourse for reasons other than endometriosis, or the following items did not apply. - None (0 points): No discomfort. - Mild (1 point): Tolerable discomfort. - Moderate (2 points): Moderate discomfort or pain occurred, and sexual intercourse was discontinued. - Severe (3 points): Severe pain occurred, and sexual intercourse was avoided.

[0424] (3) Percentage of Responders (Responders) with Treatment of Nonmenstrual Pelvic Pain Using Patient Global Impression of Change (PGIC) Subjects were asked to evaluate the degree of satisfaction with the treatment of endometriosis-associated pain using the human anti-IL-33 antibody using the following evaluation value (on a 7-point scale).

[0425] <Evaluation score> After starting the administration of the human anti-IL-33 antibody, the pain associated with endometriosis was: 1. Very much improved 2. Much improved 3. Mildly improved 4. No change 5. Mildly worsened 6. Worsened 7. Very worsened

[0426] The comparison results between baseline (immediately before administration) and Day 113 (week 16) for the treatment group and placebo group are shown in Tables 2-4. For statistical analysis, a two-sample t-test was used, with a significance level of 5% set, and p = 0.05 or less was considered statistically significant.

[0427] Figure 3-6 is a graph showing the rate of reduction in nonmenstrual pelvic pain, the primary endpoint, at weeks 4, 8, 12, and 16, when the baseline score on the modified B&B scale was set to zero. The rate of reduction is expressed as "(least squares mean of the score at the week being evaluated) - (least squares mean of the score at baseline)," and a larger rate of reduction indicates a greater therapeutic effect.

[0428] Table 2-4 shows the "least squares mean value (standard error) of the reduction rate" and the "difference between the least squares mean values ​​(standard error) of the reduction rate" for the administration group and the placebo group. As shown in Table 2-4, administration of the human anti-IL-33 antibody significantly reduced the evaluation score for nonmenstrual pelvic pain. In addition, the evaluation scores for menstrual pain and dyspareunia were also reduced.

[0429] Furthermore, adverse events were observed with equal frequency in the treatment group and the placebo group, and were all mild. Therefore, it was found that the pharmaceutical composition containing the anti-IL-33 antibody is highly effective and safe in the treatment of endometriosis or adenomyosis when administered intravenously.

[0430] The trough serum concentration of the anti-IL-33 antibody at this time was 18.3 μg / mL at week 4. This trough serum concentration can be used as a standard for the trough serum concentration that achieves the effect of reducing the need for surgery and the effect of reducing the impact on daily life. Taking into account individual differences, etc., 15.0 μg / mL, 17.5 μg / mL, or 18.3 μg / mL can also be used as the standard for the trough serum concentration that achieves the effect of reducing the need for surgery and the effect of reducing the impact on daily life.

[0431]

[0432] Furthermore, in the 7-point rating of patient satisfaction with treatment based on PGIC, the proportion of patients who rated their symptoms as "very much improved" (highest rating) or "very much improved" (second best rating) was 12 (n=30; 40.0%) in the placebo group and 18 (n=31; 58.1%) in the treatment group, with a p-value of 0.204. This indicates that the number of patients satisfied with treatment by administration of the human anti-IL-33 antibody increased.

[0433] [Example 2-6] Based on the results of the above-mentioned clinical trials, an appropriate dose of the human anti-IL-33 antibody when administered subcutaneously was determined by simulation of serum concentration time courses (population pharmacokinetic analysis) using NONMEM.

[0434] Simulations were performed using a population pharmacokinetic analysis model created as follows. First, a population pharmacokinetic analysis model was constructed using PK data from the antibody-administered groups (18 subjects in total) belonging to the 1 mg / kg, 3 mg / kg, or 10 mg / kg dose groups in Example 2-3, the antibody-administered groups (12 subjects in the subcutaneous administration group and 12 subjects in the intravenous administration group, totaling 24 subjects), and the administration groups (37 subjects in total) in Example 2-5. The serum concentration profiles were represented by a three-compartment model, and subcutaneous administration could be represented by first-order absorption. Body weight was incorporated into the clearance (CL) and central compartment distribution volume (V2) as covariates affecting the pharmacokinetics of the human anti-IL-33 antibody. The final model is shown in Figure 3-7, and the estimated parameters are listed in Table 2-5.

[0435] Using the constructed final model, a simulation was performed of the serum concentration transition when subcutaneously administered to 1,000 patients assumed to be endometriosis patients. Random weight numbers were generated for each patient so that their weights would be similar to the tabulated results in Example 2-5. The arithmetic mean and standard deviation, which needed to be specified when generating random numbers, were set to the arithmetic mean and standard deviation of the patient weights in Example 2-5. However, in generating random numbers, values ​​exceeding the upper limit in Example 2-5 were replaced with the upper limit of weight (109.40 kg), and values ​​below the lower limit were replaced with the lower limit of weight (50.35 kg). The random effects were fixed to zero.

[0436]

[0437] The abbreviations in Tables 2-5 and Figures 3-7 represent the following: CL: Clearance V2: Volume of distribution in the central compartment Q3: Clearance between the central compartment and peripheral compartment 1 V3: Volume of distribution in peripheral compartment 1 Q4: Clearance between the central compartment and peripheral compartment 2 V4: Volume of distribution in peripheral compartment 2 KA: Absorption rate constant F1: Absolute bioavailability WT on CL: Effect of body weight on clearance WT on V2: Effect of body weight on the volume of distribution in the central compartment Res. prop: Proportional error Res. add: Absolute error Res. prop for example 2-5: Proportional error for example 2-5 Res. Add for example 2-5: Absolute error for Example 2-5 f(wt): Function with body weight (wt) as explanatory variable Dose: Dose amount Depot: Administration compartment RSE: Relative standard error IIV: Inter-individual variability TVCL: Population estimate of clearance TVV2: Population estimate of distribution volume of the central compartment THETA: Population average parameter

[0438] The dose of the human anti-IL-33 antibody was set to 60 mg, 200 mg, or 600 mg per dose, and the results of simulation of the time course of serum concentration when this antibody was administered subcutaneously once every four weeks are shown in Figure 3-8.

[0439] Furthermore, the simulation results of the serum concentration transition when subcutaneously administered once every two weeks are shown in Figure 3-9.

[0440] The simulation results of the serum concentration transition when subcutaneously administered once every six weeks are shown in Figure 3-10.

[0441] Furthermore, the simulation results of the serum concentration transition when subcutaneously administered once every 8 weeks are shown in Figure 3-11.

[0442] 3-8 , it was found that when the human anti-IL-33 antibody was subcutaneously administered at a dose of 600 mg, the serum concentration could be maintained at or above the trough serum concentration (18.3 μg / mL) found in Example 2-5. This means that, as is clear from the results of Examples 2-4 and 2-5, when the antibody was subcutaneously administered multiple times at a dose of 600 mg / individual / dose with intervals between doses, it was possible to achieve both efficacy and safety in reducing the need for surgery for endometriosis or adenomyosis and the impact on daily life over a long period of time.

[0443] 3-9 , it was found that when the human anti-IL-33 antibody was subcutaneously administered at a dose of 200 mg, the serum concentration was generally maintained at or above the trough value (18.3 μg / mL) found in Example 2-5, and when the human anti-IL-33 antibody was subcutaneously administered at a dose of 600 mg, the serum concentration was able to remain at or above the trough value (18.3 μg / mL) found in Example 2-5. This means that, as is clear from the results of Examples 2-4 and 2-5, when the antibody was administered subcutaneously multiple times at intervals at a dose of 600 mg / individual / single dose or 200 mg / individual / single dose, the antibody was able to achieve both efficacy and safety in reducing the need for surgery for endometriosis or adenomyosis and the impact on daily life over a long period of time.

[0444] 3-10 , it was found that when the human anti-IL-33 antibody was subcutaneously administered at a dose of 600 mg, the serum concentration could be maintained at or above the trough serum concentration (18.3 μg / mL) found in Example 2-5. This means that, as is clear from the results of Examples 2-4 and 2-5, when the antibody was subcutaneously administered multiple times at a dose of 600 mg / individual / dose with intervals between doses, it was possible to achieve both efficacy and safety in reducing the need for surgery for endometriosis or adenomyosis and the impact on daily life over a long period of time.

[0445] 3-11 , it was found that when the human anti-IL-33 antibody was subcutaneously administered at a dose of 600 mg, the serum concentration could be maintained at a level equal to or higher than the trough serum concentration (18.3 μg / mL) found in Example 2-5. This means that, as is clear from the results of Examples 2-4 and 2-5, when the antibody was subcutaneously administered multiple times at a dose of 600 mg / individual / dose with intervals between doses, it was possible to achieve both efficacy and safety in reducing the need for surgery for endometriosis or adenomyosis and the impact on daily life over a long period of time.

[0446] When the human anti-IL-33 antibody was administered subcutaneously to monkeys weekly (100 mg / kg / week, for a total of 13 weeks), no toxicity was observed in the central nervous system, cardiovascular system, or respiratory system, and a large safety margin based on AUC was ensured, at approximately 45. Therefore, it was inferred that the antibody would be highly safe even when administered subcutaneously multiple times to humans at doses exceeding 600 mg.

[0447] As shown by the results in Figure 3-8, when the human anti-IL-33 antibody was subcutaneously administered at a dose of 60 mg / individual / single administration, repeated administration at intervals of 4 weeks increased the serum concentration of the human anti-IL-33 antibody to the IC50 calculated in Example 2-2. ９０ It was found that the value (6.7 μg / mL) may be exceeded.

[0448] Furthermore, as shown by the results in Figure 3-9, when the human anti-IL-33 antibody was subcutaneously administered at a dose of 60 mg / individual / single administration, the serum concentration of the human anti-IL-33 antibody increased to the IC50 calculated in Example 2-2 by repeated administration at intervals of 2 weeks. ９０ It was found that the value (6.7 μg / mL) could be significantly exceeded.

[0449] Furthermore, as shown by the results in Figure 3-10, when the human anti-IL-33 antibody was subcutaneously administered at a dose of 60 mg / individual / single administration, the serum concentration of the human anti-IL-33 antibody increased to the IC50 calculated in Example 2-2 by repeated administration at intervals of 6 weeks. ９０ It was found that the value (6.7 μg / mL) may be exceeded.

[0450] Furthermore, as shown by the results in Figure 3-11, when the human anti-IL-33 antibody was subcutaneously administered at a dose of 200 mg / individual / single administration, the serum concentration of the human anti-IL-33 antibody increased to the IC50 calculated in Example 2-2 by repeated administration at intervals of 8 weeks. ９０ When subcutaneously administered at a dose of 600 mg / individual / single dose, the IC value calculated in Example 2-2 (6.7 μg / mL) may be exceeded to some extent. ９０ It was found that the value (6.7 μg / mL) could be significantly exceeded.

[0451] Therefore, when the administration interval is set to 2 weeks, 4 weeks, and 6 weeks, subcutaneous administration at a dose of 60 mg / individual / dose may be effective in reducing the need for surgery and the impact on daily life in endometriosis or adenomyosis patients.Furthermore, when the administration interval is set to 8 weeks, subcutaneous administration at a dose of 200 mg / individual / dose may be effective in reducing the need for surgery and the impact on daily life in endometriosis or adenomyosis patients.

[0452] Next, when subcutaneously administered at administration intervals of every 2 weeks, every 4 weeks, every 6 weeks, and every 8 weeks, the IC calculated in Example 2-2 was ９０ The dose required to maintain the serum concentration at or above the trough value (6.7 μg / mL) of the serum concentration found in Example 2-5 (18.3 μg / mL) was calculated based on a serum concentration transition simulation. The results are as follows:

[0453]

[0454] Furthermore, these results suggest that the human anti-IL-33 antibody is effective in reducing the need for surgery and reducing the impact on daily life in endometriosis or adenomyosis patients, even when administered subcutaneously to a patient at any dose between 60 mg and 2000 mg per dose (e.g., 60 mg, 80 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg, etc.).

[0455] The present disclosure can provide a technique useful in the medical field.

Claims

1. A pharmaceutical composition for treating or preventing antineutrophil cytoplasmic antibody-associated vasculitis, comprising an anti-IL-33 antibody as an active ingredient.

2. The pharmaceutical composition according to claim 1, wherein the anti-IL-33 antibody comprises: a first heavy chain complementarity determining region H1 consisting of the amino acid sequence represented by SEQ ID NO:11; a second heavy chain complementarity determining region H2 consisting of the amino acid sequence represented by SEQ ID NO:12; a third heavy chain complementarity determining region H3 consisting of the amino acid sequence represented by SEQ ID NO:13; a first light chain complementarity determining region L1 consisting of the amino acid sequence represented by SEQ ID NO:14; a second light chain complementarity determining region L2 consisting of the amino acid sequence represented by SEQ ID NO:15; and a third light chain complementarity determining region L3 consisting of the amino acid sequence represented by SEQ ID NO:

16.

3. The pharmaceutical composition according to claim 1, wherein the anti-IL-33 antibody comprises: a heavy chain variable region consisting of an amino acid sequence having 80% or more identity with the amino acid sequence shown in SEQ ID NO:38; and a light chain variable region consisting of an amino acid sequence having 80% or more identity with the amino acid sequence shown in SEQ ID NO:

39.

4. The pharmaceutical composition according to claim 1, wherein the anti-IL-33 antibody comprises: a heavy chain consisting of an amino acid sequence having 80% or more identity with the amino acid sequence shown in SEQ ID NO:1; and a light chain consisting of an amino acid sequence having 80% or more identity with the amino acid sequence shown in SEQ ID NO:

2.

5. The pharmaceutical composition according to claim 1, which is administered so that the blood trough level of the anti-IL-33 antibody is 6.7 μg / mL or more.

6. The pharmaceutical composition according to claim 5, which is administered so that the blood trough level of the anti-IL-33 antibody is 15.0 μg / mL or more.

7. The pharmaceutical composition according to claim 1, which is for intravenous or subcutaneous administration.

8. The pharmaceutical composition according to claim 7, which is for intravenous administration and the dose of the anti-IL-33 antibody is 0.1 mg / kg body weight to 10 mg / kg body weight.

9. The pharmaceutical composition according to claim 8, wherein the dosage is from 6 mg / kg body weight to 10 mg / kg body weight.

10. The pharmaceutical composition according to claim 9, wherein the dosage is 6 mg / kg body weight.

11. The pharmaceutical composition according to claim 7, which is for subcutaneous administration and the dose of the anti-IL-33 antibody is 50 mg to 2000 mg per administration.

12. The pharmaceutical composition of claim 1, which is administered once every 2 to 8 weeks.

13. The pharmaceutical composition of claim 12, administered every four weeks.

14. The pharmaceutical composition according to claim 1, wherein the number of administrations is 3 to 8.

15. The pharmaceutical composition according to claim 14, wherein the number of administrations is 6 to 8.

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