WO2023282654A1 - Composition pour la prédiction de la gravité d'une maladie médiée par il -23 - Google Patents

Composition pour la prédiction de la gravité d'une maladie médiée par il -23 Download PDF

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WO2023282654A1
WO2023282654A1 PCT/KR2022/009830 KR2022009830W WO2023282654A1 WO 2023282654 A1 WO2023282654 A1 WO 2023282654A1 KR 2022009830 W KR2022009830 W KR 2022009830W WO 2023282654 A1 WO2023282654 A1 WO 2023282654A1
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antigen
composition
disease
present
asthma
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Korean (ko)
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유지환
한승한
김보민
윤주헌
천재희
정연욱
박지혜
정다은
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연세대학교 산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • 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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4614—Monocytes; Macrophages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
    • A61K39/4622—Antigen presenting cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464402—Receptors, cell surface antigens or cell surface determinants
    • A61K39/464429—Molecules with a "CD" designation not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • 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
    • 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
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • 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
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70596—Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/12—Pulmonary diseases
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/56—Staging of a disease; Further complications associated with the disease

Definitions

  • the present invention relates to methods of providing information about the severity of diseases mediated by IL-23.
  • Asthma refers to a chronic inflammatory disease of the airways with various endotypes and excessive morbidity.
  • asthmatic airway inflammation There are several types of asthmatic airway inflammation that can be associated with TH2 cell-mediated eosinophilic, TH17 cell-mediated neutrophilic, or even agranulocyte inflammation.
  • eosinophils are important inflammatory cells present in the asthmatic lung, these eosinophils do not explain the medical symptoms of eosinophilic airway inflammation, especially in patients with increased neutrophil cells in the lung lumen during acute exacerbations.
  • Recently, a high correlation between asthma severity and exacerbation, steroid treatment response, and pulmonary neutrophil inflammation has been reported.
  • neutrophilic airway inflammation Unlike eosinophilic airway inflammation, neutrophilic airway inflammation often does not respond to inhaled or systemic corticosteroids, is less drug responsive, and may recur. Thus, there has been a significant demand for an enhanced therapeutic approach, but development of a specific treatment for neutrophil-dominant asthma, that is, neutrophil-dominant asthma, has been difficult due to lack of evidence on the underlying mechanism.
  • bone marrow cells including macrophages and dendritic cells, play an antigen-presenting role in the immune response, and in the case of asthma, instruct naive CD4+ T cells to differentiate into effector TH2 and TH17 cells, and develop resistance to inhaled antigens. to control
  • TH17 differentiation is induced by low antigen dose and expression of OX40 ligand, and becomes jagged by antigen-presenting cells in a cytokine environment in which high levels of IL-4, IL-5 and IL-13 are present .
  • TH17 differentiation occurs when the expression of CD40 and CD86 and the expression of pro-inflammatory cytokines including IL-6, IL-1 beta and IL-24 and TGF-beta (transforming growth factor-beta) are high. It is advantageous.
  • IL-23 induces infiltration of neutrophils into the airways, activates TH17 cells, and induces severe asthma through secretion of IL-17.
  • IL-23 In pediatric asthma, the serum level of IL-23 is inversely proportional to the forced expiratory volume in FEV1 (Forced Expiratory Volume in One second) value, so IL-23 can be used as an auxiliary biomarker when assessing the severity of asthma.
  • FEV1 Forced Expiratory Volume in One second
  • One object of the present invention is to provide a composition for predicting the severity of a disease mediated by IL-23.
  • Another object of the present invention is to provide a method for providing information for predicting the severity of a disease mediated by IL-23.
  • Another object of the present invention is to provide a cell therapy composition for preventing or treating IL-23 mediated diseases.
  • One embodiment of the present invention provides a composition for predicting the severity of a disease mediated by IL-23.
  • composition of the present invention comprises any one protein selected from the group consisting of monocyte CD39 antigen, CD9 antigen, Ly6G antigen, CD11b antigen and CD11c antigen; or an agent capable of measuring the expression level of a gene encoding the same.
  • the “Cluster of Differentiation 39 (CD39) antigen” of the present invention is a surface-expressed enzyme that hydrolyzes extracellular ATP (eATP), a pro-inflammatory metabolite present in high concentration in the tumor gap.
  • the CD39 antigen of the present invention may consist of the amino acid sequence represented by SEQ ID NO: 1, but is not limited thereto.
  • the “Cluster of Differentiation 9 (CD9) antigen” of the present invention is a molecular marker of immune cells, and the CD9 antigen of the present invention may consist of the amino acid sequence represented by SEQ ID NO: 2, but is not limited thereto.
  • the “Lymphocyte antigen 6G (Ly6G) antigen” of the present invention is a 21-25 kD glycosyl phosphatidylinositol (GPI)-linked differentiation antigen expressed by bone marrow-derived cells. Ly6G can be transiently expressed in monocytes during bone marrow development, and Ly6G expression in granulocytes and peripheral neutrophils is directly related to the level of differentiation and maturation of the cells.
  • the Ly6G antigen of the present invention may consist of the amino acid sequence represented by SEQ ID NO: 3, but is not limited thereto.
  • the "CD11b antigen" of the present invention is involved in various adhesions between cells such as monocytes, macrophages, NK cells and granulocytes.
  • the CD11b antigen of the present invention may consist of the amino acid sequence represented by SEQ ID NO: 4, but is not limited thereto.
  • the "CD11c antigen” of the present invention is a type 1 transmembrane protein in monocytes, macrophages, neutrophils and B cells, which activates cells and causes neutrophil respiratory burst.
  • the CD11c antigen of the present invention may consist of the amino acid sequence represented by SEQ ID NO: 5, but is not limited thereto.
  • the monocytes may have CD39 antigen, CD9 antigen, and CD11b antigen expressed on the surface of monocytes, and/or the monocytes may not express Ly6G antigen and CD11c antigen on the surface of monocytes. It may be, but is not limited thereto.
  • the monocytes when the number of CD39+CD9+Ly6G-CD11b+CD11c- monocytes present in the sample of interest is reduced compared to the normal control group, NETosis, a neutrophil extracellular trap, is not effectively inhibited, thereby reducing the severity of the disease. can indicate Therefore, by measuring the expression levels of the proteins of the antigens or genes encoding them, it can be predicted that the severity of the disease can be expressed when the expression level is changed compared to a normal control group, but is not limited thereto.
  • the “disease mediated by IL-23” of the present invention refers to a disease caused by IL-23 or in which IL-23 may be involved in the progression of the disease, and is mediated by IL-23.
  • Possible diseases include respiratory diseases; multiple sclerosis; rheumatoid arthritis; psoriasis; inflammatory bowel disease; And it may be any one selected from the group consisting of ankylosing spondylitis, but is not limited thereto.
  • the respiratory disease of the present invention may be asthma or sinusitis, but is not limited thereto.
  • the asthma of the present invention may be neutrophil-dominant asthma, but is not limited thereto.
  • the “neutrophil-dominant asthma” of the present invention may be one in which the number of neutrophils in the lung tissue is significantly increased compared to eosinophils compared to mild asthma, the symptoms of which can be alleviated by general treatment methods, As not limited thereto, various terms such as refractory allergic asthma, steroid-dependent allergic asthma, and treatment-refractory allergic asthma may be referred to.
  • the "severity" of the present invention may include the degree of increase or decrease in the risk of developing a disease, the degree of progression of a disease, and the degree of increase or decrease in the risk of recurrence.
  • the degree of increase or decrease in the risk of developing the disease is meant to include the degree of risk of developing the disease or the possibility of developing the disease.
  • the degree of progression of the lesion means that the disease has developed and the lesion has progressed to include a mild to severe degree of the disease.
  • the degree of increase or decrease in the risk of recurrence means the degree to which there is a risk of recurrence or a possibility of recurrence after the disease is determined to be cured.
  • the severity of the disease may be expressed qualitatively and/or quantitatively, and the severity may be classified according to the degree.
  • the "asthma severity" can be classified through the patient's symptoms and lung function indicators, and can be classified into mild intermittent, mild persistent, moderate persistent, and severe persistent.
  • moderate persistence it means that there are asthma symptoms every day, symptom exacerbations are 2 weeks a week, the FEV is 60-80%, and the PEFR diurnal variation is ⁇ 30%.
  • severe persistence it means that there are persistent asthma symptoms, activity limitation and frequent worsening of symptoms, FEV is ⁇ 60%, and PEFR diurnal variation is ⁇ 30%.
  • Multiple sclerosis which is a disease mediated by IL-23 of the present invention, is a Th1 type T cell-mediated autoimmune disease, and IL-23 affects the immune system in a way that polarizes the innate immune response against Th1 bias, thereby preventing multiple sclerosis.
  • IL-23 composed of p19 and p40 subunits interacts with the IL-23 receptor complex to induce excessive biochemical actions, mainly IL-23. 17 and TH17 cells to exert an osteoclastogenic effect, allowing rheumatoid arthritis to be exerted (Immunopharmacol Immunotoxicol. 2019 Apr;41(2):185-191.).
  • IL-23 which is mainly secreted from dendritic cells in the inflammatory skin, increases the number of cells that secrete IL-17, and produces a large amount of IL-17, resulting in upregulation of psoriasis-related genes produced by epidermal keratinocytes, leading to psoriasis.
  • Inflammatory bowel disease which is a disease mediated by IL-23 of the present invention, can contribute to the onset and maintenance of IL-23 through a process in which inflammation is generated in the intestine through the Th-17 pathway (Science 2006 Dec 1;314 (5804):1461-3).
  • Ankylosing spondylitis a disease mediated by IL-23 of the present invention, has been proven to be associated with an increased risk of IL-23 receptor (IL-23R) polymorphism, and IL-23 receptor (IL-23R) polymorphism is associated with an increased risk of IL-23 in the joints of patients with such a disease. It was confirmed that the number of cells producing -23 was increased (Ann Rheum Dis. 2019 Aug;78(8):1015-1018).
  • the number of CD39+CD9+Ly6G-CD11b+CD11c- monocytes may be reduced compared to a normal control group, but is not limited thereto.
  • An agent capable of measuring the expression level of the protein of the present invention may be at least one selected from the group consisting of primers, probes, and antisense nucleotides that complementarily bind to the gene, but is not limited thereto.
  • the agent capable of measuring the expression level of the protein of the present invention is not limited as long as it can specifically bind to the protein and measure the expression level of the protein.
  • the agent capable of measuring the expression level of the protein is at least selected from the group consisting of an antibody, an oligopeptide, a ligand, a peptide nucleic acid (PNA), and an aptamer that binds specifically to the protein. It may be one.
  • antibody of the present invention refers to a substance that specifically binds to an antigen and causes an antigen-antibody reaction.
  • antibody means an antibody that specifically binds to said protein.
  • Antibodies of the present invention include both polyclonal antibodies, monoclonal antibodies and recombinant antibodies. Such antibodies can be readily prepared using techniques well known in the art. For example, polyclonal antibodies can be produced by a method well known in the art, including a process of injecting an antigen of the protein into an animal and collecting blood from the animal to obtain serum containing the antibody. Such polyclonal antibodies can be prepared from any animal, such as goat, rabbit, sheep, monkey, horse, pig, cow, dog, and the like.
  • monoclonal antibodies can be prepared using the hybridoma method well known in the art (see Kohler and Milstein (1976) European Journal of Immunology 6:511-519), or the phage antibody library technique (Clackson et al, Nature, 352). :624-628, 1991; Marks et al, J. Mol. Biol., 222:58, 1-597, 1991).
  • Antibodies prepared by the above methods may be separated and purified using methods such as gel electrophoresis, dialysis, salt precipitation, ion exchange chromatography, and affinity chromatography.
  • the antibodies of the present invention include functional fragments of antibodies as well as complete forms having two full-length light chains and two full-length heavy chains.
  • the functional fragment of the antibody of the present invention means a fragment having at least an antigen-binding function, and includes Fab, F(ab'), F(ab')2 and Fv.
  • PNA Peptide Nucleic Acid
  • DNA has a phosphate-ribose backbone
  • PNA has a repeated N-(2-aminoethyl)-glycine backbone linked by peptide bonds, which greatly increases the binding force and stability to DNA or RNA, and is thus used in molecular biology. , diagnostic assays and antisense therapies.
  • PNA is described by Nielsen PE, Egholm M, Berg RH, Buchardt O (December 1991). “Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide”. Science 254 (5037): 1497-1500.
  • the "aptamer” of the present invention is an oligonucleic acid or peptide molecule, and the general description of aptamers is described in the literature [Bock LC et al., Nature 355(6360):5646(1992); Hoppe-Seyler F, Butz K “Peptide aptamers: powerful new tools for molecular medicine”. J Mol Med. 78(8):42630 (2000); Cohen BA, Colas P, Brent R. “An artificial cell-cycle inhibitor isolated from a combinatorial library”. Proc Natl Acad Sci USA. 95(24): 142727 (1998).
  • the antibody, PNA and aptamer of the present invention can be easily prepared by a person skilled in the art based on the amino acid sequence of the protein of the present invention.
  • agent capable of measuring the expression level of the gene of the present invention may be included without limitation as long as it can measure the expression level by complementary binding to the gene of the present invention.
  • the agent capable of measuring the expression level of the gene may be at least one selected from the group consisting of primers, probes, and antisense nucleotides that complementarily bind to the gene.
  • the "primer” of the present invention is a fragment that recognizes a target gene sequence, and includes a pair of forward and reverse primers, preferably a primer pair that provides analysis results having specificity and sensitivity. High specificity can be imparted when the nucleic acid sequence of the primer is a sequence that is inconsistent with the non-target sequence present in the sample, so that the primer amplifies only the target gene sequence containing a complementary primer binding site and does not cause non-specific amplification. .
  • the "probe” of the present invention means a substance capable of complementarily binding to a target substance to be detected in a sample, and means a substance capable of specifically confirming the presence of a target substance in a sample through the binding.
  • the type of probe is not limited as a material commonly used in the art, but preferably may be peptide nucleic acid (PNA), locked nucleic acid (LNA), peptide, polypeptide, protein, RNA or DNA, and most preferably Most likely it is PNA.
  • the probe is a biomaterial, including one derived from or similar to a living organism or manufactured in vitro, for example, enzymes, proteins, antibodies, microorganisms, animal and plant cells and organs, nerve cells, DNA, and It may be RNA, DNA includes cDNA, genomic DNA, and oligonucleotides, and RNA includes genomic RNA, mRNA, and oligonucleotides.
  • LNA Locked nucleic acids
  • the "LNA (Locked nucleic acids)" of the present invention means a nucleic acid analog containing a 2'-O, 4'-C methylene bridge [J Weiler, J Hunziker and J Hall Gene Therapy (2006) 13, 496.502 ].
  • LNA nucleosides contain the common nucleic acid bases of DNA and RNA, and can base pair according to the Watson-Crick base pairing rules. However, due to molecular ‘locking’ due to methylene bridges, LNAs do not form ideal shapes in Watson-Crick bonds. When LNAs are included in DNA or RNA oligonucleotides, they can more rapidly pair with complementary nucleotide chains to increase the stability of the double helix.
  • the "antisense” of the present invention is a sequence of nucleotide bases in which an antisense oligomer is hybridized with a target sequence in RNA by Watson-Crick base pairing, allowing formation of a typical mRNA and RNA: oligomeric heteroduplex in the target sequence and an oligomer having an inter-subunit backbone. Oligomers may have exact sequence complementarity or near complementarity to the target sequence.
  • the agent capable of measuring the expression level of the gene of the present invention can derive the nucleotide sequence of the gene based on the amino acid sequence for the protein of the present invention, a person skilled in the art can complement the gene based on this. Binding primers, probes, etc. can be easily prepared.
  • Another embodiment of the present invention provides a kit for predicting the severity of a disease mediated by IL-23.
  • the kit of the present invention includes the composition for predicting the severity of a disease mediated by IL-23 according to the present invention.
  • the contents related to IL-23-mediated disease, severity, monocyte CD39 antigen, CD9 antigen, Ly6G antigen, CD11b antigen, and CD11c antigen are the same as described above, thereby avoiding excessive complexity of the specification. omit for
  • the kit of the present invention may be an RT-PCR kit, a DNA chip kit, an ELISA kit, a protein chip kit, a rapid kit, or a multiple reaction monitoring (MRM) kit, but is not limited thereto.
  • MRM multiple reaction monitoring
  • the kit of the present invention may further include one or more other component compositions, solutions or devices suitable for the assay method.
  • the diagnostic kit of the present invention may further include essential elements necessary for carrying out the reverse transcription polymerase reaction.
  • the reverse transcription polymerase reaction kit contains a pair of primers specific for a gene encoding a protein.
  • the primer is a nucleotide having a sequence specific to the nucleic acid sequence of the gene, and may have a length of about 7 bp to 50 bp, more preferably about 10 bp to 30 bp.
  • a primer complementary to the nucleic acid sequence of the control gene may be included.
  • reverse transcription polymerase reaction kits contain a test tube or other suitable container, reaction buffer (with varying pH and magnesium concentration), deoxynucleotides (dNTPs), enzymes such as Taq-polymerase and reverse transcriptase, DNase and RNase inhibitor DEPC. -Water (DEPC-water), sterilized water, etc. may be included.
  • the diagnostic kit of the present invention may include essential elements required to perform a DNA chip.
  • the DNA chip kit may include a substrate to which cDNA or oligonucleotides corresponding to genes or fragments thereof are attached, and reagents, reagents, enzymes, and the like for producing fluorescently labeled probes.
  • the substrate may include a cDNA or oligonucleotide corresponding to a control gene or a fragment thereof.
  • the diagnostic kit of the present invention may contain essential elements required to perform ELISA.
  • ELISA kits contain antibodies specific for the protein.
  • An antibody is an antibody that has high specificity and affinity for a marker protein and little cross-reactivity to other proteins, and is a monoclonal antibody, polyclonal antibody, or recombinant antibody.
  • ELISA kits may also include antibodies specific for a control protein.
  • Other ELISA kits include reagents capable of detecting bound antibodies, such as labeled secondary antibodies, chromophores, enzymes (eg, conjugated with antibodies) and substrates thereof or those capable of binding the antibody. may contain other substances and the like.
  • Another embodiment of the present invention provides a method for providing information for predicting the severity of a disease mediated by IL-23.
  • the disease compared to a normal control group, when monocytes on the surface of which the CD39 antigen, CD9 antigen and CD11b antigen are expressed, and the Ly6G antigen and CD11c antigen are not expressed on the surface of monocytes are present at low levels, the disease
  • the severity of can be predicted as high, but is not limited thereto.
  • the contents related to IL-23-mediated disease, severity, monocyte CD39 antigen, CD9 antigen, Ly6G antigen, CD11b antigen, CD11c antigen, etc. are the same as described above, to avoid excessive complexity of the specification. omit for
  • the step of measuring the expression level of the protein of the present invention is carried out using a preparation capable of measuring the expression level of the protein, protein chip analysis, immunoassay, ligand binding assay, MALDI-TOF (Matrix Assisted Laser Desorption / Ionization Time of Flight Mass Spectrometry) analysis, SELDI-TOF (Sulface Enhanced Laser Desorption/Ionization Time of Flight Mass Spectrometry) analysis, radioimmunoassay, radioimmunodiffusion method, Oukteroni immunodiffusion method, rocket immunoelectrophoresis, tissue immunostaining, complement Immobilization method, two-dimensional electrophoretic analysis, liquid chromatography-Mass Spectrometry (LC-MS), liquid chromatography-Mass Spectrometry/ Mass Spectrometry (LC-MS/MS), flow cytometry, Western blotting and It may be at least one selected from the group consisting of ELISA (enzyme linked immunosorbent assay).
  • MALDI-TOF Micro
  • Another embodiment of the present invention provides a cell therapy composition for preventing or treating diseases mediated by IL-23.
  • composition of the present invention expresses CD39 antigen, CD9 antigen and CD11b antigen; Subtype monocytes that do not express Ly6G antigen and CD11c antigen are included as active ingredients.
  • composition of the present invention the contents related to IL-23-mediated disease, severity, monocyte CD39 antigen, CD9 antigen, Ly6G antigen, CD11b antigen, CD11c antigen, etc. are the same as described above, to avoid excessive complexity of the specification. omit for
  • the "cell therapy agent" of the present invention refers to 'proliferating/selecting living autologous, allogenic, or xenogenic cells in vitro or using other methods to restore the tissue and function of cells. It means 'drugs used for the purpose of treatment, diagnosis, and prevention through a series of actions such as changing characteristics'.
  • the cell therapy agent may be a cell having the antigen expression characteristics of the present invention, for example, monocytes, but is not limited thereto.
  • the cells corresponding to the cell therapy agent in one embodiment of the present invention, are 1 ⁇ 10 5 ⁇ 5 ⁇ 10 5 , 5 ⁇ 10 5 ⁇ 1 ⁇ 10 6 , 1 ⁇ 10 6 ⁇ 2 ⁇ 10 6 2 ⁇ 10 6 ⁇ 3 ⁇ 10 6 , 3 ⁇ 10 6 ⁇ 4 ⁇ 10 6 , 4 ⁇ 10 6 ⁇ 5 ⁇ 10 6 , 5 ⁇ 10 6 ⁇ 6 ⁇ 10 6 , 6 ⁇ 10 6 ⁇ 7 ⁇ 10 6 , 7 ⁇ 10 6 ⁇ 8 ⁇ 10 6 6 to 5 ⁇ 10 6 , 5 ⁇ 10 6 to 7 ⁇ 10 6 , 2 ⁇ 10 6 to 4 ⁇ 10 6 , 1 ⁇ 10 6 to 5 ⁇ 10 6 or 5 ⁇ 10 6 to 1 ⁇ 10 7 may be administered at any one cell/subject dose, but is not limited thereto .
  • the cell therapy agent of the present invention may be used for combined administration with an anti-IL-23 antibody, for example, Risankizumab.
  • the anti-IL-23 antibody of the present invention may target IL-23p19, but is not limited thereto.
  • the cell therapy composition of the present invention may be a pharmaceutical composition.
  • prevention of the present invention means any action that suppresses or delays the onset of a disease or condition.
  • the composition means to delay the onset of a disease mediated by IL-23 or to suppress the onset of the disease.
  • treatment of the present invention refers to any action that delays, stops, or reverses the progression of a disease or condition, and for the purpose of the present invention, the composition is used to stop, alleviate, It means to alleviate or eliminate or reverse.
  • the pharmaceutical composition of the present invention may be in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be intended for humans.
  • the pharmaceutical compositions of the present invention are not limited thereto, but are formulated in the form of oral formulations such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods, respectively.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a colorant, a flavoring agent, etc.
  • a buffer, a preservative, A pain reliever, solubilizer, isotonic agent, stabilizer, etc. may be mixed and used, and in the case of topical administration, a base, excipient, lubricant, preservative, etc. may be used.
  • Formulations of the pharmaceutical composition of the present invention may be variously prepared by mixing with the pharmaceutically acceptable carrier as described above.
  • the pharmaceutically acceptable carrier for example, for oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in unit dosage ampoules or multiple dosage forms. there is.
  • it may be formulated into solutions, suspensions, tablets, capsules, sustained-release preparations, and the like.
  • Examples of carriers, excipients and diluents suitable for the formulation of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate , cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil may be used.
  • fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like may be further included.
  • the route of administration of the pharmaceutical composition of the present invention is not limited thereto, but is not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, This includes sublingual or rectal. Oral or parenteral administration is preferred.
  • the "parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition may be administered in the form of a suppository for rectal administration.
  • the pharmaceutical composition of the present invention depends on various factors including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, route of administration, excretion rate, drug combination and severity of the specific disease to be prevented or treated.
  • the dosage of the pharmaceutical composition may be variously varied, and the dosage of the pharmaceutical composition varies depending on the patient's condition, body weight, disease severity, drug type, administration route and period, but may be appropriately selected by those skilled in the art, and is 0.0001 to 50 mg/day. kg or 0.001 to 50 mg/kg.
  • Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way.
  • the pharmaceutical composition according to the present invention may be formulated into a pill, dragee, capsule, liquid, gel, syrup, slurry, or suspension.
  • the present invention expresses the CD39 antigen, the CD9 antigen and the CD11b antigen;
  • a method for preventing or treating a disease mediated by IL-23 comprising administering subtype monocytes that do not express Ly6G antigen and CD11c antigen. Since monocytes used in the present invention and diseases mediated by IL-23 that are prevented or treated using the same have already been described above, description thereof is omitted to avoid excessive redundancy.
  • SEQ ID NO: 1 CD39 antigen
  • SEQ ID NO: 2 CD9 antigen
  • SEQ ID NO: 4 CD11b antigen
  • VLAEDAQRLF TALFPFEKNC GNDNICQDDL SITFSFMSLD CLVVGGPREF
  • NVTVTVRNDG EDSYRTQVTF FFPLDLSYRK VSTLQNQRSQ RSWRLACESA
  • SEQ ID NO: 5 CD11c antigen
  • the present invention relates to a composition for predicting the severity of a disease mediated by IL-23 and a method for providing information for the prediction, wherein the number of CD39+CD9+Ly6G-CD11b+CD11c- monocytes present in a target sample is normal in the control group. If it is reduced compared to NETosis, the severity of the disease can be predicted by indicating the severity of the disease because NETosis is not effectively suppressed.
  • CD39+CD9+Ly6G-CD11b+CD11c- monocytes can directly suppress NETosis without the help of other monocytes, diseases mediated by IL-23 can be prevented or treated very effectively if the monocytes are used.
  • the therapeutic effect can be significantly increased when used in combination with an existing anti-IL-23 antibody.
  • Figure 1 shows the results of confirming the NETosis phenomenon through a fluorescence microscope in the experimental group according to an embodiment of the present invention.
  • Figure 2 shows the result of quantifying the area of the NETosis phenomenon clustering area in the experimental group according to an embodiment of the present invention.
  • FIG. 3 is a graph showing the ratio of Ly6G+ cells among CD11b+CD11c- cells in an experimental group according to an embodiment of the present invention.
  • FIG. 4 is a graph showing the ratio of Ly6G-CD39+CD9+ cells among CD11b+CD11c- cells in an experimental group according to an embodiment of the present invention.
  • 5 is a graph showing the total number of cells in an experimental group according to an embodiment of the present invention.
  • FIG. 6 is a graph showing the number of neutrophil cells in an experimental group according to an embodiment of the present invention.
  • FIG. 7 to 9 are graphs showing the expression levels of cytokines (IL-17, IL-22, IFN-gamma) measured in the serum of the experimental group according to an embodiment of the present invention.
  • FIG. 10 shows the result of confirming the degree of infiltration of inflammatory cells in tissues according to an embodiment of the present invention through H&E staining.
  • 11 is a graph showing the Penh values confirmed in the experimental group according to an embodiment of the present invention.
  • FIG. 12 is a graph showing the expression level of IL-23 measured in serum of an experimental group according to an embodiment of the present invention.
  • FIG. 13 is a graph comparing the degree of NETosis of neutrophils according to the presence or absence of CD39+ CD9+ cells according to an embodiment of the present invention, and the degree of NETosis was measured by the area of the MPO and citH3 colonization area.
  • FIG. 14 is a graph showing an inverse correlation between the severity of sinusitis and the ratio of CD39+ CD9+ cells among CD45+ cells according to an embodiment of the present invention.
  • Figure 15 is a CD39 + CD9 + cell among CD45 + cells in mucosal tissue of bone (ethmoid) in the roof of the nose of sinusitis patients classified as mild and moderate-severe according to an embodiment of the present invention. ratio is shown graphically.
  • Figure 16 shows the expression levels of CD9, CD39, and CD45 in Ulcerative Colitis (UC) and Crohn's Disease (CD) according to an embodiment of the present invention, relative abundance compared to the control group (HC). It is shown through a heat map.
  • UC Ulcerative Colitis
  • CD Crohn's Disease
  • 17 is a graph showing the measurement of the relative abundance of CD9 or CD39 expression level with CD45 according to an embodiment of the present invention.
  • CD9 is red
  • CD39 is purple
  • CD45 is green. dyed with
  • Wild-type C57BL/6 mice (6-8 weeks old) were purchased from Orient Bio (Gyeonggi-do, Korea) and used as mice used in the experiment. The mice were bred under specific pathogen-free conditions until the experiment began. Such animal experiments were performed with the approval of the Institutional Review Board of Yonsei University College of Medicine.
  • mice were primary sensitized by intraperitoneal injection of 200 ⁇ g of OVA (Ovalbumin) in 2.5 mg of aluminum hydroxide. Eleven days after the first sensitization, the same amount of OVA was injected intraperitoneally to sensitize, and 10 days later, on days 21, 22, and 23, respectively, the mice were anesthetized and sensitized with 50 ⁇ g of OVA intranasally. . Finally, on day 25, mice were intranasally administered with 100 ⁇ g of OVA, and mice were sacrificed 48 hours later to perform the experiment.
  • mice were sensitized by intranasal injection of 100 ⁇ g of LPS (E. coli) and 75 ⁇ g of OVA. After 5 days of the third sensitization corresponding to 2 days, sensitization was performed by intranasal injection of the same amount of LPS and OVA. Thus, 7 days after the last sensitization, 14 days, 15 days, 21 days, and 22 days, respectively, 50 ⁇ g of OVA dissolved in PBS was intranasally injected into mice, and mice were sacrificed 48 hours later to experiment was performed.
  • LPS E. coli
  • IL-23p19 neutralizing antibody BioxCell, West Riverside, NH, USA
  • an amount of 1 mg/kg per mouse was intraperitoneally injected 1 hour before the first sensitization described in Experimental Method 2 above.
  • mice IgG2a isotype 400 ⁇ g of mouse IgG2a isotype was intraperitoneally injected at the same time as the neutralizing antibody, and POM1 (20 mg/kg per mouse, TOCRIS a biotechne brand), aCD9 (20 mg/kg per mouse, BD Pharmingen) and GSK484 (4 mg/kg per mouse, CAYMAN CHEMICAL COMPANY) were injected intraperitoneally at the same time as the neutralizing antibody.
  • inhaled methacholine (Sigma-Aldrich, St. Louis, MO) was measured.
  • Lung tissues of experimental animals were collected, fixed in a 4% formaldehyde solution, and then embedded in paraffin to make blocks. Then, the blocks were made into 3 ⁇ m thick slices.
  • paraffin sections were dried at 60 °C for 30 minutes, peeled with xylene for 15 minutes, and hydrated with 100%, 95%, 80%, and 75% alcohol in that order.
  • the prepared tissue slide was reacted for 3 minutes by dropping hematoxylin solution, washed with distilled water three times for 1 minute each, reacted with eosin solution for 10 minutes, and washed with distilled water. After mounting it with a permount, structural changes in the lung tissue were observed using an optical microscope.
  • hematoxylin stains the chromatin and nuclear membrane in the cell nucleus with a basic dye, and appears purple, and eosin, an acidic dye, combines with basic cytoplasmic proteins and collagen, and is observed pink.
  • Penh is an index representing airway resistance, and Penh was derived by quantifying the value measured using the airway resistance meter in the mouse model through the following formula.
  • Penh (Te/RT-1) X PEF (peak expiratory flow rat, mL/s)/PIF (peak inspiratory flow rat, mL/s)
  • RT Time taken for the expiratory volume to remain at 30% of the tidal volume during expiration (relaxation time, sec)
  • the levels of IL-17, IL-22, IFN-gamma, and IL-23 present in the serum of the mouse model were measured using an ELISA kit. Specifically, 100 ⁇ l of the primary antibody diluted in 0.1 M sodium carbonate solution was added to a 96-well ELISA plate and reacted at 4° C. overnight. Thereafter, the plate was washed three times with 1X washing buffer, and then 1X PBS containing 10% BSA was put into each well and allowed to stand at room temperature for 1 hour to block the plate.
  • Bronchoalveolar lavage fluid was obtained from the mouse model, washed once with PBS, mixed with fluorescent substance-conjugated antibodies, reacted at 4° C. for 1 hour, and analyzed by flow cytometry to detect The phenotype of the immune cells was confirmed.
  • NETosis was increased in Experimental Group 2 compared to Experimental Group 1, and NETosis was significantly reduced in Experimental Groups 3 and 4. Furthermore, NETosis decreased in Experimental Group 4 was increased again in Experimental Group 5 treated with POM1 as in Experimental Group 1, and decreased again in Experimental Group 6 treated with GSK484. Also, as shown in Experimental Group 7, NETosis was increased in the same way as POM1 treatment when treated with anti-CD9 antibody. In addition, as shown in Experimental Group 8, the effect of increasing NETosis by treatment with anti-CD9 antibody was reduced by treatment with GSK484.
  • IL-23-dependent NETosis in neutrophil-dominant asthma was reduced by dendritic cell and IL-23-producing immune cells can be activated to induce inflammation, and it can be seen that CD9 is involved in the suppression of NETosis induced in this way.
  • LyG + CD11b + CD11c-, Ly6G-CD39 + CD9 + CD11b + CD11c-, total cell count, neutrophil count and cytokine (IL -23, IL-17, IL-22 and IFN-gamma) were measured, and the results are shown in FIGS. 3 to 10.
  • the CD39+CD9+Ly6G-CD11b+CD11c- monocyte ratio which was reduced in Experimental Group 2 was anti-IL- It was increased in experimental groups 3 and 4 treated with 23p19 and GSK484.
  • the CD39+CD9+Ly6G-CD11b+CD11c- monocytes decreased in Experimental Group 5 were increased in Experimental Groups 6 and 8 treated with GSK484.
  • the total number of cells in BALF (FIG. 5), the number of neutrophils (FIG. 6), IL-17 (FIG. 7), and IL-22 (FIG. 7) increased in experimental groups 2, 5, and 7. 8), IFN-gamma (FIG. 9), immune cell infiltration (FIG. 10), and Pehn value (FIG. 11) were decreased in experimental group 3, experimental group 4, experimental group 6, and experimental group 8.
  • the level of IL-23 present is IL-17, IL-22, and Th-1 cell-mediated cytokine. Similar to IFN-gamma, it was increased in Experimental Group 2 compared to Experimental Group 1, and this increased value was decreased in Experimental Groups 3 and 4. Furthermore, the expression level of IL-23 decreased in Experimental Group 3 was increased to the same level as Experimental Group 2 in Experimental Groups 5 and 7 treated with POM1 and anti-CD9 antibody.
  • both CD39 and CD9 can suppress IL-23-dependent neutrophil inflammation through inhibition of NETosis in a neutrophil-dominant mouse animal model.
  • CD39+CD9+Ly6G-CD11b+CD11c- monocytes directly suppress NETosis of Ly6G+CD11b+CD11c- neutrophils
  • NETosis of CD39-CD9-Ly6G+CD11b+CD11c- neutrophils was compared with CD39+ CD11c- isolated from Experimental Group 4.
  • CD9+Ly6G-CD11b+CD11c- monocytes were stained with MPO, Cit histone H3, and DAPI, followed by fluorescence microscopy analysis, and the results are shown in FIG. 13 .
  • CD39+CD9+ Ly6G-CD11b+CD11c- monocytes excluding other CD39+CD9+ immune cells, directly suppress NETosis of Ly6G+CD11b+CD11c- neutrophils in a manner dependent on CD39 and CD9.
  • Sinusitis patients are classified into mild symptoms and moderate-severe, and the ratio of CD39+CD9+ cells among CD45+ cells in the tissue is measured by collecting the bone (ethmoid) mucous membrane on the ceiling of the patient's nose, The results are shown in Figures 14 and 15.
  • CD39+CD9+CD45+ cells were observed in the colonic mucosa of healthy controls (HC), but not in UC and CD patients (FIG. 18).
  • the immune cells can be used as an important target for the treatment of IL-23-Th17 cell-associated immune diseases. I was able to confirm that it could.

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Abstract

La présente invention se rapporte à une composition pour la prédiction de la gravité d'une maladie médiée par IL-23, et une méthode permettant de fournir des informations pour la prédiction. La gravité de la maladie peut être prédite si la nétose n'est pas efficacement inhibée, ce qui montre que la maladie est grave, lorsque le nombre de CD39+CD9+Ly6G-CD11b+CD11c-monocytes présents dans un échantillon d'intérêt est réduit par rapport à un groupe témoin normal. En outre, les CD39+CD9+Ly6G-CD11b+CD11c-monocytes peuvent inhiber directement la nétose sans l'aide d'autres monocytes, et peuvent donc non seulement être utilisés pour prévenir ou traiter de manière très efficace des maladies médiées par IL-23, mais peuvent également être utilisés en combinaison avec des anticorps anti-IL-23 existants pour augmenter significativement l'effet thérapeutique.
PCT/KR2022/009830 2021-07-09 2022-07-07 Composition pour la prédiction de la gravité d'une maladie médiée par il -23 WO2023282654A1 (fr)

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US20130273566A1 (en) * 2007-03-30 2013-10-17 Lee Denson Serological Markers of Inflammatory Bowel Disease Phenotype and Disease Progression

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ARNOLD I C, MATHISEN S, SCHULTHESS J, DANNE C, HEGAZY A N, POWRIE F: "CD11c+ monocyte/macrophages promote chronic Helicobacter hepaticus-induced intestinal inflammation through the production of IL-23", MUCOSAL IMMUNOLOGY, NATURE PUBLISHING GROUP US, NEW YORK, vol. 9, no. 2, 1 March 2016 (2016-03-01), New York, pages 352 - 363, XP093020433, ISSN: 1933-0219, DOI: 10.1038/mi.2015.65 *
MIKKEL CARSTENSEN; TOVE CHRISTENSEN; MORTEN STILUND; HOLGER J MØLLER; EVA L PETERSEN; THOR PETERSEN: "Activated monocytes and markers of inflammation in newly diagnosed multiple sclerosis", IMMUNOLOGY AND CELL BIOLOGY, CARLTON, AU, vol. 98, no. 7, 5 May 2020 (2020-05-05), AU , pages 549 - 562, XP071705079, ISSN: 0818-9641, DOI: 10.1111/imcb.12337 *
TOKER A., C.Y. SLANEY, B.T. BÄCKSTRÖM, J.L. HARPER: "Glatiramer acetate treatment directly targets CD11b+Ly6G- monocytes and enhances the suppression of autoreactive T cells in experimental autoimmune encephalomyelitis", SCANDINAVIAN JOURNAL OF IMMUNOLOGY, vol. 74, no. 3, 30 September 2011 (2011-09-30), pages 235 - 243, XP093020434, DOI: 10.1111/j.1365-3083.2011.02575.x *
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