WO2024090571A1 - Ｍｍｐ１２を指標とした免疫介在性炎症性疾患の診断、及びｍｍｐ１２阻害による免疫介在性炎症性疾患の治療用医薬 - Google Patents

Ｍｍｐ１２を指標とした免疫介在性炎症性疾患の診断、及びｍｍｐ１２阻害による免疫介在性炎症性疾患の治療用医薬 Download PDF

Info

Publication number
WO2024090571A1
WO2024090571A1 PCT/JP2023/038959 JP2023038959W WO2024090571A1 WO 2024090571 A1 WO2024090571 A1 WO 2024090571A1 JP 2023038959 W JP2023038959 W JP 2023038959W WO 2024090571 A1 WO2024090571 A1 WO 2024090571A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmp12
immune
mediated inflammatory
subject
increased expression
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2023/038959
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
紘太郎 松本
祐子 金子
勝也 鈴木
健二郎 花岡
栄太 佐々木
勝 竹下
創太 山田
龍太 丸岡
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Keio University
Original Assignee
Keio University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Keio University filed Critical Keio University
Priority to CN202380074661.6A priority Critical patent/CN120129835A/zh
Priority to EP23880904.0A priority patent/EP4610657A1/en
Priority to JP2024553261A priority patent/JPWO2024090571A1/ja
Publication of WO2024090571A1 publication Critical patent/WO2024090571A1/ja
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0056—Peptides, proteins, polyamino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96486—Metalloendopeptidases (3.4.24)
    • G01N2333/96491—Metalloendopeptidases (3.4.24) with definite EC number
    • G01N2333/96494—Matrix metalloproteases, e. g. 3.4.24.7
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/06—Gastro-intestinal diseases
    • G01N2800/065—Bowel diseases, e.g. Crohn, ulcerative colitis, IBS
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/20—Dermatological disorders
    • G01N2800/205—Scaling palpular diseases, e.g. psoriasis, pytiriasis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/24—Immunology or allergic disorders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/70—Mechanisms involved in disease identification
    • G01N2800/7095—Inflammation

Definitions

  • the present invention relates to a method for detecting immune-mediated inflammatory diseases, a biomarker for diagnosing immune-mediated inflammatory diseases, a diagnostic agent for immune-mediated inflammatory diseases, a therapeutic agent for immune-mediated inflammatory diseases, and a diagnostic kit.
  • Granulomatous vasculitis is a type of immune-mediated inflammatory disease, and Takayasu arteritis (TAK), giant cell arteritis (GCA), eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), which are classified as ANCA (anti-neutrophil cytoplasmic antibody)-associated vasculitis, and microscopic polyangiitis (MPA) are all designated intractable diseases.
  • TAK Takayasu arteritis
  • GCA giant cell arteritis
  • EGPA eosinophilic granulomatosis with polyangiitis
  • GPA granulomatosis with polyangiitis
  • MPA microscopic polyangiitis
  • the number of recipients of benefit certificates is approximately 4,700 patients with Takayasu's arteritis, approximately 1,700 patients with giant cell arteritis, approximately 5,200 patients with eosinophilic granulomatosis with polyangiitis, approximately 3,200 patients with granulomatosis with polyangiitis, and approximately 11,000 patients with microscopic polyangiitis.
  • Treatments include immunosuppressive therapies such as steroids (Prednisolone (registered trademark)), cyclophosphamide (Endoxan (registered trademark)), and methotrexate (Rheumatrex (registered trademark)), as well as the B-cell targeted therapy rituximab (Rituxan (registered trademark)), the complement C5a selective inhibitor avacopan (Taboones (registered trademark)), and the interleukin-6 (IL-6) inhibitor tocilizumab (Actemra (registered trademark)) (Non-patent documents 1 and 2), but long-term administration can cause asymptomatic progression of large blood vessel stenosis and dilation.
  • immunosuppressive therapies such as steroids (Prednisolone (registered trademark)), cyclophosphamide (Endoxan (registered trademark)), and methotrexate (Rheumatrex (registered trademark)
  • the problem to be solved by the present invention is to provide a method for detecting immune-mediated inflammatory diseases characterized by increased expression of MMP12, which does not use IL-6 as an indicator, a biomarker for diagnosing said immune-mediated inflammatory diseases, a diagnostic agent for said immune-mediated inflammatory diseases, a diagnostic kit for said immune-mediated inflammatory diseases, and a therapeutic agent for said immune-mediated inflammatory diseases.
  • Item 1. A method for detecting an immune-mediated inflammatory disease in a subject, characterized by increased expression of MMP12, comprising: A method comprising measuring the level of MMP12 protein in a biological sample obtained from a subject. Item 2. contacting the biological sample obtained from the subject with a substance that binds MMP12; Item 2. The method according to Item 1, wherein measuring the level of MMP12 protein comprises measuring the level of a complex between MMP12 protein and a substance that binds to MMP12 protein. Item 3. Item 2.
  • the immune-mediated inflammatory disease characterized by increased expression of MMP12 is selected from the group consisting of vasculitis syndrome, granulomatous vasculitis, IgG4-related disease, inflammatory bowel disease, sarcoidosis, tuberculous mycobacterial disease, and nontuberculous mycobacterial disease.
  • Item 4. Item 10. The method of item 1, wherein the biological sample is blood, serum, or plasma.
  • Item 5. The method according to item 1, wherein the immune-mediated inflammatory disease characterized by increased expression of MMP12 is Takayasu's arteritis.
  • measuring the level of MMP12 protein comprises measuring a change caused by cleavage of a peptide having a site cleavable by MMP12.
  • Item 7 The method is a method for predicting the likelihood of developing an immune-mediated inflammatory disease characterized by increased expression of MMP12 in a subject, The method further comprises comparing the level of MMP12 protein in the biological sample obtained from the subject to a reference value; Item 6.
  • the method is a method for predicting the prognosis of a subject suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12, the subject has been treated for an immune-mediated inflammatory disease characterized by increased expression of MMP12;
  • the method further comprises comparing the level of MMP12 protein in the biological sample obtained from the subject to a reference value; Item 6.
  • the method according to any one of Items 1 to 5, wherein a high protein level of MMP12 in a biological sample obtained from the subject compared to a reference value indicates a high possibility of relapse of an immune-mediated inflammatory disease characterized by increased expression of MMP12 in the subject.
  • the method is for predicting a post-treatment condition of a subject suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12, the subject is being treated for an immune-mediated inflammatory disease characterized by increased expression of MMP12;
  • the method further comprises comparing the level of MMP12 protein in the biological sample obtained from the subject with a reference value; Item 6.
  • the method according to any one of Items 1 to 5, wherein when the MMP12 protein level in the biological sample obtained from the subject is lower than the reference value, this indicates that an immune-mediated inflammatory disease characterized by increased expression of MMP12 in the subject is likely to be in remission.
  • Item 10 The method according to any one of Items 1 to 5, wherein when the MMP12 protein level in the biological sample obtained from the subject is lower than the reference value, this indicates that an immune-mediated inflammatory disease characterized by increased expression of MMP12 in the subject is likely to be in remission.
  • the method is a method for evaluating the timing of administration of a therapeutic agent for an immune-mediated inflammatory disease characterized by increased expression of MMP12 to a subject suffering from the immune-mediated inflammatory disease characterized by increased expression of MMP12,
  • the method further comprises comparing the level of MMP12 protein in the biological sample obtained from the subject to a reference value; Item 6.
  • the method according to any one of Items 1 to 5, wherein a lower level of MMP12 protein in a biological sample obtained from the subject compared to a reference value is an indication for ceasing administration of the drug to the subject.
  • Item 11 A biomarker for the diagnosis of immune-mediated inflammatory diseases, including MMP12, characterized by increased expression of MMP12.
  • a diagnostic agent for immune-mediated inflammatory diseases characterized by increased expression of MMP12 comprising a substance that specifically interacts with MMP12.
  • Item 13 The diagnostic agent according to Item 12, which comprises a conjugate of a peptide having a site cleavable by MMP12 and a labeling substance.
  • Item 14. Item 13. The diagnostic agent according to Item 12, wherein the conjugate comprises a peptide having a site cleavable by MMP12, a fluorophore bound to one end of the peptide, and a quencher bound to the other end of the peptide.
  • Item 15. Item 15.
  • the diagnostic agent according to any one of Items 12 to 14, wherein the immune-mediated inflammatory disease characterized by increased expression of MMP12 is selected from the group consisting of vasculitis syndrome, granulomatous vasculitis, IgG4-related disease, inflammatory bowel disease, sarcoidosis, tuberculous mycobacterial disease, and nontuberculous mycobacterial disease.
  • Item 16 A diagnostic kit for diagnosing an immune-mediated inflammatory disease characterized by increased expression of MMP12, the diagnostic kit comprising a substance that specifically interacts with MMP12 protein.
  • Item 17. Item 17.
  • the diagnostic kit according to Item 16, wherein the substance that specifically interacts with the MMP12 protein comprises an antibody against MMP12, an antigen-binding fragment of an antibody against MMP12, an aptamer against MMP12, or a peptide having a site cleavable by MMP12.
  • Item 18 A method for screening for a substance effective in treating an immune-mediated inflammatory disease characterized by increased expression of MMP12, comprising: measuring the protein level of MMP12 in a biological sample obtained from the subject after administration of a test substance; and if the protein level of MMP12 is reduced by administration of the test substance, selecting the test substance as a candidate substance effective for treating an immune-mediated inflammatory disease characterized by increased expression of MMP12.
  • a therapeutic agent for immune-mediated inflammatory diseases characterized by increased expression of MMP12 comprising an MMP12 inhibitor.
  • diagnostic agent and diagnostic kit for detecting immune-mediated inflammatory diseases characterized by increased expression of MMP12 of the present invention, it is possible to detect or diagnose the disease using MMP12 with the same or higher accuracy as conventional prediction methods.
  • the diagnostic agent and diagnostic kit do not use IL-6 as an indicator and can be used even under IL-6 inhibitory treatment.
  • the screening method of the present invention for a substance effective in treating an immune-mediated inflammatory disease characterized by increased expression of MMP12 makes it possible to effectively screen for a therapeutic agent for the disease.
  • the therapeutic agent for immune-mediated inflammatory diseases of the present invention characterized by increased expression of MMP12, can treat the disease.
  • ROC analysis graph (A) Comparison between the group of patients with vasculitis syndrome and the group of healthy subjects, (B) Comparison between the group of patients with vasculitis syndrome and the group of patients with immune-mediated inflammatory diseases other than vasculitis syndrome. Graph showing serum MMP12 levels in each patient group.
  • IBD inflammatory bowel disease
  • TAK Takayasu arteritis
  • NTM nontuberculous mycobacterial infection
  • IgG4RD IgG4 related disease
  • PAN polyarteritis nodosa
  • MPA microscopic polyangiitis
  • GPA granulomatosis with polyangiitis
  • EGPA eosinophilic granulomatosis with polyangiitis
  • GCA giant cell arteritis Expression of MMP12 in the aorta of a patient with Takayasu's arteritis.
  • A HE staining
  • B Enlarged photograph of the boxed area in Fig.
  • FIG. 5(C) Immunohistochemical staining of MMP12.
  • D Enlarged image of the boxed area in Fig. 5(C). Graph showing correlation of PETVAS and MMP12 at the time of diagnosis of Takayasu's arteritis and giant cell arteritis. Graph showing the relationship between PETVAS values and serum MMP12 levels and relapse rate.
  • A Time course of MMP12 levels before and after treatment in a patient with monotonically declining type.
  • (B) Image of the vascular wall before treatment in one male patient with monotonically declining type of Takayasu's arteritis.
  • C Image of the vascular wall of the same patient as in Fig. 8(B) 8 months after the start of treatment.
  • the upper or lower limit of a certain numerical range can be arbitrarily combined with the upper or lower limit of a numerical range of another stage.
  • the upper or lower limit of the numerical range may be replaced with a value shown in an example or a value that can be unambiguously derived from an example.
  • a numerical value connected with " ⁇ " means a numerical range that includes the numerical values before and after " ⁇ " as the upper and lower limits.
  • MMP12 refers to matrix metalloproteinase 12 protein.
  • Human MMP12 is a 470 amino acid protein represented by NCBI Reference Sequence: NP#002417 (Uniprot P39900), and mouse MMP12 is a 473 amino acid protein represented by NCBI Reference Sequence NP#032631 (Uniprot 34690).
  • MMP12 is sometimes referred to as MMP-12, and these terms can be used interchangeably.
  • vasculitis syndromes include vasculitis syndromes, granulomatous vasculitis, IgG4-related disease, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), sarcoidosis, tuberculous mycobacterial disease, and nontuberculous mycobacterial disease.
  • Vasculitis is a general term for diseases in which inflammation is observed in the blood vessels themselves, and is also called vasculitis syndromes.
  • Vasculitis syndromes are classified into three categories, large vessel vasculitis, medium vessel vasculitis, and small vessel vasculitis, depending on the size of the blood vessels.
  • Large vessel vasculitis includes Takayasu arteritis (TAK) and giant cell arteritis (GCA).
  • Medium vessel vasculitis includes polyarteritis nodosa and Kawasaki disease.
  • Small-vessel vasculitis includes eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA), which are classified as ANCA (anti-neutrophil cytoplasmic antibody)-associated vasculitis.
  • EGPA polyangiitis
  • GPA granulomatosis with polyangiitis
  • MPA microscopic polyangiitis
  • detection of an immune-mediated inflammatory disease characterized by increased expression of MMP12 includes diagnosis of the disease, diagnosis of patients (responders) who respond to a therapeutic agent (companion diagnostic method), diagnosis of the preventive effect of the disease, diagnosis of the therapeutic effect of the disease, tests to assist in the diagnosis of the disease, and tests for the treatment of the disease (particularly early treatment).
  • assessment of an immune-mediated inflammatory disease characterized by increased expression of MMP12 includes not only determining whether or not the disease has developed, but also preventatively determining the possibility of development of the disease, predicting the prognosis of the disease after treatment, determining the possibility of remission, determining the possibility of relapse, assessing the timing of discontinuing drug administration, and determining the therapeutic effect of a therapeutic agent for the disease.
  • the term "increased expression of MMP12" in "immune-mediated inflammatory disease characterized by increased expression of MMP12” refers to an increase in the level of MMP12 in a biological sample obtained from a subject, compared to either the level of MMP12 in the subject before the onset of the immune-mediated inflammatory disease or the average level of MMP12 in healthy individuals.
  • immune-mediated inflammatory disease refers to a chronic inflammatory disease in which the immune system causes damage to tissues through an immune response (e.g., a B cell response or a T cell response) to antigens that are part of the normal host (i.e., self-antigens) or without an immune response to antigens.
  • an immune response e.g., a B cell response or a T cell response
  • antigens that are part of the normal host (i.e., self-antigens) or without an immune response to antigens.
  • treatment means curing or ameliorating a disease or symptom, or suppressing a symptom, and includes “prevention.”
  • Prevention means preventing the onset of a disease or symptom.
  • the term "subject” refers to a mammal, including humans, mice, rats, cows, horses, pigs, monkeys, dogs, cats, rabbits, goats, sheep, etc., preferably humans and mice, and more preferably humans.
  • biological sample may be a bodily fluid, tissue, or cell.
  • Bodily fluids include blood (e.g., whole blood), blood cells, serum, plasma, pleural fluid, peritoneal fluid, cerebrospinal fluid, saliva, urine, stool, and the like.
  • Tissues include blood vessels of the heart, arteries, kidneys, lungs, inner ear, sinuses, skin, nerves, and other organs, and the like.
  • Biological samples may be obtained from a patient and used directly, or may be pretreated by filtration, distillation, extraction, concentration, centrifugation, inactivation of interfering components, addition of reagents, or other methods known in the art to modify the characteristics of the sample.
  • the "level" of MMP12 can be the amount (e.g., expression level) or concentration of MMP12 protein.
  • the inventors used cross-disease serum proteome analysis to identify multiple molecules specific to vasculitis. Using the identified molecules, they compared a group of patients with vasculitis syndromes with a group of healthy subjects, and a group of patients with vasculitis syndromes with a group of patients with immune-mediated inflammatory diseases other than vasculitis syndromes, and found that MMP12 had the highest sensitivity for ROC curve judgment. MMP12 was normal in patients with general bacterial infections and viral infections, and MMP12 could also be used to distinguish these from vasculitis syndromes.
  • MMP12 was examined in vasculitis tissues of Takayasu's arteritis (TAK), giant cell arteritis (GCA), and granulomatosis with polyangiitis (GPA), immune-mediated inflammatory diseases characterized by increased expression of MMP12. Expression was confirmed in the aortas of patients with Takayasu's arteritis, in the temporal arteries of patients with giant cell arteritis, and in the lungs of patients with granulomatosis with polyangiitis, confirming expression in vasculitis tissues.
  • TAK Takayasu's arteritis
  • GCA giant cell arteritis
  • GPA granulomatosis with polyangiitis
  • MMP12 is associated with the onset of some immune-mediated inflammatory diseases characterized by increased expression of MMP12, and that MMP12 can be used as a diagnostic marker for immune-mediated inflammatory diseases characterized by increased expression of MMP12. They have also discovered a diagnostic agent for immune-mediated inflammatory diseases characterized by increased expression of MMP12, a screening method for substances effective in treating immune-mediated inflammatory diseases characterized by increased expression of MMP12, and a therapeutic agent for immune-mediated inflammatory diseases characterized by increased expression of MMP12.
  • a method for detecting an immune-mediated inflammatory disease characterized by increased expression of MMP12 in a subject comprising measuring the level of MMP12 in a biological sample obtained from the subject.
  • This method allows an examiner to easily and accurately detect immune-mediated inflammatory diseases in vitro based on the test results. Furthermore, this method does not include diagnostic methods for humans, which are medical procedures.
  • the method for measuring the level of MMP12 in a biological sample obtained from a subject is not particularly limited, and the level can be measured using a substance that specifically interacts with MMP12.
  • substances that specifically interact with MMP12 include substances that bind to MMP12, and substances that are cleaved by MMP12 due to the protease activity of MMP12.
  • the level of MMP12 in a biological sample obtained from a subject may be measured by known protein identification methods, including, but not limited to, immunoassays and mass spectrometry.
  • immunological measurement methods include, but are not limited to, enzyme antibody methods (such as ELISA), fluorescent antibody methods, radioimmunoassays, solid-phase methods, sandwich methods, etc.
  • enzyme antibody methods such as ELISA
  • fluorescent antibody methods fluorescent antibody methods
  • radioimmunoassays radioimmunoassays
  • solid-phase methods such as sandwich methods, etc.
  • the method further comprises contacting the biological sample obtained from the subject with a substance that binds to MMP12, and measuring the level of MMP12 comprises measuring the level of a complex of MMP12 and the substance that binds to MMP12.
  • the substance that binds to MMP12 is preferably a substance that specifically binds to MMP12. Note that "specifically bind” means a bond that is measurably different from a non-specific interaction, and refers to binding to each other.
  • the substance that binds to MMP12 can be selected from the group consisting of an antibody against MMP12, an antigen-binding fragment of an antibody against MMP12, and an aptamer against MMP12.
  • MMP12 and/or substances that bind to MMP12 may be further conjugated to radioisotopes, enzymes, fluorescent dyes, and contrast agents (e.g., paramagnetic ions) as detection labels or imaging probes.
  • radioisotopes e.g., radioisotopes, enzymes, fluorescent dyes, and contrast agents (e.g., paramagnetic ions) as detection labels or imaging probes.
  • contrast agents e.g., paramagnetic ions
  • Antibodies against MMP12 i.e., anti-MMP12 antibodies, can be produced using known antibody production methods.
  • antibodies include polyclonal and monoclonal antibodies, as well as modified antibodies such as chimeric and humanized antibodies.
  • antibody production can be induced by immunizing a host animal with the full-length MMP12 polypeptide or a fragment thereof as an immunogen, i.e., an epitope.
  • an MMP12 fragment the region of the polypeptide that serves as the immunogen can be selected arbitrarily, or, since many examples of the preparation of anti-MMP12 antibodies, including commercially available products, have been published, these published examples can be used as a reference.
  • the polypeptide that serves as the immunogen can be produced by known standard methods, and can be chemically synthesized or biochemically synthesized as a recombinant protein. It can also be obtained by using commercially available contract synthesis services.
  • the polypeptide to be used as an immunogen may be used for immunization, or a reconstituted membrane or recombinant cells presenting a recombinant protein containing the polypeptide on the membrane may be used for immunization.
  • a reconstituted membrane or recombinant cells presenting a recombinant protein containing the polypeptide on the membrane may be used for immunization.
  • animal species such as mouse, rat, rabbit, guinea pig, sheep, goat, donkey, chicken, or camel are preferred. More preferred are mouse or rat, and particularly preferred are mouse.
  • Antisera containing anti-MMP12 antibodies can be prepared by known standard methods. The antibody may be any of the five classes of immunoglobulin molecules (IgG, IgM, IgA, IgD, IgE). IgG or IgM is preferred, and IgG is more preferred.
  • Anti-MMP12 monoclonal antibodies can be prepared by fusing the antibody-producing cells obtained in the above preparation process with myeloma cells and then cloning them. Alternatively, they can be produced by expressing chemically synthesized antibody genes in Escherichia coli or the like using genetic engineering techniques.
  • the method of fusing antibody-producing cells with myeloma cells, the method of screening desired cells from a group of cells including the fused cells, the method of monocloning the cells selected by screening, and the method of preparing monoclonal antibodies from clones can all be carried out by known standard methods.
  • the desired monoclonal antibody can also be synthesized based on sequence information by known standard methods.
  • the MMP12 monoclonal antibody can be artificially modified to become a genetically modified antibody for the purpose of reducing heterologous antigenicity to humans.
  • examples of such antibodies include chimeric antibodies and humanized antibodies. These modified antibodies can be produced by known methods.
  • the chimeric antibody can be prepared by linking DNA encoding the variable (V) region of the anti-MMP12 monoclonal antibody of this embodiment to DNA encoding the constant (C) region of a human antibody, incorporating this into an expression vector, and introducing it into a host for production.
  • Humanized antibodies are antibodies in which the CDRs of an antibody from a mammal other than human, such as a mouse, have been transplanted (CDR grafted) onto the CDRs of a human antibody. They can be prepared as appropriate using common genetic recombination techniques. For example, a DNA sequence designed to code for an amino acid sequence linking each CDR of a mouse anti-MMP12 monoclonal antibody to the framework region of a human antibody can be synthesized by PCR using multiple oligonucleotides as primers that have been created to have overlapping portions at the terminal regions of both the CDRs and FRs.
  • the FRs of the variable regions of human antibodies can be obtained from published DNA databases, etc.
  • the constant regions of chimeric and humanized antibodies can be those of human antibodies.
  • C ⁇ 1, C ⁇ 2, C ⁇ 3, and C ⁇ 4 can be used for the heavy chain
  • C ⁇ and C ⁇ can be used for the light chain.
  • Antigen-binding fragment of an antibody means a fragment containing the antigen-binding portion of an antibody molecule. As long as it can exhibit sufficient specificity and affinity to confer specific antigen binding, the substance that binds to MMP12 does not necessarily have to maintain the structure of the entire immunoglobulin molecule. Since the antigen-binding ability of an antibody is controlled by the variable region of the antibody, the constant region of the immunoglobulin molecule does not necessarily have to be present.
  • antigen-binding fragments of antibodies in this embodiment include Fab, Fab', F(ab')2, Fd obtained by removing VL from Fab, single-chain Fv fragment (scFv), which are fragments consisting of the variable region of an immunoglobulin molecule, and bispecific antibodies (diabodies) which are dimers thereof.
  • Aptamers are oligonucleotides that bind to their targets with high affinity and specificity.
  • Aptamers are a class of molecules that replace antibodies in molecular recognition
  • aptamers for MMP12 are oligonucleotides that have the ability to recognize MMP12 with high affinity and specificity.
  • aptamers can be obtained as substances that specifically bind to target compounds by known methods that repeat a series of processes including "selection and amplification" in vitro, such as the method known as the Systematic Evolution of Ligands by Exponential enrichment (SELEX) method (see, for example, JP 2006-320289 A, JP 2009-207491 A, or JP 2009-165394 A).
  • the nucleic acid aptamer as a substance that binds to MMP12 can be selected by adopting MMP12 as the target compound, typically the full-length polypeptide of human MMP12 or a fragment thereof.
  • the nucleic acid aptamer used in this embodiment may have any binding activity as long as it specifically binds to the target compound MMP12 and functions as an MMP12 inhibitor through said binding, but has a binding ability that shows a dissociation constant (KD) of 2 ⁇ M or less, preferably 600 nM or less, for human MMP12.
  • KD dissociation constant
  • the dissociation constant (KD) is defined herein as a constant obtained from the ratio of Kd to Ka (i.e., Kd/Ka) and is expressed as a molar concentration (M).
  • KD value of a nucleic acid aptamer can be determined using methods established in the art.
  • a preferred method for determining the KD of a nucleic acid aptamer is using surface plasmon resonance, preferably using a biosensor system such as a Biacore® system.
  • the method further comprises contacting the biological sample obtained from the subject with a substance cleaved by MMP12, and measuring the level of MMP12 comprises measuring a change (e.g., fluorescence, etc.) caused by cleavage of the substance cleaved by MMP12.
  • the substance that binds to MMP12 includes, for example, a peptide having a site cleavable by MMP12.
  • the diagnostic agent of the third aspect described below can be used as the substance cleaved by MMP12.
  • the immune-mediated inflammatory disease characterized by increased expression of MMP12 is selected from the group consisting of vasculitic syndromes, granulomatous vasculitis, IgG4-related disease, inflammatory bowel disease, sarcoidosis, tuberculous mycobacterial disease, and nontuberculous mycobacterial disease.
  • the immune-mediated inflammatory disease characterized by increased expression of MMP12 is granulomatous vasculitis.
  • the biological sample is blood, serum, or plasma.
  • the method for detecting immune-mediated inflammatory diseases characterized by increased expression of MMP12 according to the first aspect can be used in various tests or assessments.
  • the method is a method for predicting the likelihood of developing an immune-mediated inflammatory disease characterized by increased expression of MMP12 in a subject, and the method further includes comparing the level of MMP12 in a biological sample obtained from the subject with a reference value, and if the level of MMP12 in the biological sample obtained from the subject is higher than the reference value, this indicates that the subject is more likely to develop an immune-mediated inflammatory disease characterized by increased expression of MMP12.
  • the above-mentioned reference value may be an average or median value calculated from measurements of the MMP12 levels of multiple healthy subjects, a cutoff value (e.g., within the range of 50 pg/ml to 200 pg/ml, preferably 100 pg/ml) that separates a group of healthy subjects from a group of patients diagnosed by a doctor as suffering from an immune-mediated inflammatory disease characterized by increased MMP12 expression, or a certain value (e.g., within the range of 250 pg/ml to 1000 pg/ml, preferably 500 pg/ml) that is higher than the average or median value calculated from measurements of the MMP12 levels of multiple healthy subjects and lower than the average or median value calculated from measurements of the MMP12 levels of multiple patients suffering from an immune-mediated inflammatory disease characterized by increased MMP12 expression.
  • a cutoff value e.g., within the range of 50 pg/ml to 200 pg/ml, preferably 100 pg/ml
  • this determination result can be taken into consideration when determining the subject's future treatment policy, such as diagnosing additional immune-mediated inflammatory diseases.
  • the method of this embodiment is useful as a means for diagnosing (particularly early diagnosis) or assisting in diagnosis of the possibility of developing an immune-mediated inflammatory disease.
  • the method is a method for predicting the likelihood of developing an immune-mediated inflammatory disease characterized by increased expression of MMP12 in a subject, and the method further includes comparing the level of MMP12 in a biological sample obtained from the subject with a reference value, and if the level of MMP12 in the biological sample obtained from the subject is equal to or lower than the reference value, this indicates that the subject is unlikely to develop an immune-mediated inflammatory disease characterized by increased expression of MMP12.
  • the above-mentioned reference value may be the average or median calculated from the measurement of MMP12 levels in multiple healthy individuals, or a value lower than these.
  • the method is a method for predicting the prognosis of a subject suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12, the subject having been treated for the immune-mediated inflammatory disease characterized by increased expression of MMP12, and the method further comprises comparing the level of MMP12 in a biological sample obtained from the subject with a reference value, and when the level of MMP12 in the biological sample obtained from the subject is higher than the reference value, this indicates a high possibility of relapse of the immune-mediated inflammatory disease characterized by increased expression of MMP12 in the subject.
  • Subjects who have been treated for an immune-mediated inflammatory disease characterized by increased expression of MMP12 also include patients who have been treated for an immune-mediated inflammatory disease characterized by increased expression of MMP12 and then discontinued the treatment.
  • Treatments include the administration of drugs useful for treating immune-mediated inflammatory diseases characterized by increased expression of MMP12, radiation therapy, exercise therapy, dietary therapy, and the administration of supplements.
  • the above-mentioned reference value may be the level of MMP12 in a sample obtained from the same subject before undergoing treatment for treating an immune-mediated inflammatory disease characterized by increased expression of MMP12, or a cutoff value (e.g., within the range of 50 pg/ml to 200 pg/ml, preferably 100 pg/ml) that separates a group of healthy subjects from a group of patients diagnosed by a doctor as suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12, or a certain value (e.g., within the range of 250 pg/ml to 1000 pg/ml, preferably 500 pg/ml) that is higher than the mean or median value calculated from measurements of the MMP12 levels of multiple healthy subjects and lower than the mean or median value calculated from measurements of the MMP12 levels of multiple patients suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12.
  • a cutoff value e.g., within the range of 50 pg/
  • this determination result can be taken into consideration when deciding on the subject's future treatment policy, such as resuming administration of a therapeutic drug. Treatment for the subject can be more appropriately administered. Since an increase in the level of MMP12 occurs prior to the appearance of symptoms related to a relapse of an immune-mediated inflammatory disease, the method of this embodiment is useful as a means for diagnosing (particularly early diagnosis) or assisting in diagnosis of the possibility of a relapse of an immune-mediated inflammatory disease.
  • the inventors have demonstrated that MMP12 is positively correlated with the PET vascular activity score (PETVAS) used in PET-CT examinations.
  • PETVAS PET vascular activity score
  • the method of this embodiment may be a better evaluation tool than PETVAS and is useful for stratifying the risk of relapse in subjects.
  • the method is a method for predicting the prognosis of a subject suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12, the subject having been treated for the immune-mediated inflammatory disease characterized by increased expression of MMP12, and the method further comprises comparing the level of MMP12 in a biological sample obtained from the subject with a reference value, and when the level of MMP12 in the biological sample obtained from the subject is equal to or lower than the reference value, this indicates a low possibility of relapse of the immune-mediated inflammatory disease characterized by increased expression of MMP12 in the subject.
  • Subjects who have been treated for an immune-mediated inflammatory disease characterized by increased expression of MMP12 also include patients who have been treated for an immune-mediated inflammatory disease characterized by increased expression of MMP12 and then discontinued the treatment.
  • Treatments include the administration of drugs useful for treating immune-mediated inflammatory diseases characterized by increased expression of MMP12, radiation therapy, exercise therapy, dietary therapy, and the administration of supplements.
  • Examples of the reference value include the level of MMP12 in a sample obtained from the same subject before undergoing treatment for treating an immune-mediated inflammatory disease characterized by increased expression of MMP12, a cutoff value (e.g., within the range of 50 pg/ml to 200 pg/ml, preferably 100 pg/ml) that separates a group of healthy subjects from a group of patients diagnosed by a doctor as suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12, or a certain value (e.g., within the range of 250 pg/ml to 1000 pg/ml, preferably 500 pg/ml) that is higher than the average or median value calculated from measurements of the MMP12 levels of multiple healthy subjects and lower than the average or median value calculated from measurements of the MMP12 levels in multiple patients suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12.
  • a cutoff value e.g., within the range of 50 pg/ml to 200 p
  • the "cut-off value" can be determined by various statistical analysis methods well known to those skilled in the art.
  • the average or median level of MMP12 in patients suffering from immune-mediated inflammatory disease characterized by an increase in the expression of MMP12 the value at which the effect of the above-mentioned treatment to separate the healthy group and the patient group is the minimum P value in a log-rank test or the value at which the P value is less than a certain level (e.g., the value at which the P value is less than 0.1, the value at which the P value is less than 0.05), the value determined based on ROC (Receive Operating Characteristic) analysis so that the sum of sensitivity and specificity is maximized from the relationship between the expression level of MMP12 in the treated patient and the effect of the treatment; the value at which the effect of the treatment between the healthy group and the patient group is the minimum P value in a chi-square test or the value at which the P value is less than a certain level (e.g., the value at which the P
  • this determination result can be taken into consideration when deciding on the subject's future treatment policy, such as refraining from further treatment, which is advantageous from the standpoint of the burden on the subject and economics.
  • the method is a method for predicting the post-treatment state of a subject suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12, the subject having been treated for the immune-mediated inflammatory disease characterized by increased expression of MMP12, and the method further comprises comparing the level of MMP12 in a biological sample obtained from the subject with a reference value, and when the level of MMP12 in the biological sample obtained from the subject is lower than the reference value, this indicates that the immune-mediated inflammatory disease characterized by increased expression of MMP12 in the subject is likely to be in remission.
  • Treatments include the administration of drugs useful for treating immune-mediated inflammatory diseases characterized by increased expression of MMP12, radiation therapy, exercise therapy, dietary therapy, and the administration of supplements.
  • Medications useful for treating immune-mediated inflammatory diseases characterized by increased expression of MMP12 include, but are not limited to, steroids (Prednisolone®), cyclophosphamide (Endoxan®), methotrexate (Rheumatrex®), rituximab (Rituxan®), avacopan (Taboones®), tocilizumab (Actemra®), etc.
  • the above-mentioned reference value may be the level of MMP12 in a sample obtained from the same subject before undergoing treatment for treating an immune-mediated inflammatory disease characterized by increased expression of MMP12, or a cutoff value (e.g., within the range of 50 pg/ml to 200 pg/ml, preferably 100 pg/ml) that separates a group of healthy subjects from a group of patients diagnosed by a doctor as suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12, or a certain value (e.g., within the range of 250 pg/ml to 1000 pg/ml, preferably 500 pg/ml) that is higher than the mean or median value calculated from measurements of the MMP12 levels of multiple healthy subjects and lower than the mean or median value calculated from measurements of the MMP12 levels of multiple patients suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12.
  • a cutoff value e.g., within the range of 50 pg/
  • the effectiveness of the treatment the subject has received can be evaluated, and this determination result can be taken into consideration in determining the subject's future treatment plan, such as withholding administration of therapeutic drugs, which is advantageous from the standpoint of the burden on the subject and economics.
  • the method is for evaluating the timing of administration of a therapeutic agent for an immune-mediated inflammatory disease characterized by increased expression of MMP12 to a subject suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12, and the method further comprises comparing the level of MMP12 in a biological sample obtained from the subject to a reference value, and a lower level of MMP12 in the biological sample obtained from the subject compared to the reference value is an indication for ceasing administration of the drug to the subject.
  • the above-mentioned reference value may be a cutoff value (e.g., within the range of 50 pg/ml to 200 pg/ml, preferably 100 pg/ml) that separates a group of healthy subjects from a group of patients diagnosed by a doctor as suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12, or a certain value (e.g., within the range of 250 pg/ml to 1000 pg/ml, preferably 500 pg/ml) that is higher than the average or median value calculated from measurements of the MMP12 levels of multiple healthy subjects and lower than the average or median value calculated from measurements of the MMP12 levels of multiple patients suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12.
  • a cutoff value e.g., within the range of 50 pg/ml to 200 pg/ml, preferably 100 pg/ml
  • a certain value e.g., within the range of 250 p
  • the level of MMP12 in a biological sample obtained from a subject is lower than the reference value, it is determined that it is appropriate to suspend administration of the drug to the subject, and this determination result can be taken into consideration in determining the subject's future treatment plan, such as refraining from administering therapeutic drugs, which is advantageous from the standpoint of the burden on the subject and the economics.
  • the method is a method for determining the therapeutic effect of a treatment in a subject suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12, the subject being treated for an immune-mediated inflammatory disease characterized by increased expression of MMP12, the method further comprising comparing the level of MMP12 in a biological sample obtained from the subject with a reference value, and when the level of MMP12 in the biological sample obtained from the subject is lower than the reference value, this indicates that the therapeutic effect of the immune-mediated inflammatory disease characterized by increased expression of MMP12 as a result of the treatment in the subject is high.
  • Treatments include the administration of drugs useful for treating immune-mediated inflammatory diseases characterized by increased expression of MMP12, radiation therapy, exercise therapy, dietary therapy, and the administration of supplements.
  • the reference value may be the level of MMP12 in a sample obtained from the same subject before undergoing treatment for treating an immune-mediated inflammatory disease characterized by increased MMP12 expression, or a cutoff value (e.g., within the range of 50 pg/ml to 200 pg/ml, preferably 100 pg/ml) that separates a group of healthy subjects from a group of patients diagnosed by a doctor as suffering from an immune-mediated inflammatory disease characterized by increased MMP12 expression, or a certain value (e.g., within the range of 250 pg/ml to 1000 pg/ml, preferably 500 pg/ml) that is higher than the mean or median value calculated from measurements of the MMP12 levels of multiple healthy subjects and lower than the mean or median value calculated from measurements of the MMP12 levels of multiple patients suffering from an immune-mediated inflammatory disease characterized by increased MMP12 expression.
  • a cutoff value e.g., within the range of 50 pg/ml to 200 pg/
  • the effectiveness of the treatment received by the subject can be evaluated, and the results of this determination can be taken into consideration in determining the subject's future treatment plan, such as withholding administration of therapeutic drugs, which is advantageous from the standpoint of the burden on the subject and economics.
  • a biomarker for diagnosing or detecting immune-mediated inflammatory diseases including MMP12, characterized by increased expression of MMP12.
  • MMP12 in a biological sample obtained from a subject is used as a biomarker for the diagnosis or detection of an immune-mediated inflammatory disease characterized by increased expression of MMP12.
  • a diagnostic agent for immune-mediated inflammatory diseases characterized by increased expression of MMP12, which contains a substance that specifically interacts with MMP12.
  • Specifically interacting refers to an interaction that is measurably different from a non-specific interaction, and refers to interaction with each other.
  • substances that specifically interact with MMP12 include substances that bind to MMP12, as described in the first embodiment, and substances that are cleaved by MMP12 due to the protease activity of MMP12, such as peptides that have a site that can be cleaved by MMP12.
  • the diagnostic agent comprises a substance that binds to MMP12, and the substance that binds to MMP12 can be selected from the group consisting of an antibody against MMP12, an antigen-binding fragment of an antibody against MMP12, and an aptamer against MMP12.
  • the diagnostic agent utilizes the protease activity of MMP12 and includes a conjugate of a peptide having a site cleavable by MMP12 as a substrate site for MMP12 and a labeling substance.
  • the peptide having a site cleavable by MMP12 and the labeling substance may be directly bonded or may be bonded via a linker.
  • the peptide having a site cleavable by MMP12 and the labeling substance may be bonded by any known method with or without a linker.
  • the linker may be interchangeably referred to as a "spacer.” Examples of linkers include, but are not limited to, saturated hydrocarbon groups having 5 to 12 carbon atoms or 1 to 5 amino acids that may have a substituent.
  • the linker may be bonded to the N-terminus, C-terminus, or both of the peptide.
  • Linkers that separate the peptide recognized by the protein to be detected and the labeling substance are well known, and one of skill in the art can easily select such a linker.
  • the diagnostic agent may be an in vitro diagnostic agent or an in vivo diagnostic agent.
  • the length of the peptide having a site cleavable by MMP12 is not particularly limited, but from the viewpoint of MMP12 detection sensitivity, it is preferable that the peptide consists of a sequence of 8 to 25 amino acids, more preferably a sequence of 10 to 20 amino acids, and even more preferably a sequence of 12 to 18 amino acids.
  • Peptides having a site cleavable by MMP12 can be determined based on the peptide sequence of a protein known to be a selective substrate of MMP12.
  • Proteins known to be selective substrates of MMP12 include, for example, human CCL-14 (UniPlot Q16627), mouse CXCL1 (UniPlot A2RTH0), mouse CXCL2 (UniPlot P12850), mouse CXCL3 (UniPlot P10889), mouse CXCL5 (UniPlot P50228), human CXCL1 (UniPlot P09341), human CXCL2 (UniPlot P19875), human CXCL3 (UniPlot P19876), human CXCL5 (UniPlot P42830), human CXCL6 (P80162), human CXCL7 (UniPlot P02775), human CXCL8 (UniPlot P10145), human IFN- ⁇ -2 (UniPlot P01563), and human IFN- ⁇ -6 (UniPlot P10145).
  • human CCL-14 UniPlot Q16627
  • mouse CXCL1 UniPlot A2RTH0
  • A0A0A0MQU8 human IFN- ⁇ -8 (UniPlot P32881), human IFN- ⁇ -10 (UniPlot P01566), human IFN- ⁇ (UniPlot P01579), mouse IFN- ⁇ (UniPlot P01580), etc. See, for example, J Biol Chem 2012, 287, 5848-60, Blood 2008, 112, 3455-64, Nat Med. 2014, 20, 493-502, Nat Commun. 2018, 9, 2416.
  • the peptide having a site cleavable by MMP12 is selected from the group consisting of human CCL-14 (hCCL-14), mouse CXCL1 (mCXCL1), mouse CXCL2 (mCXCL2), mouse CXCL3 (mCXCL3), mouse CXCL5 (mCXCL5), human CXCL1 (hCXCL1), human CXCL2 (hCXCL2), human CXCL3 (hCXCL3), human CXCL5 (hCXCL5), human CXCL6 (hCXCL6), human CXCL7 (hCXCL7), human CXCL8 (hCXCL8), human INF- ⁇ -2 (hINF- ⁇ -2), human INF- ⁇ -6 (hINF- ⁇ -6), human INF- ⁇ -
  • the peptide comprises a sequence of 8 to 25 consecutive amino acids, preferably 10 to 20 amino acids, and more preferably 12 to 18 amino acids, including an amino acid sequence having a site cleavable by
  • Sites in peptides that are specifically recognized and cleavable by MMP12 are known, and examples include, but are not limited to, ELRCXC (cleavage between E and LRCXC, where X is preferably Q or V), PLGLAG (cleavage between PLG and LAG, see J.Am.Chem.Soc., 2012, 134, 13730-1373), PLGLR (cleavage between LG and LR, see Chemistry and Biology, 2015, 22, 1122-1133), FGALT (cleavage between FGA and LT, see above), VYDLK (cleavage between VYD and LK, see above), and PWAWR (cleavage between PWA and WR, see above).
  • ELRCXC cleavage between E and LRCXC, where X is preferably Q or V
  • PLGLAG cleavage between PLG and LAG, see J.Am.Chem.Soc., 2012, 134, 13730-1373
  • PLGLR clea
  • the amino acid sequence of a peptide having a site cleavable by MMP12 is the same as or close to the natural amino acid sequence.
  • a peptide having a site cleavable by MMP12 that is the same as or close to the natural amino acid sequence is a partial peptide or a variant thereof that contains the ELRCXC sequence of CXC ( ⁇ -chemokine), a subfamily of chemokine proteins.
  • the peptide having a site cleavable by MMP12 is a peptide consisting of an 8-25 amino acid sequence having the amino acid sequence ELRCXC (X is Q or V).
  • X is Q or V.
  • the sequences upstream and downstream of ELRCXC can be designed by a person skilled in the art using ordinary skill based on the amino acid sequence of the CXC protein, provided that the peptide has the cleavage ability of MMP12.
  • the peptide having a site cleavable by MMP12 is either (i) or (ii) below: (i) a partial sequence of any of the amino acid sequences of human CXCL1 (UniPlot P09341), human CXCL2 (UniPlot P19875), human CXCL3 (UniPlot P19876), human CXCL5 (UniPlot P42830), human CXCL8 (UniPlot P10145), mouse CXCL1 (UniPlot A2RTH0), mouse CXCL2 (UniPlot P12850), mouse CXCL3 (UniPlot P10889), or mouse CXCL5 (UniPlot P50228), wherein the ELRC (ii) A peptide having an amino acid sequence of XC (X is Q or V), a sequence of at least 1 to 5 amino acids upstream thereof, and a sequence of 1 or 2 or more amino acids downstream thereof, with a total length of 8 to 25 amino acids; (X is Q or
  • the peptide having a site cleavable by MMP12 is any of the following (i) to (vi): (i) a peptide having any of the amino acid sequences of SEQ ID NOs: 1 to 9; (ii) a peptide consisting of only any of the amino acid sequences of SEQ ID NOs: 1 to 9; (iii) a peptide consisting of a partial sequence of a peptide having any of the amino acid sequences of SEQ ID NOs: 1 to 9, which has the portion ELRCXC (X is Q or V); (iv) a peptide of the above (i) to (iii), in which one or more of the amino acids 1 to 5 of any of the amino acid sequences of SEQ ID NOs: 1 to 9 have been substituted, one or more of the amino acids 12 to 13 of any of the amino acid sequences of SEQ ID NOs: 1 to 9 have been substituted, or both one or more of the amino acids 1 to 5 of any of the
  • Amino acid sequence of peptide derived from human CXCL1 ASVAT ELRCQC LQ (SEQ ID NO: 1) Amino acid sequence of a peptide derived from human CXCL2 APLAT ELRCQC LQ (SEQ ID NO: 2) Amino acid sequence of peptide derived from human CXCL3 ASVVT ELRCQC LQ (SEQ ID NO: 3) Amino acid sequence of a peptide derived from human CXCL5 AAVLR ELRCVC LQ (SEQ ID NO: 4) Amino acid sequence of a peptide derived from human CXCL8 PRSAK ELRCQC IK (SEQ ID NO:5) Amino acid sequence of peptide derived from mouse CXCL1 APIAN ELRCQC LQ (SEQ ID NO: 6) Amino acid sequence of peptide derived from mouse CXCL2 AVVAS ELRCQC LK (SEQ ID NO: 7) Amino acid sequence of peptide derived from mouse
  • any of the peptides (i) to (v) is a peptide consisting of a sequence of 8 to 25 amino acids, preferably a peptide consisting of a sequence of 10 to 20 amino acids, and more preferably a peptide consisting of a sequence of 12 to 18 amino acids.
  • the amino acid sequence at positions 1-12 of hCCL-14 is TKTESSSRGPYH (SEQ ID NO:10).
  • the cleavable sites are TE at positions 3-4 and SS at positions 6-7.
  • the amino acid sequence at positions 61-74 of hCCL-14 is DKWVQDYIKDMKEN (SEQ ID NO:11).
  • the cleavable sites are MK at positions 11-12 and KE at positions 12-13.
  • the amino acid sequence at positions 154-165 of hIFN- ⁇ -10 is STNLQKRLRRKD (SEQ ID NO:12).
  • the cleavable sites are LQ at positions 4-5 and LR at positions 8-9.
  • the amino acid sequence at positions 150-161 of hIFN- ⁇ -10 is SLSFSTNLQKRL (SEQ ID NO:13).
  • the cleavable site is LQ at positions 8-9.
  • the amino acid sequence at positions 154-165 of hIFN- ⁇ -6 is SRNLQERLRRKE (SEQ ID NO:14).
  • the amino acid sequence of positions 150-161 of hIFN- ⁇ -6, in which LQ at positions 4-5 and LR at positions 8-9 are cleavable sites, is SFSSSRNLQERL (SEQ ID NO: 15).
  • the amino acid sequence of positions 154-165 of hIFN- ⁇ -2, in which LQ at positions 8-9 are cleavable sites, is STNLQESLRRKE (SEQ ID NO: 16).
  • the amino acid sequence of positions 150-161 of hIFN- ⁇ -2, in which LQ at positions 4-5 and LR at positions 8-9 are cleavable sites, is SFSLSTNLQESL (SEQ ID NO: 17).
  • the amino acid sequence of positions 154-165 of hIFN- ⁇ -8, in which LQ at positions 8-9 and LR at positions 8-9 are cleavable sites, is SINLQKRLKSKE (SEQ ID NO: 18).
  • the amino acid sequence of positions 150-161 of hIFN- ⁇ -8, in which LQ at positions 4-5 and LK at positions 8-9 are cleavable sites, is SFSLSINLQKRL (SEQ ID NO: 19).
  • LQ at positions 8-9 is the cleavable site of the amino acid sequence of positions 126-139 of hIFN- ⁇ LNVQRKAIHELIQV (SEQ ID NO: 20)
  • EL at positions 10-11 is the cleavable site of the amino acid sequence of positions 130-143 of hIFN- ⁇ RKAIHELIQVMAEL (SEQ ID NO: 21)
  • EL at positions 6-7 is the cleavable site of the amino acid sequence of positions 151-165 of hIFN- ⁇ KRKRSQMLFRGRRAS (SEQ ID NO: 22)
  • ML at positions 7-8 is the cleavable site of the amino acid sequence of positions 125-137 of mIFN- ⁇ QVQRQAFNEKIRV (SEQ ID NO: 23)
  • EL at positions 9-10 is the cleavable site of the amino acid sequence of positions 128-141 of mIFN- ⁇ RQAFNEKIRVVHQL (SEQ ID NO:
  • Labeling substances include radioisotopes, enzymes, fluorescent dyes, and contrast agents (e.g., paramagnetic ions).
  • radioisotopes examples include [ 3H ], [ 11C ], [ 14C ], [ 18F ], [ 34Cl ], [ 38Cl ], [ 75Br ], [ 76Br ], [ 77Br ], [ 80Br ], [ 82Br ], [ 121I ], [ 123I ], [ 124I ], [ 125I ], [ 127I ], [ 131I ], [ 64Cu ], [ 90Y ], [ 67Ga ], [ 51Cr ], [ 192Ir ], [ 99Mo ], [ 153Sm ], and [ 201Tl ].
  • Fluorescent dyes include phenyl and its derivatives, naphthalene and its derivatives such as 5-dimethylaminonaphthalene-1-sulfonic acid and hydroxynaphthalenes, anthracene and its derivatives such as 9,10-diphenylnaphthalene and 9-methylanthracene, pyrene and its derivatives such as N-(1-pyrene) iodoacetamide and hydroxypyrenes, biphenyl and its derivatives, acridine and its derivatives such as hydroxyacridines and 9-methylacridine, coumarin and its derivatives such as 7-dialkylamino-4-methylcoumarin and 4-bromomethyl-7-methoxycoumarin, xanthene and its derivatives, phthalocyanine and its derivatives, stilbene and its derivatives such as 6,6'-dibromostilbene and hydroxystilbenes, furan and its derivatives, oxazole and its derivatives
  • amidofluorescein and derivatives thereof such as fluorescein-5-maleimide
  • rhodamine and derivatives thereof such as tetramethylrhodamine, tetraethylrhodamine, carboxytetramethylrhodamine, BODIPY® and derivatives thereof
  • eosin and derivatives thereof erythrosine and derivatives thereof such as hydroxyerythrosines and 5-iodoacetamidoerythrosine
  • resorufin and derivatives thereof such as hydroxyresorufin
  • quinoline and derivatives thereof such as 6-hydroxyquinoline and 6-aminoquinoline
  • carbazole and derivatives thereof such as N-methylcarbazole
  • cyanine and derivatives thereof such as hydroxycyanine, carbocyanine and derivatives thereof such as phenylcarbocyanine, pyridinium salts and derivatives thereof such as 4-(4-dialkyldiamidostyryl)-N
  • Fluorescent dyes having a maximum excitation wavelength in the range of 400 nm to 1200 nm are suitable for optical imaging, and fluorescent dyes having a maximum excitation wavelength (or maximum absorption wavelength) in the near infrared range of 650 nm to 900 nm are preferred in that they enable fluorescent imaging of deep tissues of a subject.
  • Fluorescent dyes such as fluorescein and its derivatives, rhodamine and its derivatives, BODIPY (registered trademark) and its derivatives, cyanine and its derivatives, etc., can be advantageously selected from molecules having a fluorescence emission wavelength in the range of 400 to 900 nanometers, particularly 500 to 900 nanometers, and more particularly 600 to 900 nanometers.
  • Specific fluorescent dyes are the following compounds:
  • the diagnostic agent is a fluorescent probe for detecting MMP12, which comprises a peptide having a site cleavable by MMP12 and a fluorophore bound to the peptide.
  • the peptide having a site cleavable by MMP12 and the fluorophore may be bound directly or via a linker.
  • the peptide having a site cleavable by MMP12 can be synthesized by a known method.
  • the fluorophore can be formed by binding any of the fluorescent dyes listed above to the middle or end of the amino acid sequence of the peptide.
  • the diagnostic agent is a fluorescent probe for detecting MMP12, which comprises a conjugate including a peptide having a site cleavable by MMP12, a fluorophore bound to one end of the peptide, and a quencher bound to the other end of the peptide.
  • the peptide having a site cleavable by MMP12 and the quencher may be bound directly or via a linker. Examples of linkers include, but are not limited to, saturated hydrocarbon groups having 5 to 12 carbon atoms or 3 to 5 amino acids, which may have a substituent.
  • the quencher may be formed by binding a quencher compound to the middle or end of the amino acid sequence of the peptide.
  • fluorophores and quenchers When both fluorophores and quenchers are present in a fluorescent probe molecule, the quencher suppresses the fluorescence of the fluorophore, causing the fluorescence to disappear, but the fluorescence increases upon cleavage of the amino acid sequence of the peptide.
  • FRET fluorescence resonance energy transfer
  • Fluorophores include those formed by binding the fluorescent dye of the labeling substance to a peptide, and preferred examples include fluorescein and its derivatives, cyanine and its derivatives, rhodamine and its derivatives, BODIPY (registered trademark) and its derivatives, coumarin and its derivatives, anthracene and its derivatives, and compounds containing aminobenzyl.
  • a quencher is a compound or part thereof that, when spatially close to a fluorophore, causes the fluorescent dye to lose its fluorescence through energy transfer, stacking, etc.
  • quenching compounds include compounds in which phenyl groups are bonded to the nitrogen atoms at the 3 and 6 positions of the xanthene ring (e.g., the QSY series compounds from ThermoFisher Scientific), compounds in which aromatic rings are bonded to the nitrogen atoms at the 3 and 6 positions of the xanthene ring of rhodamine compounds (SiR dyes) in which the oxygen atoms of rhodamine or its derivatives are replaced with silicon atoms, making them non-fluorescent with a fluorescence quantum yield of 0.001 or less (e.g., the SinQ series compounds invented by one of the inventors, Dr. Kenjiro Hanaoka; see J. Am. Chem. Soc., 137, 4759-4765 (2015)), (e.g., the Black Hole Quencher (BHQ) series compounds from Sigma-Aldrich), and compounds containing dinitrophenol.
  • phenyl groups are bonded to the nitrogen atoms at
  • the fluorescent dye and quenching compound can be bound to a peptide having a site cleavable by MMP12 by known methods, such as by reacting the functional groups (carboxyl group, amino group, etc.) of the fluorescent dye and quenching compound with the functional group of the terminal amino acid of the peptide, or by forming a covalent bond via a linker.
  • the efficiency of peptide cleavage by MMP can be analyzed by high performance liquid chromatography. An amino acid sequence with high cleavage activity and selectivity is determined and completed as a probe.
  • the immune-mediated inflammatory disease characterized by increased expression of MMP12 is selected from the group consisting of vasculitis syndromes, granulomatous vasculitis, IgG4, inflammatory bowel disease, sarcoidosis, tuberculous mycobacterial disease, and nontuberculous mycobacterial disease.
  • a diagnostic or detection kit for diagnosing or detecting an immune-mediated inflammatory disease characterized by increased expression of MMP12, the diagnostic or detection kit comprising a substance that specifically interacts with MMP12.
  • the substance that specifically interacts with MMP12 may be the substance that specifically interacts with MMP12 described in relation to the diagnostic agent of the third embodiment.
  • the labeling substance described in relation to the first or third embodiment may be bound to the substance that specifically interacts with MMP12.
  • the diagnostic agent of the third embodiment may be used as the substance that specifically interacts with MMP12.
  • the diagnostic or detection kit may contain other substances necessary in the reaction to detect the level of MMP12, and which do not adversely affect the reaction when stored in the presence of other substances, such as various reagents such as color-developing reagents, labeled secondary antibodies, and blocking agents.
  • the diagnostic or detection kit may further contain buffer solutions, washing solutions, instructions for use, etc.
  • the substance that specifically interacts with MMP12 may be provided in a state immobilized on a suitable solid support.
  • suitable solid supports include various carriers made of insoluble polysaccharides (e.g., agarose, dextran, cellulose, etc.), synthetic resins, glass, metals, etc., that are used in conventional antigen-antibody reactions, such as microplates, tubes, membranes, columns, beads, sensor chips, etc. Immobilization may be performed using physical adsorption, or chemical bonds that are normally used to insolubilize and immobilize proteins may be used.
  • the diagnostic or detection kit of the present invention can be applied to clinical tests such as the diagnosis, detection, or monitoring of immune-mediated inflammatory diseases characterized by increased expression of MMP12, and can be used in drug discovery research, etc.
  • the substance that specifically interacts with MMP12 is a substance that binds to MMP12 selected from the group consisting of an antibody against MMP12, an antigen-binding fragment of an antibody against MMP12, and an aptamer against MMP12.
  • a diagnostic or detection kit comprising such a substance that binds to MMP12 can be used as an in vitro diagnostic or detection kit.
  • the substance that specifically interacts with MMP12 is a substance that is cleaved by MMP12 due to the protease activity of MMP12, for example a peptide having a site that can be cleaved by MMP12.
  • the substance that is cleaved by MMP12 may be bound to a labeling substance described in the third aspect, or a fluorophore and a quencher may be bound to the substance.
  • a diagnostic or detection kit comprising such a substance that is cleaved by MMP12 due to the protease activity of MMP12 can be used as an in vivo diagnostic or detection kit.
  • a method for screening for a substance effective in treating an immune-mediated inflammatory disease characterized by increased expression of MMP12 comprising: measuring the level of MMP12 in a biological sample obtained from a subject after administration of a test substance; and, if the level of MMP12 is reduced by administration of the test substance, selecting the test substance as a candidate substance effective in treating an immune-mediated inflammatory disease characterized by increased expression of MMP12.
  • the biological sample expressing MMP12 may be a body fluid, tissue, or cells.
  • the subject is a human suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12 or a non-human mammalian model of an immune-mediated inflammatory disease characterized by increased expression of MMP12.
  • the level of MMP12 can be measured using methods similar to those described with respect to the first aspect of the invention.
  • the level of MMP12 in a biological sample obtained from a subject administered a test substance is compared with a control value, and if the former is lower than the latter, it is determined that the test substance has reduced MMP12 in the biological sample, and the test substance can be selected as a candidate substance effective in treating an immune-mediated inflammatory disease characterized by increased expression of MMP12.
  • the control value may be the level of MMP12 in a biological sample obtained from the same subject before administration of the test substance, or the average or median value calculated from measurements of the MMP12 levels in multiple healthy subjects, or a cutoff value separating a group of healthy subjects from a group of patients diagnosed with an immune-mediated inflammatory disease characterized by increased expression of MMP12, or a certain value that is higher than the average or median value calculated from measurements of the MMP12 levels in multiple healthy subjects and lower than the average or median value calculated from measurements of the MMP12 levels in multiple patients suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12.
  • a therapeutic agent for immune-mediated inflammatory diseases characterized by increased expression of MMP12, which comprises an MMP12 inhibitor.
  • MMP12 degrades extracellular matrices such as collagen, elastin, fibronectin, fibrin, fibrinogen, and proteoglycans, causing the rupture of connective tissues such as the elastic lamina in blood vessel walls and glomeruli.
  • the MMP12 inhibitor refers to a substance that binds to MMP12 and inhibits the substrate decomposition action of MMP12 and subsequent tissue damage, and the same substances as those described with respect to the "substance that binds to MMP12" in the method of the first embodiment can be used.
  • the MMP12 inhibitor can be contained as an active ingredient of a therapeutic agent.
  • the MMP12 inhibitor may be a commercially available MMP12 inhibitor or an MMP12 inhibitor obtained or produced by a known method described in the literature.
  • Zinc is required for activation of MMP12, and in some embodiments, the MMP12 inhibitor is an MMP12 inhibitor that inhibits zinc binding to the active center region of MMP12 or the catalytic action of MMP12 by zinc.
  • MMP12 inhibitors include, but are not limited to, selective MMP12 inhibitors such as MMP408 (CAS No. 1258003-93-8) and RXP470.1 (CAS No. 891198-31-5.
  • the MMP12 inhibitor can be selected from the group consisting of an antibody against MMP12 (anti-MMP12 antibody), an antigen-binding fragment of an anti-MMP12 antibody, and an aptamer against MMP12.
  • the route of administration of the therapeutic agent for immune-mediated inflammatory diseases characterized by increased expression of MMP12, which contains the MMP12 inhibitor of this embodiment, is not particularly limited, and may be an oral or parenteral agent.
  • the agent may be in the form of an oral agent, such as a tablet, capsule, granule, powder, or syrup.
  • the agent may also be in the form of a parenteral agent, such as an injection, eye drops, nasal drops, ointment, cream, lotion, gel, or spray. These preparations can be manufactured by known methods.
  • solubilizers such as gum tragacanth, gum arabic, sucrose fatty acid esters, lecithin, olive oil, soybean oil, PEG 400, etc.
  • excipients such as starch, mannitol, lactose, etc.
  • binders such as methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, etc.
  • disintegrants such as crystalline cellulose, calcium carboxymethylcellulose, etc.
  • lubricants such as talc, magnesium stearate, etc.
  • flow improvers such as light anhydrous silicic acid, etc.
  • a typical example of a formulation for parenteral administration is an injection.
  • an injection preparation can be prepared by dissolving or diluting an anti-MMP12 antibody or an aptamer for MMP12, which is an MMP12 inhibitor, with physiological saline or a buffer solution for intravenous injection.
  • known methods can be appropriately used, such as changing the solvent, changing the salt contained in the solution, changing the salt strength, or including the MMP12 inhibitor in cyclodextrins.
  • Subcutaneous, intramuscular, and intravenous injections can be produced by adding a pH regulator, a buffer, a stabilizer, an isotonicity agent, a local anesthetic, etc.
  • the eye drops may be any of aqueous eye drops, non-aqueous eye drops, suspension eye drops, emulsion eye drops, eye ointments, etc.
  • a preparation can be prepared by a method for preparing a preparation known to those skilled in the art, by blending a pharma- ceutically acceptable carrier, particularly an acceptable carrier for eye drops, such as an isotonicity agent, a chelating agent, a stabilizer, a pH regulator, a preservative, an antioxidant, a solubilizing agent, a thickening agent, etc., as necessary, as a composition suitable for the administration form.
  • a pharma- ceutically acceptable carrier particularly an acceptable carrier for eye drops, such as an isotonicity agent, a chelating agent, a stabilizer, a pH regulator, a preservative, an antioxidant, a solubilizing agent, a thickening agent, etc.
  • the MMP12 inhibitor When preparing eye drops, the MMP12 inhibitor is dissolved or suspended in an aqueous solvent such as sterilized purified water or saline, or a non-aqueous solvent such as a vegetable oil such as cottonseed oil, soybean oil, sesame oil, or peanut oil, and the like, adjusted to a predetermined osmotic pressure, and subjected to a sterilization treatment such as filtration sterilization.
  • an aqueous solvent such as sterilized purified water or saline, or a non-aqueous solvent such as a vegetable oil such as cottonseed oil, soybean oil, sesame oil, or peanut oil, and the like.
  • a sterilization treatment such as filtration sterilization sterilization.
  • aqueous base for eye drops commonly used additives such as an isotonicity agent, a buffer, and a preservative are appropriately blended.
  • isotonicity agents include sodium chloride, potassium chloride, polyhydric alcohols, sugars, etc.
  • buffers include sodium borate, sodium citrate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc.
  • preservatives include benzethonium hydrochloride, benzalkonium hydrochloride, chlorobutanol, etc.
  • stabilizers such as glycerin or polysorbate 80 and pH adjusters are added as necessary.
  • Nasal drops and sprays are prepared as liquid preparations containing an MMP12 inhibitor. Nasal drops are preferably placed in a container with a shape suitable for application into the nasal cavity.
  • Sprays are prepared in a form in which the liquid preparation is stored in a spray container containing a propellant.
  • the propellant is a gas such as carbon dioxide gas.
  • Sprays may be used not only on the epidermis but also in the nasal cavity or oral cavity, and a spray container with a shape suitable for the mode of use is appropriately selected for preparation.
  • the effective dose of the MMP12 inhibitor is changed as appropriate depending on various factors such as the patient's condition and symptoms. Usually, it can be determined as appropriate from the range of 0.001 to 10 mg/kg/day, preferably 0.01 to 1 mg/kg/day. However, it can be adjusted depending on the administration form, such as using a high dose for systemic administration and a low dose for local administration.
  • the daily dose of the MMP12 inhibitor can be administered once a day or in several divided doses. Conversely, it is also possible to administer the drug once every two or more days by administering a dose for several days at once.
  • the dose of the MMP12 inhibitor can also be administered once a day or in several divided doses.
  • administer the drug once every two or more days by injecting a dose for several days at once. It is also possible to administer the drug continuously by infusion, etc.
  • parenteral agents such as eye drops, nasal drops, ointments, lotions, creams, gels, and sprays are administered locally
  • the amount of MMP12 inhibitor in the topical treatment, the frequency of local administration, and the area of application can be adjusted as appropriate.
  • administration does not necessarily have to be continuous or regular, and can be performed at appropriate intervals depending on changes in symptoms. If a single administration results in cure or remission, there is no need to administer multiple times. Administration may be resumed if symptoms recur or worsen.
  • the method of administration of the therapeutic agent of this embodiment is not particularly limited, but since vasculitis syndrome, which is a representative example of a disease to be treated, causes inflammation in blood vessels, systemic administration by intravenous injection or drip infusion is preferable.
  • vasculitis syndrome which is a representative example of a disease to be treated, causes inflammation in blood vessels
  • systemic administration by intravenous injection or drip infusion is preferable.
  • an anti-MMP12 antibody or aptamer is used as the MMP12 inhibitor, it is considered difficult to deliver a therapeutically effective amount to the affected area by oral administration, so parenteral administration is mainly selected.
  • parenteral administration is mainly selected.
  • the administration period can be appropriately adjusted depending on the patient's condition.
  • the administration dose during the administration period can be appropriately adjusted, but examples of the administration form include continuous administration of a fixed amount, or administration of a relatively high dose only at the beginning of administration followed by a transition to a smaller maintenance dose.
  • the therapeutic agent containing the MMP12 inhibitor of this embodiment can also be used in combination with components that contribute to the treatment of immune-mediated inflammatory diseases characterized by increased expression of MMP12, independent of the MMP12 inhibitor, or other additives.
  • the components used in combination with the MMP12 inhibitor can be administered simultaneously with the MMP12 inhibitor or at different times, and the administration routes for both can be the same or different.
  • the components used in combination can be purchased commercially or obtained or prepared by methods described in the literature.
  • the amount of each component to be applied can be appropriately determined based on publicly known information.
  • Item 1. A method for detecting an immune-mediated inflammatory disease in a subject, characterized by increased expression of MMP12, comprising: A method comprising measuring the level of MMP12 in a biological sample obtained from a subject. Item 2. Item 2. The method according to Item 1, wherein the measuring of the level of MMP12 is measuring the level of MMP12 protein. Item 3. contacting the biological sample obtained from the subject with a substance that binds MMP12; Item 2. The method according to Item 1, wherein measuring the level of MMP12 comprises measuring the level of a complex between MMP12 and a substance that binds to MMP12. Item 4. Item 2.
  • the immune-mediated inflammatory disease characterized by increased expression of MMP12 is selected from the group consisting of vasculitis syndrome, granulomatous vasculitis, IgG4-related disease, inflammatory bowel disease, sarcoidosis, tuberculous mycobacterial disease, and nontuberculous mycobacterial disease.
  • Item 5. Item 10. The method of item 1, wherein the biological sample is blood, serum, or plasma.
  • Item 6. Item 2.
  • the method according to item 1, wherein the immune-mediated inflammatory disease characterized by increased expression of MMP12 is Takayasu's arteritis.
  • measuring the level of MMP12 comprises measuring a change caused by cleavage of a peptide having a site cleavable by MMP12.
  • Item 8. The method is a method for predicting the likelihood of developing an immune-mediated inflammatory disease characterized by increased expression of MMP12 in a subject, The method further comprises comparing the level of MMP12 in the biological sample obtained from the subject to a reference value; Item 8.
  • the method is a method for predicting the prognosis of a subject suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12, the subject has been treated for an immune-mediated inflammatory disease characterized by increased expression of MMP12;
  • the method further comprises comparing the level of MMP12 in the biological sample obtained from the subject to a reference value; Item 8.
  • Item 10 The method according to any one of Items 1 to 7, wherein a high level of MMP12 in a biological sample obtained from the subject compared to a reference value indicates a high possibility of relapse of an immune-mediated inflammatory disease characterized by increased expression of MMP12 in the subject.
  • the method is for predicting a post-treatment condition of a subject suffering from an immune-mediated inflammatory disease characterized by increased expression of MMP12, the subject has been treated for an immune-mediated inflammatory disease characterized by increased expression of MMP12;
  • the method further comprises comparing the level of MMP12 in the biological sample obtained from the subject to a reference value; Item 8.
  • Item 11 The method according to any one of Items 1 to 7, wherein when the level of MMP12 in the biological sample obtained from the subject is lower compared to the reference value, this indicates that an immune-mediated inflammatory disease characterized by increased expression of MMP12 in the subject is likely to be in remission.
  • the method is a method for evaluating the timing of administration of a therapeutic agent for an immune-mediated inflammatory disease characterized by increased expression of MMP12 to a subject suffering from the immune-mediated inflammatory disease characterized by increased expression of MMP12, The method further comprises comparing the level of MMP12 in the biological sample obtained from the subject to a reference value; Item 8. The method according to any one of Items 1 to 7, wherein a lower level of MMP12 in a biological sample obtained from the subject compared to a reference value is an indication for ceasing administration of the drug to the subject.
  • Item 12. A biomarker for the diagnosis of immune-mediated inflammatory diseases, including MMP12, characterized by increased expression of MMP12.
  • Item 13 Item 13.
  • Item 14 A diagnostic agent for immune-mediated inflammatory diseases characterized by increased expression of MMP12, comprising a substance that specifically interacts with MMP12. Item 15. Item 15. The diagnostic agent according to Item 14, which is an in vivo diagnostic agent comprising a conjugate of a peptide having a site cleavable by MMP12 and a labeling substance. Item 16. the substance that specifically interacts with MMP12 is a peptide having a site cleavable by MMP12; Item 16.
  • the diagnostic agent according to Item 15, wherein the conjugate comprises a peptide having a site cleavable by MMP12, a fluorophore bound to one end of the peptide, and a quencher bound to the other end of the peptide.
  • the labeling substance includes a fluorescent dye having a fluorescent group
  • the conjugate includes a conjugate comprising a peptide having a site cleavable by MMP12, a fluorescent group bound to one end of the peptide, and a quencher group bound to the other end of the peptide.
  • the diagnostic agent according to any one of Items 14 to 17, wherein the peptide having a site cleavable by MMP12 is either the following (i) or (ii): (i) A peptide having a partial sequence of any of the amino acid sequences of human CXCL1 (UniPlot P09341), human CXCL2 (UniPlot P19875), human CXCL3 (UniPlot P19876), human CXCL5 (UniPlot P42830), human CXCL8 (UniPlot P10145), mouse CXCL1 (UniPlot A2RTH0), mouse CXCL2 (UniPlot P12850), mouse CXCL3 (UniPlot P10889), and mouse CXCL5 (UniPlot P50228), which has the amino acid sequence of ELRCXC (X is Q or V), at least 1 to 5 amino acid sequences upstream thereof, and one or more amino acid sequences downstream thereof, and has a total length of 8 to 25 amino acids.
  • Item 20 The diagnostic agent according to any one of Items 14 to 17, wherein the peptide having a site cleavable by MMP12 is any one of the following (i) to (v): (i) a peptide having an amino acid sequence of any one of SEQ ID NOs: 10 to 32; (ii) a peptide consisting of only any one of the amino acid sequences of SEQ ID NOs: 10 to 32; (iii) a peptide consisting of a partial sequence of a peptide having any one of the amino acid sequences of SEQ ID NOs: 10 to 32, which has a site cleaved by MMP12, and which has a total length of 8 to 25 amino acids; (iv) A peptide in which one or two of the amino acids other than the amino acid having the site cleaved by MMP12 in any of the above peptides (i) to (iii) are substituted.
  • the diagnostic agent according to any one of Items 14 to 21, wherein the peptide having a site cleavable by MMP12 is a peptide consisting of a sequence of 12 to 18 amino acids.
  • the labeling substance includes a fluorescent dye having a fluorescent group, and the fluorescent dye is, for example, phenyl and derivatives thereof, naphthalene and derivatives thereof such as 5-dimethylaminonaphthalene-1-sulfonic acid and hydroxynaphthalenes, anthracene and derivatives thereof such as 9,10-diphenylnaphthalene and 9-methylanthracene, pyrene and derivatives thereof such as N-(1-pyrene)iodoacetamide and hydroxypyrenes, biphenyl and derivatives thereof, acridine and derivatives thereof such as hydroxyacridines and 9-methylacridine, coumarin and derivatives thereof such as 7-dialkylamino-4-methylcoumarin and 4-bromo
  • the diagnostic agent according to Item 15 or 16 which is at least one fluorescent dye selected from midofluorescein and derivatives thereof such as fluorescein-5-maleimide, rhodamine and derivatives thereof such as tetramethylrhodamine, tetraethylrhodamine, and carboxytetramethylrhodamine, BODIPY (registered trademark) and derivatives thereof, eosin and derivatives thereof, erythrosine and derivatives thereof such as hydroxyerythrosines and 5-iodoacetamidoerythrosine, resorufin and derivatives thereof such as hydroxyresorufin, quinoline and derivatives thereof such as 6-hydroxyquinoline and 6-aminoquinoline, carbazole and derivatives thereof such as N-methylcarbazole, cyanine and derivatives thereof such as hydroxycyanine, carbocyanine and derivatives thereof such as phenylcarbocyanine, pyridinium salts and derivatives thereof such as
  • Item 26 The diagnostic agent according to Item 15 or 16, wherein the labeling substance comprises a fluorescent dye having a fluorescent group, and the fluorescent dye is at least one fluorescent dye selected from the group consisting of fluorescein and derivatives thereof, rhodamine and derivatives thereof, BODIPY (registered trademark) and derivatives thereof, and cyanine and derivatives thereof.
  • the fluorescent dye is at least one fluorescent dye selected from the group consisting of fluorescein and derivatives thereof, rhodamine and derivatives thereof, BODIPY (registered trademark) and derivatives thereof, and cyanine and derivatives thereof.
  • the diagnostic agent according to any one of Items 14 to 26, wherein the immune-mediated inflammatory disease characterized by increased expression of MMP12 is selected from the group consisting of vasculitis syndrome, granulomatous vasculitis, IgG4-related disease, inflammatory bowel disease, sarcoidosis, tuberculous mycobacterial disease, and nontuberculous mycobacterial disease.
  • Item 28. A diagnostic kit for diagnosing an immune-mediated inflammatory disease characterized by increased expression of MMP12, the diagnostic kit comprising a substance that specifically interacts with MMP12. Item 29. Item 29.
  • the diagnostic kit according to Item 28, wherein the substance that specifically interacts with MMP12 is a substance that binds to MMP12 and is selected from the group consisting of an antibody against MMP12, an antigen-binding fragment of an antibody against MMP12, and an aptamer against MMP12. Item 30.
  • Item 29. The diagnostic kit according to Item 28, wherein the substance that specifically interacts with MMP12 comprises a peptide having a site cleavable by MMP12. Item 31.
  • Item 29. The diagnostic kit according to Item 28, wherein a labeling substance is bound to the peptide having a site cleavable by MP12. Item 32. Item 27.
  • the diagnostic kit according to Item 26 wherein a fluorophore is bound to one end of the peptide having a site cleavable by MP12, and a quencher is bound to the other end of the peptide.
  • Item 33 The diagnostic kit according to any one of Items 30 to 32, wherein the peptide having a site cleavable by MMP12 is either the following (i) or (ii): (i) A peptide having a partial sequence of any of the amino acid sequences of human CXCL1 (UniPlot P09341), human CXCL2 (UniPlot P19875), human CXCL3 (UniPlot P19876), human CXCL5 (UniPlot P42830), human CXCL8 (UniPlot P10145), mouse CXCL1 (UniPlot A2RTH0), mouse CXCL2 (UniPlot P12850), mouse CXCL3 (UniPlot P10889), and mouse CXCL5 (Uni
  • the peptide having a site cleavable by MMP12 is any one of the following (i) to (vi): (i) a peptide having an amino acid sequence of any one of SEQ ID NOs: 1 to 9; (ii) a peptide consisting of only any one of the amino acid sequences of SEQ ID NOs: 1 to 9; (iii) a peptide consisting of a partial sequence of a peptide having an amino acid sequence of any one of SEQ ID NOs: 1 to 9, which has a portion of ELRCXC (X is Q or V); (iv) A peptide according to any one of (i) to (iii) above, further comprising a substitution of one or more of the amino acids at positions 1 to 5 in the amino acid sequence of any one of SEQ ID NOs: 1 to 9, a substitution of one or more of the amino acids at positions 12 to 13 in the amino acid sequence of any one of SEQ ID NOs
  • Item 35 The diagnostic kit according to any one of Items 30 to 32, wherein the peptide having a site cleavable by MMP12 is any one of the following (i) to (v): (i) a peptide having an amino acid sequence of any one of SEQ ID NOs: 10 to 32; (ii) a peptide consisting of only any one of the amino acid sequences of SEQ ID NOs: 10 to 32; (iii) a peptide consisting of a partial sequence of a peptide having any one of the amino acid sequences of SEQ ID NOs: 10 to 32, which has a site cleaved by MMP12, and which has a total length of 8 to 25 amino acids; (iv) A peptide in which one or two of the amino acids other than the amino acid having the site cleaved by MMP12 in any of the above peptides (i) to (iii) are substituted.
  • the diagnostic kit according to any one of Items 30 to 37, wherein the peptide having a site cleavable by MMP12 is a peptide consisting of a sequence of 12 to 18 amino acids.
  • the labeling substance includes a fluorescent dye having a fluorescent group, and the fluorescent dye is, for example, phenyl and derivatives thereof, naphthalene and derivatives thereof such as 5-dimethylaminonaphthalene-1-sulfonic acid and hydroxynaphthalenes, anthracene and derivatives thereof such as 9,10-diphenylnaphthalene and 9-methylanthracene, pyrene and derivatives thereof such as N-(1-pyrene)iodoacetamide and hydroxypyrenes, biphenyl and derivatives thereof, acridine and derivatives thereof such as hydroxyacridines and 9-methylacridine, coumarin and derivatives thereof such as 7-dialkylamino-4-methylcoumarin and 4-brom
  • Item 32 The diagnostic kit according to Item 31, wherein the fluorescent dye is at least one selected from amidofluorescein and derivatives thereof such as fluorescein-5-maleimide, rhodamine and derivatives thereof such as tetramethylrhodamine, tetraethylrhodamine, and carboxytetramethylrhodamine, BODIPY (registered trademark) and derivatives thereof, eosin and derivatives thereof, erythrosine and derivatives thereof such as hydroxyerythrosines and 5-iodoacetamidoerythrosine, resorufin and derivatives thereof such as hydroxyresorufin, quinoline and derivatives thereof such as 6-hydroxyquinoline and 6-aminoquinoline, carbazole and derivatives thereof such as N-methylcarbazole, cyanine and derivatives thereof such as hydroxycyanine, carbocyanine and derivatives thereof such as phenylcarbocyanine, pyridinium salts and derivatives
  • Item 41 The diagnostic kit according to Item 31, wherein the labeling substance includes a fluorescent dye having a fluorescent group, and the fluorescent dye is at least one fluorescent dye selected from the group consisting of fluorescein and its derivatives, rhodamine and its derivatives, BODIPY (registered trademark) and its derivatives, and cyanine and its derivatives.
  • the labeling substance includes a fluorescent dye having a fluorescent group, and the fluorescent dye is at least one fluorescent dye selected from the group consisting of fluorescein and its derivatives, rhodamine and its derivatives, BODIPY (registered trademark) and its derivatives, and cyanine and its derivatives.
  • Item 42 Item 42.
  • the diagnostic kit according to any one of Items 28 to 41, wherein the immune-mediated inflammatory disease characterized by increased expression of MMP12 is selected from the group consisting of vasculitis syndrome, granulomatous vasculitis, IgG4-related disease, inflammatory bowel disease, sarcoidosis, tuberculous mycobacterial disease, and nontuberculous mycobacterial disease.
  • Item 43. A method for diagnosing an immune-mediated inflammatory disease characterized by increased expression of MMP12 in a subject, using the diagnostic agent according to any one of Items 14 to 27 or the diagnostic kit according to any one of Items 28 to 42.
  • Item 44 A method for diagnosing an immune-mediated inflammatory disease characterized by increased expression of MMP12 in a subject, using the diagnostic agent according to any one of Items 14 to 27 or the diagnostic kit according to any one of Items 28 to 42.
  • a method for screening for a substance effective in treating an immune-mediated inflammatory disease characterized by increased expression of MMP12 comprising: measuring the level of MMP12 in a biological sample obtained from the subject after administration of a test substance; and if administration of the test substance reduces the level of MMP12, selecting the test substance as a candidate substance effective for treating an immune-mediated inflammatory disease characterized by increased expression of MMP12.
  • Item 45 The method according to Item 44, wherein measuring the level of MMP12 comprises measuring the level of a complex between MMP12 and a substance that binds to MMP12.
  • Item 46 comprises measuring the level of a complex between MMP12 and a substance that binds to MMP12.
  • Item 45 wherein the substance that binds to MMP12 is selected from the group consisting of an antibody against MMP12, an antigen-binding fragment of an antibody against MMP12, and an aptamer against MMP12.
  • Item 47 The method according to any one of Items 44 to 46, wherein the immune-mediated inflammatory disease characterized by increased expression of MMP12 is selected from the group consisting of vasculitis syndrome, granulomatous vasculitis, IgG4-related disease, inflammatory bowel disease, sarcoidosis, tuberculous mycobacterial disease, and nontuberculous mycobacterial disease.
  • Item 48 Item 48.
  • Item 49 A therapeutic agent for immune-mediated inflammatory diseases characterized by increased expression of MMP12, which contains an MMP12 inhibitor.
  • Item 50 The therapeutic agent according to Item 49, wherein the immune-mediated inflammatory disease characterized by increased expression of MMP12 is selected from the group consisting of vasculitis syndrome, granulomatous vasculitis, IgG4-related disease, inflammatory bowel disease, sarcoidosis, tuberculous mycobacterial disease, and nontuberculous mycobacterial disease.
  • Item 51 Item 50.
  • the therapeutic agent according to Item 49, wherein the immune-mediated inflammatory disease characterized by increased expression of MMP12 includes ANCA-associated vasculitis.
  • Item 52. A method for treating an immune-mediated inflammatory disease in a subject, the method comprising administering to the subject in need of treatment for an immune-mediated inflammatory disease characterized by increased expression of MMP12 an effective amount of an MMP12 inhibitor.
  • the immune-mediated inflammatory disease characterized by increased expression of MMP12 is selected from the group consisting of vasculitis syndromes, granulomatous vasculitis, IgG4-related disease, inflammatory bowel disease, sarcoidosis, tuberculous mycobacterial disease, and nontuberculous mycobacterial disease.
  • the immune-mediated inflammatory disease characterized by increased expression of MMP12 comprises vasculitis or granulomatous vasculitis.
  • Example 1 Identification of vasculitis-specific molecules
  • Inflammation panel Immune response panel
  • Cardiovascular II panel and Cardiovascular III panel of Olink proximity extension assay (Uppsala)
  • Uppsala Olink proximity extension assay
  • GCA giant cell arteritis
  • TAK Takayasu arteritis
  • PAN polyarteritis nodosa
  • GPA granuromatosis with polyangiitis
  • GPA granuromatosis with polyangiitis
  • MPA microscopic polyangiitis
  • BD Behcet disease
  • RP relapsing polychondritis
  • AOSD adult onset Still disease
  • ROC analysis was performed using NPX values measured by Olink to compare the vasculitis syndrome patient group with the healthy control group, and the vasculitis syndrome patient group with the immune-mediated inflammatory disease patient group other than vasculitis syndrome.
  • MMP12 solid line
  • Example 2 Expression of MMP12 in tissues MMP12 is not expressed in peripheral blood immune cells. To clarify whether MMP12 originates from tissues, immunohistochemical staining of MMP12 was performed on vasculitis tissues of Takayasu's arteritis (TAK), giant cell arteritis (GCA), and granulomatosis with polyangiitis (GPA), which are immune-mediated inflammatory diseases characterized by increased expression of MMP12. MMP12 was stained with Goat anti-human MMP12 (R&D) and compared with HE staining of serial sections and immunohistochemical staining of CD68 and CD206.
  • TAK Takayasu's arteritis
  • GCA giant cell arteritis
  • GPA granulomatosis with polyangiitis
  • MMP12 was derived from tissue macrophages of vasculitis, as MMP12 was positive for CD68 and CD206, whereas alveolar macrophages were negative for MMP12, revealing the presence of an MMP12-positive phenotype in a portion of CD206-positive macrophages.
  • PET-CT score MMP12 was measured by ELISA (Thermo Fisher Scientific) using serum samples from patients with Takayasu's arteritis and giant cell arteritis before treatment.
  • the PET vascular activity score (PETVAS) used in PET-CT examinations is known to be associated with the relapse rate, which is an indicator of the prognosis of treatment for Takayasu's arteritis and giant cell arteritis (Arthritis Rheumatol 2018;70:439-449.), so the correlation was clarified by targeting patients who had both serum MMP12 values and PETVAS.
  • the PETVAS cutoff was set to 20 or higher, which has been reported to be associated with a high relapse rate
  • the serum MMP12 cutoff was set to a value (100 pg/ml) that separates healthy subjects from patients diagnosed by a doctor as suffering from an immune-mediated inflammatory disease characterized by increased MMP12 expression, and a fixed value (500 pg/ml) that is higher than the average value calculated from measuring the MMP12 levels of multiple healthy subjects and lower than the average value calculated from measuring the MMP12 levels of multiple patients suffering from an immune-mediated inflammatory disease characterized by increased MMP12 expression.
  • the method of this embodiment can be a better evaluation means than PETVAS and is useful for stratifying the risk of relapse in subjects.
  • vascular wall thickening persisted, reflecting latent disease activity (Figs. 9(B) and (C)).
  • Example 5 Evaluation of drug withdrawal using MMP12 as an index Among patients 1-19 with Takayasu's arteritis and giant cell arteritis who maintained remission without relapse, patient 19 maintained drug-free remission.
  • MMP12 was measured by ELISA (Thermo Fisher Scientific) using serum samples from patients who maintained drug-free remission before and after treatment. (result) After discontinuation of steroids and tocilizumab (Actemra®), a transient increase in serum MMP12 was observed, but it subsequently decreased and remained normal ( ⁇ 100 pg/ml). Normal MMP12 may be useful as an indicator for discontinuing medication.
  • imaging tests such as contrast CT, contrast MRI, and PET-CT, which are indicators of vasculitis activity.
  • SCG/ThpNkc mice are a model mouse for ANCA-associated vasculitis produced by crossbreeding two strains, MRL/lpr and BXSB, and are available from the Laboratory Animal Research Resource Bank of the National Institutes of Biomedical Innovation, Health and Nutrition (resource number nbio133).
  • MMP408 CAS No. 1258003-93-8
  • MMP12 selective inhibitor an MMP12 selective inhibitor
  • Example 8 Development of a probe for detecting MMP12 1.
  • Peptide Selection As a component of a probe for detecting MMP12, we searched for a substrate peptide that is highly selective for MMP12. First, in preparing the MMP12 detection probe, the peptide portion was investigated around the cleavage sites of known proteins known to be cleaved by MMP12, and candidate peptides No. 1 to 23 were selected (Figs. 13 and 14, Tables 1 and 2). PP-2b and PJ-8 are positive controls, and the arrows in Figs. 13 and 14 indicate the cleavage sites by MMP12. The following 1) to 4) were taken into consideration in the selection of peptides: 1) The fluorescent dye was introduced at the N-terminus.
  • Glycine Gly was introduced as a spacer to reduce the effect of the fluorescent dye on enzyme recognition.
  • the length of the amino acid was set to about 15 residues to make it easy to synthesize the peptide.
  • peptides were synthesized using a Biotage® peptide synthesizer (resin MBHA, condensation agent DIC/Oxyma, detergent DMF, 5 equivalents of amino acid).
  • the peptides were modified with 5-carboxyfluorescein (5-CF) (5-CF: 1.2 equivalents, condensation agent: DIC/Oxyma, detergent: DMF/DCM, dried in a desiccator for 2 hours).
  • the peptide side chains were deprotected and the peptides were deresinized (using TFA/Water/TIS, detergent TFA).
  • the products were crudely purified by ether precipitation, purified by HPLC, and the purity was confirmed by HPLC analysis.
  • the synthesis of the desired peptide was confirmed by mass spectrometry, and the synthesized peptides were subjected to the cleavage evaluation described below.
  • hMMP12 50 ⁇ L each of hMMP12 (2.0 ng/ ⁇ L) and substrate (peptide) were mixed and incubated at 37°C for 16 hours.
  • the blank was a mixture of equal amounts of assay buffer and substrate (peptide).
  • 100 ⁇ L of acetonitrile was added to the mixture from the second day, and the mixture was centrifuged for 10 minutes. The supernatant was then collected and 10 ⁇ L of the supernatant was analyzed by ultra-performance liquid chromatography (UPLC).
  • UPLC ultra-performance liquid chromatography
  • UPLC UPLC was performed under the following conditions: measurement wavelength: 440 nm, flow rate: 0.4 mL/min, A: H2O with 0.1% TFA, B: CH3CN with 0.1% TFA, elution conditions: 10% B ⁇ 70% B in 9.5 min. It was confirmed that the two positive controls were cleaved by MMP12 (data not shown).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Pathology (AREA)
  • General Physics & Mathematics (AREA)
  • Food Science & Technology (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
PCT/JP2023/038959 2022-10-28 2023-10-27 Ｍｍｐ１２を指標とした免疫介在性炎症性疾患の診断、及びｍｍｐ１２阻害による免疫介在性炎症性疾患の治療用医薬 Ceased WO2024090571A1 (ja)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN202380074661.6A CN120129835A (zh) 2022-10-28 2023-10-27 以mmp12为指标的免疫介导的炎症性疾病的诊断、以及基于抑制mmp12的免疫介导的炎症性疾病的治疗用药物
EP23880904.0A EP4610657A1 (en) 2022-10-28 2023-10-27 Diagnosis of immune-mediated inflammatory diseases using mmp12 as indicator, and medicine for treating immune-mediated inflammatory diseases via mmp12 inhibition
JP2024553261A JPWO2024090571A1 (https=) 2022-10-28 2023-10-27

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2022-173336 2022-10-28
JP2022173336 2022-10-28

Publications (1)

Publication Number Publication Date
WO2024090571A1 true WO2024090571A1 (ja) 2024-05-02

Family

ID=90831066

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2023/038959 Ceased WO2024090571A1 (ja) 2022-10-28 2023-10-27 Ｍｍｐ１２を指標とした免疫介在性炎症性疾患の診断、及びｍｍｐ１２阻害による免疫介在性炎症性疾患の治療用医薬

Country Status (4)

Country Link
EP (1) EP4610657A1 (https=)
JP (1) JPWO2024090571A1 (https=)
CN (1) CN120129835A (https=)
WO (1) WO2024090571A1 (https=)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119534864A (zh) * 2025-01-22 2025-02-28 首都医科大学附属北京友谊医院 一种新型的IgG4相关性疾病的标志物及其应用

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006320289A (ja) 2005-05-20 2006-11-30 National Institute Of Advanced Industrial & Technology 異常型プリオン蛋白質由来の原繊維に結合するｒｎａアプタマー
JP2009165394A (ja) 2008-01-15 2009-07-30 National Institute Of Advanced Industrial & Technology ペルオキシレドキシン６（Ｐｒｘ６）に対するアプタマー
JP2009207491A (ja) 2008-02-06 2009-09-17 National Institute Of Advanced Industrial & Technology 単純ヘルペスウイルスに対するアプタマー
JP2009294096A (ja) * 2008-06-05 2009-12-17 St Marianna Univ School Of Medicine 高安動脈炎の診断方法およびそれに用いられる診断キット
JP2011517319A (ja) * 2008-03-03 2011-06-02 ダイアックス コーポレーション メタロプロテアーゼ１２結合タンパク質
WO2012039161A1 (ja) * 2010-09-22 2012-03-29 国立大学法人 千葉大学 新規血管炎の検査方法および検査用試薬
US20130310273A1 (en) * 2011-01-27 2013-11-21 Torsten Witte Methods and Means for Diagnosing Vasculitis
CN104792979A (zh) * 2014-09-05 2015-07-22 昆明医科大学第一附属医院 一种检测人基质金属蛋白酶-12活性的荧光多肽底物
JP2019168403A (ja) * 2018-03-26 2019-10-03 国立大学法人東北大学 高安動脈炎の診断方法、診断マーカー及び診断キット

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006320289A (ja) 2005-05-20 2006-11-30 National Institute Of Advanced Industrial & Technology 異常型プリオン蛋白質由来の原繊維に結合するｒｎａアプタマー
JP2009165394A (ja) 2008-01-15 2009-07-30 National Institute Of Advanced Industrial & Technology ペルオキシレドキシン６（Ｐｒｘ６）に対するアプタマー
JP2009207491A (ja) 2008-02-06 2009-09-17 National Institute Of Advanced Industrial & Technology 単純ヘルペスウイルスに対するアプタマー
JP2011517319A (ja) * 2008-03-03 2011-06-02 ダイアックス コーポレーション メタロプロテアーゼ１２結合タンパク質
JP2009294096A (ja) * 2008-06-05 2009-12-17 St Marianna Univ School Of Medicine 高安動脈炎の診断方法およびそれに用いられる診断キット
WO2012039161A1 (ja) * 2010-09-22 2012-03-29 国立大学法人 千葉大学 新規血管炎の検査方法および検査用試薬
US20130310273A1 (en) * 2011-01-27 2013-11-21 Torsten Witte Methods and Means for Diagnosing Vasculitis
CN104792979A (zh) * 2014-09-05 2015-07-22 昆明医科大学第一附属医院 一种检测人基质金属蛋白酶-12活性的荧光多肽底物
JP2019168403A (ja) * 2018-03-26 2019-10-03 国立大学法人東北大学 高安動脈炎の診断方法、診断マーカー及び診断キット

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
"Antibodies: A Laboratory Manual", 1988, COLD SPRING HARBOR LABORATORY PRESS
ANN RHEUM DIS., vol. 77, no. 3, March 2018 (2018-03-01), pages 348 - 354
ARTHRITIS RHEUMATOL, vol. 70, 2018, pages 439 - 449
BLOOD, vol. 112, 2008, pages 3455 - 64
CHEMISTRY AND BIOLOGY, vol. 22, 2015, pages 1122 - 1133
J BIOL CHEM, vol. 287, 2012, pages 5848 - 60
J. AM. CHEM. SOC., vol. 137, 2015, pages 4759 - 4765
J.AM.CHEM.SOC., vol. 134, 2012, pages 13730 - 1373
MATSUYAMA, AKIFUMI ET AL. : "Matrix metalloproteinases as novel disease markers in Takayasu Arteritis -possible implication in pathophysiology-", CONNECTIVE TISSUE, JAPANESE SOCIETY FOR CONNECTIVE TISSUE RESEARCH, TOKYO, JP, vol. 36, no. 4, 25 December 2004 (2004-12-25), JP , pages 239 - 244, XP009554673, ISSN: 0916-572X *
N ENGL J MED, vol. 377, 2017, pages 317 - 328
NAT COMMUN., vol. 9, 2018, pages 2416
NAT MED., vol. 20, 2014, pages 493 - 502
PROC NATL ACAD SCI U S A., vol. 90, no. 8, 15 April 1993 (1993-04-15), pages 3413 - 7

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119534864A (zh) * 2025-01-22 2025-02-28 首都医科大学附属北京友谊医院 一种新型的IgG4相关性疾病的标志物及其应用
CN119534864B (zh) * 2025-01-22 2025-06-24 首都医科大学附属北京友谊医院 一种新型的IgG4相关性疾病的标志物及其应用

Also Published As

Publication number Publication date
EP4610657A1 (en) 2025-09-03
CN120129835A (zh) 2025-06-10
JPWO2024090571A1 (https=) 2024-05-02

Similar Documents

Publication Publication Date Title
JP6449441B2 (ja) ＦｃＲｎ特異的ヒト抗体及びこれを含む自己免疫疾患治療用組成物
ES2771252T3 (es) Anticuerpos monoclonales anti-GP73 y métodos para obtener los mismos
JP7065516B2 (ja) アミロイドベータのｎ末端エピトープおよびそれに対する立体配座選択的抗体
JP2019520550A (ja) Ｄｐｐ３の定量方法および治療方法
US11208478B2 (en) Methods of detecting and treating a tumor expressing pT346 PDK1
US20190315846A1 (en) Antibodies to Human Alpha-Synuclein
AU2018350861A1 (en) Therapy monitoring under treatment with an anti-adrenomedullin (ADM) binder
WO2019154900A1 (en) Adrenomedullin (adm) for diagnosis and/or prediction of dementia and anti-adrenomedullin binder for use in therapy or prevention of dementia
JP2024521638A (ja) 好酸球トラップの阻害
US12545728B2 (en) Treatment of cancer metastasis by targeting exosome proteins
US20230357383A1 (en) Anti-ADM-antibodies binding to the free N-terminus for accelerated transition of ADM-Gly to bio-ADM in patients with ADM-Gly/ bio-ADM ratio above a threshold and combination with vitamin C
EP4610657A1 (en) Diagnosis of immune-mediated inflammatory diseases using mmp12 as indicator, and medicine for treating immune-mediated inflammatory diseases via mmp12 inhibition
WO2015048929A1 (en) Biomarkers for breast cancer
CN110678757B (zh) 诊断或监测肾功能或诊断肾功能障碍的方法
US20220064271A1 (en) Methods for treating tauopathies
EP3239295A1 (en) Antibody highly specifically recognizing turn structure at 22- and 23-positions in amyloid beta
CN115975025B (zh) C反应蛋白（crp）检测试剂盒
CN120359042A (zh) 改善危重病患者肺功能的dpp3抑制剂
BR112019020166A2 (pt) anticorpo que se liga especificamente a região n-terminal de lisil-trna sintetase exposta na membrana celular
US20180259516A1 (en) Means and methods for diagnosing and treating inflammatory disorders
JP6407990B2 (ja) アウグリン免疫学的検定
EP4710108A1 (en) Mid-regional pro-adrenomedullin immunoassay with monoclonal antibodies
BR112021004982A2 (pt) anticorpo, polinucleotídeo, vetor de expressão, célula transformada, métodos para produzir um anticorpo, para prevenir ou inibir o câncer e metástase do câncer, para diagnosticar câncer ou metástase do câncer, para tratar uma doença e para diagnosticar uma doença, composição farmacêutica, composições para diagnóstico e composição para prevenção ou tratamento de uma doença e uso do anticorpo
HK40018330A (en) Antibody binding to fcrn for treating autoimmune diseases
HK40018330B (zh) 治疗自身免疫疾病的结合fcrn的抗体

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23880904

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2024553261

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 202380074661.6

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 202517044157

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2023880904

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

WWP Wipo information: published in national office

Ref document number: 202517044157

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 2023880904

Country of ref document: EP

Effective date: 20250528

WWP Wipo information: published in national office

Ref document number: 202380074661.6

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 2023880904

Country of ref document: EP