Drug and anti-gpNMB antibody for removing disease-related cells

Abstract

The present invention provides a novel means capable of effectively eliminating disease-related cells that induce or promote the progression of various diseases. A pharmaceutical composition, which is a pharmaceutical composition for eliminating disease-related cells, comprising an anti-gpNMB antibody, a fragment thereof, or a derivative thereof, which specifically binds to at least one of the regions from the V78 to the PKD domain of human gpNMB.

Description

Technical Field

[0001] This invention relates to a novel drug for eliminating disease-related cells and a novel anti-gpNMB antibody for the drug. Background Technology

[0002] <Immunoglobulins (antibodies)> Human immunoglobulins (antibodies) are classified into five classes—IgG, IgM, IgA, IgD, and IgE—based on the number of Y-shaped units or the type of heavy chain. The heavy chains of IgG, IgM, IgA, IgD, and IgE are denoted as γ, μ, α, δ, and ε, respectively. IgG contains four subclasses: IgG1, IgG2, IgG3, and IgG4. Antibody light chains can be classified into either kappa (κ) or lambda (λ) types based on subtle differences in polypeptide structure, but the antibody subclass is determined by the heavy chain.

[0003] <Phlephagocytes> Phagocytes include macrophages, microglia, dendritic cells, monocytes, and neutrophils. Examples of resident phagocytes in tissues include Kupffer cells, Langerhans cells, and osteoclasts. Macrophages include cancer-infiltrating macrophages, senescent macrophages, adipose-accumulating macrophages, sphingomyelin-accumulating macrophages, foam cells, alveolar macrophages, peritoneal macrophages, splenic macrophages, and thymic macrophages. Microglia include cancer-infiltrating microglia, senescent microglia, adipose-accumulating microglia, and sphingomyelin-accumulating microglia. Dendritic cells include subtypes such as conventional type 1 dendritic cells (cDC1), conventional type 2 dendritic cells (cDC2), monocyte-derived dendritic cells (MoDC), and plasmacytoid dendritic cells (pDC).

[0004] Macrophages Macrophages include various types. Broadly speaking, based on their origin, they can be divided into resident macrophages that reside in tissues, and infiltrative macrophages such as monocytes that migrate and differentiate from the blood and other tissue environments according to changes in the tissue environment. Resident macrophages in the liver are called Kupffer cells, those in the brain are called microglia, those in bone tissue are called osteoclasts, those in the skin are called Langerhans cells, and those in the lungs are called alveolar macrophages, etc.

[0005] Furthermore, from a qualitative perspective, macrophages are broadly classified into M1 macrophages, which induce inflammation and tissue repair, and M2 macrophages, which are anti-inflammatory. However, in recent years, various macrophage subtypes have been identified through scRNA-seq (single-cell RNA sequencing) analysis, and the presence of many disease-specific macrophages has been reported in various diseases. As mentioned above, macrophages differentiate into various types according to their environment. Moreover, it has been clarified that each subtype plays a role in injury healing, or conversely, induces disease or accelerates its progression.

[0006] Senescent cells Senescent cells are those whose proliferation has been persistently halted due to DNA damage, activation of oncogenes, stress, and other factors. In recent years, it has been established that senescent cells acquire an inflammatory-promoting phenotype known as SASP (Senescence-associated secretory phenotype), suggesting its association with various diseases (Non-Patent Literature 1). Cellular senescence is considered a mechanism to prevent the malignant transformation and carcinogenesis of damaged cells; on the other hand, many insights have been reported regarding its association with various age-related pathologies (tissue degeneration, chronic inflammation, cancer progression, etc.).

[0007] Thus, the biological effects of cellular senescence are highly complex, with both beneficial and harmful effects reported, varying depending on the physiological condition. On the other hand, various clinical trials are underway using drugs that eliminate senescent cells to treat refractory diseases.

[0008] <Refractory Cancers> Since the development of molecularly targeted drugs, some efficacy has been achieved in treating cancers that have been difficult to treat until now. Furthermore, with the emergence of immune checkpoint inhibitors and the deepening understanding of cancer immunotherapy, the efficacy of molecularly targeted drugs has been further improved (Non-Patent Literature 2). However, because there are still many cancer patients suffering from refractory cancers (melanoma, TNBC, glioblastoma, multiple myeloma, etc.) for which drug efficacy has not yet been fully demonstrated, there is a need to develop more groundbreaking, highly effective agents. In particular, for glioblastoma, which requires intrabrain delivery and exhibits diverse antigenic variations, drug development remains highly challenging.

[0009] In recent years, with the aim of further improving the cancer cell killing effect of T cells, bispecific antibodies targeting T cell engagement (anti-T cell antibodies and anti-cancer antigen antibodies) and CAR-T cell therapy that directly delivers T cells to cancer cells have been developed, achieving higher efficacy. However, the activity of T cells is not fully utilized, and many patients develop treatment resistance, indicating a high unmet need. Based on this, NK cell engagement antibodies (non-patent literature 5), CAR-NK delivering NK cells (non-patent literature 6), macrophage engagement antibodies (non-patent literature 7), and CAR macrophages (chimeric antigen receptor macrophages) delivering macrophages have also been proposed (non-patent literature 8, non-patent literature 9). In addition, the combined use of tumor-lysing viruses and T cell engagement has been studied (non-patent literature 10).

[0010] One reason why cancer treatment is difficult is the formation of the cancer microenvironment. Within the cancer microenvironment, cytokines produced by cancer cells themselves, or macrophages or microglia infiltrating cancer tissue, create an immunosuppressive environment through the secretion of humoral factors or direct interactions. Furthermore, it has been reported that senescent cells can create an immunosuppressive or chronic inflammatory environment, supporting cancer invasion and proliferation (Non-Patent Literature 11).

[0011] The cancer microenvironment can allow cancer cells to evade host immune attacks or support cancer cell proliferation and stem cell formation. Reports indicate that refractory tumors and tumors with poor prognosis are associated with an immunosuppressive cancer environment, leading to resistance to treatments such as immune checkpoint inhibitors. Therefore, disrupting the cancer microenvironment is crucial in cancer treatment (Non-Patent Literature 12).

[0012] To date, several attempts to eliminate cancer-infiltrating macrophages have been reported. For example, non-specific elimination of macrophages using CSF1R inhibitors (Non-Patent Literature 13) or elimination of cancer-infiltrating macrophages using anti-TREM2 antibodies (Non-Patent Literature 14) have been reported. Furthermore, focusing on senescent macrophages, the elimination of cancer-infiltrating senescent macrophages using senescence cell-clearing drugs has been reported, resulting in inhibited cancer proliferation and improved survival rate and duration in lung cancer-bearing mouse models (Non-Patent Literature 15).

[0013] <Refractory Cancers and gpNMB> Reports indicate that elevated gpNMB levels were observed in the blood of cancer patients with poor response to immune checkpoint inhibitors, and that the combined effect of immune checkpoint inhibitors and anti-gpNMB antibodies was demonstrated in mouse models with melanoma transplantation (Non-Patent Literature 16).

[0014] Even in glioblastoma, microglia and macrophages infiltrating glioblastoma show different characteristics from M1 and M2, and highly express gpNMB and Spp1. This shows that the high expression of gpNMB and Spp1 in glioblastoma patients is associated with poor prognosis (Non-Patent Literature 17).

[0015] The above report suggests that gpNMB is associated with the immunosuppressive environment that forms the cancer microenvironment.

[0016] <Fibrosis> Fibrosis is a disease caused by temporary or chronic damage to vital organs such as the lungs, liver, kidneys, heart, skin, and blood vessels. During the repair process, excessive or abnormal accumulation of collagen and other fibers leads to loss of elasticity and hardening of the organs, resulting in their inability to function normally. There is currently no fundamental cure for this disease.

[0017] Idiopathic pulmonary fibrosis (IPF), a type of pulmonary fibrosis, is a difficult condition for which there is no cure. Clinical trials have been conducted to investigate the efficacy of using D+Q (dasatinib and quercetin), a combination of anticancer agents, to clear senescent cells (Non-Patent Literature 18). However, limitations such as dosage restrictions to avoid side effects have prevented the achievement of adequate efficacy. Furthermore, the results of a recent phase III clinical trial of an anti-CTGF antibody (Non-Patent Literature 19) have been reported, but no efficacy was observed.

[0018] Chronic kidney disease (CKD) is a condition characterized by abnormalities in kidney structure or function for more than 3 months. There is no effective treatment, and if it progresses, it can lead to end-stage renal failure, requiring dialysis or kidney transplantation. Although clinical trials have been conducted using senescent cell-clearing drugs for diabetic nephropathy, no efficacy has been shown (Non-Patent Literature 20).

[0019] Nonalcoholic steatohepatitis (NASH), which induces liver fibrosis and progresses, is a refractory disease without any therapeutic agents. Fibrosis has been reported to be induced by adipose-accumulated macrophages (Non-Patent Literature 21). On the other hand, improvements in the fatty liver condition have also been reported by clearing senescent cells (Non-Patent Literature 22).

[0020] Vasculitis is an autoimmune inflammatory disease of blood vessels of unknown cause, leading to destruction of the vessel wall and inducing fibrosis. It has been reported that in conditions such as high-grade vasculitis or giant cell arteritis (GCA), stimulation of fibroblasts and induction of fibrosis by monocytes or macrophages is associated with pathogenesis (Non-Patent Literature 23).

[0021] Duchenne muscular dystrophy (DMD) is a progressive muscular atrophy that has been reported to induce fibrosis in skeletal muscle and is associated with a certain type of macrophage (Non-Patent Literature 24). Additionally, there are reports of improved pathological condition and muscle strength in a rat model of DMD using senescent cell scavenging agents (Non-Patent Literature 25).

[0022] <Fibrosis and gpNMB> While some reports suggest that gpNMB is associated with fibrosis, there are both reports suggesting that it inhibits or promotes fibrosis.

[0023] In silicosis, a pulmonary fibrosis disease, scRNA-seq analysis using a mouse model showed that gpNMB induces epithelial-mesenchymal transition in alveolar epithelial cells and promotes fibrosis (Non-Patent Literature 26).

[0024] gpNMB expression was reported in a subset of macrophages (Scar-associated macrophages: SAM) that is believed to induce fibrosis in liver or lung fibrosis (Non-Patent Literature 27).

[0025] On the other hand, regarding the pathogenesis of nonalcoholic fatty liver disease (NAFLD) induced by a high-fat, high-sucrose (HFHS) diet, it has been reported that overexpression of gpNMB can improve fat accumulation and fibrosis in the liver (Non-Patent Literature 28).

[0026] In addition, there are reports that the repair of skin damage is promoted by gpNMB derived from macrophages (Non-Patent Literature 29).

[0027] The study reported that in Takayasu arteritis, a type of vascular fibrosis, fibrosis of the vessel wall was observed, and macrophages produced TGFβ and gpNMB, thereby activating fibroblasts (Non-Patent Literature 30).

[0028] A database analysis of genes expressed in the skeletal muscle tissue of DMD patients was used to report DMD-specific genes, including gpNMB (Non-Patent Literature 31).

[0029] <Metabolic Diseases> Metabolic diseases include diabetes, hypertension, lipid dyslipidemia (high cholesterol, high triglycerides, etc.), arteriosclerosis, fatty liver, hyperuricemia (gout), metabolic syndrome, obesity, etc. Most of these diseases are believed to be caused by chronic inflammation.

[0030] High blood sugar in diabetes can induce various diseases (Non-Patent Literature 32). These include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. Diabetic retinopathy (DR) is a microvascular complication characterized by abnormal angiogenesis and is the most common cause of irreversible blindness. Diabetic nephropathy results from persistent hyperglycemia caused by diabetes, which damages the tiny blood vessels that fill the kidneys. If it worsens, it can progress to renal insufficiency and may require hemodialysis. Diabetic neuropathy is caused by long-term persistent hyperglycemia, which not only damages the blood vessels surrounding the nerves but also alters the nature of the nerves themselves, leading to various dysfunctions in nerve function.

[0031] Lipid dyslipidemia includes abnormal blood concentrations of LDL cholesterol (so-called bad cholesterol), HDL cholesterol (so-called good cholesterol), and triglycerides (neutral fats), all of which have been reported to be associated with promoting atherosclerosis. In atherosclerosis, in the vascular endothelium, macrophages engulf oxidized LDL and transform into fat-accumulating macrophages called foam cells (Non-Patent Literature 33), forming a lipid core that becomes the center of atherosclerotic foci (plaques), thereby narrowing the lumen of the blood vessel.

[0032] If fat accumulates abnormally in the liver, it becomes fatty liver disease. Non-alcoholic fatty liver disease (NAFLD) is a general term for fatty liver disease not caused by alcohol or viruses. It manifests as a phenotype of lifestyle-related diseases such as obesity, diabetes, and metabolic syndrome in the liver. Even people who do not drink alcohol regularly can progress to liver disease like those with alcoholic liver disorder. Moreover, 20-30% of these cases will metastasize to non-alcoholic steatohepatitis (NASH), which carries the risk of progression to cirrhosis and liver cancer accompanied by inflammation and fibrosis. Research on macrophage subsets involved in these progression processes is ongoing (Non-Patent Literature 34).

[0033] <Metabolic diseases and gpNMB> A paper reported that gpNMB in the blood has become a disease-related biomarker in diabetes and its complications (Non-Patent Literature 35).

[0034] For diabetes, it is important to improve insulin resistance. It has been reported that in diabetic mice with a high-fat diet load, soluble gpNMB produced from the liver promotes lipid synthesis in white adipocytes, and that obesity and insulin resistance were improved by administering anti-gpNMB polyclonal antibodies (Non-Patent Literature 36).

[0035] In addition, in human retinal microvascular endothelial cells (HRMECs), high glucose treatment increased gpNMB and integrin β1, suggesting that gpNMB functions as an angiogenic factor via integrin β1 / VEGFA. By knocking down gpNMB using lentivirus expressing shRNA, cell survival, migration, and tube formation in HRMECs were inhibited, thus suggesting that gpNMB is associated with the pathological progression of diabetic retinopathy (Non-Patent Literature 37).

[0036] It has been reported that macrophages associated with atherosclerosis in ApoE-KO mice subjected to a high-fat diet are gpNMB-positive (Non-Patent Literature 38). Additionally, gpNMB has been reported to be expressed in lipid-laden macrophages, a type of atherosclerotic cell known as foam cells (Non-Patent Literature 39).

[0037] <Circulatory Organ Diseases> Circulatory organ diseases refer to diseases in which organs such as the heart and blood vessels, which are responsible for circulating blood throughout the body, cannot function properly. They are classified into hypertension, heart diseases (ischemic heart diseases such as acute myocardial infarction or heart failure), cerebrovascular diseases (cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage), aneurysms, etc.

[0038] In cardiac diseases, increased infiltration of inflammatory cells such as monocytes and lymphocytes after myocardial infarction induces chronic inflammation, leading to myocardial remodeling and heart failure. Reports indicate that controlling inflammatory cell infiltration, increased expression of inflammatory cytokines, and cardiac macrophages are crucial for inhibiting progression (Non-Patent Literature 40). Studies analyzing common macrophage subsets associated with cardiac diseases have also been reported (Non-Patent Literature 41).

[0039] <Circulatory organ diseases and gpNMB> This suggests that macrophages are involved in myocardial remodeling after myocardial infarction, and gpNMB is reported to be expressed in these macrophages (Non-Patent Literature 42).

[0040] <Lysosomal Stress-Related Diseases> Lysosomes can become dysfunctional due to various stresses, leading to the accumulation of toxic proteins and inducing various diseases. Among these, lysosomal diseases are genetic disorders caused by a deficiency or reduced activity of lysosomal enzymes, resulting in the accumulation of mucopolysaccharides and lipids within the lysosomes, ultimately leading to lysosomal and even cellular dysfunction and the development of symptoms. Examples of lysosomal diseases include Gaucher disease or Pompe disease, and Niemann-Pick disease types A, B, and C.

[0041] <Lysosomal stress-related diseases and gpNMB> gpNMB is an important protein in the breakdown of proteins and lipids in lysosomes. Its expression increases when cells are subjected to lysosomal stress due to the accumulation of substances that must be broken down. Therefore, it serves as an indicator of cells subjected to excessive lysosomal stress. Moreover, high expression has also been observed in senescent cells that have become dysfunctional.

[0042] This report describes the observation of lipid-accumulating gpNMB-highly-expressing cells in lysosomal diseases such as Gaucher disease and Niemann-Pick disease. In Gaucher disease, macrophages accumulating lipids, known as Gaucher cells, were observed. In Niemann-Pick disease types A and B (acid sphingomyelinase deficiency (ASMD)), sphingomyelin-accumulating macrophages accumulated in the spleen and liver were also observed (Non-Patent Literature 43).

[0043] <Disorders Related to Neurogenic Pain> Neuropathic pain is caused by direct disturbances in the brain or nerves (such as nerve compression due to stroke, spinal cord injury, surgery, or cancer infiltration). It is poorly treated with antipyretics and analgesics, difficult to manage, and has a high likelihood of becoming chronic, thus requiring fundamental treatment. Fibromyalgia pain is classified as neuropathic pain and is believed to be caused by inflammation of the nerves in the brain induced by some cause.

[0044] <Neurogenic pain-related disorders and gpNMB> It has been reported that in rats with neuropathic pain, pain was alleviated by injecting siRNA that inhibits gpNMB expression into the subarachnoid space (Non-Patent Literature 97).

[0045] <gpNMB> gpNMB (Glycoprotein nonmetastatic melanoma protein B) (also known as Osteoactivin, DC-HIL, Nonpatent Document 44) is a single-transmembrane glycoprotein with up to 12 glycosylation sites in the human body. It is normally expressed in intracellular organelles (endoplasmic reticulum, lysosomes, Golgi apparatus, melanosomes, etc.) (Nonpatent Document 45). However, it has been reported to be expressed on the cell membrane under overexpression (Nonpatent Document 46). gpNMB has also been reported to be expressed in cancer cells (Nonpatent Document 47), and there are reports that the KLD (kringle-like domain) is crucial for cell proliferation, or that the intracellular ITIM motif induces signaling (Nonpatent Document 48).

[0046] Furthermore, gpNMB possesses a region similar to the CAF (Core Amyloid Fragment) region (Non-Patent Document 49) of the family protein PMEL (Premelanosome Protein) (hereinafter referred to as the PMEL-CAF-like domain) or the PKD (Polycystic Kidney Disease homology) domain. The PKD domain is a domain in which β-sheets composed of 3 chains and β-sheets composed of 4 chains are folded to form a β-layer structure. Because it is a characteristic structure of polycystic kidney protein 1 (polycystin-1), which is a pathogenic gene for polycystic kidney disease, it was named the PKD domain (Non-Patent Document 50).

[0047] As molecules interacting with gpNMB, syndecan-4 (SD4, SDC4) or CD44, integrins, Na+ / K+-ATPases, EGFR, etc., have been reported (Non-Patent Literature 98). The interaction between SD4 and the PKD domain of gpNMB has been reported, with gpNMB controlling T cell activity via SD4 on T cells. CD44 expression in mesenchymal stem cells, osteoclasts, astrocytes, or adipocytes has been reported, with gpNMB interacting with CD44 to control cell proliferation, adhesion, migration, and activity. Furthermore, gpNMB possesses an RGD sequence at its N-terminus, which, through interaction with integrins as adhesion molecule, controls the migration or adhesion of various cells. Soluble gpNMB, bound to cells via the RGD sequence, can also modify various physiological functions or pathological conditions. Moreover, the interaction between gpNMB and EGFR in intracellular domains to control cell proliferation has also been reported. In addition, the interaction between gpNMB and the α subunit of Na+ / K+-ATPase has been reported, demonstrating a cytoprotective effect.

[0048] gpNMB is essential for the function of phagosomes or lysosomes (Non-Patent Literature 51), and reduced lysosomal function has been reported in gpNMB-deficient mice (Non-Patent Literature 52). In addition, iris abnormalities and glaucoma have been reported in gpNMB-deficient mice (Non-Patent Literature 53), and cutaneous amyloidosis has been reported in gpNMB-deficient humans (Non-Patent Literature 54).

[0049] In recent years, GWAS (Genome-wide association studies) analyses have reported gpNMB as a risk gene for Parkinson's disease (Non-Patent Literature 55), and have also suggested a link to the spread of α-synuclein, a pathogenic substance in Parkinson's disease (Non-Patent Literature 56). On the other hand, there are also reports that even in the absence of gpNMB, synuclein-related pathology remains unchanged (Non-Patent Literature 57).

[0050] It is known that gpNMB is cleaved by membrane-type proteases such as ADAM10, releasing it as soluble gpNMB (Non-Patent Literature 58). Soluble gpNMB has been reported to participate in various physiological and pharmacological effects, including cell protection (Non-Patent Literature 59), neuroprotection (Non-Patent Literature 60), inflammation (Non-Patent Literature 45, 61, 62), and cell proliferation (Non-Patent Literature 63). Furthermore, gpNMB has been reported to have a protective effect against obesity-induced metabolic abnormalities (Non-Patent Literature 64). Moreover, improved neurological function has been reported in transgenic mice that overexpress soluble gpNMB (extracellular gpNMB) (Non-Patent Literature 65), and increased cognitive function in Alzheimer's disease model mice (APP / PS1) has been reported by promoting autophagy through gpNMB expression using a lentiviral vector (Non-Patent Literature 66).

[0051] On the other hand, reports have shown that administering a mouse gpNMB-specific vaccine peptide containing a portion of the mouse gpNMB amino acid sequence reduced senescent vascular endothelial cells and fibroblasts, improved insulin resistance or arteriosclerosis in high-fat diet-loaded mice, and prolonged survival in aging-promoting mice. Furthermore, reports indicate that antibody-dependent cellular cytotoxicity (ADCC) activity is crucial at this stage, and a partial gpNMB peptide sequence effective in clearing senescent cells has been disclosed (Patent Document 1, Non-Patent Document 67). Additionally, reports have shown that in high-fat diet-loaded mice, administering a polyclonal antibody against mouse gpNMB inhibited the production of soluble gpNMB from the liver, thereby improving obesity and insulin resistance (Non-Patent Document 68).

[0052] Numerous studies have also been conducted on soluble gpNMB as a biomarker. A correlation has been reported between blood gpNMB concentration and the progression of diabetes-related diseases (Non-Patent Literature 35).

[0053] Regarding the concentration of soluble gpNMB in cerebrospinal fluid, there are reports of its correlation with Parkinson's disease (Non-Patent Literature 69). Additionally, a correlation with ALS has been reported (Non-Patent Literature 70). There are also reports of it being a biomarker for cerebral adrenoleukodystrophy (Non-Patent Literature 71). On the other hand, regarding its relationship with Alzheimer's disease, there are reports of elevated concentrations in Alzheimer's patients (Non-Patent Literature 72), while there are also reports of no correlation (Non-Patent Literature 73).

[0054] <Anti-gpNMB antibody> As an anti-gpNMB antibody, glembatumumab (Patent Document 2) is known as a human antibody specific to human gpNMB. Vedotin (Glembatumumab Vedotin) (Non-Patent Document 74), a conjugate of glembatumumab and an anticancer agent, was developed as a cancer treatment candidate and progressed to Phase II trials, but development has been discontinued. This antibody has also been explored for use in imaging diagnostics (Non-Patent Document 75). Furthermore, other anti-gpNMB antibodies have been developed that bind to gpNMB expressed on the surface of cancer cells and treat cancer using immunotoxins (Patent Document 3). Moreover, there are reports on obtaining other anti-human gpNMB specific antibodies, illustrating their application in the diagnosis or treatment of human-derived cancer cells (Non-Patent Document 76). Additionally, an anti-rat gpNMB specific antibody that activates rat microglia has been reported (Non-Patent Document 77). In addition, there are reports of anti-mouse DC-HIL specific antibodies being able to introduce signals into cells (Non-Patent Literature 78).

[0055] <gpNMB expressing cells> Because high expression of gpNMB has been observed in various cancer tissues (breast cancer (non-patent literature 79), lung cancer (non-patent literature 80), hepatocellular carcinoma (non-patent literature 81), glioblastoma multiforme (non-patent literature 82), mesothelioma (non-patent literature 83), etc.), the clinical development of ADCs (antibody-drug complexes) targeting gpNMB and delivering anticancer agents via anti-gpNMB antibodies has progressed to Phase II clinical trials in various refractory cancers (non-patent literature 74). Furthermore, high expression of gpNMB has been reported in cancers with poor prognosis (non-patent literature 84), in cancer stem cells (non-patent literature 85), and in infiltrating macrophages or microglia, myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), etc., which form the cancer microenvironment (non-patent literature 86). Furthermore, there are reports that the glycan-4 (SD4, SDC4) on T cells interacts with gpNMB-expressing cells (infiltrating macrophages or microglia that form the cancer microenvironment, myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), etc.), thereby inhibiting T cell activity (Non-Patent Literature 87).

[0056] gpNMB has also been reported as a marker of senescent cells. Reports indicate that administering a portion of gpNMB peptides to aging-promoting mouse models cleared gpNMB-expressing senescent vascular endothelial cells or gpNMB-expressing senescent fibroblasts, thus improving arteriosclerosis and diabetes (Non-Patent Literature 71). Furthermore, gpNMB expression has also been observed in adipose-tissue macrophages with crown-like structures in obese individuals (Non-Patent Literature 88).

[0057] gpNMB expression was reported in a subset of macrophages (SAM: scar-associated macrophages) that are thought to induce fibrosis in liver or lung fibrosis (Non-Patent Literature 27).

[0058] Macrophages associated with atherosclerosis in ApoE-KO mice subjected to a high-fat diet, etc., were reported to be gpNMB positive (Non-Patent Literature 38). Additionally, gpNMB expression has been reported in lipid-laden macrophages, a type of atherosclerosis known as foam cells (Non-Patent Literature 39). Furthermore, similar cells highly expressing lipid-laden gpNMB have been reported in lysosomal diseases such as Gaucher disease or Niemann-Pick disease. In Gaucher disease, lipid-laden macrophages, known as Gaucher cells, have been observed; in Niemann-Pick disease A and B (acid sphingomyelinase deficiency (ASMD)), sphingomyelin-laden macrophages accumulate in the spleen or liver (Non-Patent Literature 43). Furthermore, gpNMB has been reported to be highly expressed in myelin-laden macrophages (foamy macrophages) that accumulate lipid-rich myelin in multiple sclerosis (Non-Patent Literature 96).

[0059] Existing technical documents Patent documents Patent Document 1: International Publication No. 2021 / 020047 Patent Document 2: Japanese Patent No. 6334496 Patent Document 3: International Publication No. 2007 / 053718 Non-patent literature Non-patent literature 1: Zhang et al., J. Clin. Invest., 2022, 132

[15] : e158450 Non-patent literature 2: Kurt et al., J. Clin. Invest., 2023, 133

[13] : e170762 Non-patent literature 3: Wei et al., Front. Immunol., 2022, 13: 103527 Non-patent literature 4: Geng et al., Front. Cell Dev. Biol., 2023, 11: 1158539 Non-patent literature 5: Pinto et al., Trends Immunol., 2022, 43

[11] : 932-946 Non-patent literature 6: Klaihmon et al., Int. J. Mol. Sci., 2023, 24

[13] : 10508 Non-patent literature 7: Kaiuchi-Kiyota et al., Leukemia, 2022, 36: 1006-1014 Non-patent literature 8: Gatto et al., Immunotherapy, 2021, 13

[11] : 879-883 Non-patent literature 9: Unver et al., Clin. Exp. Med., 2023, doi 10.100_s10238-023-01106-0 Non-patent literature 10: Huang et al., Am. J. Cancer Res., 2021, 11[6]: 2430-2455 Non-patent literature 11: Malayaperumal et al., Clin. Pract., 2023, 13: 838-852 Non-patent literature 12: Zhao et al., Front. Immunol., 2023, 14: 1157537 Non-patent literature 13: Jahchan et al., Front. Immunol., 2019, 10: 1611 Non-patent literature 14: Binnewies et al., Cell Reports, 2021, 37: 109844 Non-patent literature 15: Haston et al., Cancer Cell, 2023, 41: 1242-1260 Non-patent literature 16: Chung et al., Clin. Cancer Res., 2020, 26[6]: 1449-1459 Non-patent literature 17: Szulzewsky et al., PLoS ONE, 2015, 10[2]: e0116644 Non-patent literature 18: Nambiar et al., eBioMedicine, 2023, 90: 104481 Non-patent literature 19: Leask et al., J. Cell Commun. and Signaling, 2019, 13:441-442 Non-patent literature 20: Hickson et al., EBioMedicine, 2019, 47: 446-456 Non-patent literature 21: Shimizu et al., Am. J. Pathol., 2022, 192: 31-42 Non-patent literature 22: Ogrodnik et al., Nat. Commun., 2017, 8: 15691 Non-patent literature 23: Watanabe et al., Front. Immunol., 2022, 13: 859502 Non-patent literature 24: Coulis et al., Sci. Adv., 2023, 9: eadd9984 Non-patent literature 25: Sugihara et al., Sci. Rep., 2020, 10: 16385 Non-patent literature 26: Yang et al., Part. Fibre Toxicol., 2023, 20: 29 Non-patent literature 27: Fabre et al., Sci. Immunol., 2023, 8: eadd8945 Non-patent literature 28: Katayama et al., Sci. Rep., 2015, 5: 16920 Non-patent literature 29: Silva et al., Exp. Dermatol., 2018, 27: 630-635 Non-patent literature 30: Dai et al., Transl. Res., 2023, 255: 128-139 Non-patent literature 31: An et al., J. Zheijang Univ-Sci. G., 2013, 14

[11] : 973-982 Non-patent literature 32: Reynolds et al., Front. Immunol., 2023, 14: 1219598 Non-patent literature 33: Cervantes et al., Front. Cardiovasc. Med., 2023, 10:1213177 Non-patent literature 34: He et al., J. Trans. Med., 2023, 21: 448 Non-patent literature 35: Huo et al., Front. Endocrinol., 2023, 14: 1110337 Non-patent literature 36: Gong et al., Nat. Metab., 2019, 1[5]: 570-583 Non-patent literature 37: Quin et al., Mol. Cell Biochem., 2023, 478: 697-706 Non-patent literature 38: Haerdtner et al., Atherosclerosis, 2023, 371: 1-13 Non-patent literature 39: van Eijk et al., Int. J. Mol. Sci., 2021, 22: 4039 Non-patent literature 40: Chen et al., Front. Immunol., 2023, 14: 1207100 Non-patent literature 41: Li et al., J. Leukoc. Biol., 2023, 113: 139-148 Non-patent literature 42: Jarve et al., FASEB J., 2017, 31: 556-568 Non-patent literature 43: Eskes et al., Mol. Genet. Metab., 2023, 139: 107631 Non-patent literature 44: Shikano et al., J. Biol. Chem., (2001), 276

[11] : 8125-8134 Non-patent literature 45: Ripoll et al., J. Immunol., (2007), 178: 6557-6566 Non-patent literature 46: Tse et al., Clin. Cancer Res., (2006), 12[4]: 1373-1382 Non-patent literature 47: Maric et al., OncoTargets Ther., (2013), 6: 839-852 Non-patent literature 48: Xie et al., Cancer Sci., (2019), 110[7]: 2237-2246 Non-patent literature 49: Hee et al., Scientific Reports, (2017), 7: 44064 Non-patent literature 50: Bycroft et al., EMBO J., (1999), 18[2]: 297-305 Non-patent literature 51: Li et al., FASEB J., (2010), 24

[12] : 4767-4781 Non-patent literature 52: Robinet et al., Scientific Reports, (2021), 11: 10249 Non-patent literature 53: Anderson et al., Nat. Genet., (2002), 30: 81-85 Non-patent literature 54: Yang et al., Am. J. Hum. Genet., (2018), 102[2]: 219-232 Non-patent literature 55: Murthy et al., Neurogenetics, 2017, 18: 121-133 Non-patent literature 56: Diaz-Ortiz et al., Science, 2022, 377: 833 Non-patent literature 57: Grendza et al., Neurobiol. Dis., 2021, 159: 105494 Non-patent literature 58: Rose et al., PLoS One, (2010), 5[8]: e12093 Non-patent literature 59: Wang et al., Int. J. Mol. Sci., 2021, 22: 10843 Non-patent literature 60: Nakano et al., Neuroscience, (2014), 277: 123-131 Non-patent literature 61: Saade et al., Front. Immunol., 2021, 12: 674739 Non-patent literature 62: Neal et al., J. Neuroinflammation, 2018, 15: 73 Non-patent literature 63: Wang et al., Cancer Sci. (2021), 112: 4187-4197 Non-patent literature 64: Prabata et al., J. Biol. Chem., 2021, 297[5]: 101232 Non-patent literature 65: Murata et al., J. Neurochem., (2015), 132: 583-594 Non-patent literature 66: Zhu et al., Neurosci. Lett., (2022), 767: 136300 Non-patent literature 67: Suda et al., Nat. Aging, (2021), 1: 1117-1126 Non-patent literature 68: Gong et al., Nat. Metab., (2019), 1[5]: 570-583 Non-patent literature 69: Hansson et al., EMBO Mol. Med., 2023, 15: e16359 Non-patent literature 70: Oh et al., Biomedicines, 2023, 11: 1250 Non-patent literature 71: Taghizadeh et al., Sci. Rep., 2022, 12: 7985 Non-patent literature 72: Huettenrauch et al., Acta Neuropathol. Commun., 2018, 6:108 Non-patent literature 73: Aichholzer et al., Alzheimers Res. Ther., (2021), 13: 94 Non-patent literature 74: Vahdat et al., npj Breast Cancer, 2021, 7: 57 Non-patent literature 75: Li et al., Cancers, 2023, 15: 1589 Non-patent literature 76: Zhang et al., Monoclon. Antibodies Immunodiagn. Immunother., (2013), .32[4]: 265-269 Non-patent literature 77: Kawahara et al., Glia, (2016), 64

[11] : 1938-1961 Non-patent literature 78: Chung et al., J. Immunol., (2019), 183[5]: 5190-5198 Non-patent literature 79: Huang et al., Sci. Rep. 2021, 11: 12171 Non-patent literature 80: Han et al., Cancer Sci., 2021, 112: 1911-1923 Non-patent literature 81: Sakano et al., Cancer Sci., 2022, 113[5]: 1625-1638 Non-patent literature 82: Kuan et al., Clin. Cancer Res., 2006, 12[7]: 1970-1982 Non-patent literature 83: Wu et al., PNAS, 2023, 120[9]: e2210836120 Non-patent literature 84: Feng., Oncol. Lett., 2020, 20[3]: 2356-2368 Non-patent literature 85: Okita et al., Oncotarget, 2018, 9

[99] : 37289-37290 Non-patent literature 86: Lazaratos et al., Oncogene, 2022, 41:4573-4590 Non-patent literature 87: Tomihari et al., Cancer Res., 2010, 70

[14] : 5778-5787 Non-patent literature 88: Gabriel et al., Diabetes, 2014, 63: 3310-3323 Non-patent literature 89: Chrystal et al., Molecules, 2021, 26: 3529 Non-patent literature 90: Alexander et al., Pigment Cell Melanoma Res. 2013, 26[4]: 470-486 Non-patent literature 91: Strohl et al., Current Opinion in Biotechnology 2009, 20, pp685-691 Non-patent literature 92: Lee et al., Nat Commun. 2019 Nov 6; 10(1), 5031 Non-patent literature 93: Kouhi et al., Int. J. Mol. Sci. 2019, 20, 3108 Non-patent literature 94: C. Spiess et al., Molecular Immunology 2015, Vol.67, pp95-106 Non-patent literature 95: Chocarro et al., Biomedicines 2022, 10: 3035 Non-patent literature 96: Hendrickx et al., Front Immunol. 2017, 8: 1810 Non-patent literature 97: Hou et al., J Mol Neurosci, 2015, 55: 533-540 Non-patent literature 98: Tsou et al., The FASEB Journal., (2020), 34: 8810-8823. Summary of the Invention

[0060] The problem that the invention aims to solve Previously, attempts have been made to develop methods for eliminating various cells that induce or promote the progression of various diseases (appropriately termed "disease-associated cells"). However, reports on methods for eliminating these disease-associated cells have been extremely limited to date. In particular, the development of methods that can specifically eliminate highly malignant disease-associated cells that are the root cause of disease induction has not yet been achieved.

[0061] This invention was made in view of the aforementioned issues. Specifically, one object of this invention is to provide a novel means for effectively eliminating various disease-related cells.

[0062] Methods for solving problems In order to develop a method for specifically eliminating highly malignant disease-associated cells, the inventors conducted in-depth research, focusing on gpNMB (glycoprotein nonmetastatic melanoma protein B), a common antigen in disease-associated cells related to various diseases. Based on this, and under various limiting conditions, through in-depth research using various experimental methods and techniques, a novel anti-gpNMB antibody, different from previously known antibodies, binding to a new epitope on gpNMB was successfully obtained, thus completing this invention.

[0063] That is, the present invention relates to the following.

[0064] [Item 1] A pharmaceutical composition for clearing disease-associated cells, comprising an anti-gpNMB antibody or a fragment thereof or a derivative thereof specifically binding to at least one of the regions from V78 to the PKD domain of human gpNMB (glycoprotein nonmetastatic melanoma protein B), said human gpNMB having the amino acid sequence of SEQ ID NO: 209.

[0065] [Item 2] The pharmaceutical composition of Item 1, wherein the anti-gpNMB antibody specifically binds to a region of human gpNMB containing amino acid residues D287 and / or H301, the human gpNMB having the amino acid sequence SEQ ID NO: 209.

[0066] [Item 3] The pharmaceutical composition of Item 1 or 2, wherein the anti-gpNMB antibody specifically binds to a region of human gpNMB containing amino acid residues R214 and / or R215, the human gpNMB having the amino acid sequence of SEQ ID NO: 209.

[0067] [Item 4] The pharmaceutical composition of Item 2 or 3, wherein the anti-gpNMB antibody further specifically binds to one or more of the following regions of human gpNMB: a region containing amino acid residues K257 and / or D258, a region containing amino acid residues H268 and / or D269, a region containing amino acid residues K282, a region containing amino acid residues K316, a region containing amino acid residues K186, and a region containing amino acid residues H216 and / or R218, wherein the human gpNMB has the amino acid sequence of SEQ ID NO: 209.

[0068] [Item 5] The pharmaceutical composition of Item 1, wherein the anti-gpNMB antibody specifically binds to at least one of the regions from V78 to S92 of human gpNMB, the human gpNMB having the amino acid sequence of SEQ ID NO: 209.

[0069] [Item 6] The pharmaceutical composition of any one of items 1 to 5, wherein the anti-gpNMB antibody further specifically binds to at least one of the regions of mouse gpNMB from V78 to the PKD domain, the mouse gpNMB having the amino acid sequence of SEQ ID NO: 211.

[0070] [Item 7] The pharmaceutical composition of any one of items 1 to 6, wherein the anti-gpNMB antibody is a monoclonal antibody or a fragment thereof or a derivative thereof.

[0071] [Item 8] The pharmaceutical composition of any one of items 1 to 7, wherein the anti-gpNMB antibody comprises at least a heavy chain variable region, and the heavy chain variable region has: (1) As CDR-H1, it is the amino acid sequence described in SEQ ID NO: 1, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 1, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 1. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 3, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 3, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 3, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 5, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 5, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 75.0%, 83.3%, or 91.6% or more to the amino acid sequence described in SEQ ID NO: 5; or (2) As CDR-H1, the amino acid sequence described in SEQ ID NO: 17, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 17, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 17. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 19, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 19, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 19. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 21, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 21, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 21; or (3) As CDR-H1, the amino acid sequence described in SEQ ID NO: 33, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 33, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 33. As CDR-H2, the amino acid sequence described in SEQ ID NO: 35, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 35, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 35, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 37, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 37, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 37; or (4) As CDR-H1, the amino acid sequence described in SEQ ID NO: 49, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 49, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 49. As CDR-H2, the amino acid sequence described in SEQ ID NO: 51, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 51, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 51, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 53, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 53, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 68.7%, 75.0%, 81.2%, 87.5%, or 93.7% or more to the amino acid sequence described in SEQ ID NO: 53; or (5) As CDR-H1, the amino acid sequence described in SEQ ID NO: 65, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 65, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 65. As CDR-H2, the amino acid sequence described in SEQ ID NO: 67, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 67, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 67, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 69, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, or five amino acid residues in the amino acid sequence described in SEQ ID NO: 69, or an amino acid sequence having a similarity (preferably identical) of 64.2%, 71.4%, 78.5%, 85.7%, or 92.8% or more to the amino acid sequence described in SEQ ID NO: 69; or (6) As CDR-H1, the amino acid sequence described in SEQ ID NO: 81, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 81, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 81. As CDR-H2, the amino acid sequence described in SEQ ID NO: 83, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 83, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 83, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 85, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 85, or an amino acid sequence having a similarity (preferably identical) of 63.6%, 72.7%, 81.8%, or 90.9% or more to the amino acid sequence described in SEQ ID NO: 85; or (7) As CDR-H1, the amino acid sequence described in SEQ ID NO: 97, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 97, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 97. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 99, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 99, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 99. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 101, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 101, or an amino acid sequence having 60.0% or more or 80.0% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 101; or (8) As CDR-H1, the amino acid sequence described in SEQ ID NO: 113, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 113, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 113. As CDR-H2, the amino acid sequence described in SEQ ID NO: 115, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 115, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 115, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 117, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 117, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 117; or (9) As CDR-H1, the amino acid sequence described in SEQ ID NO: 129, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 129, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 129. As CDR-H2, the amino acid sequence described in SEQ ID NO: 131, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 131, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 131, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 133, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 133, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 133; or (10) As CDR-H1, the amino acid sequence described in SEQ ID NO: 145, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 145, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 145. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 147, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 147, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 147. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 149, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 149, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 149; or (11) As CDR-H1, the amino acid sequence described in SEQ ID NO: 161, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 161, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 161. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 163, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 163, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 163. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 165, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 165, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 165; or (12) As CDR-H1, the amino acid sequence described in SEQ ID NO: 255, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 255, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 255. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 257, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 257, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 257. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 259, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 259, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 259; or (13) As CDR-H1, the amino acid sequence described in SEQ ID NO: 283, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 283, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 283. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 285, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 285, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 285. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 287, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 287, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 287; or (14) As CDR-H1, the amino acid sequence described in SEQ ID NO: 311, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 311, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 311. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 313, or an amino acid sequence formed by substituting, deleting, or inserting any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 313, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 313. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 315, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 315, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 315; or (15) As the CDR grafting region -H1, an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 271, except for tyrosine at position 27, asparagine at position 32, and tryptophan at position 33. As the CDR transplantation region -H2, it is an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 273, except for aspartic acid at position 55, phenylalanine at position 57, threonine at position 58, asparagine at position 59, tyrosine at position 60, and asparagine at position 61. As the CDR transplantation region -H3, it is an amino acid sequence described in SEQ ID NO: 275, or an amino acid sequence described in SEQ ID NO: 275 in which any one, two, three, four, five, or six amino acid residues other than arginine at position 98, glycine at position 100, and glycine at position 109 are substituted, deleted, or inserted; or (16) As the CDR transplantation region-H1, an amino acid sequence formed by the substitution, deletion or insertion of any one, two, three or four amino acid residues in the amino acid sequence described in SEQ ID NO: 299. As the CDR transplantation region -H2, it is an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 301, except for aspartic acid at position 52, tryptophan at position 54, aspartic acid at position 58, and proline at position 63. As the CDR transplantation region -H3, it is an amino acid sequence consisting of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 303, excluding arginine at position 99, threonine at position 100, tyrosine at position 102, tyrosine at position 105, tyrosine at position 107, and methionine at position 110, formed by substitution, deletion, or insertion; or (17) As CDR-H1, the amino acid sequence described in SEQ ID NO: 177, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 177, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 177. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 179, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 179, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 179. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 181, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 181, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 181; or (18) As CDR-H1, the amino acid sequence described in SEQ ID NO: 330, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 330, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 330. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 331, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 331, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 331. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 332, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 332, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 332; or (19) As CDR-H1, the amino acid sequence described in SEQ ID NO: 337, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 337, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 337. As CDR-H2, the amino acid sequence described in SEQ ID NO: 338, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 338, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 338, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 339, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 339, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 339; or (20) As CDR-H1, the amino acid sequence described in SEQ ID NO: 344, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 344, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 344. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 345, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 345, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 345. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 346, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 346, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 346; or (21) As the CDR transplantation region -H1, the amino acid sequence described in SEQ ID NO: 327, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 327, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 327. As the CDR transplantation region -H2, it is the amino acid sequence described in SEQ ID NO: 328, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 328, or an amino acid sequence having a similarity (preferably identical) of 64.7%, 70.5%, 76.4%, 82.3%, 88.2%, or 94.1% or more to the amino acid sequence described in SEQ ID NO: 328. As the CDR transplantation region -H3, it is the amino acid sequence described in SEQ ID NO: 329, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 329, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 329; or (22) As the CDR transplantation region -H1, the amino acid sequence described in SEQ ID NO: 334, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 334, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 334. As the CDR transplantation region -H2, it is the amino acid sequence described in SEQ ID NO: 335, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 335, or an amino acid sequence having a similarity (preferably identical) of 64.7%, 70.5%, 76.4%, 82.3%, 88.2%, or 94.1% or more to the amino acid sequence described in SEQ ID NO: 335. As the CDR transplantation region -H3, it is the amino acid sequence described in SEQ ID NO: 336, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 336, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 336; or (23) As the CDR transplantation region -H1, the amino acid sequence described in SEQ ID NO: 341, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 341, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 341. As the CDR transplantation region -H2, it is the amino acid sequence described in SEQ ID NO: 342, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 342, or an amino acid sequence having a similarity (preferably identical) of 64.7%, 70.5%, 76.4%, 82.3%, 88.2%, or 94.1% or more to the amino acid sequence described in SEQ ID NO: 342. As the CDR transplantation region -H3, it is the amino acid sequence described in SEQ ID NO: 343, or an amino acid sequence formed by replacing, deleting, or inserting any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 343, or an amino acid sequence having more than 66.6% or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 343.

[0072] [Item 9] The pharmaceutical composition of any one of items 1 to 7, wherein the anti-gpNMB antibody comprises at least a heavy chain variable region, and the heavy chain variable region has: (1) The amino acid sequence described in SEQ ID NO: 13, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 13; or (2) The amino acid sequence described in SEQ ID NO: 29, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 29; or (3) The amino acid sequence described in SEQ ID NO: 45, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 45; or (4) The amino acid sequence described in SEQ ID NO: 61, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 61; or (5) The amino acid sequence described in SEQ ID NO: 77, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 77; or (6) The amino acid sequence described in SEQ ID NO: 93, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 93; or (7) The amino acid sequence described in SEQ ID NO: 109, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 109; or (8) The amino acid sequence described in SEQ ID NO: 125, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 125; or (9) The amino acid sequence described in SEQ ID NO: 141, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 141; or (10) The amino acid sequence described in SEQ ID NO: 157, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 157; or (11) The amino acid sequence described in SEQ ID NO: 173, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 173; or (12) The amino acid sequence described in SEQ ID NO: 267, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 267; or (13) The amino acid sequence described in SEQ ID NO: 295, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 295; or (14) The amino acid sequence described in SEQ ID NO: 323, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 323; or (17) The amino acid sequence described in SEQ ID NO: 189, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 189; or (18) The amino acid sequence described in SEQ ID NO: 333, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 333; or (19) The amino acid sequence described in SEQ ID NO: 340, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 340; or (20) The amino acid sequence described in SEQ ID NO: 347, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 347.

[0073] [Item 10] The pharmaceutical composition of Item 8 or 9, wherein the heavy chain variable region comprises a framework sequence of any class of human immunoglobulins as a framework sequence.

[0074] [Item 11] The pharmaceutical composition of any one of items 8 to 10, wherein the anti-gpNMB antibody further comprises a heavy chain constant region, and the heavy chain constant region has the amino acid sequence of a heavy chain constant region of any class of human immunoglobulins.

[0075] [Item 12] The pharmaceutical composition of any one of items 1 to 11, wherein the anti-gpNMB antibody comprises at least a light chain variable region, and the light chain variable region has: (1) As CDR-L1, it is the amino acid sequence described in SEQ ID NO: 7, or an amino acid sequence formed by substituting, deleting, or inserting any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 7, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 7. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 9, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 9, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 9. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 11, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 11, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 11; or (2) As CDR-L1, it is the amino acid sequence described in SEQ ID NO: 23, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 23, or an amino acid sequence having 60.0% or more or 80.0% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 23. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 25, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 25, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 25. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 27, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 27, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 27; or (3) As CDR-L1, it is the amino acid sequence described in SEQ ID NO: 39, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 39, or an amino acid sequence having 60.0% or more or 80.0% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 39. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 41, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 41, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 41. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 43, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 43, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 43; or (4) As CDR-L1, the amino acid sequence described in SEQ ID NO: 55, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 55, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 55. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 57, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 57, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 57. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 59, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 59, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 59; or (5) As CDR-L1, the amino acid sequence described in SEQ ID NO: 71, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 71, or an amino acid sequence having 60.0% or more or 80.0% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 71. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 73, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 73, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 73, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 75, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 75, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 75; or (6) As CDR-L1, the amino acid sequence described in SEQ ID NO: 87, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 87, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 87. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 89, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 89, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 89. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 91, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 91, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 91; or (7) As CDR-L1, the amino acid sequence described in SEQ ID NO: 103, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 103, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 103. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 105, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 105, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 105, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 107, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 107, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 107; or (8) As CDR-L1, the amino acid sequence described in SEQ ID NO: 119, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 119, or an amino acid sequence having a similarity (preferably identical) of 63.6%, 72.7%, 81.8%, or 90.9% or more to the amino acid sequence described in SEQ ID NO: 119. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 121, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 121, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 121. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 123, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 123, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 123; or (9) As CDR-L1, the amino acid sequence described in SEQ ID NO: 135, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 135, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 135. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 137, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 137, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 137. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 139, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 139, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 139; or (10) As CDR-L1, the amino acid sequence described in SEQ ID NO: 151, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 151, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 151. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 153, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 153, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 153, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 155, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 155, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 155; or (11) As CDR-L1, the amino acid sequence described in SEQ ID NO: 167, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 167, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 167. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 169, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 169, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 169, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 171, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 171, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 171; or (12) As CDR-L1, it is the amino acid sequence described in SEQ ID NO: 261, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 261, or an amino acid sequence having a similarity (preferably identical) of 63.6%, 72.7%, 81.8%, or 90.9% or more to the amino acid sequence described in SEQ ID NO: 261. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 263, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 263, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 263, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 265, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 265, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 265; or (13) As CDR-L1, the amino acid sequence described in SEQ ID NO: 289, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 289, or an amino acid sequence having 60.0% or more or 80.0% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 289. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 291, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 291, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 291. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 293, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 293, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 293; or (14) As CDR-L1, the amino acid sequence described in SEQ ID NO: 317, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 317, or an amino acid sequence having a similarity (preferably identical) of 63.6%, 72.7%, 81.8%, or 90.9% or more to the amino acid sequence described in SEQ ID NO: 317. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 319, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 319, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 319. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 321, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 321, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 321; or (15) As the CDR transplantation region-L1, an amino acid sequence formed by the substitution, deletion or insertion of any one, two, three or four amino acid residues in the amino acid sequence described in SEQ ID NO: 277, except for isoleucine at position 29, tyrosine at position 31 and histidine at position 33. As the CDR transplantation region -L2, it is an amino acid sequence formed by the substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 279, except for threonine at position 50. As the CDR transplantation region - L3, the amino acid sequence described in SEQ ID NO: 281, or the amino acid sequence described in SEQ ID NO: 281, wherein any one, two, or three amino acid residues other than histidine at position 88, glutamine at position 89, tryptophan at position 90, serine at position 92, tyrosine at position 93, proline at position 94, and cysteine ​​at position 95 are replaced, deleted, or inserted; or (16) As the CDR transplantation region-L1, an amino acid sequence formed by the substitution, deletion or insertion of any one, two, three, four, five or six amino acid residues in the amino acid sequence described in SEQ ID NO: 305, except for leucine at position 31, tyrosine at position 37 and glutamic acid at position 39. As the CDR transplantation region -L2, it is an amino acid sequence formed by the substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 307, except for lysine at position 55. As the CDR transplantation region - L3, the amino acid sequence described in SEQ ID NO: 309, or the amino acid sequence described in SEQ ID NO: 309, wherein any one, two, or three amino acid residues other than phenylalanine at position 94 are replaced, deleted, or inserted; or (17) As CDR-L1, the amino acid sequence described in SEQ ID NO: 183, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 183, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 183. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 185, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 185, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 185. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 187, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 187, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 187; or (18) As CDR-L1, the amino acid sequence described in SEQ ID NO: 351, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 351, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 351. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 352, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 352, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 352. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 353, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 353, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 353; or (19) As CDR-L1, the amino acid sequence described in SEQ ID NO: 358, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 358, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 358. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 359, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 359, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 359. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 360, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 360, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 360; or (20) As CDR-L1, the amino acid sequence described in SEQ ID NO: 365, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 365, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 365. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 366, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 366, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 366. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 367, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 367, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 367; or (21) As the CDR transplantation region-L1, the amino acid sequence described in SEQ ID NO: 348, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 348, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 348. As the CDR transplantation region -L2, it is the amino acid sequence described in SEQ ID NO: 349, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 349, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 349. As the CDR transplantation region -L3, it is the amino acid sequence described in SEQ ID NO: 350, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 350, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 350; or (22) As the CDR transplantation region-L1, the amino acid sequence described in SEQ ID NO: 355, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 355, or an amino acid sequence having a similarity (preferably identical) of 63.6%, 72.7%, 81.8%, or 90.9% or more to the amino acid sequence described in SEQ ID NO: 355. As the CDR transplantation region -L2, it is the amino acid sequence described in SEQ ID NO: 356, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 356, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 356. As the CDR transplantation region -L3, it is the amino acid sequence described in SEQ ID NO: 357, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 357, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 357; or (23) As the CDR transplantation region-L1, the amino acid sequence described in SEQ ID NO: 362, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 362, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 362. As the CDR transplantation region -L2, it is the amino acid sequence described in SEQ ID NO: 363, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 363, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 363. As the CDR transplantation region -L3, it is the amino acid sequence described in SEQ ID NO: 364, or an amino acid sequence formed by the substitution, deletion or insertion of any one, two or three amino acid residues in the amino acid sequence described in SEQ ID NO: 364, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7% or more or 88.8% or more to the amino acid sequence described in SEQ ID NO: 364.

[0076] [Item 13] The pharmaceutical composition of any one of items 1 to 11, wherein the anti-gpNMB antibody comprises at least a light chain variable region, and the light chain variable region has: (1) The amino acid sequence described in SEQ ID NO: 15, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 15; or (2) The amino acid sequence described in SEQ ID NO: 31, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 31; or (3) The amino acid sequence described in SEQ ID NO: 47, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 47; or (4) The amino acid sequence described in SEQ ID NO: 63, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 63; or (5) The amino acid sequence described in SEQ ID NO: 79, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 79; or (6) The amino acid sequence described in SEQ ID NO: 95, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 95; or (7) The amino acid sequence described in SEQ ID NO: 111, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 111; or (8) The amino acid sequence described in SEQ ID NO: 127, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 127; or (9) The amino acid sequence described in SEQ ID NO: 143, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 143; or (10) The amino acid sequence described in SEQ ID NO: 159, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 159; or (11) The amino acid sequence described in SEQ ID NO: 175, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 175; or (12) The amino acid sequence described in SEQ ID NO: 269, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 269; or (13) The amino acid sequence described in SEQ ID NO: 297, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 297; or (14) The amino acid sequence described in SEQ ID NO: 325, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 325; or (17) The amino acid sequence described in SEQ ID NO: 191, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 191; or (18) The amino acid sequence described in SEQ ID NO: 354, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 354; or (19) The amino acid sequence described in SEQ ID NO: 361, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 361; or (20) The amino acid sequence described in SEQ ID NO: 368, or an amino acid sequence that has more than 60% similarity to the amino acid sequence described in SEQ ID NO: 368.

[0077] [Item 14] The pharmaceutical composition of Item 12 or 13, wherein the light chain variable region comprises a framework sequence of any class of human immunoglobulins as a framework sequence.

[0078] [Item 15] The pharmaceutical composition of any one of items 12 to 14, wherein the anti-gpNMB antibody further comprises a light chain constant region, and the light chain constant region has the amino acid sequence of a light chain constant region of any class of human immunoglobulins.

[0079] [Item 16] The pharmaceutical composition of any one of items 1 to 15, wherein the anti-gpNMB antibody is Fab, scFv, a diabody, a nanobody, VHH, a bispecific antibody, or a multispecific antibody, or a derivative thereof.

[0080] [Item 17] A pharmaceutical composition for clearing disease-related cells, comprising an anti-gpNMB antibody or a fragment thereof or a derivative thereof, said anti-gpNMB antibody or a fragment thereof or a derivative thereof binding to at least one of the regions of human gpNMB (glycoprotein nonmetastatic melanoma protein B) having the amino acid sequence of SEQ ID NO: 209 from V78 to the PKD domain, said binding being competitive with the anti-gpNMB antibody or a fragment thereof or a derivative thereof as described in any one of items 1 to 16.

[0081] [Item 18] A pharmaceutical composition for eliminating disease-related cells, comprising: Nucleic acid molecules consisting of polynucleotide sequences of any of the anti-gpNMB antibodies or fragments thereof or derivatives thereof, as defined in any of items 1 to 17, and / or Cloning vectors or expression vectors containing at least one of the said nucleic acid molecules, and / or Recombinant cells containing the vector were introduced.

[0082] [Item 19] The pharmaceutical composition of any one of items 1 to 18, wherein the disease-related cells are selected from senescent cells, cancer-related cells and phagocytes.

[0083] [Item 20] The pharmaceutical composition of Item 19, wherein the cancer-associated cells are selected from cancer cells, cancer stem cells, precancerous cells and cancer-infiltrating cells.

[0084] [Item 21] The pharmaceutical composition of any one of items 1 to 20, wherein the disease is selected from obesity, diabetes, arteriosclerosis, fibrosis, cancer, metabolic diseases, circulatory system diseases, lysosomal stress-related diseases (e.g., lysosomal diseases), autoimmune diseases (e.g., multiple sclerosis), neurogenic pain, fibromyalgia and glioblastoma.

[0085] [Item 22] The pharmaceutical composition of any one of items 1 to 21, which treats or prevents disease by eliminating disease-related cells.

[0086] [Item 23] An anti-gpNMB antibody or a fragment thereof or a derivative thereof, which specifically binds to at least one of the regions from V78 to S92 of human gpNMB (glycoprotein nonmetastatic melanoma protein B), said human gpNMB having the amino acid sequence of SEQ ID NO: 209.

[0087] [Item 24] The anti-gpNMB antibody or fragment thereof or derivative thereof described in Item 23, which also specifically binds to the region of human gpNMB containing the amino acid residue K186, said human gpNMB having the amino acid sequence of SEQ ID NO: 209.

[0088] [Item 25] The anti-gpNMB antibody or fragment thereof or derivative thereof as described in Item 23 or 24, wherein the anti-gpNMB antibody also specifically binds to at least one of the regions from V78 to S92 of mouse gpNMB, the mouse gpNMB having the amino acid sequence of SEQ ID NO: 211.

[0089] [Item 26] The anti-gpNMB antibody or fragment thereof or derivative thereof, as described in any one of items 23 to 25, wherein it is a monoclonal antibody or fragment thereof or derivative thereof.

[0090] [Item 27] ​​The anti-gpNMB antibody or fragment thereof or derivative thereof described in Item 26, comprising at least a heavy chain variable region, wherein the heavy chain variable region has: (17) As CDR-H1, the amino acid sequence described in SEQ ID NO: 177, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 177, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 177. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 179, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 179, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 179. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 181, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 181, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 181; or (18) As CDR-H1, the amino acid sequence described in SEQ ID NO: 330, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 330, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 330. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 331, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 331, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 331. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 332, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 332, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 332; or (19) As CDR-H1, the amino acid sequence described in SEQ ID NO: 337, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 337, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 337. As CDR-H2, the amino acid sequence described in SEQ ID NO: 338, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 338, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 338, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 339, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 339, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 339; or (20) As CDR-H1, the amino acid sequence described in SEQ ID NO: 344, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 344, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 344. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 345, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 345, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 345. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 346, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 346, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 346; or (21) As the CDR transplantation region -H1, the amino acid sequence described in SEQ ID NO: 327, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 327, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 327. As the CDR transplantation region -H2, it is the amino acid sequence described in SEQ ID NO: 328, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 328, or an amino acid sequence having a similarity (preferably identical) of 64.7%, 70.5%, 76.4%, 82.3%, 88.2%, or 94.1% or more to the amino acid sequence described in SEQ ID NO: 328. As the CDR transplantation region -H3, it is the amino acid sequence described in SEQ ID NO: 329, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 329, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 329; or (22) As the CDR transplantation region -H1, the amino acid sequence described in SEQ ID NO: 334, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 334, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 334. As the CDR transplantation region -H2, it is the amino acid sequence described in SEQ ID NO: 335, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 335, or an amino acid sequence having a similarity (preferably identical) of 64.7%, 70.5%, 76.4%, 82.3%, 88.2%, or 94.1% or more to the amino acid sequence described in SEQ ID NO: 335. As the CDR transplantation region -H3, it is the amino acid sequence described in SEQ ID NO: 336, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 336, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 336; or (23) As the CDR transplantation region -H1, the amino acid sequence described in SEQ ID NO: 341, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 341, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 341. As the CDR transplantation region -H2, it is the amino acid sequence described in SEQ ID NO: 342, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 342, or an amino acid sequence having a similarity (preferably identical) of 64.7%, 70.5%, 76.4%, 82.3%, 88.2%, or 94.1% or more to the amino acid sequence described in SEQ ID NO: 342. As the CDR transplantation region -H3, it is the amino acid sequence described in SEQ ID NO: 343, or an amino acid sequence formed by replacing, deleting, or inserting any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 343, or an amino acid sequence having more than 66.6% or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 343.

[0091] [Item 28] The anti-gpNMB antibody or fragment thereof or derivative thereof described in Item 26 or 27, comprising at least a heavy chain variable region, wherein the heavy chain variable region has: (17) The amino acid sequence described in SEQ ID NO: 189, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 189; or (18) The amino acid sequence described in SEQ ID NO: 333, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 333; or (19) The amino acid sequence described in SEQ ID NO: 340, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 340; or (20) The amino acid sequence described in SEQ ID NO: 347, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 347.

[0092] [Item 29] The anti-gpNMB antibody or a fragment thereof or a derivative thereof, as described in any one of items 25 to 28, wherein the heavy chain variable region comprises a framework sequence of any class of human immunoglobulins as a framework sequence.

[0093] [Item 30] The anti-gpNMB antibody or fragment thereof or derivative thereof as described in any one of Items 25 to 29, further comprising a heavy chain constant region, wherein the heavy chain constant region has the amino acid sequence of a heavy chain constant region of any class of human immunoglobulins.

[0094] [Item 31] The anti-gpNMB antibody or fragment thereof or derivative thereof, as described in any one of items 25 to 30, comprising at least a light chain variable region, wherein the light chain variable region has: (17) As CDR-L1, the amino acid sequence described in SEQ ID NO: 183, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 183, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 183. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 185, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 185, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 185. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 187, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 187, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 187; or (18) As CDR-L1, the amino acid sequence described in SEQ ID NO: 351, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 351, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 351. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 352, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 352, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 352. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 353, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 353, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 353; or (19) As CDR-L1, the amino acid sequence described in SEQ ID NO: 358, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 358, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 358. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 359, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 359, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 359. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 360, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 360, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 360; or (20) As CDR-L1, the amino acid sequence described in SEQ ID NO: 365, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 365, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 365. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 366, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 366, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 366. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 367, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 367, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 367; or (21) As the CDR transplantation region-L1, the amino acid sequence described in SEQ ID NO: 348, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 348, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 348. As the CDR transplantation region -L2, it is the amino acid sequence described in SEQ ID NO: 349, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 349, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 349. As the CDR transplantation region -L3, it is the amino acid sequence described in SEQ ID NO: 350, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 350, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 350; or (22) As the CDR transplantation region-L1, the amino acid sequence described in SEQ ID NO: 355, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 355, or an amino acid sequence having a similarity (preferably identical) of 63.6%, 72.7%, 81.8%, or 90.9% or more to the amino acid sequence described in SEQ ID NO: 355. As the CDR transplantation region -L2, it is the amino acid sequence described in SEQ ID NO: 356, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 356, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 356. As the CDR transplantation region -L3, it is the amino acid sequence described in SEQ ID NO: 357, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 357, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 357; or (23) As the CDR transplantation region-L1, the amino acid sequence described in SEQ ID NO: 362, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 362, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 362. As the CDR transplantation region -L2, it is the amino acid sequence described in SEQ ID NO: 363, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 363, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 363. As the CDR transplantation region -L3, it is the amino acid sequence described in SEQ ID NO: 364, or an amino acid sequence formed by the substitution, deletion or insertion of any one, two or three amino acid residues in the amino acid sequence described in SEQ ID NO: 364, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7% or more or 88.8% or more to the amino acid sequence described in SEQ ID NO: 364.

[0095] [Item 32] The anti-gpNMB antibody or fragment thereof or derivative thereof, as described in any one of items 25 to 31, comprising at least a light chain variable region, wherein the light chain variable region has: (17) The amino acid sequence described in SEQ ID NO: 191, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 191; or (18) The amino acid sequence described in SEQ ID NO: 354, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 354; or (19) The amino acid sequence described in SEQ ID NO: 361, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 361; or (20) The amino acid sequence described in SEQ ID NO: 368, or an amino acid sequence that has more than 60% similarity to the amino acid sequence described in SEQ ID NO: 368.

[0096] [Item 33] The anti-gpNMB antibody or fragment thereof or derivative thereof as described in Item 31 or 32, wherein the light chain variable region comprises a framework sequence of any class of human immunoglobulins as a framework sequence.

[0097] [Item 34] The anti-gpNMB antibody or fragment thereof or derivative thereof, as described in any one of items 25 to 33, further comprising a light chain constant region, wherein the light chain constant region has the amino acid sequence of a light chain constant region of any class of human immunoglobulins.

[0098] [Item 35] The anti-gpNMB antibody or fragment thereof or derivative thereof as described in any one of Items 25 to 34, wherein the anti-gpNMB antibody is Fab, scFv, biantibody, nanobody, VHH, bispecific antibody, or multispecific antibody, or derivative thereof.

[0099] Invention Effects According to the present invention, a novel method is provided to effectively eliminate various disease-associated cells that are positive for gpNMB by utilizing a novel anti-gpNMB antibody that binds to a specific epitope on gpNMB. Attached Figure Description

[0100] [ Figure 1 ] Figure 1 This is a diagram showing the amino acid sequence alignment of human gpNMB (isotype a) and mouse gpNMB. In the diagram, the region from amino acid residue 78 (valine, V78) to the PKD domain is enclosed by a single-dotted line. As an example of the PKD domain, the region from amino acid residues 256 to 319 is enclosed by a dashed line. As an example of the PMEL-CAF-like domain, the region from amino acid residues 172 to 246 is enclosed by a solid line.

[0101] [ Figure 2 ] Figure 2 This is a graph representing the evaluation results of the clearance capacity of human gpNMB-expressing cells based on anti-gpNMB antibody clones.

[0102] [ Figure 3 ] Figure 3 This is a graph representing the evaluation results of the cell clearance ability of mouse gpNMB-expressing cells based on anti-gpNMB antibody clones.

[0103] [ Figure 4 ] Figure 4 This is a diagram showing the alignment of humanized mutant sequences hGPN06-1_VH1~VH5 with mouse GPN06-1_VH.

[0104] [ Figure 5 ] Figure 5 This is a diagram showing the alignment of humanized mutant sequences hGPN06-1_VL1~VL5 with mouse GPN06-1_VL.

[0105] [ Figure 6 ] Figure 6 This is a diagram showing the alignment of humanized mutant sequences hGPN18-2_VH1~VH5 with mouse GPN18-2_VH.

[0106] [ Figure 7 ] Figure 7This is a diagram showing the alignment of humanized mutant sequences hGPN18-2_VL1~VL5 with mouse GPN18-2_VL.

[0107] [ Figure 8 ] Figure 8 This is a diagram showing the comparison between humanized anti-gpNMB antibody variants hGPN18-5_VH1~VH3 and mouse GPN18-5_VH0.

[0108] [ Figure 9 ] Figure 9 This is a diagram showing the comparison between humanized anti-gpNMB antibody variants hGPN18-5_VL1~VL3 and mouse GPN18-5_VL0.

[0109] [ Figure 10 ] Figure 10 This is a graph representing the evaluation results of the pain-improving effect of an anti-gpNMB antibody clone in a mouse model of neuropathic pain.

[0110] [ Figure 11 ] Figure 11 This is a diagram schematically showing the dosing schedule of the anti-gpNMB antibody clone against obese mouse models.

[0111] [ Figure 12 ] Figure 12 This is a graph representing the evaluation results of the number of gpNMB-positive SA-β-Gal-positive macrophages in the epididymal fat of obese model mice using anti-gpNMB antibody clones.

[0112] [ Figure 13 ] Figure 13 This is a graph representing the evaluation results of TNF-α gene expression in epididymal fat cloned using an anti-gpNMB antibody clone from an obese mouse model. Detailed Implementation

[0113] The present invention will now be described with reference to specific embodiments, but the present invention is not limited to these embodiments in any way. It should be noted that all documents cited in this specification, including patent gazettes, patent application publications, and non-patent gazettes, are incorporated herein by reference in their entirety for all purposes.

[0114] [summary] In the past, attempts have been made to develop methods for eliminating various cells (disease-associated cells) that induce or promote disease progression in various diseases. Examples include senescent cell-clearing drugs that target senescent cells, anticancer agents that target specific cancer cells (cancer-targeted drugs), anticancer agents that target cancer-infiltrating macrophages, and drugs that target non-specific macrophages or microglia.

[0115] However, reports on methods for eliminating such disease-related cells are extremely limited to date. In particular, no method has yet been developed that can specifically eliminate highly malignant disease-related cells that are the root cause of disease. Examples of such highly malignant disease-related cells include senescent infiltrating cells or senescent resident cells that have a significant impact on surrounding cells or tissues, causing pathological changes or disease progression, or extremely malignant cancer cells or cancer stem cells.

[0116] The inventors conducted in-depth research to develop a means to effectively eliminate disease-associated cells, focusing on gpNMB (glycoprotein nonmetastatic melanoma protein B), a common antigen in cells associated with various highly malignant diseases. Cells highly expressing gpNMB (gpNMB-positive cells) have been observed in various diseases and may therefore be closely related to the pathogenesis or progression of these diseases. Specific examples of such disease-associated cells that highly express gpNMB include senescent cells, cancer-associated cells (e.g., cancer cells, precancerous cells, cancer-infiltrating cells (e.g., cancer-infiltrating immune cells), tissue-infiltrating phagocytes, or phagocytes such as macrophages or microglia, which are chronically or abnormally activated (resident) phagocytes.

[0117] On the other hand, while gpNMB has been suggested to be associated with various diseases, it remains unclear whether it plays a protective role or exacerbates these diseases, and its suitability as a therapeutic target is also uncertain. Specifically, it is anticipated that soluble gpNMB secreted by various cells will exert a protective effect under various pathological conditions. Therefore, a hypothesis is proposed: without adversely affecting the gpNMB-secreting cells (as anticipated) to exert this protective effect, simply eliminating disease-related cells that chronically overexpress gpNMB could yield therapeutic effects targeting the underlying disease.

[0118] To verify the hypothesis, a method for eliminating gpNMB-overexpressing cells needs to be designed first. Antibodies were chosen as the most specific method for eliminating gpNMB-overexpressing cells. To obtain anti-gpNMB antibodies, the focus was on developing an antibody with mouse-human cross-reactivity that could be validated for efficacy in animal models and directly used in human clinical trials.

[0119] To date, no examples of anti-gpNMB antibodies exhibiting cross-reactivity in mice and humans have been obtained. Glembatumumab is the only anti-gpNMB antibody that has reached clinical trials (Patent Document 2), and it is a human gpNMB-specific antibody used to deliver anticancer agents to cancer cells. As mentioned above, an antibody-drug conjugate (ADC) using glebatumumab, known as Vitin-glebatumumab, was developed as a cancer treatment candidate and entered Phase II trials, but development was subsequently discontinued.

[0120] Furthermore, as a means of eliminating disease-related cells, utilizing clearance activities based on T cells or NK cells may induce inflammation. Therefore, efforts are being made to obtain antibodies that can induce clearance activities based on phagocytes such as macrophages, rather than T cell or NK cell-based clearance activities.

[0121] Under these various limiting conditions, the inventors conducted in-depth research using various experimental methods and techniques, and successfully obtained anti-gpNMB antibodies with mouse-human cross-reactivity at levels that can exhibit effects in vivo. Analysis of the epitopes of these anti-gpNMB antibodies confirmed that they are novel antibodies that recognize epitopes different from those of previously reported vaccine peptides (Patent Document 1, Non-Patent Document 67) that have been shown to clear cells.

[0122] Furthermore, the inventors selected several antibodies that identify representative epitopes of the acquired anti-gpNMB antibodies and constructed a system for evaluating phagocytic clearance activity. Specifically, antibodies with high clearance capacity were selected to evaluate the clearance effect of macrophage-derived cell lines on gpNMB-expressing cells. As a result, the clearance capacity of gpNMB-expressing cells was confirmed by several antibodies that identified epitope regions different from those in previous vaccines, thus completing this invention.

[0123] The anti-gpNMB antibody of the present invention can effectively eliminate gpNMB-positive cells associated with the progression of various diseases through phagocytic clearance without inducing inflammation. Therefore, it can provide effective treatment for a variety of diseases that have been difficult to treat until now.

[0124] In the following description, the details of the anti-gpNMB antibody (the anti-gpNMB antibody of the present invention) used in the present invention to clear disease-related cells and its manufacturing method will be described first. Based on this, the pharmaceutical composition (the pharmaceutical composition of the present invention) and the treatment method (the treatment method of the present invention) for clearing disease-related cells using the antibody will be described.

[0125] It should be noted that among the anti-gpNMB antibodies of the present invention described below, there are anti-gpNMB antibodies that are neither disclosed nor implied in previous literature and are patentable. Therefore, these novel anti-gpNMB antibodies are also included in the subject matter of the present invention.

[0126] [Anti-gpNMB antibody] One aspect of the present invention is an anti-gpNMB antibody, preferably an anti-gpNMB antibody (hereinafter sometimes appropriately referred to as "the anti-gpNMB antibody of the present invention" or "the antibody of the present invention") that specifically binds to at least one region of gpNMB from V78 via a PMEL-CAF-like (PMEL Core Amyloid Fragment-like) domain to a PKD domain. At least one region of gpNMB from V78 to the PKD domain refers to, for example, at least one region of amino acid residues from 78 to 319 of human gpNMB, which has the amino acid sequence SEQ ID NO: 209.

[0127] ·Antibody: In this invention, "antibody" refers to a glycoprotein containing at least two heavy (H) chains and two light (L) chains linked together by disulfide bonds. The heavy chain comprises a heavy chain variable region (VH) and a heavy chain constant region, the latter containing three domains: CH1, CH2, and CH3. The light chain comprises a light chain variable region (VL) and a light chain constant region. The light chain constant region contains one domain: CL. Two chains, referred to as λ and κ, exist within the light chain constant region. The heavy chain constant region contains γ, μ, α, δ, and ε chains, and based on the different heavy chains, antibody isotypes are respectively designated as IgG, IgM, IgA, IgD, and IgE. The VH and VL regions are further subdivided into four more conserved regions (FR-1, FR-2, FR-3, FR-4) called framework regions (FR-1, FR-2, FR-3) and three variable regions (CDR-1, CDR-2, CDR-3) called complementarity-determining regions (CDR-1, CDR-2, CDR-3). The VH contains three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the order FR-1, CDR-1 (CDR-H1), FR-2, CDR-2 (CDR-H2), FR-3, CDR-3 (CDR-H3), FR-4. The VL contains three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the order FR-1, CDR-1 (CDR-L1), FR-2, CDR-2 (CDR-L2), FR-3, CDR-3 (CDR-L3), FR-4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen.

[0128] The antibodies of the present invention may be fragments (e.g., antigen-binding fragments) and / or derivatives, provided they have activity specifically binding to at least one of the regions from the V78 to the PKD domain of gpNMB. Examples of antibody fragments include F(ab')2, Fab, Fv, etc. Examples of antibody derivatives include antibodies with artificially introduced amino acid mutations in the constant region, antibodies whose constant region domain structure is modified, antibodies having two or more Fcs per molecule, antibodies composed only of heavy chains or only of light chains, glycan-modified antibodies, bispecific antibodies, antibody conjugates binding to antibodies or antibody fragment compounds or proteins other than antibodies, antibody enzymes, nanobodies, tandem scFvs, bispecific tandem scFvs, diabetic antibodies, VHHs, etc. It should be noted that, in the present invention, the term "antibody" generally includes antibody fragments and / or derivatives unless otherwise specified.

[0129] The antibodies of this invention can be monoclonal or polyclonal, but are preferably monoclonal. Monoclonal antibodies traditionally refer to antibody molecules obtained from a clone derived from a single antibody-producing cell, but also to single-type antibody molecules containing a combination of VH and VL consisting of specific amino acid sequences. For monoclonal antibodies, nucleic acid molecules having a gene sequence encoding the amino acid of the antibody protein can also be obtained, and antibodies can be genetically engineered using such nucleic acid molecules. Furthermore, techniques well known to those skilled in the art include using genetic information such as the H chain, L chain, their variable regions, or CDR sequences to modify antibodies for improved binding or specificity, or modifying antibodies from animals such as mice into human-type antibodies to create antibodies with structures suitable for therapeutic use. Additionally, human monoclonal antibodies can also be obtained by using transgenic animals with introduced human antibody genes as antigen-sensitized animals. In addition, as a method that does not require sensitizing animals, those skilled in the art may appropriately perform the following techniques: using a phage library expressing the antigen-binding region of a human antibody or a portion thereof (human antibody phage display), obtain an antibody that specifically binds to the corresponding antigen or a phage clone composed of a specific amino acid sequence, and prepare a human antibody based on this information (e.g., see the review in Keio J. Med., (2011), 60: 37-46). Furthermore, in the case of designing antibodies for administration to animals other than humans, similar to humanization techniques, those skilled in the art may appropriately use the amino acid sequence information of the CDR or variable region for design.

[0130] Antibody specificity refers to the high antigen-antibody reaction exhibited by an antibody against a specific antigen. For the determination of antigen-antibody reactions, those skilled in the art can appropriately choose to perform the binding assay in a solid-phase or liquid-phase system. Examples of such methods include enzyme-linked immunosorbent assay (ELISA), enzyme immunoassay (EIA), surface plasmon resonance (SPR), fluorescence resonance energy transfer (FRET), and luminescence resonance energy transfer (LRET), but are not limited to these methods. Furthermore, when determining such antigen-antibody binding, antibodies and / or antigens can be labeled with enzymes, fluorescent substances, luminescent substances, radioactive isotopes, etc., and assay methods suitable for the physical and / or chemical properties of the labeled substance can be used to detect the antigen-antibody reaction.

[0131] • Specifically binds to at least one location in the region from V78 to the PKD domain of gpNMB: The antibody of this invention specifically binds to at least one region of human gpNMB from valine (V78) to the PKD domain. This region comprises a region from valine (V78) to serine (S92), a PMEL-CAF-like domain, a PKD domain, and a region sandwiched between these regions. In this invention, "gpNMB" (glycoprotein nonmetastatic melanoma protein B) (also known as osteoactivin, DC-HIL) is the aforementioned single-transmembrane glycoprotein. For details, please refer to the aforementioned documents (especially Non-Patent Document 20, etc.).

[0132] The amino acid sequence of the full-length protein of human gpNMB (isotype a) is shown in SEQ ID NO: 209, and the nucleic acid sequence of the gene encoding this protein is shown in SEQ ID NO: 210. The amino acid sequence of the full-length protein of mouse gpNMB is shown in SEQ ID NO: 211, and the nucleic acid sequence of the gene encoding this protein is shown in SEQ ID NO: 212. The amino acid sequence of the full-length protein of rat gpNMB is shown in SEQ ID NO: 213, and the nucleic acid sequence of the gene encoding this protein is shown in SEQ ID NO: 214. Furthermore, the amino acid sequence alignment of human gpNMB (isotype a) and mouse gpNMB is shown in... Figure 1 middle.

[0133] The region from V78 to S92 of gpNMB refers to the region containing seven amino acid residues before and after the aspartic acid residue at position 85 (D85) of gpNMB. It should be noted that... Figure 1 In the diagram, the regions from V78 to S92 of human gpNMB and mouse gpNMB are represented by single-dotted dashed lines.

[0134] The PKD (Polycystic Kidney Disease homology) domain of gpNMB is a domain in which a β-sheet composed of three chains and a β-sheet composed of four chains are folded to form a β-layer structure. Because it is a characteristic structure of polycystic kidney protein 1 (polycystin-1), a gene causing polycystic kidney disease, it is named the PKD domain (Non-Patent Document 26). According to one embodiment, in the cases of human gpNMB shown in SEQ ID NO: 209 and mouse gpNMB shown in SEQ ID NO: 211, the regions of amino acid residues 256–319 correspond to the PKD domain. According to one embodiment, the region of amino acid residues 256–316 is preferred as the PKD domain, particularly the region of residues 257–316, especially the region of residues 268–316, further preferably the region of residues 270–316, even more preferably the region of residues 282–316, and particularly preferably the region of residues 287–316. According to one scheme, the region from amino acid residues 257 to 319 is preferred as the PKD domain, particularly the region from 257 to 316, and even more preferably the region from 257 to 301. According to another scheme, the region from amino acid residues 287 to 301 is especially preferred as the PKD domain. It should be noted that... Figure 1 In the example, the regions of amino acid residues 256–319 are indicated by dashed lines, serving as examples of the respective PKD domains of human gpNMB and mouse gpNMB.

[0135] As described above, the PMEL-CAF-like (PMEL Core Amyloid Fragment-like) domain of gpNMB is a region similar to the CAF region in PMEL proteins of the same family, and is the region that induces amyloid aggregate formation in PMEL proteins (Non-Patent Literature 89). Since the PMEL-CAF-like domain of gpNMB has many N-type glycan binding sites in the adjacent PKD region, it is believed to prevent aggregation formation (Non-Patent Literature 90). According to one scheme, in the cases of human gpNMB shown in SEQ ID NO: 209 and mouse gpNMB shown in SEQ ID NO: 211, the regions of amino acid residues 172–246 correspond to the PMEL-CAF-like domains. Among these, the region of amino acid residues 178–228 is preferred as the PMEL-CAF-like domain, and the region of amino acid residues 186–218 is further preferred. It should be noted that… Figure 1 In the figure, as examples of PMEL-CAF-like domains in human gpNMB and mouse gpNMB, the region from amino acid residues 172 to 246 is enclosed by solid lines.

[0136] As described above, in this invention, "the region of gpNMB from V78 to the PKD domain" refers to the region, in addition to the region from V78 to S92, the PMEL-CAF-like domain, and the PKD domain, including the region sandwiched between the region from V78 to S92 and the PMEL-CAF-like domain, and the region sandwiched between the PMEL-CAF-like domain and the PKD domain. According to one embodiment, in the cases of human gpNMB shown in SEQ ID NO: 209 and mouse gpNMB shown in SEQ ID NO: 211, the regions at positions 78-319 of amino acid residues respectively correspond to the regions from V78 to the PKD domain.

[0137] The antibodies of the present invention can specifically bind to at least one region from the V78 to the PKD domain of gpNMB in any vertebrate, but considering human pharmaceutical use, it is preferable to specifically bind to at least one region from the V78 to the PKD domain of human gpNMB as shown in SEQ ID NO: 209. Furthermore, from the viewpoint of evaluating the effect on endogenous gpNMB in disease model mice or disease model rats, in addition to specifically binding to at least one region from the V78 to the PKD domain of human gpNMB, the antibodies of the present invention are further preferably specifically bound to at least one region from the V78 to the PKD domain of mouse gpNMB as shown in SEQ ID NO: 211. It should be noted that, in the present invention, "specifically" binding of the antibody to gpNMB means that the gpNMB binding strength is 10 times or more, preferably 100 times or more, and more preferably 1000 times or more, relative to binding to proteins other than gpNMB (e.g., albumin). In addition, the “region from V78 to the PKD domain” refers to the region from V78 to S92, the PMEL-CAF sample domain, the PKD domain, the region between the region from V78 to S92 and the PMEL-CAF sample domain, and the region between the PMEL-CAF sample domain and the PKD domain.

[0138] According to another embodiment, the antibody of the present invention preferably binds to at least one of the regions from V78 to S92 of human gpNMB shown in SEQ ID NO: 209, that is, the region containing 7 amino acid residues before and after D85 centered on D85, more preferably specifically binds to at least one of the regions containing 4 amino acid residues before and after D85 centered on D85, even more preferably specifically binds to at least one of the regions containing 2 amino acid residues before and after D85 centered on D85, and particularly preferably specifically binds to at least D85.

[0139] There are no particular limitations on the epitope, provided that the antibody of the present invention specifically binds to at least one of the regions from the V78 to the PKD domain of human gpNMB. However, according to one embodiment, the antibody of the present invention preferably binds to at least one of the regions from the PMEL-CAF-like domain to the PKD domain, and more preferably specifically binds to one or more of the following regions of the human gpNMB PKD domain shown in SEQ ID NO: 209: the region containing amino acid residues K257 and / or D258, the region containing amino acid residues H268 and / or D269, the region containing amino acid residues K282, the region containing amino acid residues D287 and / or H301, the region containing amino acid residues K316, the region containing amino acid residues K186, the region containing amino acid residues R214 and / or R215, and the region containing amino acid residues H216 and / or R218. In particular, the antibody of the present invention preferably specifically binds to at least one or both of the regions of human gpNMB shown in SEQ ID NO: 209 containing amino acid residues D287 and / or H301 and amino acid residues R214 and / or R215. More preferably, in addition to these regions, it also specifically binds to one or more of the following regions: regions containing amino acid residues K257 and / or D258, regions containing amino acid residues H268 and / or D269, regions containing amino acid residues K282, regions containing amino acid residues K316, regions containing amino acid residues K186, and regions containing amino acid residues H216 and / or R218.

[0140] It should be noted that the epitopes of human gpNMB bound by the antibodies of this invention, as long as they include at least one of the regions from V78 to the PKD domain, can be linear epitopes composed of continuous regions on the primary structure of human gpNMB (amino acid sequence shown in SEQ ID NO: 209), or stereoepitaxes composed of two or more discrete partial regions on the primary structure. The regions constituting the linear epitopes and the partial regions constituting the stereoepitaxes can be regions existing within any one of the following: the region from V78 to S92, the region between the region from V78 to S92 and the PMEL-CAF-like domain, the PMEL-CAF-like domain, the PKD domain, and the region between the PMEL-CAF-like domain and the PKD domain; or they can span two or more regions. Furthermore, they can exist only within the region from V78 to the PKD domain, or they can span other regions. Furthermore, among the multiple regions constituting a stereotopic, if at least one part of a region exists within the region from V78 to the PKD structural domain, then other regions may also exist outside the region from V78 to the PKD structural domain.

[0141] Regarding the binding strength of the antibody of the present invention to the region of gpNMB from V78 to PKD domain, there is no particular limitation, but preferably: a 50% effective concentration (EC50) of gpNMB to the region of gpNMB from V78 to PKD domain, as determined by antigen ELISA using recombinant gpNMB and / or cell ELISA using gpNMB-expressing cells. 50 ), usually 1×10 -7 Below M, or 1×10 -8 Below M, or 1×10 -9 Below M. It should be noted that the "50% effective concentration" (EC50) of the antibody in this instruction manual... 50 This refers to the antibody concentration that exhibits 50% of the maximum binding affinity between the antibody and the antigen. ECMO (Extracorporeal Membrane Electron Microscopy) is based on an antigen ELISA using recombinant gpNMB and / or a cell ELISA using gpNMB-expressing cells. 50 The specific measurement conditions can be found in the examples described below.

[0142] In addition to the region from V78 to the PKD domain of gpNMB, the antibodies of the present invention can also bind to one or more other regions. There are no limitations on the amino acid sites that the antibodies of the present invention can bind to, other than the region from V78 to the PKD domain of gpNMB; for example, E385 of human gpNMB shown in SEQ ID NO: 209 can be cited.

[0143] • Amino acid and nucleic acid sequences of each region of the antibody chain: The antibodies of the present invention do not have particularly limited amino acid sequences, provided they possess specific binding activity to at least one of the regions of gpNMB from V78 to the PKD domain. However, the antibodies of the present invention preferably have specific amino acid sequences as each CDR sequence. Specifically, as described below. It should be noted that in this specification, "identity" of the amino acid sequence refers to the proportion of identical amino acid residues, and "similarity" refers to the proportion of identical or similar amino acid residues. The similarity and identity of the amino acid sequences can be determined, for example, by the BLAST method (the default condition of NCBI's PBLAST). In addition, for example, when "more than 80% similarity" is expressed, it obviously includes the case of "more than 80% identity".

[0144] Here, "similar amino acid residues" refers to amino acid residues having side chains with the same chemical properties (e.g., charge or hydrophobicity). Examples of similar amino acid residues include the following combinations.

[0145] (1) Amino acid residues with aliphatic side chains: glycine (Gly or G), alanine (Ala or A), valine (Val or V), leucine (Leu or L) and isoleucine (Ile or I) residues.

[0146] (2) Amino acid residues with aliphatic hydroxyl side chains: serine (Ser or S) and threonine (Thr or T) residues.

[0147] (3) Amino acid residues with amide side chains: asparagine (Asn or N) and glutamine (Gln or Q) residues.

[0148] (4) Amino acid residues with aromatic side chains: phenylalanine (Phe or F), tyrosine (Tyr or Y) and tryptophan (Trp or W) residues.

[0149] (5) Amino acid residues with basic side chains: lysine (Lys or K), arginine (Arg or R) and histidine (His or H) residues.

[0150] (6) Amino acid residues with acidic side chains: aspartic acid (Asp or D) and glutamic acid (Glu or E) residues.

[0151] (7) It has amino acid groups with sulfur-containing side chains: cysteine ​​(Cys or C) and methionine (Met or M) residues.

[0152] Moreover, the combination of (1) with methionine (Met or M) and the combination of (4) with histidine (His or H) residues are also considered to be similar amino acid residues.

[0153] Additionally, referring to the germline sequence, substitutions can sometimes be made regardless of similarity, provided a corresponding mutant is present. Mutants in the germline include substitutions, deletions, or additions. Substitutions also include cases where amino acids that could potentially affect the orientation of the side chain can be replaced with proline (Pro or P) or glycine (Gly or G).

[0154] As one embodiment of the antibody of the present invention, an antibody comprising a heavy chain variable region having the following CDR-H1 to H3 sequences (1) to (14) can be cited. It should be noted that, in this specification, "CDR transplantation region" refers to a region of the antibody's amino acid sequence that has the same or repeated amino acid sequence as the CDR as defined in this specification, and is a region of the antibody's amino acid sequence that, like the CDR, contacts the antigen to determine antigen specificity and is important for binding to the antigen.

[0155] (1) As CDR-H1, it is the amino acid sequence described in SEQ ID NO: 1, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 1, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 1. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 3, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 3, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 3, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 5, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 5, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 75.0%, 83.3%, or 91.6% or more to the amino acid sequence described in SEQ ID NO: 5.

[0156] (2) As CDR-H1, the amino acid sequence described in SEQ ID NO: 17, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 17, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 17. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 19, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 19, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 19. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 21, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 21, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 21.

[0157] (3) As CDR-H1, the amino acid sequence described in SEQ ID NO: 33, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 33, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 33. As CDR-H2, the amino acid sequence described in SEQ ID NO: 35, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 35, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 35, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 37, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 37, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 37.

[0158] (4) As CDR-H1, the amino acid sequence described in SEQ ID NO: 49, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 49, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 49. As CDR-H2, the amino acid sequence described in SEQ ID NO: 51, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 51, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 51, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 53, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 53, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 68.7%, 75.0%, 81.2%, 87.5%, or 93.7% or more to the amino acid sequence described in SEQ ID NO: 53.

[0159] (5) As CDR-H1, the amino acid sequence described in SEQ ID NO: 65, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 65, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 65. As CDR-H2, the amino acid sequence described in SEQ ID NO: 67, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 67, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 67, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 69, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, or five amino acid residues in the amino acid sequence described in SEQ ID NO: 69, or an amino acid sequence having a similarity (preferably identical) of 64.2%, 71.4%, 78.5%, 85.7%, or 92.8% or more to the amino acid sequence described in SEQ ID NO: 69.

[0160] (6) As CDR-H1, the amino acid sequence described in SEQ ID NO: 81, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 81, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 81. As CDR-H2, the amino acid sequence described in SEQ ID NO: 83, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 83, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 83, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 85, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 85, or an amino acid sequence having a similarity (preferably identical) of 63.6%, 72.7%, 81.8%, or 90.9% or more to the amino acid sequence described in SEQ ID NO: 85.

[0161] (7) As CDR-H1, the amino acid sequence described in SEQ ID NO: 97, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 97, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 97. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 99, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 99, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 99. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 101, or an amino acid sequence formed by substituting, deleting, or inserting any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 101, or an amino acid sequence having 60.0% or more or 80.0% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 101.

[0162] (8) As CDR-H1, the amino acid sequence described in SEQ ID NO: 113, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 113, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 113. As CDR-H2, the amino acid sequence described in SEQ ID NO: 115, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 115, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 115, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 117, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 117, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 117.

[0163] (9) As CDR-H1, the amino acid sequence described in SEQ ID NO: 129, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 129, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 129. As CDR-H2, the amino acid sequence described in SEQ ID NO: 131, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 131, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 131, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 133, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 133, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 133.

[0164] (10) As CDR-H1, the amino acid sequence described in SEQ ID NO: 145, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 145, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 145. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 147, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 147, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 147. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 149, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 149, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 149.

[0165] (11) As CDR-H1, the amino acid sequence described in SEQ ID NO: 161, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 161, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 161. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 163, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 163, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 163. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 165, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 165, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 165.

[0166] (12) As CDR-H1, the amino acid sequence described in SEQ ID NO: 255, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 255, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 255. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 257, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 257, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 257. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 259, or an amino acid sequence formed by substituting, deleting, or inserting any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 259, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 259.

[0167] (13) As CDR-H1, the amino acid sequence described in SEQ ID NO: 283, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 283, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 283. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 285, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 285, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 285. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 287, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 287, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 287.

[0168] (14) As CDR-H1, the amino acid sequence described in SEQ ID NO: 311, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 311, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 311. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 313, or an amino acid sequence formed by substituting, deleting, or inserting any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 313, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 313. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 315, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 315, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 315.

[0169] It should be noted that, as described in Example 11 below, the inventors investigated the importance of each amino acid residue in the CDR transplantation region sequence in the maintenance binding of the humanized anti-gpNMB antibody H1L1 (clone hGPN06-1_H1L1) by alanine scanning. The results showed that the following amino acid residues in the heavy chain variable region (SEQ ID NO: 295) of the humanized anti-gpNMB antibody hGPN06-1_H1L1—specifically, tyrosine at position 27, asparagine at position 32, and tryptophan at position 33 in the CDR transplantation region-H1 (SEQ ID NO: 271); aspartic acid at position 55, phenylalanine at position 57, threonine at position 58, asparagine at position 59, tyrosine at position 60, and asparagine at position 61 in the CDR transplantation region-H2 (SEQ ID NO: 273); and arginine at position 98, glycine at position 100, and glycine at position 109 in the CDR transplantation region-H3 (SEQ ID NO: 275)—were crucial for maintaining binding. Conversely, the amino acid residues in other CDR transplantation region sequences were identified as having little effect on maintaining binding. Based on these insights, as one embodiment of the antibody of the present invention, an antibody comprising a heavy chain variable region having the following (15) CDR transplantation region -H1 to H3 sequence is also provided (it should be noted that the following amino acid positions are based on the amino acid sequence (SEQ ID NO: 295) of the heavy chain variable region of the humanized anti-gpNMB antibody hGPN06-1_H1L1).

[0170] (15) As the CDR transplantation region-H1, an amino acid sequence formed by the substitution, deletion or insertion of any one, two, three or four amino acid residues in the amino acid sequence described in SEQ ID NO: 271, except for tyrosine at position 27, asparagine at position 32 and tryptophan at position 33. As the CDR transplantation region -H2, it is an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 273, except for aspartic acid at position 55, phenylalanine at position 57, threonine at position 58, asparagine at position 59, tyrosine at position 60, and asparagine at position 61. As the CDR transplantation region -H3, it is an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence recorded in SEQ ID NO: 275, except for arginine at position 98, glycine at position 100, and glycine at position 109.

[0171] Furthermore, as shown in Example 15 described later, the inventors investigated the importance of each amino acid residue in the CDR transplantation region sequences for maintaining binding in the humanized anti-gpNMB antibody H2L3 (clone hGPN18-2_H2L3) using alanine scanning. The results identified as follows: aspartic acid at position 52, tryptophan at position 54, aspartic acid at position 58, and proline at position 63 in the CDR transplantation region-H2 (SEQ ID NO: 301) of the heavy chain variable region (SEQ ID NO: 323); and arginine at position 99, threonine at position 100, tyrosine at position 102, tyrosine at position 105, tyrosine at position 107, and methionine at position 110 in the CDR transplantation region-H3 (SEQ ID NO: 303). On the other hand, it was determined that amino acid residues in the CDR transplantation region sequences other than those described above had almost no effect on maintaining binding. Based on these insights, as one embodiment of the antibody of the present invention, an antibody comprising a light chain variable region having the following (16) CDR transplantation region -H1 to H3 sequence (it should be noted that the following amino acid positions are based on the amino acid sequence of the heavy chain variable region of the humanized anti-gpNMB antibody H2L3 (SEQ ID NO: 323)).

[0172] (16) As the CDR transplantation region-H1, an amino acid sequence formed by the substitution, deletion or insertion of any one, two, three or four amino acid residues in the amino acid sequence described in SEQ ID NO: 299. As the CDR transplantation region -H2, it is an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 301, except for aspartic acid at position 52, tryptophan at position 54, aspartic acid at position 58, and proline at position 63. As the CDR transplantation region -H3, it is an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 303, except for arginine at position 99, threonine at position 100, tyrosine at position 102, tyrosine at position 105, tyrosine at position 107, and methionine at position 110.

[0173] As one embodiment of the antibody of the present invention, an antibody comprising a heavy chain variable region having the following CDR-H1 to H3 sequences (17) to (23) can also be cited. It should be noted that antibodies comprising a heavy chain variable region having the following CDR-H1 to H3 sequences (17) to (23) are neither disclosed nor implied in existing literature, and are equivalent to novel anti-gpNMB antibodies.

[0174] (17) As CDR-H1, the amino acid sequence described in SEQ ID NO: 177, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 177, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 177. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 179, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 179, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 179. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 181, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 181, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 181.

[0175] (18) As CDR-H1, the amino acid sequence described in SEQ ID NO: 330, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 330, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 330. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 331, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 331, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 331. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 332, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 332, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 332.

[0176] (19) As CDR-H1, the amino acid sequence described in SEQ ID NO: 337, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 337, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 337. As CDR-H2, the amino acid sequence described in SEQ ID NO: 338, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 338, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 338, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 339, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 339, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 339.

[0177] (20) As CDR-H1, the amino acid sequence described in SEQ ID NO: 344, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 344, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 344. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 345, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 345, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 345. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 346, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 346, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 346.

[0178] (21) As the CDR transplantation region -H1, the amino acid sequence described in SEQ ID NO: 327, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 327, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 327. As the CDR transplantation region -H2, it is the amino acid sequence described in SEQ ID NO: 328, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 328, or an amino acid sequence having a similarity (preferably identical) of 64.7%, 70.5%, 76.4%, 82.3%, 88.2%, or 94.1% or more to the amino acid sequence described in SEQ ID NO: 328. As the CDR transplantation region -H3, it is the amino acid sequence described in SEQ ID NO: 329, or an amino acid sequence formed by replacing, deleting, or inserting any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 329, or an amino acid sequence having more than 66.6% or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 329.

[0179] (22) As the CDR transplantation region -H1, the amino acid sequence described in SEQ ID NO: 334, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 334, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 334. As the CDR transplantation region -H2, it is the amino acid sequence described in SEQ ID NO: 335, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 335, or an amino acid sequence having a similarity (preferably identical) of 64.7%, 70.5%, 76.4%, 82.3%, 88.2%, or 94.1% or more to the amino acid sequence described in SEQ ID NO: 335. As the CDR transplantation region -H3, it is the amino acid sequence described in SEQ ID NO: 336, or an amino acid sequence formed by replacing, deleting, or inserting any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 336, or an amino acid sequence having more than 66.6% or 83.3% similarity (preferably identity) to the amino acid sequence described in SEQ ID NO: 336.

[0180] (23) As the CDR transplantation region -H1, the amino acid sequence described in SEQ ID NO: 341, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 341, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 341. As the CDR transplantation region -H2, it is the amino acid sequence described in SEQ ID NO: 342, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 342, or an amino acid sequence having a similarity (preferably identical) of 64.7%, 70.5%, 76.4%, 82.3%, 88.2%, or 94.1% or more to the amino acid sequence described in SEQ ID NO: 342. As the CDR transplantation region -H3, it is the amino acid sequence described in SEQ ID NO: 343, or an amino acid sequence formed by replacing, deleting, or inserting any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 343, or an amino acid sequence having more than 66.6% or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 343.

[0181] As one embodiment of the antibody of the present invention, an antibody comprising a light chain variable region having the following CDR-L1 to L3 sequences (1) to (14) can be cited.

[0182] (1) As CDR-L1, it is the amino acid sequence described in SEQ ID NO: 7, or an amino acid sequence formed by substituting, deleting, or inserting any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 7, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 7. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 9, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 9, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 9. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 11, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 11, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 11.

[0183] (2) As CDR-L1, it is the amino acid sequence described in SEQ ID NO: 23, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 23, or an amino acid sequence having 60.0% or more or 80.0% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 23. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 25, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 25, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 25. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 27, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 27, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 27.

[0184] (3) As CDR-L1, it is the amino acid sequence described in SEQ ID NO: 39, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 39, or an amino acid sequence having 60.0% or more or 80.0% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 39. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 41, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 41, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 41. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 43, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 43, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 43.

[0185] (4) As CDR-L1, the amino acid sequence described in SEQ ID NO: 55, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 55, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 55. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 57, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 57, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 57. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 59, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 59, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 59.

[0186] (5) As CDR-L1, the amino acid sequence described in SEQ ID NO: 71, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 71, or an amino acid sequence having 60.0% or more or 80.0% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 71. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 73, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 73, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 73, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 75, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 75, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 75.

[0187] (6) As CDR-L1, the amino acid sequence described in SEQ ID NO: 87, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 87, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 87. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 89, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 89, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 89. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 91, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 91, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 91.

[0188] (7) As CDR-L1, the amino acid sequence described in SEQ ID NO: 103, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 103, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 103. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 105, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 105, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 105, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 107, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 107, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 107.

[0189] (8) As CDR-L1, the amino acid sequence described in SEQ ID NO: 119, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 119, or an amino acid sequence having a similarity (preferably identical) of 63.6%, 72.7%, 81.8%, or 90.9% or more to the amino acid sequence described in SEQ ID NO: 119. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 121, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 121, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 121. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 123, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 123, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 123.

[0190] (9) As CDR-L1, the amino acid sequence described in SEQ ID NO: 135, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 135, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 135. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 137, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 137, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 137. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 139, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 139, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 139.

[0191] (10) As CDR-L1, the amino acid sequence described in SEQ ID NO: 151, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 151, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 151. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 153, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 153, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 153, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 155, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 155, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 155.

[0192] (11) As CDR-L1, the amino acid sequence described in SEQ ID NO: 167, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 167, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 167. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 169, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 169, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 169, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 171, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 171, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 171.

[0193] (12) As CDR-L1, it is the amino acid sequence described in SEQ ID NO: 261, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 261, or an amino acid sequence having a similarity (preferably identical) of 63.6%, 72.7%, 81.8%, or 90.9% or more to the amino acid sequence described in SEQ ID NO: 261. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 263, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 263, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 263, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 265, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 265, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 265.

[0194] (13) As CDR-L1, the amino acid sequence described in SEQ ID NO: 289, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 289, or an amino acid sequence having 60.0% or more or 80.0% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 289. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 291, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 291, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 291. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 293, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 293, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 293.

[0195] (14) As CDR-L1, the amino acid sequence described in SEQ ID NO: 317, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 317, or an amino acid sequence having a similarity (preferably identical) of 63.6%, 72.7%, 81.8%, or 90.9% or more to the amino acid sequence described in SEQ ID NO: 317. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 319, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 319, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 319. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 321, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 321, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 321.

[0196] It should be noted that, as shown in Example 11 described later, the inventors investigated the importance of each amino acid residue in the CDR transplantation region sequence for maintaining binding of the humanized anti-gpNMB antibody H1L1 (clone hGPN06-1_H1L1) using alanine scanning. The results identified isoleucine at position 29, tyrosine at position 31, and histidine at position 33 in the CDR transplantation region-L1 (SEQ ID NO: 277) of the light chain variable region (SEQ ID NO: 297); threonine at position 50 in the CDR transplantation region-L2 (SEQ ID NO: 279); and histidine at position 88, glutamine at position 89, tryptophan at position 90, serine at position 92, tyrosine at position 93, proline at position 94, and cysteine ​​at position 95 in the CDR transplantation region-L3 (SEQ ID NO: 281). On the other hand, it was found that the amino acid residues of each CDR transplantation region sequence other than those mentioned above had almost no effect on its maintenance binding. Based on these insights, as an antibody of the present invention, an antibody comprising a light chain variable region having the following (15) CDR transplantation region -L1 to L3 sequence can also be cited (it should be noted that the following amino acid positions are based on the amino acid sequence of the light chain variable region of humanized anti-gpNMB antibody H1L1 (SEQ ID NO:297)).

[0197] (15) As the CDR transplantation region-L1, an amino acid sequence formed by the substitution, deletion or insertion of any one, two, three or four amino acid residues in the amino acid sequence described in SEQ ID NO: 277, except for isoleucine at position 29, tyrosine at position 31 and histidine at position 33. As the CDR transplantation region -L2, it is an amino acid sequence formed by the substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 279, except for threonine at position 50. As the CDR transplantation region - L3, it is an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 281, except for histidine at position 88, glutamine at position 89, tryptophan at position 90, serine at position 92, tyrosine at position 93, proline at position 94, and cysteine ​​at position 95.

[0198] Furthermore, as shown in Example 15 described later, the inventors investigated the importance of each amino acid residue in the CDR transplantation region sequences for maintaining binding of the humanized anti-gpNMB antibody H2L3 (clone hGPN18-2_H2L3) using alanine scanning. The results identified leucine at position 31 and tyrosine at position 37 in the CDR transplantation region-L1 (SEQ ID NO: 305) of the light chain variable region (SEQ ID NO: 325) of the humanized anti-gpNMB antibody H2L3; lysine at position 55 in the CDR transplantation region-L2 (SEQ ID NO: 307); and phenylalanine at position 94 in the CDR transplantation region-L3 (SEQ ID NO: 309). On the other hand, the amino acid residues in the CDR transplantation region sequences other than those described above had almost no effect on maintaining binding. Based on these insights, as one embodiment of the antibody of the present invention, an antibody comprising a light chain variable region having the following (16) CDR transplantation region - L1 to L3 sequence (it should be noted that the following amino acid positions are based on the amino acid sequence of the light chain variable region of humanized anti-gpNMB antibody H2L3 (SEQ ID NO: 325)).

[0199] (16) As the CDR transplantation region-L1, an amino acid sequence formed by the substitution, deletion or insertion of any one, two, three, four, five or six amino acid residues in the amino acid sequence described in SEQ ID NO: 305, except for leucine at position 31, tyrosine at position 37 and glutamic acid at position 39. As the CDR transplantation region -L2, it is an amino acid sequence formed by the substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 307, except for lysine at position 55. As the CDR transplantation region - L3, it is an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 309, except for phenylalanine at position 94.

[0200] As one embodiment of the antibody of the present invention, an antibody comprising a light chain variable region having the following CDR-H1 to H3 sequences (17) to (23) can also be cited. It should be noted that antibodies comprising a heavy chain variable region having the following CDR-L1 to L3 sequences (17) to (23) are neither disclosed nor implied in existing literature, and are equivalent to novel anti-gpNMB antibodies.

[0201] (17) As CDR-L1, the amino acid sequence described in SEQ ID NO: 183, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 183, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 183. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 185, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 185, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 185. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 187, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 187, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 187.

[0202] (18) As CDR-L1, the amino acid sequence described in SEQ ID NO: 351, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 351, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 351. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 352, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 352, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 352. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 353, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 353, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 353.

[0203] (19) As CDR-L1, the amino acid sequence described in SEQ ID NO: 358, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 358, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 358. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 359, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 359, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 359. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 360, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 360, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 360.

[0204] (20) As CDR-L1, the amino acid sequence described in SEQ ID NO: 365, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 365, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 365. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 366, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 366, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 366. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 367, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 367, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 367.

[0205] (21) As the CDR transplantation region-L1, the amino acid sequence described in SEQ ID NO: 348, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 348, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 348. As the CDR transplantation region -L2, it is the amino acid sequence described in SEQ ID NO: 349, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 349, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 349. As the CDR transplantation region -L3, it is an amino acid sequence described in SEQ ID NO: 350, or an amino acid sequence formed by the substitution, deletion or insertion of any one, two or three amino acid residues in the amino acid sequence described in SEQ ID NO: 350, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7% or more or 88.8% or more to the amino acid sequence described in SEQ ID NO: 350.

[0206] (22) As the CDR transplantation region-L1, the amino acid sequence described in SEQ ID NO: 355, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 355, or an amino acid sequence having a similarity (preferably identical) of 63.6%, 72.7%, 81.8%, or 90.9% or more to the amino acid sequence described in SEQ ID NO: 355. As the CDR transplantation region -L2, it is the amino acid sequence described in SEQ ID NO: 356, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 356, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 356. As the CDR transplantation region -L3, it is an amino acid sequence described in SEQ ID NO: 357, or an amino acid sequence formed by the substitution, deletion or insertion of any one, two or three amino acid residues in the amino acid sequence described in SEQ ID NO: 357, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7% or more or 88.8% or more to the amino acid sequence described in SEQ ID NO: 357.

[0207] (23) As the CDR transplantation region-L1, the amino acid sequence described in SEQ ID NO: 362, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 362, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 362. As the CDR transplantation region -L2, it is the amino acid sequence described in SEQ ID NO: 363, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 363, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 363. As the CDR transplantation region -L3, it is the amino acid sequence described in SEQ ID NO: 364, or an amino acid sequence formed by the substitution, deletion or insertion of any one, two or three amino acid residues in the amino acid sequence described in SEQ ID NO: 364, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7% or more or 88.8% or more to the amino acid sequence described in SEQ ID NO: 364.

[0208] As one embodiment of the antibody of the present invention, an antibody can be provided by combining a heavy chain variable region having any of the aforementioned CDR-H1 to H3 sequences and a light chain variable region having any of the aforementioned CDR-L1 to L3 sequences.

[0209] As one embodiment of the antibody of the present invention, an antibody having any of the following amino acid sequences (a) to (c) as the heavy chain variable region sequence can be cited. It should be noted that the antibody containing the amino acid sequence of SEQ ID NO:189 among the following amino acid sequences (a), or the corresponding amino acid sequences of the following (b) or (c), is neither disclosed nor implied in the existing literature, and is equivalent to a novel anti-gpNMB antibody.

[0210] (a) Any one amino acid sequence selected from SEQ ID NO: 13, SEQ ID NO: 29, SEQ ID NO: 45, SEQ ID NO: 61, SEQ ID NO: 77, SEQ ID NO: 93, SEQ ID NO: 109, SEQ ID NO: 125, SEQ ID NO: 141, SEQ ID NO: 157, SEQ ID NO: 173, SEQ ID NO: 189 and SEQ ID NO: 267.

[0211] (b) An amino acid sequence having at least 60%, or 65%, or 70%, or 75%, or 80%, or 85%, or 90%, or 95%, or 96%, or 97%, or 98%, or 99% similarity (preferably identical) to the amino acid sequence of (a) above.

[0212] (c) An amino acid sequence in which 1 to 12 (preferably 1 to 11, more preferably 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2 or 1) amino acid residues are replaced, deleted or added.

[0213] As one embodiment of the antibody of the present invention, an antibody (especially a humanized antibody) having any of the following amino acid sequences (a) to (c) as the heavy chain variable region sequence can be cited. It should be noted that antibodies (especially humanized antibodies) containing the amino acid sequence of SEQ ID NO: 333, SEQ ID NO: 340, or SEQ ID NO: 347 among the following amino acid sequences (a), or the corresponding amino acid sequences of the following (b) or (c), are neither disclosed nor implied in existing literature, and are equivalent to novel anti-gpNMB antibodies (especially humanized antibodies).

[0214] (a) Selected from any one amino acid sequence from SEQ ID NO: 295, SEQ ID NO: 323, SEQ ID NO: 333, SEQ ID NO: 340 and SEQ ID NO: 347.

[0215] (b) An amino acid sequence having at least 60%, or 65%, or 70%, or 75%, or 80%, or 85%, or 90%, or 95%, or 96%, or 97%, or 98%, or 99% similarity (preferably identical) to the amino acid sequence of (a) above.

[0216] (c) An amino acid sequence in which 1 to 12 (preferably 1 to 11, more preferably 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2 or 1) amino acid residues are replaced, deleted or added.

[0217] As one embodiment of the antibody of the present invention, an antibody having any of the following (a) to (c) as the light chain variable region sequence can be cited. It should be noted that the antibody containing the amino acid sequence of SEQ ID NO: 191 among the following amino acid sequences (a), or the corresponding amino acid sequences of the following (b) or (c), is neither disclosed nor implied in the existing literature, and is equivalent to a novel anti-gpNMB antibody.

[0218] (a) Any one amino acid sequence selected from SEQ ID NO: 15, SEQ ID NO: 31, SEQ ID NO: 47, SEQ ID NO: 63, SEQ ID NO: 79, SEQ ID NO: 95, SEQ ID NO: 111, SEQ ID NO: 127, SEQ ID NO: 143, SEQ ID NO: 159, SEQ ID NO: 175, SEQ ID NO: 191 and SEQ ID NO: 269.

[0219] (b) An amino acid sequence having at least 60%, or 65%, or 70%, or 75%, or 80%, or 85%, or 90%, or 95%, or 96%, or 97%, or 98%, or 99% similarity (preferably identical) to the amino acid sequence of (a) above.

[0220] (c) An amino acid sequence formed by substituting, deleting or adding 1 to 10 (preferably 1 to 9, more preferably 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2 or 1) amino acid residues in the amino acid sequence of (a) above.

[0221] As one embodiment of the antibody of the present invention, an antibody (especially a humanized antibody) having any of the following amino acid sequences (a) to (c) as the light chain variable region sequence can be cited. It should be noted that antibodies (especially humanized antibodies) containing the amino acid sequences of SEQ ID NO: 354, SEQ ID NO: 361, and SEQ ID NO: 368 among the following amino acid sequences (a), or the corresponding amino acid sequences of the following (b) or (c), are neither disclosed nor implied in existing literature, and are equivalent to novel anti-gpNMB antibodies (especially humanized antibodies).

[0222] (a) Selected from any one amino acid sequence from SEQ ID NO: 297, SEQ ID NO: 325, SEQ ID NO: 354, SEQ ID NO: 361 and SEQ ID NO: 368.

[0223] (b) An amino acid sequence having at least 60%, or 65%, or 70%, or 75%, or 80%, or 85%, or 90%, or 95%, or 96%, or 97%, or 98%, or 99% similarity (preferably identical) to the amino acid sequence of (a) above.

[0224] (c) An amino acid sequence in which 1 to 12 (preferably 1 to 11, more preferably 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2 or 1) amino acid residues are replaced, deleted or added.

[0225] As one embodiment of the antibody of the present invention, an antibody formed by combining any of the aforementioned heavy chain variable regions and any of the aforementioned light chain variable regions can be cited.

[0226] It should be noted that methods for identifying the sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, or CDR-L3 in antibodies include, for example, the Kabat method (NIH Publication, (1991), No. 91-3242) or the Chothia method (J. Mol. Biol., (1997), 273[4]: 927-48). These methods are common knowledge to those skilled in the art, and can be summarized, for example, from the webpage of Dr. Andrew CR Martin's team (http: / / www.bioinf.org.uk / abs / ). It should be noted that the CDR in this invention is referred to as the Kabat CDR.

[0227] The framework sequences of the heavy chain variable region and light chain variable region of the immunoglobulin used as the antibody of the present invention are preferably framework sequences from various types of vertebrate immunoglobulins. Particularly preferred are framework sequences from various types of human immunoglobulins, or those from non-human animals including mice or rats.

[0228] By appropriately combining the amino acid sequences of the structural regions and / or constant regions of the heavy and light chains of human or non-human animal antibodies (including mice or rats) from the CDRs and / or variable regions of the heavy and light chains described above, those skilled in the art can design the anti-gpNMB specific antibody of the present invention. In particular, humanized anti-gpNMB specific antibodies can be prepared by using the amino acid sequences of the structural regions and / or constant regions of the heavy and light chains of human antibodies. The amino acid sequences of the structural regions and / or constant regions of the heavy and light chains of the humanized antibody can be selected, for example, from various types of human IgG, IgA, IgM, IgE, IgD, or their mutants. For IgG, there are four subclasses: IgG1, IgG2, IgG3, and IgG4. In the case where the anti-gpNMB specific antibody of the present invention is a humanized antibody comprising each structural region and / or each constant region of the heavy and light chains of human IgG, the amino acid sequence of each structural region and / or each constant region of the heavy and light chains of human IgG can be derived from any one of the amino acid sequences of human IgG1 subclass, human IgG2 subclass, human IgG3 subclass, and human IgG4 subclass.

[0229] The antibodies of the present invention are preferably IgG class or mutants thereof. The antibodies of the present invention are more preferably human IgG class or mutants thereof, human IgG4 subclass or mutants thereof, or human IgG1 subclass or mutants thereof. In one example, the stabilized IgG4 constant region contains proline at position 241 of the hinge region according to the Kabat system. This position corresponds to position 228 of the hinge region according to EU numbering scheme (Proc.Natl. Acad. Sci. USA, (1969), 63[1]: 78-85), protein sequences of immunological interest (Washington, D.C., U.S. Department of Health and Human Services, 2001 and NIH Publication, (1991), No. 91-3242). In human IgG4, this residue is usually serine, and stabilization can be induced by replacing serine with proline. In one example, the N297A mutation may be incorporated into the constant region of IgG1 to suppress the ability to bind to the Fc receptor and / or fix complement as much as possible.

[0230] • Competition combined: As one aspect of the present invention, for the binding itself to at least one of the regions from the V78 to the PKD domain of gpNMB, antibodies that compete with the antibodies of the present invention for binding can also be cited. These competing antibodies are also included within the scope of the present invention. In the present invention, "competitive binding" refers to the phenomenon where, when multiple monoclonal antibodies coexist with an antigen, the binding of one antibody to the antigen is inhibited by the binding of another antibody to the antigen. Generally, this can be determined as follows: for a certain amount (concentration) of monoclonal antibody, when other monoclonal antibodies are added in varying amounts (concentrations), the amount (concentration) of the added monoclonal antibody that reduces the binding of the former to the antigen is measured. The degree of inhibition can be expressed using IC50. 50 Or a value like Ki. A monoclonal antibody that competes with the antibody of the present invention refers to, for example, when using the antibody of the present invention at 10 nM, competitive antigen-antibody binding to at least one site in the region from V78 to the PKD domain of gpNMB is detected, IC50. 50 Antibodies typically have a molecular weight of 1000 nM or less, especially 100 nM or less, and further down to 10 nM or less. In the case of competitive binding assays, the antibody to be used can also be labeled with enzymes, fluorescent substances, luminescent substances, radioactive isotopes, etc., and the assay can be performed using a method suitable for the physical and / or chemical properties of the labeled substance. Alternatively, biosensors such as surface plasmon resonance (SPR) or bio-layer interferometry (BLI) can be used.

[0231] • Disease-associated cell clearance activity: As described below, the anti-gpNMB antibody of the present invention has the activity of clearing various disease-associated cells that highly express gpNMB. Therefore, as described below, by utilizing the anti-gpNMB antibody of the present invention, various disease-associated cells can be effectively cleared, thereby preventing or treating various diseases related to said disease-associated cells. It should be noted that although preferred features of the antibody of the present invention are exemplified in the context of clearing said disease-associated cells and treating or preventing diseases mediated by such cells, the antibody of the present invention is not limited to antibodies having these features. It should be noted that, in embodiments of the present invention, it has also been confirmed that a portion of the anti-gpNMB antibody includes an antibody with gpNMB-mediated signal induction activity that causes increased phosphorylation of ERK1 / 2 (extracellular signal-regulated kinase), S6 (ribosomal protein), and Akt (serine-threonine kinase). That is, according to one embodiment, an anti-gpNMB antibody having gpNMB-mediated signal induction activity is provided as the anti-gpNMB antibody of the present invention. In addition, according to one embodiment, as the anti-gpNMB antibody of the present invention, an anti-gpNMB antibody that does not have gpNMB-mediated signal induction activity is provided.

[0232] It should be noted that the disease-associated cell scavenging activity of the anti-gpNMB antibody of the present invention can be exerted in vivo, in vitro, or both. Furthermore, whether in vivo or in vitro, it is acceptable as long as it exerts its activity in any subject, but it is preferred to exert its activity at least in vertebrates, more preferably at least in mammals, and particularly preferably in humans or non-human animals.

[0233] The following examples illustrate preferred embodiments of the antibodies of the present invention in the context of envisioning the elimination of disease-related cells and the treatment or prevention of cell-mediated diseases, but the antibodies of the present invention are not limited to antibodies having these characteristics.

[0234] • Effector function of antibodies According to one embodiment, the antibody of the present invention preferably has the ability to clear disease-associated cells. In particular, it is preferred to have an Fc structure that confers phagocytic ability based on phagocytes for clearing disease-associated cells. On the other hand, it is preferred to have a subclass or mutant that does not confer or inhibits the function of inducing inflammation. However, it is also contemplated that the effector function may be exercised differently depending on the disease or the cells to be cleared and the tissue present, and therefore is not necessarily limited to the above, but rather preferably confers effector function and intensity corresponding to the respective disease treatment (Non-Patent Document 91).

[0235] antibody half-life According to one approach, the antibody of the present invention can have its blood half-life prolonged by using previously reported Fc mutants such as the YTE mutation. By prolonging the blood half-life of the antibody, the number of dosing sessions can be reduced (Non-Patent Literature 92).

[0236] Antibodies cross the blood-tissue barrier According to one embodiment, the antibody of the present invention can be enhanced to transfer to tissues isolated from the blood, such as the blood-tissue barrier (BBB), by fusing with the anti-transferrin antibody, etc. (Non-Patent Document 93).

[0237] Bispecific antibodies, multivalent antibodies The inventors have developed an anti-gpNMB antibody that possesses the specificity and binding affinity required for producing highly effective bispecific or multivalent antibodies, and can eliminate gpNMB-positive cells. Specifically, according to one protocol, by using the antibody of this invention, T cells, NK cells, macrophages, etc., can engage with and attract various gpNMB-positive disease-related cells (dysfunctional macrophages, senescent cells, cancer cells, cancer-infiltrating cells, etc.), thereby eliminating disease-related cells (Non-Patent Literature 94).

[0238] CAR cells The inventors have developed a low-molecular-weight antibody, including a single-chain variable region fragment (scFv), against gpNMB. This antibody possesses specificity and binding affinity for the production of highly effective CAR (Chimeric Antigen Receptor) cells and can eliminate gpNMB-positive cells. Specifically, according to one protocol, by producing CAR cells using the antibody of this invention, T cells, NK cells, macrophages, etc., can be delivered to various gpNMB-positive disease-related cells (dysfunctional macrophages, senescent cells, cancer cells, cancer-infiltrating cells, etc.), thereby eliminating disease-related cells (Non-Patent Literature 95). Furthermore, by pre-treating with the anti-gpNMB antibody of this invention, even higher efficacy of CAR cell therapy can be achieved.

[0239] [Manufacturing method of anti-gpNMB antibody] The antibodies in this invention can be obtained using techniques well known to those skilled in the art. The antibodies in this invention are polyclonal or monoclonal antibodies (Nature, (1983), 305(5934): 537-40). For example, polyclonal antibodies are administered intramuscularly or subcutaneously to mammals using human gpNMB protein having the amino acid sequence shown in SEQ ID NO: 209, or a partial peptide of gpNMB having a portion of its amino acid sequence (e.g., a peptide containing a PKD domain composed of amino acid residues 256-319, etc.) as an antigen, or using an antigen-expressing polynucleotide encoding the amino acid sequence of said human gpNMB protein or gpNMB partial peptide, thereby sensitizing the animal by antigen expression in vivo, and thus recovering it from the animal's serum, etc. Alternatively, when using a peptide as an antigen, an antigen in a form bound to a carrier protein such as BSA or KLH, or polylysine, can be used.

[0240] Regarding the non-humanized monoclonal antibody in this invention, as described above, it can be sensitized by administering human gpNMB protein or gpNMB partial peptide, or antigen-expressing polynucleotides encoding said human gpNMB protein or gpNMB partial peptide, to a mammal, from which immune cells are extracted and fused with myeloma cells, etc., and the hybridoma clone obtained thereby is recovered from its culture. Such methods for obtaining monoclonal antibodies (Nature, (1992), 356

[6365] : 152-4) and cell fusion methods (Nature, (1975), 256

[5517] : 495-7) have been reported and are widely used, and the efficiency of acquisition can be further improved by administering immunomodulatory substances (Cancer Gene Ther., (2007), 14

[11] : 904-17). There are no limitations on the monoclonal antibodies obtained by such methods, and the following are some examples. It should be noted that among the following antibodies, the anti-gpNMB monoclonal antibody (GPN18-5), which contains a heavy chain variable region with the amino acid sequence of SEQ ID NO: 189 and a light chain variable region with the amino acid sequence of SEQ ID NO: 191, is neither disclosed nor implied in existing literature and is equivalent to a novel anti-gpNMB antibody (especially a humanized antibody).

[0241] • Antibody (GPN05-1), which has: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 13 and a light chain variable region having the amino acid sequence of SEQ ID NO: 15.

[0242] • Antibody (GPN06-1), which has: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 29 and a light chain variable region having the amino acid sequence of SEQ ID NO: 31.

[0243] • Antibody (GPN07-1), which has: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 45 and a light chain variable region having the amino acid sequence of SEQ ID NO: 47.

[0244] • Antibody (GPN11-10) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 61 and a light chain variable region having the amino acid sequence of SEQ ID NO: 63.

[0245] • Antibody (GPN15-2) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 77 and a light chain variable region having the amino acid sequence of SEQ ID NO: 79.

[0246] • Antibody (GPN15-3) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 93 and a light chain variable region having the amino acid sequence of SEQ ID NO: 95.

[0247] • Antibody (GPN18-4) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 109 and a light chain variable region having the amino acid sequence of SEQ ID NO: 111.

[0248] • Antibody (GPN18-1) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 125 and a light chain variable region having the amino acid sequence of SEQ ID NO: 127.

[0249] • Antibody (GPN18-2) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 141 and a light chain variable region having the amino acid sequence of SEQ ID NO: 143.

[0250] • Antibody (GPN18-6) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 157 and a light chain variable region having the amino acid sequence of SEQ ID NO: 159.

[0251] • Antibody (GPN18-7) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 173 and a light chain variable region having the amino acid sequence of SEQ ID NO: 175.

[0252] • Antibody (GPN18-5) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 189 and a light chain variable region having the amino acid sequence of SEQ ID NO: 191.

[0253] • Antibody (GPN09-1), which has: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 267 and a light chain variable region having the amino acid sequence of SEQ ID NO: 269.

[0254] Alternatively, as another manufacturing method, a nucleic acid molecule encoding the heavy and / or light chains of an antibody, or more specifically, the heavy and / or light chains of an immunoglobulin, is produced from a hybridoma that generates the desired antibody or from a phage clone obtained through human antibody phage display. Here, a vector or plasmid containing the nucleic acid molecule can also be prepared by introducing the nucleic acid molecule into various vectors or plasmids. Then, a host cell is transformed with the aforementioned nucleic acid molecule, vector, or plasmid. Examples of host cells include eukaryotic cells such as mammalian cells, insect cells, yeast cells, or plant cells, or bacterial cells. Next, the transformed host cell is cultured under suitable conditions for producing the anti-gpNMB specific antibody of the present invention. Here, the obtained anti-gpNMB specific antibody of the present invention can be isolated from the host cell as needed. Various methods for these procedures are well known to those skilled in the art.

[0255] Here, for genes encoding the heavy and / or light chains of immunoglobulins, antibody chimeric proteins, low-molecular-weight antibodies, scaffold antibodies, etc., can be produced by gene modification to introduce the desired trait, or by utilizing the structural information of the variable or CDR regions of the heavy and / or light chains of immunoglobulins. This is something that those skilled in the art can do using well-known techniques. Furthermore, to improve antibody performance or avoid side effects, modifications can be introduced into the constant region structure of the antibody, or modifications can be made to the glycan portion; this can also be appropriately performed using techniques well known to those skilled in the art.

[0256] [Humanized Antibody] According to one embodiment, the anti-gpNMB antibody of the present invention is a humanized antibody. Hereinafter, the humanized anti-gpNMB antibody of the present invention will sometimes be appropriately referred to as "the humanized anti-gpNMB antibody of the present invention" or simply "the humanized antibody of the present invention." Furthermore, "the anti-gpNMB antibody of the present invention" naturally also includes "the humanized anti-gpNMB antibody of the present invention."

[0257] The humanization of the non-humanized anti-gpNMB antibody of the present invention, i.e., the manufacture of the anti-gpNMB humanized antibody of the present invention, can be carried out, for example, through the following procedure.

[0258] That is, based on the amino acid sequence of the non-humanized (e.g., mouse) anti-gpNMB antibody obtained through the aforementioned methods, the CDR region was identified with reference to the numbering of IMGT (Lefranc, M.-P., Pommie, C., Ruiz, M., Giudicelli, V., Foulquier, E., Truong, L., Thouvenin-Contet, V. and Lefranc, G. "IMGT unique numberingfor immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains". Dev. Comp. Immunol., 27, 55-77 (2003) PMID: 12477501 LIGM:268.) and Kabat. The IMGT / Kabat combination method was used to optimally maintain the CDR loop structure. Next, using the CDR transplantation method, a human antibody framework was selected to maintain the CDR loop structure, resulting in antibody variants. Humanized antibodies can be obtained by selecting antibodies from the resulting antibody variants that have the desired binding affinity (e.g., binding affinity to at least one location in the region from the PMEL-CAF-like region to the PKD region of gpNMB).

[0259] Specifically, one human germline gene was selected that most closely resembled the amino acid sequences of the heavy and light chain variable regions of the non-humanized (e.g., mouse) anti-gpNMB antibody obtained through the aforementioned methods. On the other hand, approximately 200 human IgG sequences with high similarity to the heavy and light chain variable regions were selected as candidates using a BLAST search. Then, based on considerations such as scaffold homology, retention of key amino acids in the scaffold, and loop structure, for example, four scaffold sequences were selected. These were then subjected to CDR transplantation to obtain four humanized variants. Additionally, a human germline sequence was used as a scaffold for CDR transplantation to obtain one humanized variant. The resulting five heavy and light chain humanized variants were combined to express and purify 25 humanized antibody variants, and their binding activity was evaluated. By comparing the activity of human chimeric antibodies with mouse heavy and light chains possessing parental antibodies using SPR-based methods, antibodies with a specified (e.g., 3 to 1 / 3) binding affinity were selected, thereby obtaining humanized antibodies.

[0260] As another example, anti-gpNMB antibodies can also be obtained directly from mice that produce human antibodies or from human antibody phage particle libraries, etc., and these anti-gpNMB antibodies recognize at least one of the regions from the PMEL-CAF-like region to the PKD region recognized by the anti-gpNMB antibodies disclosed in this specification.

[0261] There are no limitations on the types of humanized anti-gpNMB monoclonal antibodies obtained by such methods, and the following are some examples. It should be noted that among the following antibodies, the humanized anti-gpNMB monoclonal antibodies (hGPN18-5_H1~H3·L1~L3) containing the heavy chain variable region having the amino acid sequence of SEQ ID NO: 333, SEQ ID NO: 340, or SEQ ID NO: 347 and the light chain variable region having the amino acid sequence of SEQ ID NO: 354, SEQ ID NO: 361, or SEQ ID NO: 368, which are neither disclosed nor implied in existing literature, are equivalent to novel anti-gpNMB antibodies (especially humanized antibodies).

[0262] • Antibody (hGPN06-1_H1L1) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 295 and a light chain variable region having the amino acid sequence of SEQ ID NO: 297.

[0263] • Antibody (hGPN18-2_H2L3) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 323 and a light chain variable region having the amino acid sequence of SEQ ID NO: 325.

[0264] • Antibody (hGPN18-5_H1L1) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 333 and a light chain variable region having the amino acid sequence of SEQ ID NO: 354.

[0265] • Antibody (hGPN18-5_H1L2) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 333 and a light chain variable region having the amino acid sequence of SEQ ID NO: 361.

[0266] • Antibody (hGPN18-5_H1L3) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 333 and a light chain variable region having the amino acid sequence of SEQ ID NO: 368.

[0267] • Antibody (hGPN18-5_H2L1) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 340 and a light chain variable region having the amino acid sequence of SEQ ID NO: 354.

[0268] • Antibody (hGPN18-5_H2L2) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 340 and a light chain variable region having the amino acid sequence of SEQ ID NO: 361.

[0269] • Antibody (hGPN18-5_H2L3) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 340 and a light chain variable region having the amino acid sequence of SEQ ID NO: 368.

[0270] • Antibody (hGPN18-5_H3L1) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 347 and a light chain variable region having the amino acid sequence of SEQ ID NO: 354.

[0271] • Antibody (hGPN18-5_H3L2) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 347 and a light chain variable region having the amino acid sequence of SEQ ID NO: 361.

[0272] • Antibody (hGPN18-5_H3L3) having: a heavy chain variable region having the amino acid sequence of SEQ ID NO: 347 and a light chain variable region having the amino acid sequence of SEQ ID NO: 368.

[0273] [Pharmaceutical Composition] One aspect of the present invention relates to a pharmaceutical composition (hereinafter appropriately referred to collectively as "the pharmaceutical composition of the present invention") for eliminating disease-related cells, comprising the anti-gpNMB specific antibody of the present invention as an active ingredient. That is, by utilizing the anti-gpNMB antibody of the present invention as an active ingredient, the pharmaceutical composition of the present invention can eliminate various disease-related cells. Therefore, the pharmaceutical composition of the present invention can be used to treat or prevent various diseases.

[0274] The disease-related cells that can be cleared by the anti-gpNMB antibody of the present invention are not limited, and examples include senescent cells, cancer-related cells, phagocytes, etc.

[0275] As mentioned above, senescent cells refer to cells whose continuous cell proliferation has ceased due to DNA damage, activation of oncogenes, stress, etc. In recent years, it has been clearly established that senescent cells acquire an inflammatory-promoting phenotype known as SASP (Senescence-associated secretory phenotype), suggesting its association with many diseases (Non-Patent Literature 1). Cellular senescence is considered a mechanism to prevent damaged cells from undergoing malignant transformation and carcinogenesis. On the other hand, there are many reports of its association with various age-related pathologies (tissue degeneration, chronic inflammation, cancer progression, etc.). In addition, particularly as highly malignant senescent cells, examples include senescent infiltrating cells or senescent resident cells that have a significant impact on surrounding cells or tissues, leading to the formation or progression of pathologies.

[0276] Examples of cancer-associated cells include cancer cells, cancer stem cells, precancerous cells, and cancer-infiltrating cells. Examples of cancer-infiltrating cells include cancer-infiltrating macrophages, cancer-infiltrating microglia, myeloid-derived suppressor cells (MDSCs), and cancer-infiltrating dendritic cells.

[0277] Examples of phagocytes include macrophages, microglia, dendritic cells, monocytes, Kupffer cells, Langerhans cells, and osteoclasts, but are not limited to these cell types. Examples of macrophages include cancer-infiltrating macrophages, senescent macrophages, adipose-accumulating macrophages, sphingomyelin-accumulating macrophages, foam cells, alveolar macrophages, peritoneal macrophages, splenic macrophages, and thymic macrophages. Examples of microglia include cancer-infiltrating microglia, senescent microglia, adipose-accumulating microglia, and sphingomyelin-accumulating microglia. Dendritic cells include subtypes such as conventional type 1 dendritic cells (cDC1), conventional type 2 dendritic cells (cDC2), monocyte-derived dendritic cells (MoDC), and plasmacytoid dendritic cells (pDC).

[0278] Examples of diseases involving disease-related cells cleared by the pharmaceutical composition of the present invention include obesity / metabolic diseases (e.g., diabetes, fibrosis, etc.), circulatory system diseases (e.g., cardiomyopathy, arteriosclerosis, etc.), lysosomal stress-related diseases (e.g., lysosomal diseases, etc.), autoimmune diseases (e.g., multiple sclerosis, etc.), and cancers (TNBC (Triple Negative Breast Cancer), melanoma, non-small cell lung cancer, glioblastoma, etc.), but are not limited to these diseases.

[0279] The pharmaceutical compositions of the present invention can be formulated into a pharmaceutical composition form, wherein, in addition to the anti-gpNMB specific antibody of the present invention as the active ingredient, the pharmaceutical composition contains a pharmaceutically acceptable carrier and / or other additives. Formulations using pharmaceutically acceptable carriers and / or other additives can be carried out, for example, by the method described in Philadelphia Institute of Technology, "Remington: The Science and Practice of Pharmacy, 20th Edition", Lippincott Williams & Wilkins, (2000).

[0280] As a form of such therapeutic or preventative agent, it is provided as a liquid or lyophilized preparation made by dissolving, suspending, or emulsifying in a sterile aqueous or oily solution. Examples of aqueous solutions include distilled water for injection and physiological saline. In addition, when osmotic pressure regulators (e.g., D-glucose, D-sorbitol, D-mannitol, sodium chloride, etc.) are added, suitable solubilizing agents may sometimes be used in conjunction, such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants (e.g., polysorbate 80, polyoxyethylene hydrogenated castor oil 50). Furthermore, oily solutions are sometimes used as solvents or solutions; examples of oily solutions include sesame oil and soybean oil, and sometimes benzyl benzoate, benzyl alcohol, etc., are used as solubilizing agents. In such formulations, additives such as buffers (e.g., phosphate buffers, acetate buffers), soothing agents (e.g., benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (e.g., human serum albumin, polyethylene glycol, etc.), preservatives (e.g., ascorbic acid, isoascorbic acid and their salts, etc.), colorants (e.g., copper chlorophyll, β-carotene, Red No. 2, Blue No. 1, etc.), preservatives (e.g., parabens, phenol, benzyl chloride, benzalkonium chloride, etc.), thickeners (e.g., hydroxypropyl cellulose, carboxymethyl cellulose and their salts, etc.), stabilizers (e.g., human serum albumin, mannitol, sorbitol, etc.), and deodorants (e.g., menthol, citrus flavorings, etc.) may be appropriately used.

[0281] In addition, other forms of therapeutic or preventative agents include solid dosage forms such as powders, tablets, granules, capsules, pills, suppositories, and tablet lozenges. In the case of solid dosage forms administered orally, excipients (e.g., crystalline cellulose, lactose, starch, etc.), lubricants (e.g., magnesium stearate, talc, etc.), binders (e.g., hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol (macrogol), etc.), and disintegrants (e.g., starch, calcium carboxymethyl cellulose, etc.) may be used as additives. Furthermore, preservatives (e.g., benzyl alcohol, chlorobutanol, methylparaben, propylparaben, etc.), antioxidants, colorants, sweeteners, etc., may be used as needed. In other forms, therapeutic or preventative agents for mucosal applications may also be cited. These formulations, primarily intended to impart adsorption and retention properties to mucous membranes, sometimes contain adhesives, adhesion enhancers, thickeners, and solubilizers (e.g., mucin, agar, gelatin, pectin, carrageenan, sodium alginate, locust bean gum, xanthan gum, tragacanth gum, gum arabic, chitosan, pullulan, waxy starch, sucralfate, cellulose, and their derivatives) as additives. However, the form, solvent, and additives of the therapeutic or preventative agents provided to organisms are not limited to these, and those skilled in the art can make appropriate selections.

[0282] In addition to the anti-gpNMB specific antibody of the present invention as the active ingredient, the pharmaceutical composition of the present invention may also contain other existing pharmaceutical ingredients. There are no limitations on such other existing pharmaceutical ingredients, and examples include various drugs for treating central nervous system diseases, neurodegenerative diseases, neurological function recovery, and Alzheimer's disease. Specific examples include anti-Tau antibodies, anti-amyloid β antibodies, anti-CD33 antibodies, anti-brain signaling protein 4D antibodies, anti-TNFα antibodies, anti-sortilin antibodies, anti-galactose-specific lectin 3 antibodies, and anti-TREM2 (Triggering receptor expressed on myeloid cells 2) antibodies. These may be used alone or in combination with two or more.

[0283] In addition, the pharmaceutical composition of the present invention can be combined with other existing pharmaceuticals, or it can be formulated into a kit. As an active ingredient in combination with the anti-gpNMB specific antibody of the present invention, other pharmaceuticals (active ingredients) related to the above-mentioned compounding agents can also be mentioned. The dosage of these pharmaceuticals, other than the anti-gpNMB specific antibody, used in the form of compounding agents or kits, can be the dosage used in conventional treatment, but can also be increased or decreased as appropriate.

[0284] To improve symptoms, the pharmaceutical composition of the present invention can be administered parenterally. In the case of parenterally administration, it can be formulated as a nasal preparation, such as a liquid, suspension, or solid form. Alternatively, it can be formulated as an injection; as an injection, options include subcutaneous injection, intravenous injection, drip injection, intramuscular injection, intraventricular injection, or intraperitoneal injection. Other formulations for parenterally administration include suppositories, sublingual preparations, transdermal preparations, and transmucosal preparations other than nasal preparations. Furthermore, it can be administered intravascularly in a manner containing or coated with a stent or intravascular embolizing agent. Depending on the circumstances, it can also be administered in the form of DNA or RNA encoding the antibody, or in the form of cells or resident bacteria that produce the antibody.

[0285] The dosage of the pharmaceutical composition of the present invention varies depending on the patient's age, sex, weight, symptoms, efficacy, method of administration, treatment time, or the type of active ingredient contained in the pharmaceutical composition. Generally, for each adult, the main agent can be administered once every 1 to 4 weeks, or once every 1 to 6 months, at a dose ranging from 0.1 mg to 1 g, preferably from 0.5 mg to 300 mg. However, since the dosage and frequency of administration can vary under various conditions, sometimes a dosage and frequency lower than those described above are sufficient, and sometimes a dosage and frequency exceeding the aforementioned range are required. Furthermore, the therapeutic or preventative agents of the present invention can achieve effects within a shorter administration period or can be administered for a longer period by reducing side effects.

[0286] The target of administration of the pharmaceutical compositions of the present invention is not limited, and can generally be human or non-human animals (e.g., dogs, cats, cattle, horses, sheep, pigs, etc.). Among them, administration to humans is preferred.

[0287] [Disease treatment and prevention] According to the pharmaceutical composition of the present invention, various diseases can be treated or prevented by eliminating disease-related cells associated with various diseases through the action of the anti-gpNMB antibody of the present invention. Examples of treatment and prevention for some specific diseases are described below, but the diseases that can be treated or prevented by the pharmaceutical composition of the present invention are not limited to these, but are applicable to the treatment and prevention of various diseases described above.

[0288] Treatment and prevention of obesity, diabetes, and arteriosclerosis: Obesity, diabetes, and arteriosclerosis can be treated by using the anti-gpNMB antibody of the present invention. Specifically, by administering the antibody of the present invention to wild-type mice or ApoE-KO mice fed a high-fat diet, gpNMB-positive fat-accumulating macrophages can be reduced, thus improving arteriosclerosis. Furthermore, it can improve insulin resistance, inhibit weight gain, and reduce fat accumulation. It can also improve fatty liver.

[0289] Treatment and prevention of fibrosis: gpNMB-positive macrophages present in fibrotic tissues are believed to induce hypercollagen production or be hypercollagen-producing cells. By administering the anti-gpNMB antibody of this invention, which has the activity of clearing gpNMB-positive cells, to fibrotic model mice, gpNMB-positive macrophages in tissues can be cleared, improving fibrotic conditions in various organs. Specifically, by administering the anti-gpNMB antibody to bleomycin or silica models, UUO renal fibrosis models, and liver fibrosis models, fibrosis in organs can be inhibited. In addition, by administering the antibody of this invention to DMD model animals, gpNMB-positive cells in skeletal muscle tissue can be cleared, inhibiting muscle fibrosis or improving muscle quality.

[0290] Cancer treatment and prevention: By administering the antibody of this invention, immunosuppressive macrophages, microglia, dendritic cells, and myeloid-derived suppressor cells (MDSCs) that infiltrate cancer cells can be eliminated, thereby inhibiting cancer cell proliferation and improving survival time and survival rate. Furthermore, by administering this antibody pretreatment or in combination with other treatments, the efficacy of conventional anticancer agents, cancer-targeted therapies, immune checkpoint inhibitors, CAR cell therapy, and other similar treatments can be enhanced.

[0291] For example, in a mouse model of melanoma transplantation, administration of the antibody of the present invention can eliminate macrophages infiltrating cancer cells, inhibit cancer cell proliferation, and improve survival time and survival rate. Furthermore, by using anticancer agents or immune checkpoint inhibitors in combination with the antibody of the present invention, survival time and survival rate can be further improved.

[0292] Treatment of glioblastoma: In a mouse model where glioblastoma is transplanted into the brain, administration of the antibody of this invention can eliminate immunosuppressive microglia or macrophages infiltrating the glioblastoma, inhibiting its proliferation and improving survival time and survival rate. Furthermore, combining the antibody of this invention with anticancer agents such as temozolomide or immune checkpoint inhibitors can further improve survival time and survival rate.

[0293] Treatment of age-related diseases: The accumulation of senescent cells can induce various diseases and accelerate their progression. By using the anti-gpNMB antibody of this invention, senescent cells, which are the primary cause of these diseases, can be specifically eliminated. As a senescent cell scavenger with few side effects, it can treat various diseases and inhibit their progression. For example, specifically, by administering this antibody to mice with a high-fat diet load model exhibiting accelerated aging and senescent cell accumulation, chronic inflammatory conditions were improved, and insulin resistance, fat accumulation, organ fibrosis, and arteriosclerosis were inhibited. Furthermore, in the treatment of diseases accompanied by various chronic inflammations, the efficacy of the original medication can be enhanced by pre-administering or using this antibody concurrently.

[0294] Treatment of lysosomal stress disorder: In lysosomal stress disorders, which are caused by the accumulation of sugars, glycolipids, and proteins in lysosomes due to the deficiency or reduced activity of various lysosomal enzymes, and by decreased cellular function due to stress, some therapeutic effect can be expected by clearing dysfunctional senescent cells. Specifically, by using mouse models with reduced or absent lysosomal enzyme activity and administering this antibody, senescent cells can be cleared, inflammation reduced, and improvement of the condition is expected.

[0295] [other] As described above, when the anti-gpNMB specific antibody of the present invention is administered to humans or other subjects, it exhibits activity in clearing various disease-related cells. Based on this activity, the anti-gpNMB specific antibody of the present invention can be used for the treatment or prevention of various diseases. Therefore, in addition to the pharmaceutical compositions of the present invention described above, several other embodiments can be cited as examples of the objects of the present invention.

[0296] Specifically, one aspect of the present invention relates to a method for eliminating various disease-related cells in a subject by administering an effective amount of the anti-gpNMB specific antibody of the present invention to the subject in need. Another aspect of the present invention relates to a method for treating or preventing various diseases by eliminating various disease-related cells in a subject by administering an effective amount of the anti-gpNMB specific antibody of the present invention to the subject in need. Details of such methods using the antibodies of the present invention are as described above.

[0297] Additionally, one aspect of the invention relates to an anti-gpNMB specific antibody of the present invention for clearing various disease-related cells in a subject. Furthermore, another aspect of the invention relates to an anti-gpNMB specific antibody of the present invention for treating or preventing various diseases by clearing various disease-related cells in a subject. Details of such antibodies of the present invention for specific purposes are as described above.

[0298] Additionally, one aspect of the invention relates to the use of the anti-gpNMB specific antibody of the present invention in the manufacture of a medicament for clearing various disease-related cells in a subject. Another aspect of the invention relates to the use of the anti-gpNMB specific antibody of the present invention in the manufacture of a medicament for treating or preventing various diseases by clearing various disease-related cells in a subject. Details of such antibodies for manufacturing medicaments for specific purposes are as described above.

[0299] Furthermore, the anti-gpNMB specific antibody of the present invention can be used for various purposes. For example, the anti-gpNMB specific antibody of the present invention can be used as an immuno-PET probe for imaging diagnosis of the location and quantity of gpNMB-positive disease-related cells in vivo. Additionally, by using the anti-gpNMB specific antibody of the present invention, either alone or in combination of two or more, to measure specific gpNMB fragments, it is possible to select suitable patient populations for antibody therapy, and it can be used for efficacy assessment, etc. Example

[0300] The present invention will now be described in further detail with reference to embodiments. However, these embodiments are merely examples for illustrative purposes and the present invention is not limited to these embodiments in any way.

[0301] [Standard Operating Procedures] • Antigen ELISA (Enzyme-Linked Immunosorbent Assay): Recombinant soluble human or mouse gpNMB was diluted with PBS to a concentration of 2 μg / mL and added at 50 μL / well to a 96-well plate (Nunc, MaxiSorp), and incubated overnight at 4°C. The 96-well plate was then blocked with 3% BSA / PBS, and the resulting product was used as recombinant soluble gpNMB to immobilize the 96-well plate for ELISA.

[0302] Hybridoma culture supernatant containing anti-gpNMB antibody or 3% BSA / PBS solution was added at 30 μL / well to 96-well plates immobilized with the above recombinant soluble gpNMB and reacted at room temperature for 1 hour. After washing with washing buffer (TBS-T: Tris-buffered saline, 0.025% Tween 20), a solution of antibodies reacting with all isotypes of mouse IgG and anti-mouse IgG antibody-ALP conjugate (SBA, 1050-04) diluted 1000-fold with 3% BSA / PBS was added at 30 μL / well and reacted at room temperature for 1 hour. Substrate (PNPP (p-nitrophenyl phosphate), 1 mg / mL) solution was added at 100 μL / well and reacted at room temperature for 1 hour, and the absorbance from 405 to 550 nm was calculated. The obtained absorbance values ​​were used to evaluate binding activity.

[0303] • Cell-based ELISA: gpNMB-expressing cells were seeded into poly-L-lysine-coated 96-well plates. After adhesion, the culture supernatant was removed, and the cells were fixed in a solution containing 10% formalin at room temperature for 10 minutes. Subsequently, the supernatant was removed, the cells were blocked with 3% BSA / PBS solution, and stored under cold conditions.

[0304] Remove the blocking solution from the obtained cell fixation plates, add 30 μL of antibody-containing culture medium or solution to each well, and incubate at room temperature for approximately 1 hour to 1 hour and 30 minutes. Then, wash 2–4 times with wash buffer (TBS-T), add a 10,000-fold dilution of anti-mouse IgG-HRP-labeled secondary antibody, and incubate at room temperature for 1 hour. Next, wash 2–4 times with wash buffer (TBS-T), add 50 μL of substrate TMB solution to each well, and incubate at room temperature for 30 minutes. Finally, add 50 μL of 1N sulfuric acid to stop the reaction and calculate the absorbance at 450–650 nm. The obtained absorbance values ​​are used to evaluate binding activity.

[0305] • Antibody-dependent phagocytosis (ADCP) assay: AZAMI-GREEN fusion mouse gpNMB-expressing cells or AZAMI-GREEN fusion human gpNMB-expressing cells were seeded in 96-well plates (IWAKI, EZ-VIEW), suspended in medium containing anti-gpNMB antibody, and incubated at 80 μL / well at 37°C and 5% CO2 for 2 hours. Then, 20 μL of phagocytes were added, and the incubation period was 0–12 days at 37°C and 5% CO2. The fluorescence intensity of AZAMI-GREEN was measured under a fluorescence microscope, and the reduction in fluorescence was used to evaluate the cell clearance effect.

[0306] [Example 1] Preparation and screening of mouse or rat monoclonal antibodies (antigen ELISA and cell ELISA): Mouse or rat monoclonal antibodies can be prepared using the hybridoma method described in Koehler et al., Nature, (1975), 256: 495-497. For anti-gpNMB antibodies, mice or rats are immunized with a nucleic acid, protein, or peptide containing a portion or the full length of the amino acid sequence (SEQ ID NO: 209) or nucleic acid sequence (SEQ ID NO: 210) of human gpNMB (isotype a), or the amino acid sequence (SEQ ID NO: 211) or nucleic acid sequence (SEQ ID NO: 212) of mouse gpNMB, and lymphocytes are collected from mice or rats with elevated antibody titers. All animal experiments are performed according to facility guidelines. Standard hybridoma techniques are used to prepare hybridomas based on the fusion of lymphocytes collected from mice or rats with mouse myeloma cell lines (P3U1 (P3X63Ag8U.1) or SP2 / 0 (SP2 / 0-Ag14)). Hybridomas were selected using a so-called HAT medium containing hypoxanthine, aminopterin, and thymidine. It should be noted that the amino acid sequence comparisons of human gpNMB (isotype a) (SEQ ID NO: 209) and mouse gpNMB (SEQ ID NO: 211) are shown below. Figure 1 In the figure, the region from amino acid residue 78 (valine, V78) to the PKD domain is indicated by a dashed line. As an example of a PKD domain, the region from amino acid residues 256 to 319 is indicated by a dashed line. As an example of a PMEL-CAF-like domain, the region from amino acid residues 172 to 246 is indicated by a solid line.

[0307] Using the culture medium of the obtained hybridomas, binding affinity was evaluated using antigen ELISA based on recombinant human soluble gpNMB (SEQ ID NO: 221) or mouse soluble gpNMB (SEQ ID NO: 223) immobilized, and cell ELISA using cells expressing proteins containing human gpNMB (SEQ ID NO: 209). Wells containing positive hybridomas were selected. The hybridomas in these wells were monocloned using a limiting dilution method. The monocloned positive hybridomas were cultured, and the monoclonal antibodies were purified from the culture medium using a protein A column (Ab-Capcher, Protenova) to obtain multiple anti-gpNMB antibodies.

[0308] [Example 2] Determination of antibody sequence: To determine the light and heavy chain gene sequences of each anti-gpNMB antibody clone obtained in Example 1, SMARTer was implemented. (注册商标) RACE method. (Used via SMARTer) (注册商标)RACE (Rapid Enzyme Acquisition and Protection) was used to extract gene fragments containing start and stop codons of the antibody from RNA derived from hybridomas that produce antibodies, and to determine their base sequences. SMARTer was used for this process. (注册商标) The RACE 5' / 3' kit (634859, Clontech) was used to synthesize first-strand cDNA using total RNA from hybridoma as a template, followed by PCR amplification. Using this cDNA as a template, PCR was performed using primers provided with the kit, targeting a universal sequence, as well as primers specific to the heavy and light chains of the antibody. The resulting PCR product was used as the 5'RACE PCR product for TA cloning.

[0309] It should be noted that, regarding the sequencing of rat monoclonal antibody genes, PCR reactions were performed on the variable regions of the heavy and light chains of the rat antibody, and the resulting PCR fragments were bound to the mouse constant region, which were then sequenced as mouse chimeric antibodies.

[0310] In TA cloning, the 5' RACE PCR product was electrophoresed, and the cDNA fragment with the target molecular weight was purified using the QIAEX II gel extraction kit (20021, Qiagen). The purified cDNA was reacted with TaKaRa-Taq (R001A, Takara) at 72°C for 5 minutes, thereby adding adenine to the 3' end. The cDNA fragment was cloned into the pMD20-T vector (hereinafter referred to as the MD20 vector) using the Mighty TA-cloning kit (6028, Takara) according to the attached protocol. The MD20 vector containing the target cDNA was transformed into E. coli TOP10 and cultured on agar medium containing 100 μg / mL ampicillin. The insertion of the target cDNA fragment into the MD20 vector was confirmed by colony PCR. The base sequence of the cloned cDNA fragment was identified. Similarly, the base sequence of the 3' RACE PCR product was identified, and the full-length sequences of each antibody gene were determined.

[0311] In the anti-gpNMB antibody clones obtained in Example 1, the SEQ ID NO of the amino acid and base sequences of each variable region (VH and VL, respectively) of the heavy and light chains, as well as their complementaryness-determining regions (CDR-H1~H3 and CDR-L1~L3, respectively) determined by the above procedure for GPN05-1, GPN06-1, GPN07-1, GPN09-1, GPN11-10, GPN15-2, GPN15-3, GPN18-1, GPN18-2, GPN18-4, GPN18-5, GPN18-6, GPN18-7 and 1-5E, are shown in Tables 1-1 to 1-5.

[0312] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Example 3] Analysis of the binding site of anti-gpNMB antibody (antigen ELISA): To analyze the binding sites of the anti-gpNMB antibodies obtained in Example 1 to human gpNMB protein, the following experiments were performed.

[0313] First, using the amino acid sequence of the extracellular domain of human gpNMB (SEQ ID NO: 215; it should be noted that in this amino acid sequence, amino acid residues from position 1 to 21 constitute the signal peptide, and amino acid residues from position 22 onwards constitute the isolated peptide of the extracellular domain of human gpNMB) as a benchmark, the N-terminal deletion mutant (hgpNMB_d07_76-498) and C-terminal deletion mutant (hgpNMB_d03_1-251, hgpNMB_d04) of the extracellular domain of human gpNMB, as shown in Table 2 below, were prepared. The gene vectors containing the gpNMB gene were: hgpNMB_d05_1-375, hgpNMB_d06_1-418, hgpNMB_d13_1-412, hgpNMB_d14_1-406, hgpNMB_d15_1-400, hgpNMB_d16_1-394, hgpNMB_d17_1-388, hgpNMB_d18_1-382, and hgpNMB_d19_1-234. Transient animal cell expression vectors containing the gpNMB gene were prepared, and the purified gpNMB protein was expressed in culture medium using an Expi293 expression system (A14635, Thermo Fisher Scientific). Subsequently, the purified protein was obtained by affinity purification using Ni-NTA agarose (143-09763, FUJIFILM Wako) with a histidine tag added to the C-terminus.

[0314] [Table 2] Table 2: N-terminal or C-terminal deletion mutants of the extracellular domain of human gpNMB Mutant number illustrate hgpNMB_d03_1-251 C-terminal deletion mutant consisting of hgpNMB 1 to 251 hgpNMB_d04_1-321 C-terminal deletion mutant consisting of hgpNMB 1 to 321 hgpNMB_d05_1-375 C-terminal deletion mutant consisting of hgpNMB 1 to 375 hgpNMB_d06_1-418 C-terminal deletion mutant consisting of hgpNMB 1 to 418 hgpNMB_d07_76-498 N-terminal deletion mutant consisting of hgpNMB 76–498 hgpNMB_d13_1-412 C-terminal deletion mutant consisting of hgpNMB 1 to 412 hgpNMB_d14_1-406 C-terminal deletion mutant consisting of hgpNMB 1 to 406 hgpNMB_d15_1-400 C-terminal deletion mutant consisting of hgpNMB from 1 to 400 hgpNMB_d16_1-394 C-terminal deletion mutant consisting of hgpNMB 1 to 394 hgpNMB_d17_1-388 C-terminal deletion mutant consisting of hgpNMB 1 to 388 hgpNMB_d18_1-382 C-terminal deletion mutant consisting of hgpNMB 1 to 382 hgpNMB_d19_1-234 C-terminal deletion mutant consisting of hgpNMB 1-234 Next, 100 μL / well of purified recombinant human soluble gpNMB (SEQ ID NO: ) was added to each well of a 96-well ELISA plate. 221) The N-terminal deletion mutants (hgpNMB_d07_76-498) and C-terminal deletion mutants (hgpNMB_d03_1-251, hgpNMB_d04_1-321, hgpNMB_d05_1-375, hgpNMB_d06_1-418, hgpNMB_d13_1-412, hgpNMB_d14_1-406, hgpNMB_d15_1-400, hgpNMB_d16_1-394, hgpNMB_d17_1-388, hgpNMB_d18_1-382 and hgpNMB_d19_1-234) of the extracellular domain of human gpNMB shown in Table 2 above, as well as purified recombinant mouse soluble gpNMB (SEQ ID NO: 223), and let stand at room temperature for 90 minutes. Then block with 3% BSA / PBS to prepare antigen ELISA plates.

[0315] After removing the blocking buffer from the antigen ELISA plate, add 50 μL / well of anti-gpNMB antibody dilution buffer (3% BSA / PBS solution) and incubate at room temperature for 1 hour. Then, wash with washing buffer and add 50 μL / well of an antibody specifically reacting with mouse IgG, or an anti-mouse IgG antibody-ALP conjugate (SBA, 1050-04), and incubate at room temperature for 1 hour. Add 100 μL / well of substrate (PNPP), incubate at room temperature for 1 hour, and calculate the absorbance from 405 to 550 nm. The obtained absorbance values ​​are used to evaluate binding activity.

[0316] [Example 4] Identification of epitopes of anti-gpNMB antibody (antigen ELISA): To determine the epitopes of each anti-gpNMB antibody obtained in Example 1 against gpNMB, the following experiments were performed.

[0317] First, the C-terminal deletion mutant (hgpNMB_d19_1-234) and point mutation mutants (hgpNMB_d22_K245A, hgpNMB_d23_D252A, hgpNMB_d24_E253A, hgpNMB_d25_D264A, hgpNMB_d26_H272A, hgpNMB_d28_H297A, hgpNMB_d30_H) of the extracellular domain of human gpNMB, as shown in Table 3 below, were created. Transient animal cell expression vectors containing the gpNMB gene were constructed, and the purified gpNMB protein was expressed in culture medium using the Expi293 expression system (A14635, Thermo Fisher Scientific). Subsequently, the purified protein was obtained by affinity purification using Ni-NTA agarose (143-09763, FUJIFILM Wako) with a histidine tag added to the C-terminus. It should be noted that a summary of these individuals' C-terminal deletion mutants and point mutation mutants of the gpNMB extracellular domain is shown in Table 3.

[0318] [Table 3] Table 3: C-terminal deletion mutants and point mutation mutants of the extracellular domain of human gpNMB Mutant number illustrate hgpNMB_d19_1-234 C-terminal deletion mutant consisting of hgpNMB 1-234 hgpNMB_d22_K245A K245A point mutant of hgpNMB hgpNMB_d23_D252A D252A point mutant of hgpNMB hgpNMB_d24_E253A E253A point mutant of hgpNMB hgpNMB_d25_D264A D264A point mutant of hgpNMB hgpNMB_d26_H272A H272A point mutant of hgpNMB hgpNMB_d28_H297A H297A point mutant of hgpNMB hgpNMB_d30_H376A H376A point mutant of hgpNMB hgpNMBd31_D247A_R248A D247A and R248A point mutants of hgpNMB hgpNMB_d34_D287A D287A point mutant of hgpNMB hgpNMB_d35_H301A H301A point mutant of hgpNMB hgpNMB_d36_R331A_K334A R331A and K334A point mutants of hgpNMB hgpNMB_d37_K344A_D347A K344A and D347A point mutants of hgpNMB hgpNMB_d38_D356A D356A point mutant of hgpNMB hgpNMB_d39_E360A E360A point mutant of hgpNMB hgpNMB_d40_E367A E367A point mutant of hgpNMB hgpNMB_d41_R373A R373A point mutant of hgpNMB Using these human gpNMB extracellular domain alanine point mutants, antigen ELISA analysis was performed using the same procedure as shown in Example 4, and the binding affinity of each anti-gpNMB antibody was evaluated. Specifically, the C-terminal deletion mutant and alanine point mutant of the human gpNMB extracellular domain shown in Table 2 above were each added at a concentration of 17 nmol / L at 100 μL / well to a 96-well ELISA plate and incubated at room temperature for 90 minutes. The plates were then blocked with 3% BSA / PBS to prepare the antigen ELISA plates.

[0319] After removing the blocking buffer from the antigen ELISA plate, 50 μL of anti-gpNMB antibody dilution buffer (3% BSA / PBS solution) was added to each well, and the plate was incubated at room temperature for 1 hour. Following washing with washing buffer, 50 μL of an antibody specifically reacting with mouse IgG, an anti-mouse IgG antibody-ALP conjugate (SBA, 1050-04), was added to each well, and the plate was incubated at room temperature for 1 hour. 100 μL of substrate (PNPP) was added to each well, and the plate was incubated at room temperature for 1 hour. The absorbance from 405 to 550 nm was calculated. The absorbance values ​​were used to evaluate binding activity. At a 2 nM concentration, the absorbance was compared with that of mutants showing the maximum absorbance. Mutants showing a reduction of more than 50% in absorbance were marked as "+", and mutants showing more than 50% absorbance were marked as "-". The results are shown in Table 4 below.

[0320] [Table 4] Table 4: ELISA binding analysis results of various anti-gpNMB antibody clones against human gpNMB extracellular domain mutants Furthermore, using an anti-gpNMB antibody that binds to the C-terminal deletion mutant (hgpNMB_d19_1-234) of the extracellular domain of human gpNMB, the binding of the N-terminal side to the alanine point mutant of the extracellular domain of human gpNMB was similarly analyzed by antigen ELISA.

[0321] First, the C-terminal deletion mutant (hgpNMB_d19_1-234) and point mutation mutants (hgpNMB_d19_1-234, hgpNMB_d43_1-234_R77A, hgpNMB_d44_1-234_D85A, hgpNMB_d45_1-234_R104A, hgpNMB_d47_1-234_E117A, K118A, hgpNMB_d48_1-234_R121A, E123A, hgpNMB_d49_1-234_D129A, hgpNMB_d50_1-234_E14) of the extracellular domain of human gpNMB, as shown in Table 5 below, were created. 0A,D141A,hgpNMB_d51_1-234_D143A,E145A,hgpNMB_d52_1-234_H152A,H153A,hgpNMB_d53_1-234_D158A,K160A,hgpNMB_d54_1-234_H164A,H165A,hgpNMB_d55_1-234_R169A,hgpNMB_d58_1-234_R189A,hgpNMB_d59_1-234_R193A,hgpNMB_d61_1-234_R214A,R215A andhgpNMB_d64_1-234_D109A). A transient animal cell expression vector containing the gpNMB gene was constructed, and the purified gpNMB protein was expressed in culture medium using an Expi293 expression system (A14635, Thermo Fisher Scientific). Subsequently, the purified protein was obtained by affinity purification using Ni-NTA agarose gel (143-09763, FUJIFILM Wako) with a C-terminal histidine tag. It should be noted that a summary of these C-terminal deletion mutants and point mutations of the extracellular domain of gpNMB is shown in Table 5 below.

[0322] [Table 5] Table 5: C-terminal deletion mutants and point mutation mutants of the extracellular domain of human gpNMB Mutant number illustrate hgpNMB_d19_1-234 C-terminal deletion mutant consisting of hgpNMB 1-234 hgpNMB_d43_1-234_R77A R77A point mutants of hgpNMB from 1 to 234 hgpNMB_d44_1-234_D85A D85A point mutants of hgpNMB from 1 to 234 hgpNMB_d45_1-234_R104A R104A point mutants of hgpNMB from 1 to 234 hgpNMB_d47_1-234_E117A, K118A hgpNMB's 1-234 E117A and K118A point mutants hgpNMB_d48_1-234_R121A, E123A R121A and E123A point mutants of hgpNMB from 1 to 234 hgpNMB_d49_1-234_D129A The D129A point mutant of hgpNMB from 1 to 234 hgpNMB_d50_1-234_E140A, D141A hgpNMB's 1-234 E140A and D141A point mutants hgpNMB_d51_1-234_D143A, E145A Point mutants of hgpNMB from 1 to 234: D143A and E145A. hgpNMB_d52_1-234_H152A, H153A H152A and H153A point mutants of hgpNMB from 1 to 234 hgpNMB_d53_1-234_D158A, K160A Point mutants of hgpNMB from 1 to 234: D158A and K160A. hgpNMB_d54_1-234_H164A, H165A H164A and H165A point mutants of hgpNMB from 1 to 234 hgpNMB_d55_1-234_R169A R169A point mutants of hgpNMB from 1 to 234 hgpNMB_d58_1-234_R189A R189A point mutants of hgpNMB from 1 to 234 hgpNMB_d59_1-234_R193A R193A point mutants of hgpNMB from 1 to 234 hgpNMB_d61_1-234_R214A, R215A R214A and R215A point mutants of hgpNMB from 1 to 234 hgpNMB_d64_1-234_D109A D109A point mutants of hgpNMB from 1 to 234 Using these human gpNMB extracellular domain alanine point mutants, antigen ELISA analysis was performed using the same procedure as shown in Example 4, and the binding affinity of each anti-gpNMB antibody was evaluated. Specifically, the C-terminal deletion mutants shown in Table 5 above and each gpNMB alanine point mutant were added at a concentration of 17 nmol / L at 100 μL / well to 96-well ELISA plates and incubated at room temperature for 90 minutes. The plates were then blocked with 3% BSA / PBS to prepare the antigen ELISA plates.

[0323] The blocking buffer in the antigen ELISA plate was removed, and 50 μL / well of anti-gpNMB antibody dilution buffer (3% BSA / PBS solution) was added, and the plate was incubated at room temperature for 1 hour. After washing with washing buffer, 50 μL / well of an antibody specifically reacting with mouse IgG, an anti-mouse IgG antibody-ALP conjugate (SBA, 1050-04), was added, and the plate was incubated at room temperature for 1 hour. 100 μL / well of substrate (PNPP) was added, and the plate was incubated at room temperature for 1 hour, and the absorbance from 405 to 550 nm was calculated. The absorbance values ​​were used to evaluate binding activity. The results are shown in Table 6 below (Note that, as described above, in the amino acid sequence shown in SEQ ID NO: 215, amino acid residues 1-21 constitute the signal peptide, and amino acid residues from position 22 onwards constitute the separating peptide of the human gpNMB extracellular domain. Meanwhile, the mutant proteins shown in Table 6 below also begin at amino acid residue 22). The binding activity to the C-terminal deletion mutant (hgpNMB_d19_22-234) was set to 100%. Cases with binding activity below 50% were marked as "+", and cases maintaining binding activity above 50% were marked as "-".

[0324] [Table 6] Table 6: ELISA binding analysis results of various anti-gpNMB antibody clones against human gpNMB extracellular domain mutants Considering the stability of purified gpNMB mutants and the mutation sites that affect binding, the epitopes of each anti-gpNMB antibody were determined.

[0325] The results clarified that antibody clones GPN18-1, GPN18-2, GPN18-6, and GPN18-7 interact with amino acids (R214 and / or R215) present in the PMEL-CAF-like region. Furthermore, it was determined that antibody clone GPN18-5 also recognizes the N-terminal portion. Antibody clones 1-5E are anti-gpNMB antibodies obtained by immunization with the vaccine peptide described in the paper (Non-Patent Document 36), recognizing the epitope "RRGDGRWKD" at amino acid residues 63-71 of the N-terminus.

[0326] [Example 5] Manufacturing recombinant anti-gpNMB antibody: A plasmid was created by inserting a signal sequence encoding gene sequence into the 5' end of both the H-chain and L-chain coding gene sequences of the anti-gpNMB antibody obtained in Example 2. This plasmid was then inserted into the animal cell expression vector pcDNA3.4. Transient expression was performed using the ExpiCHO expression system (A29133, Thermo Fisher Scientific), resulting in antibody secretion into the culture medium. The culture supernatant was then recovered and purified using a Protein A column (Ab-Capcher, Protenova) and a gel filtration column (Superdex 200 Increase, Cytiva).

[0327] [Example 6] Interaction analysis of anti-gpNMB antibodies based on surface plasmon resonance method 1: To compare the binding characteristics (binding rate and dissociation rate) of the various anti-gpNMB antibody clones obtained in Example 1 to gpNMB, the measurements were performed using surface plasmon resonance (SPR) assay. Specifically, the assay was performed under the conditions described below.

[0328] The BIACORE T200 system was used as the assay system. Approximately 5000 RU of anti-His monoclonal antibody was immobilized in all flow cells of the CM5 sensor chip (BR-1005-30, Cytiva) using an amino-conjugation kit (BR-1000-50, GE) and a His capture kit (28-9950-56, Cytiva). HBS-EP+ (BR-1006-69, Cytiva) was used as the run buffer.

[0329] Recombinant human gpNMB-FLAG-His (SEQ ID NO: 221) or recombinant mouse gpNMB-FLAG-His (SEQ ID NO: 223) was captured and used as ligands in the assay system. As an analyte, an anti-gpNMB antibody clone at a concentration of 100 nmol / L was used. As negative controls for the analyte, Shiga toxin 2 antibody (11E10) or control mouse IgG1 (leinco: Pro # M1411) was used.

[0330] The temperature of the assay system was set to 25°C. Recombinant human gpNMB-FLAG-His was reacted with the anti-His monoclonal antibody in flow cell (2) as a ligand, with a target of less than 100 RU. Recombinant mouse gpNMB-FLAG-His was reacted with the anti-His monoclonal antibody in flow cell (4), with a target of less than 100 RU. The flow rate was set to 20 μL / min, and 10 nmol / L purified mouse IgG2a, κ, Isotype Ctrl (isotype control), and clone: ​​MG2a-53 (401502, BioLegend, hereinafter referred to as ctrlIgG2a) were reacted for 1 minute, followed by HBS-EP+ flow for at least 10 minutes. The analytes were diluted with HBS-EP+ (100 nmol / L) and reacted in each flow cell for 600 seconds to obtain binding curves. Then, HBS-EP+ was reacted for 600 seconds to obtain dissociation curves.

[0331] After the reaction was complete, regeneration buffer 1 (0.2% SDS), regeneration buffer 2 (100 mmol / L Tris-HCl (pH 8.5), 1 mol / L NaCl, 15 mmol / L MgCl2), and regeneration buffer 3 (10 mmol / L glycine-HCl (pH 1.5)) were each allowed to react for 1 minute to remove gpNMB-FLAG-His from the assay system and to wash the system. The Biacore T200 evaluation software (version 2.0) was used for analysis using a 1:1 binding model. The binding rate (Ass: 1 / Ms), binding stability (Diss: 1 / s), and equilibrium dissociation (Diss / Ass: M) values ​​were quantified as ordinal numbers. The results are shown in Table 7.

[0332] [Table 7] Table 7: SPR interaction analysis results of various anti-gpNMB antibody clones against human gpNMB and mouse gpNMB 1 [Example 7 (1)] The cell clearance capacity of human gpNMB-expressing cells was evaluated by adding anti-gpNMB antibody (cell clearance). (Except for inducing activity): The clearance capacity of human gpNMB-expressing cells based on the various anti-gpNMB antibody clones (GPN15-2, GPN15-3, GPN18-2, GPN18-5) obtained in Example 1 was evaluated. Specifically, AZAMI-GREEN fusion human gpNMB-expressing cells were used at a concentration of 7 × 10⁻⁶ cells / year. 5 Cells were seeded in 96-well plates (IWAKI, EZ-VIEW) and suspended in medium containing anti-gpNMB antibody at a total concentration of 80 μL / well. The reaction was carried out at 37°C and 5% CO2 for 2 hours. Cells were then further incubated at 8 × 10⁻⁶ cells / well. 3Cells were added to each well with 20 μL of phagocytes and cultured at 37°C and 5% CO2 for 6–7 days. Antibody concentration was evaluated at a final concentration of 100 nM. The fluorescence intensity of AZAMI-GREEN was measured under a fluorescence microscope (au = arbitrary unit), and the decrease in fluorescence was used to evaluate cell clearance induction activity. It should be noted that comparisons were made with the non-Azami-Green fusion human gpNMB expression cell group (Non) and the control mouse IgG-added group (NC IgG).

[0333] The results are shown in Figure 2 The results, as shown in the figure, confirmed the clearance-inducing activity of human gpNMB-expressing cells for antibodies GPN15-2 and GPN15-3 that recognize the PKD region, antibody GPN18-2 that recognizes the PMEL-CAF-like region, and antibody GPN18-5 that recognizes the region from V78 to S92.

[0334] [Example 7 (2)] The ability of mouse gpNMB-expressing cells to clear cells was evaluated by adding anti-gpNMB antibody. Scavenging inducible activity): The clearance capacity of mouse gpNMB-expressing cells based on two anti-gpNMB antibody clones (GPN18-5 and 1-5E) that recognize the N-terminal region obtained in Example 1 was evaluated. Specifically, AZAMI-GREEN fusion mouse gpNMB-expressing cells were used at a concentration of 7 × 10⁻⁶ cells / year. 5 Cells were seeded in 96-well plates (IWAKI, EZ-VIEW) and suspended in medium containing anti-gpNMB antibody at a total concentration of 80 μL / well. The reaction was carried out at 37°C and 5% CO2 for 2 hours. Cells were then further incubated at 8 × 10⁻⁶ cells / well. 3 Cells were added to each well with 20 μL of phagocytes and cultured at 37°C and 5% CO2 for 6–7 days. Antibody concentration was evaluated at a final concentration of 100 nM. The fluorescence intensity of AZAMI-GREEN was measured under a fluorescence microscope (au = arbitrary units), and the decrease in fluorescence was used to evaluate cell clearance induction activity. It should be noted that comparisons were made with the control mouse IgG-added group (NC IgG).

[0335] The results are shown in Figure 3 The results, as shown in the chart, indicate that among the two anti-gpNMB antibodies recognizing the N-terminal region, compared with antibody 1-5E, which is a vaccine peptide antibody, antibody GPN18-5, which recognizes the region from V78 to S92, showed stronger mouse gpNMB-expressing cell clearance induction activity.

[0336] [Example 8] Humanization design of mouse anti-gpNMB antibody: GPN06-1: Based on the amino acid sequence of the anti-gpNMB antibody GPN06-1, the CDR region was identified with reference to IMGT (Lefranc, M.-P., Pommie, C., Ruiz, M., Giudicelli, V., Foulquier, E., Truong, L., Thouvenin-Contet, V. and Lefranc, G. "IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains". Dev. Comp. Immunol., 27, 55-77 (2003) PMID: 12477501 LIGM: 268.) and Kabat numbering. The CDR loop structure was optimally maintained using a combination of IMGT and Kabat.

[0337] <Reinforced Humanized Design> The human germline gene most closely related to the amino acid sequence of the mouse heavy chain variable region (GPN06-1_VH) (SEQ ID NO: 29) is IGHV1-46*01. On the other hand, using a BLAST search, 200 human IgG sequences with high similarity to GPN06-1_VH were selected as candidates. Subsequently, based on considerations such as scaffold homology, preservation of key amino acids within the scaffold, and loop structure, four scaffold sequences were ultimately selected. CDR transplantation was performed on these sequences, resulting in humanized mutant sequences hGPN06-1_VH1, hGPN06-1_VH2, hGPN06-1_VH3, and hGPN06-1_VH4. Additionally, CDR transplantation was performed using the IGHV1-46*01 sequence as a scaffold, and the resulting sequence was designated as the humanized mutant sequence hGPN06-1_VH5. The alignment of these humanized mutant sequences hGPN06-1_VH1~VH5 with mouse GPN06-1_VH is shown in the figure. Figure 4 The underlined portions represent the identified CDR regions. Additionally, Table 8 shows the identity and similarity between these humanized mutant sequences hGPN06-1_VH1–VH5 and the mouse sequence GPN06-1_VH. When the humanized mutant sequences hGPN06-1_VH1–VH5 are arranged in descending order of identity and similarity to the mouse GPN06-1_VH, the order is VH3 = VH5 > VH2 > VH1 > VH4.

[0338] [Table 8] Table 8: Identity and similarity between humanized mutant sequences hGPN06-1_VH1~VH5 and mouse sequence GPN06-1_VH <Lightweight Chain Humanized Design> The human germline gene most closely related to the amino acid sequence of the mouse light chain variable region (GPN06-1_VL) (SEQ ID NO: 31) is IGKV1-9*01. On the other hand, using a BLAST search, 200 human IgK sequences with high similarity to GPN06-1_VL were selected as candidates. Subsequently, based on considerations such as scaffold homology, preservation of key amino acids within the scaffold, and loop structure, four scaffold sequences were ultimately selected. CDR transplantation was performed on these sequences, resulting in the humanized mutant sequences hGPN06-1_VL1, hGPN06-1_VL2, hGPN06-1_VL3, and hGPN06-1_VL4. Additionally, CDR transplantation was performed using the IGKV1-9*01 sequence as a scaffold, and the resulting sequence was designated as the humanized mutant sequence hGPN06-1_VL5. The alignment of these humanized mutant sequences hGPN06-1_VL1~VL5 with mouse GPN06-1_VL is shown in the figure. Figure 5 The underlined portions represent the identified CDR regions. Additionally, Table 9 shows the identity and similarity between these humanized mutant sequences hGPN06-1_VL1–VL5 and the mouse sequence GPN06-1_VL. When the humanized mutant sequences hGPN06-1_VL1–VL5 are arranged in descending order of i...

Claims

1. A pharmaceutical composition for eliminating disease-associated cells, comprising an anti-gpNMB antibody or a fragment thereof or a derivative thereof specifically binding to at least one location in a region from V78 to the PKD domain of human gpNMB (glycoprotein nonmetastatic melanoma protein B), said human gpNMB having the amino acid sequence of SEQ ID NO:

209.

2. The pharmaceutical composition according to claim 1, wherein, The anti-gpNMB antibody specifically binds to the region of human gpNMB containing amino acid residues D287 and / or H301, the human gpNMB having the amino acid sequence SEQ ID NO:

209.

3. The pharmaceutical composition according to claim 1 or 2, wherein, The anti-gpNMB antibody specifically binds to the region of human gpNMB containing amino acid residues R214 and / or R215, the human gpNMB having the amino acid sequence SEQ ID NO:

209.

4. The pharmaceutical composition according to claim 2 or 3, wherein, The anti-gpNMB antibody also specifically binds to one or more of the following regions of human gpNMB: a region containing amino acid residues K257 and / or D258, a region containing amino acid residues H268 and / or D269, a region containing amino acid residues K282, a region containing amino acid residues K316, a region containing amino acid residues K186, and a region containing amino acid residues H216 and / or R218, wherein the human gpNMB has the amino acid sequence SEQ ID NO:

209.

5. The pharmaceutical composition according to claim 1, wherein, The anti-gpNMB antibody specifically binds to at least one of the regions from V78 to S92 of human gpNMB, which has the amino acid sequence of SEQ ID NO:

209.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein, The anti-gpNMB antibody also specifically binds to at least one location in the region from V78 to the PKD domain of mouse gpNMB, which has the amino acid sequence of SEQ ID NO:

211.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein, The anti-gpNMB antibody is a monoclonal antibody or a fragment thereof or a derivative thereof.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein, The anti-gpNMB antibody comprises at least a heavy chain variable region, and the heavy chain variable region has: (1) As CDR-H1, it is the amino acid sequence described in SEQ ID NO: 1, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 1, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

1. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 3, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 3, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

3. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 5, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 5, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 75.0%, 83.3%, or 91.6% or more to the amino acid sequence described in SEQ ID NO: 5; or (2) As CDR-H1, the amino acid sequence described in SEQ ID NO: 17, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 17, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

17. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 19, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 19, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO:

19. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 21, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 21, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 21; or (3) As CDR-H1, the amino acid sequence described in SEQ ID NO: 33, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 33, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

33. As CDR-H2, the amino acid sequence described in SEQ ID NO: 35, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 35, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 35, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 37, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 37, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 37; or (4) As CDR-H1, the amino acid sequence described in SEQ ID NO: 49, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 49, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

49. As CDR-H2, the amino acid sequence described in SEQ ID NO: 51, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 51, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 51, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 53, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 53, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 68.7%, 75.0%, 81.2%, 87.5%, or 93.7% or more to the amino acid sequence described in SEQ ID NO: 53; or (5) As CDR-H1, the amino acid sequence described in SEQ ID NO: 65, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 65, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

65. As CDR-H2, the amino acid sequence described in SEQ ID NO: 67, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 67, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 67, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 69, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, or five amino acid residues in the amino acid sequence described in SEQ ID NO: 69, or an amino acid sequence having a similarity (preferably identical) of 64.2%, 71.4%, 78.5%, 85.7%, or 92.8% or more to the amino acid sequence described in SEQ ID NO: 69; or (6) As CDR-H1, the amino acid sequence described in SEQ ID NO: 81, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 81, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

81. As CDR-H2, the amino acid sequence described in SEQ ID NO: 83, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 83, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 83, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 85, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 85, or an amino acid sequence having a similarity (preferably identical) of 63.6%, 72.7%, 81.8%, or 90.9% or more to the amino acid sequence described in SEQ ID NO: 85; or (7) As CDR-H1, the amino acid sequence described in SEQ ID NO: 97, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 97, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

97. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 99, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 99, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO:

99. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 101, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 101, or an amino acid sequence having 60.0% or more or 80.0% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 101; or (8) As CDR-H1, the amino acid sequence described in SEQ ID NO: 113, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 113, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

113. As CDR-H2, the amino acid sequence described in SEQ ID NO: 115, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 115, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 115, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 117, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 117, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 117; or (9) As CDR-H1, the amino acid sequence described in SEQ ID NO: 129, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 129, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

129. As CDR-H2, the amino acid sequence described in SEQ ID NO: 131, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 131, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 131, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 133, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 133, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 133; or (10) As CDR-H1, the amino acid sequence described in SEQ ID NO: 145, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 145, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

145. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 147, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 147, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

147. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 149, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 149, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 149; or (11) As CDR-H1, the amino acid sequence described in SEQ ID NO: 161, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 161, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

161. As CDR-H2, the amino acid sequence described in SEQ ID NO: 163, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 163, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 163, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 165, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 165, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 165; or (12) As CDR-H1, the amino acid sequence described in SEQ ID NO: 255, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 255, or an amino acid sequence having 62.5% or more, 75.0% or more, or 87.5% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

255. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 257, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 257, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

257. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 259, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 259, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 259; or (13) As CDR-H1, the amino acid sequence described in SEQ ID NO: 283, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 283, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

283. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 285, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 285, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO:

285. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 287, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 287, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 287; or (14) As CDR-H1, the amino acid sequence described in SEQ ID NO: 311, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 311, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

311. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 313, or an amino acid sequence formed by substituting, deleting, or inserting any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 313, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

313. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 315, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 315, or an amino acid sequence having a similarity (preferably identical) of 60.0%, 66.6%, 73.3%, 80.0%, 86.6%, or 93.3% or more to the amino acid sequence described in SEQ ID NO: 315; or (15) As the CDR transplantation region-H1, an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 271, except for tyrosine at position 27, asparagine at position 32, and tryptophan at position 33. As the CDR transplantation region -H2, it is an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 273, except for aspartic acid at position 55, phenylalanine at position 57, threonine at position 58, asparagine at position 59, tyrosine at position 60, and asparagine at position 61. As the CDR transplantation region -H3, it is an amino acid sequence described in SEQ ID NO: 275, or an amino acid sequence described in SEQ ID NO: 275 in which any one, two, three, four, five, or six amino acid residues other than arginine at position 98, glycine at position 100, and glycine at position 109 are substituted, deleted, or inserted; or (16) As the CDR transplantation region-H1, an amino acid sequence formed by the substitution, deletion or insertion of any one, two, three or four amino acid residues in the amino acid sequence described in SEQ ID NO:

299. As the CDR transplantation region -H2, it is an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 301, except for aspartic acid at position 52, tryptophan at position 54, aspartic acid at position 58, and proline at position 63. As the CDR transplantation region -H3, it is an amino acid sequence consisting of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 303, excluding arginine at position 99, threonine at position 100, tyrosine at position 102, tyrosine at position 105, tyrosine at position 107, and methionine at position 110, formed by substitution, deletion, or insertion; or (17) As CDR-H1, the amino acid sequence described in SEQ ID NO: 177, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 177, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

177. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 179, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 179, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO:

179. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 181, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 181, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 181; or (18) As CDR-H1, the amino acid sequence described in SEQ ID NO: 330, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 330, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

330. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 331, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 331, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO:

331. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 332, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 332, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 332; or (19) As CDR-H1, the amino acid sequence described in SEQ ID NO: 337, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 337, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

337. As CDR-H2, the amino acid sequence described in SEQ ID NO: 338, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 338, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 338, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 339, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 339, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 339; or (20) As CDR-H1, the amino acid sequence described in SEQ ID NO: 344, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 344, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

344. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 345, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 345, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO:

345. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 346, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 346, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 346; or (21) As the CDR transplantation region -H1, the amino acid sequence described in SEQ ID NO: 327, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 327, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

327. As the CDR transplantation region -H2, it is the amino acid sequence described in SEQ ID NO: 328, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 328, or an amino acid sequence having a similarity (preferably identical) of 64.7%, 70.5%, 76.4%, 82.3%, 88.2%, or 94.1% or more to the amino acid sequence described in SEQ ID NO:

328. As the CDR transplantation region -H3, it is the amino acid sequence described in SEQ ID NO: 329, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 329, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 329; or (22) As the CDR transplantation region -H1, the amino acid sequence described in SEQ ID NO: 334, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 334, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

334. As the CDR transplantation region -H2, it is the amino acid sequence described in SEQ ID NO: 335, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 335, or an amino acid sequence having a similarity (preferably identical) of 64.7%, 70.5%, 76.4%, 82.3%, 88.2%, or 94.1% or more to the amino acid sequence described in SEQ ID NO:

335. As the CDR transplantation region -H3, it is the amino acid sequence described in SEQ ID NO: 336, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 336, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 336; or (23) As the CDR transplantation region -H1, the amino acid sequence described in SEQ ID NO: 341, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 341, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

341. As the CDR transplantation region -H2, it is the amino acid sequence described in SEQ ID NO: 342, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 342, or an amino acid sequence having a similarity (preferably identical) of 64.7%, 70.5%, 76.4%, 82.3%, 88.2%, or 94.1% or more to the amino acid sequence described in SEQ ID NO:

342. As the CDR transplantation region -H3, it is the amino acid sequence described in SEQ ID NO: 343, or an amino acid sequence formed by replacing, deleting, or inserting any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 343, or an amino acid sequence having more than 66.6% or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

343.

9. The pharmaceutical composition according to any one of claims 1 to 7, wherein, The anti-gpNMB antibody comprises at least a heavy chain variable region, and the heavy chain variable region has: (1) The amino acid sequence described in SEQ ID NO: 13, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 13; or (2) The amino acid sequence described in SEQ ID NO: 29, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 29; or (3) The amino acid sequence described in SEQ ID NO: 45, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 45; or (4) The amino acid sequence described in SEQ ID NO: 61, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 61; or (5) The amino acid sequence described in SEQ ID NO: 77, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 77; or (6) The amino acid sequence described in SEQ ID NO: 93, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 93; or (7) The amino acid sequence described in SEQ ID NO: 109, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 109; or (8) The amino acid sequence described in SEQ ID NO: 125, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 125; or (9) The amino acid sequence described in SEQ ID NO: 141, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 141; or (10) The amino acid sequence described in SEQ ID NO: 157, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 157; or (11) The amino acid sequence described in SEQ ID NO: 173, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 173; or (12) The amino acid sequence described in SEQ ID NO: 267, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 267; or (13) The amino acid sequence described in SEQ ID NO: 295, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 295; or (14) The amino acid sequence described in SEQ ID NO: 323, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 323; or (17) The amino acid sequence described in SEQ ID NO: 189, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 189; or (18) The amino acid sequence described in SEQ ID NO: 333, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 333; or (19) The amino acid sequence described in SEQ ID NO: 340, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 340; or (20) The amino acid sequence described in SEQ ID NO: 347, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO:

347.

10. The pharmaceutical composition according to claim 8 or 9, wherein, The heavy chain variable region contains a framework sequence of any class of human immunoglobulins as the framework sequence.

11. The pharmaceutical composition according to any one of claims 8 to 10, wherein, The anti-gpNMB antibody further comprises a heavy chain constant region, and the heavy chain constant region has the amino acid sequence of the heavy chain constant region of any class of human immunoglobulins.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein, The anti-gpNMB antibody comprises at least a light chain variable region, and the light chain variable region has: (1) As CDR-L1, it is the amino acid sequence described in SEQ ID NO: 7, or an amino acid sequence formed by substituting, deleting, or inserting any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 7, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

7. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 9, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 9, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

9. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 11, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 11, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 11; or (2) As CDR-L1, the amino acid sequence described in SEQ ID NO: 23, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 23, or an amino acid sequence having 60.0% or more or 80.0% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

23. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 25, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 25, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

25. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 27, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 27, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 27; or (3) As CDR-L1, the amino acid sequence described in SEQ ID NO: 39, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 39, or an amino acid sequence having 60.0% or more or 80.0% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

39. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 41, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 41, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

41. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 43, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 43, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 43; or (4) As CDR-L1, the amino acid sequence described in SEQ ID NO: 55, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 55, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

55. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 57, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 57, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

57. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 59, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 59, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 59; or (5) As CDR-L1, the amino acid sequence described in SEQ ID NO: 71, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 71, or an amino acid sequence having 60.0% or more or 80.0% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

71. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 73, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 73, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 73, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 75, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 75, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 75; or (6) As CDR-L1, the amino acid sequence described in SEQ ID NO: 87, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 87, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

87. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 89, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 89, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 89, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 91, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 91, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 91; or (7) As CDR-L1, the amino acid sequence described in SEQ ID NO: 103, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 103, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

103. As CDR-L2, the amino acid sequence described in SEQ ID NO: 105, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 105, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 105, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 107, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 107, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 107; or (8) As CDR-L1, the amino acid sequence described in SEQ ID NO: 119, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 119, or an amino acid sequence having a similarity (preferably identical) of 63.6%, 72.7%, 81.8%, or 90.9% or more to the amino acid sequence described in SEQ ID NO:

119. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 121, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 121, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

121. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 123, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 123, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 123; or (9) As CDR-L1, the amino acid sequence described in SEQ ID NO: 135, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 135, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

135. As CDR-L2, the amino acid sequence described in SEQ ID NO: 137, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 137, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 137, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 139, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 139, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 139; or (10) As CDR-L1, the amino acid sequence described in SEQ ID NO: 151, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 151, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

151. As CDR-L2, the amino acid sequence described in SEQ ID NO: 153, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 153, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 153, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 155, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 155, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 155; or (11) As CDR-L1, the amino acid sequence described in SEQ ID NO: 167, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 167, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

167. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 169, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 169, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 169, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 171, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 171, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 171; or (12) As CDR-L1, it is the amino acid sequence described in SEQ ID NO: 261, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 261, or an amino acid sequence having a similarity (preferably identical) of 63.6%, 72.7%, 81.8%, or 90.9% or more to the amino acid sequence described in SEQ ID NO:

261. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 263, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 263, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 263, and As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 265, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 265, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 265; or (13) As CDR-L1, the amino acid sequence described in SEQ ID NO: 289, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 289, or an amino acid sequence having 60.0% or more or 80.0% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

289. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 291, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 291, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

291. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 293, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 293, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 293; or (14) As CDR-L1, the amino acid sequence described in SEQ ID NO: 317, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 317, or an amino acid sequence having a similarity (preferably identical) of 63.6%, 72.7%, 81.8%, or 90.9% or more to the amino acid sequence described in SEQ ID NO:

317. As CDR-L2, the amino acid sequence described in SEQ ID NO: 319, or an amino acid sequence formed by substitution, deletion, or insertion of any amino acid residue in the amino acid sequence described in SEQ ID NO: 319, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 319, and, As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 321, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 321, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 321; or (15) As the CDR transplantation region-L1, an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 277, except for isoleucine at position 29, tyrosine at position 31, and histidine at position 33. As the CDR transplantation region -L2, it is an amino acid sequence formed by the substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 279, except for threonine at position 50. As the CDR transplantation region - L3, the amino acid sequence described in SEQ ID NO: 281, or the amino acid sequence described in SEQ ID NO: 281, wherein any one, two, or three amino acid residues other than histidine at position 88, glutamine at position 89, tryptophan at position 90, serine at position 92, tyrosine at position 93, proline at position 94, and cysteine ​​at position 95 are replaced, deleted, or inserted; or (16) As the CDR transplantation region-L1, an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 305, except for leucine at position 31, tyrosine at position 37, and glutamic acid at position 39. As the CDR transplantation region -L2, it is an amino acid sequence formed by the substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 307, except for lysine at position 55. As the CDR transplantation region - L3, the amino acid sequence described in SEQ ID NO: 309, or the amino acid sequence described in SEQ ID NO: 309, wherein any one, two, or three amino acid residues other than phenylalanine at position 94 are replaced, deleted, or inserted; or (17) As CDR-L1, the amino acid sequence described in SEQ ID NO: 183, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 183, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

183. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 185, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 185, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

185. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 187, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 187, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 187; or (18) As CDR-L1, the amino acid sequence described in SEQ ID NO: 351, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 351, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

351. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 352, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 352, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

352. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 353, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 353, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 353; or (19) As CDR-L1, the amino acid sequence described in SEQ ID NO: 358, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 358, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

358. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 359, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 359, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

359. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 360, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 360, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 360; or (20) As CDR-L1, the amino acid sequence described in SEQ ID NO: 365, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 365, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

365. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 366, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 366, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

366. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 367, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 367, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 367; or (21) As the CDR transplantation region-L1, the amino acid sequence described in SEQ ID NO: 348, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 348, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

348. As the CDR transplantation region -L2, it is the amino acid sequence described in SEQ ID NO: 349, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 349, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

349. As the CDR transplantation region -L3, it is the amino acid sequence described in SEQ ID NO: 350, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 350, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 350; or (22) As the CDR transplantation region-L1, the amino acid sequence described in SEQ ID NO: 355, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 355, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

355. As the CDR transplantation region -L2, it is the amino acid sequence described in SEQ ID NO: 356, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 356, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

356. As the CDR transplantation region -L3, it is the amino acid sequence described in SEQ ID NO: 357, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 357, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 357; or (23) As the CDR transplantation region-L1, the amino acid sequence described in SEQ ID NO: 362, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 362, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

362. As the CDR transplantation region -L2, it is the amino acid sequence described in SEQ ID NO: 363, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 363, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

363. As the CDR transplantation region -L3, it is the amino acid sequence described in SEQ ID NO: 364, or an amino acid sequence formed by the substitution, deletion or insertion of any one, two or three amino acid residues in the amino acid sequence described in SEQ ID NO: 364, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7% or more or 88.8% or more to the amino acid sequence described in SEQ ID NO:

364.

13. The pharmaceutical composition according to any one of claims 1 to 11, wherein, The anti-gpNMB antibody comprises at least a light chain variable region, and the light chain variable region has: (1) The amino acid sequence described in SEQ ID NO: 15, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 15; or (2) The amino acid sequence described in SEQ ID NO: 31, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 31; or (3) The amino acid sequence described in SEQ ID NO: 47, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 47; or (4) The amino acid sequence described in SEQ ID NO: 63, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 63; or (5) The amino acid sequence described in SEQ ID NO: 79, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 79; or (6) The amino acid sequence described in SEQ ID NO: 95, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 95; or (7) The amino acid sequence described in SEQ ID NO: 111, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 111; or (8) The amino acid sequence described in SEQ ID NO: 127, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 127; or (9) The amino acid sequence described in SEQ ID NO: 143, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 143; or (10) The amino acid sequence described in SEQ ID NO: 159, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 159; or (11) The amino acid sequence described in SEQ ID NO: 175, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 175; or (12) The amino acid sequence described in SEQ ID NO: 269, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 269; or (13) The amino acid sequence described in SEQ ID NO: 297, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 297; or (14) The amino acid sequence described in SEQ ID NO: 325, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 325; or (17) The amino acid sequence described in SEQ ID NO: 191, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 191; or (18) The amino acid sequence described in SEQ ID NO: 354, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 354; or (19) The amino acid sequence described in SEQ ID NO: 361, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 361; or (20) The amino acid sequence described in SEQ ID NO: 368, or an amino acid sequence that has more than 60% similarity to the amino acid sequence described in SEQ ID NO:

368.

14. The pharmaceutical composition according to claim 12 or 13, wherein, The light chain variable region contains a framework sequence of any class of human immunoglobulins as the framework sequence.

15. The pharmaceutical composition according to any one of claims 12 to 14, wherein, The anti-gpNMB antibody further comprises a light chain constant region, and the light chain constant region has the amino acid sequence of a light chain constant region of any class of human immunoglobulins.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein, The anti-gpNMB antibody is Fab, scFv, biantibody, nanobody, VHH, bispecific antibody, or multispecific antibody, or derivatives thereof.

17. A pharmaceutical composition for clearing disease-associated cells, comprising an anti-gpNMB antibody or a fragment thereof or a derivative thereof, said anti-gpNMB antibody or a fragment thereof or a derivative thereof binding to at least one of the regions from V78 to the PKD domain of human gpNMB (glycoprotein nonmetastatic melanoma protein B) having the amino acid sequence of SEQ ID NO:209, said binding being competitive with the binding of the anti-gpNMB antibody or a fragment thereof or a derivative thereof according to any one of claims 1 to 16.

18. A pharmaceutical composition for eliminating disease-related cells, comprising: A nucleic acid molecule consisting of a polynucleotide sequence encoding an anti-gpNMB antibody or a fragment thereof or a derivative thereof according to any one of claims 1 to 17, and / or Cloning vectors or expression vectors containing at least one of the said nucleic acid molecules, and / or Recombinant cells containing the vector were introduced.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein, Disease-related cells were selected from senescent cells, cancer-related cells, and phagocytes.

20. The pharmaceutical composition according to claim 19, wherein, Cancer-associated cells are selected from cancer cells, cancer stem cells, precancerous cells, and cancer-infiltrating cells.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein, The diseases selected include obesity, diabetes, arteriosclerosis, fibrosis, cancer, metabolic diseases, circulatory system diseases, lysosomal stress-related diseases (such as lysosomal diseases), autoimmune diseases (such as multiple sclerosis), neurogenic pain, fibromyalgia, and glioblastoma.

22. The pharmaceutical composition according to any one of claims 1 to 21, used for treating or preventing disease by eliminating disease-related cells.

23. An anti-gpNMB antibody or a fragment thereof or a derivative thereof, which specifically binds to at least one location in the V78 to S92 region of human gpNMB (glycoprotein nonmetastatic melanoma protein B), said human gpNMB having the amino acid sequence of SEQ ID NO:

209.

24. The anti-gpNMB antibody according to claim 23, or a fragment thereof or a derivative thereof, further specifically binding to a region of human gpNMB containing the amino acid residue K186, said human gpNMB having the amino acid sequence SEQ ID NO:

209.

25. The anti-gpNMB antibody according to claim 23 or 24, or a fragment thereof or a derivative thereof, wherein, The anti-gpNMB antibody also specifically binds to at least one location in the V78 to S92 region of mouse gpNMB, which has the amino acid sequence of SEQ ID NO:

211.

26. The anti-gpNMB antibody or a fragment thereof or a derivative thereof according to any one of claims 23 to 25, wherein it is a monoclonal antibody or a fragment thereof or a derivative thereof.

27. The anti-gpNMB antibody of claim 26, or a fragment thereof or a derivative thereof, comprising at least a heavy chain variable region, wherein the heavy chain variable region has: (17) As CDR-H1, the amino acid sequence described in SEQ ID NO: 177, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 177, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

177. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 179, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 179, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO:

179. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 181, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 181, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 181; or (18) As CDR-H1, the amino acid sequence described in SEQ ID NO: 330, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 330, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

330. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 331, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 331, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO:

331. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 332, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 332, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 332; or (19) As CDR-H1, the amino acid sequence described in SEQ ID NO: 337, or an amino acid sequence formed by substituting, deleting, or inserting any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 337, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

337. As CDR-H2, the amino acid sequence described in SEQ ID NO: 338, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 338, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 338, and As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 339, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 339, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO: 339; or (20) As CDR-H1, the amino acid sequence described in SEQ ID NO: 344, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 344, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

344. As CDR-H2, it is the amino acid sequence described in SEQ ID NO: 345, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 345, or an amino acid sequence having a similarity (preferably identical) of 62.5%, 75.0%, or 87.5% or more to the amino acid sequence described in SEQ ID NO:

345. As CDR-H3, it is the amino acid sequence described in SEQ ID NO: 346, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 346, or an amino acid sequence having 62.5%, 75.0%, or 87.5% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 346; or (21) As the CDR transplantation region -H1, the amino acid sequence described in SEQ ID NO: 327, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 327, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

327. As the CDR transplantation region -H2, it is the amino acid sequence described in SEQ ID NO: 328, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 328, or an amino acid sequence having a similarity (preferably identical) of 64.7%, 70.5%, 76.4%, 82.3%, 88.2%, or 94.1% or more to the amino acid sequence described in SEQ ID NO:

328. As the CDR transplantation region -H3, it is the amino acid sequence described in SEQ ID NO: 329, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 329, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 329; or (22) As the CDR transplantation region -H1, the amino acid sequence described in SEQ ID NO: 334, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 334, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

334. As the CDR transplantation region -H2, it is the amino acid sequence described in SEQ ID NO: 335, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 335, or an amino acid sequence having a similarity (preferably identical) of 64.7%, 70.5%, 76.4%, 82.3%, 88.2%, or 94.1% or more to the amino acid sequence described in SEQ ID NO:

335. As the CDR transplantation region -H3, it is the amino acid sequence described in SEQ ID NO: 336, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 336, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 336; or (23) As the CDR transplantation region -H1, the amino acid sequence described in SEQ ID NO: 341, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 341, or an amino acid sequence having 60.0% or more, 70.0% or more, 80.0% or more, or 90.0% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

341. As the CDR transplantation region -H2, it is the amino acid sequence described in SEQ ID NO: 342, or an amino acid sequence formed by the substitution, deletion, or insertion of any one, two, three, four, five, or six amino acid residues in the amino acid sequence described in SEQ ID NO: 342, or an amino acid sequence having a similarity (preferably identical) of 64.7%, 70.5%, 76.4%, 82.3%, 88.2%, or 94.1% or more to the amino acid sequence described in SEQ ID NO:

342. As the CDR transplantation region -H3, it is the amino acid sequence described in SEQ ID NO: 343, or an amino acid sequence formed by replacing, deleting, or inserting any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 343, or an amino acid sequence having more than 66.6% or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

343.

28. The anti-gpNMB antibody according to claim 26 or 27, or a fragment thereof or a derivative thereof, comprising at least a heavy chain variable region, wherein the heavy chain variable region has: (17) The amino acid sequence described in SEQ ID NO: 189, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 189; or (18) The amino acid sequence described in SEQ ID NO: 333, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 333; or (19) The amino acid sequence described in SEQ ID NO: 340, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 340; or (20) The amino acid sequence described in SEQ ID NO: 347, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO:

347.

29. The anti-gpNMB antibody or a fragment thereof or a derivative thereof according to any one of claims 25 to 28, wherein, The heavy chain variable region contains a framework sequence of any class of human immunoglobulins as the framework sequence.

30. The anti-gpNMB antibody or a fragment thereof or a derivative thereof according to any one of claims 25 to 29, further comprising a heavy chain constant region, wherein the heavy chain constant region has the amino acid sequence of a heavy chain constant region of any class of human immunoglobulins.

31. The anti-gpNMB antibody or a fragment thereof or a derivative thereof according to any one of claims 25 to 30, comprising at least a light chain variable region, wherein the light chain variable region has: (17) As CDR-L1, the amino acid sequence described in SEQ ID NO: 183, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 183, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

183. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 185, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 185, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

185. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 187, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 187, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 187; or (18) As CDR-L1, the amino acid sequence described in SEQ ID NO: 351, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 351, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

351. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 352, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 352, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

352. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 353, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 353, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 353; or (19) As CDR-L1, the amino acid sequence described in SEQ ID NO: 358, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 358, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

358. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 359, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 359, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

359. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 360, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 360, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 360; or (20) As CDR-L1, the amino acid sequence described in SEQ ID NO: 365, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 365, or an amino acid sequence having 66.6% or more or 83.3% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

365. As CDR-L2, it is the amino acid sequence described in SEQ ID NO: 366, or an amino acid sequence formed by substituting, deleting, or inserting any amino acid residue in the amino acid sequence described in SEQ ID NO: 366, or an amino acid sequence having more than 66.6% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

366. As CDR-L3, it is the amino acid sequence described in SEQ ID NO: 367, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 367, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7%, or 88.8% or more to the amino acid sequence described in SEQ ID NO: 367; or (21) As the CDR transplantation region-L1, the amino acid sequence described in SEQ ID NO: 348, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 348, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

348. As the CDR transplantation region -L2, it is the amino acid sequence described in SEQ ID NO: 349, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 349, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

349. As the CDR transplantation region -L3, it is the amino acid sequence described in SEQ ID NO: 350, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 350, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 350; or (22) As the CDR transplantation region-L1, the amino acid sequence described in SEQ ID NO: 355, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 355, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

355. As the CDR transplantation region -L2, it is the amino acid sequence described in SEQ ID NO: 356, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 356, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

356. As the CDR transplantation region -L3, it is the amino acid sequence described in SEQ ID NO: 357, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, or three amino acid residues in the amino acid sequence described in SEQ ID NO: 357, or an amino acid sequence having 66.6%, 77.7%, or 88.8% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO: 357; or (23) As the CDR transplantation region-L1, the amino acid sequence described in SEQ ID NO: 362, or an amino acid sequence formed by substitution, deletion, or insertion of any one, two, three, or four amino acid residues in the amino acid sequence described in SEQ ID NO: 362, or an amino acid sequence having 63.6% or more, 72.7% or more, 81.8% or more, or 90.9% or more similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

362. As the CDR transplantation region -L2, it is the amino acid sequence described in SEQ ID NO: 363, or an amino acid sequence formed by substitution, deletion, or insertion of any one or two amino acid residues in the amino acid sequence described in SEQ ID NO: 363, or an amino acid sequence having 71.4% or more or 85.7% similarity (preferably identical) to the amino acid sequence described in SEQ ID NO:

363. As the CDR transplantation region -L3, it is the amino acid sequence described in SEQ ID NO: 364, or an amino acid sequence formed by the substitution, deletion or insertion of any one, two or three amino acid residues in the amino acid sequence described in SEQ ID NO: 364, or an amino acid sequence having a similarity (preferably identical) of 66.6%, 77.7% or more or 88.8% or more to the amino acid sequence described in SEQ ID NO:

364.

32. The anti-gpNMB antibody or a fragment thereof or a derivative thereof according to any one of claims 25 to 31, comprising at least a light chain variable region, wherein the light chain variable region has: (17) The amino acid sequence described in SEQ ID NO: 191, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 191; or (18) The amino acid sequence described in SEQ ID NO: 354, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 354; or (19) The amino acid sequence described in SEQ ID NO: 361, or an amino acid sequence having more than 60% similarity to the amino acid sequence described in SEQ ID NO: 361; or (20) The amino acid sequence described in SEQ ID NO: 368, or an amino acid sequence that has more than 60% similarity to the amino acid sequence described in SEQ ID NO:

368.

33. The anti-gpNMB antibody according to claim 31 or 32, or a fragment thereof or a derivative thereof, wherein, The light chain variable region contains a framework sequence of any class of human immunoglobulins as the framework sequence.

34. The anti-gpNMB antibody or a fragment thereof or a derivative thereof according to any one of claims 25 to 33, further comprising a light chain constant region, wherein the light chain constant region has the amino acid sequence of a light chain constant region of any class of human immunoglobulins.

35. The anti-gpNMB antibody or its fragment or derivative thereof according to any one of claims 25 to 34, wherein it is Fab, scFv, biantibody, nanobody, VHH, bispecific antibody, or multispecific antibody, or derivative thereof.

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