WO2003063905A1 - Medicaments preventifs ou remedes pour maladies immunologiques - Google Patents

Medicaments preventifs ou remedes pour maladies immunologiques Download PDF

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WO2003063905A1
WO2003063905A1 PCT/JP2003/000826 JP0300826W WO03063905A1 WO 2003063905 A1 WO2003063905 A1 WO 2003063905A1 JP 0300826 W JP0300826 W JP 0300826W WO 03063905 A1 WO03063905 A1 WO 03063905A1
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ask1
disease
recombinant vector
dominant negative
inhibitor
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Japanese (ja)
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Hidenori Ichijo
Koji Hashimoto
Atsushi Matsuzawa
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Center For Advanced Science And Technology Incubation, Ltd.
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Publication of WO2003063905A1 publication Critical patent/WO2003063905A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/162—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/45—Transferases (2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y108/00—Oxidoreductases acting on sulfur groups as donors (1.8)
    • C12Y108/01—Oxidoreductases acting on sulfur groups as donors (1.8) with NAD+ or NADP+ as acceptor (1.8.1)
    • C12Y108/01008—Protein-disulfide reductase (1.8.1.8), i.e. thioredoxin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
    • C12Y207/11—Protein-serine/threonine kinases (2.7.11)
    • C12Y207/11025—Mitogen-activated protein kinase kinase kinase (2.7.11.25), i.e. MAPKKK or MAP3K

Definitions

  • the present invention relates to a preventive or therapeutic agent for an immune disease, comprising an ASKl (Apop tosis Signa l-regu lati ng Kinase 1) inhibitor, and a method for preventing an immune disease, comprising using an effective amount of an ASK1 inhibitor. Or a method of treatment, and the use of an ASK1 inhibitor for the manufacture of a preparation for the prevention or treatment of an immune disease.
  • ASKl Apop tosis Signa l-regu lati ng Kinase 1
  • ASK 1 is a type of kinase belonging to the MAPKK kinase (MAPKKK) family.
  • human ASK 1 is composed of 1375 amino acids (see Reference 1 below)
  • mouse ASK 1 is composed of 1379 amino acids It has been reported that human ASK1 and mouse ASK1 have an extremely high homology of 91.9% (see Reference 2 below).
  • human ASK1 cDNA see Reference 3 below
  • mouse ASK1 cDNA see Reference 2 below
  • MAPKK kinase is known to be a conserved intracellular signaling pathway from mammals, including humans, to yeast, MAP (
  • Mitogen-activated Protein Kinase is a kinase that belongs to the signal transduction cascade by the kinase superfamily. Two types of kinases, MAPK kinase (MAPKK) and MAP kinase (MAPK), exist downstream of MAPKK kinase. (See references 4 to 6 below)
  • ASK1 is distributed in almost all organs of humans, including the heart, kidney, liver, ligament, large intestine, brain, and lung, and is activated by TNF (tumor necrosis factor) - ⁇ via the TNF receptor and activated It has been confirmed that the activated AS ⁇ 1 is involved in the induction of apoptosis of “t cells” via the signaling cascade. It has been reported that when a dominant-negative mutant, which is a mutant of the present invention, was highly expressed in Jurkat cells, apoptosis induced by TNF-hi was suppressed. Therefore, it is disclosed that ASK1 is useful as a therapeutic agent for malignant tumor or a gene therapeutic agent for malignant tumor.
  • ASK1 is highly expressed in skin keratinocytes, suggesting that it is involved in promoting its differentiation. However, there is no report that ASK1 is involved in the onset or progression of immune diseases.
  • IL-1 is involved in the development of rheumatoid arthritis, type I diabetes, systemic lupus erythematosus, inflammatory bowel disease, atopic dermatitis, psoriasis, transplant rejection, bronchial asthma, etc.
  • MIP-3 also known as LARC (liver and activation-regulated chemokine)
  • LARC liver and activation-regulated chemokine
  • MlP-3 is involved in the invasion, migration and resident of immature dendritic cells, antigen-presenting cells, tissue-directed memory T cells, and Langerhans cells, which are important antigen-presenting cells of the skin. It is also involved in the development of inflammatory bowel disease, transplant rejection, and bronchial asthma. MIP-1 ⁇ and MIP_1) 3 are involved in the migration and invasion of Th1 cells and macrophages, and are expressed in conditions such as rheumatoid arthritis, transplant rejection, graft-versus-host disease, and bronchial asthma Has been reported to play an important role in the formation of the disease state. (For example, see the following references 8-28)
  • Reference 9 Masataka Kuwana, Molecular Medicine, Vol.38, No.8, pp.900-907 (2001)
  • Reference 10 Shuji Takei, Pediatrics, Vol.33, No.6, pp.861-865 (2001)
  • Reference 11 Shinki Tokura, Journal of the Japanese Society of Skin Allergy, Vol.5, No.4, pp.117-
  • Reference 12 Junichi Unohara, Clinical Pathology, Vol. 46, No. 6, pp. 587-592 (1998)
  • Reference 13 Yasushi Tanaka et al., History of Medicine, Vol. 174, No. 14, pp. 1218- 1222 (1995)
  • Article 14 Akihisa Harada et al., Inflammation and immunity, Vol.2, No.2, pp.211-220 (1994)
  • Article 15 Masamichi Sugimoto et al., Molecular Medicine, Vol.38, No.4, pp. .410-417 (2001)
  • Reference 16 Akio Otani et al., Modern Medicine, Vol.33, No.6, pp.1527-1532 (2001)
  • Reference 17 Kazuya Anezaki et al., History of Medicine, Vol.173, No.6, pp.588-592 (1995)
  • Reference 18 Makoto Sada et al., Asthma, Vol.10, No.2, pp.31-35 (1997)
  • the present invention provides a preventive or therapeutic agent for an immune disease, which has an inhibitory effect on the production of various cytokines / chemokines that are deeply involved in the onset and progress of the immune disease.
  • FIG. 1 shows various cytokines (IL-1 and IL-1 / 3) in normal cultured human skin keratinocytes when activated ASK1 (ASK1- ⁇ ) was overexpressed by the adenovirus method. Increased mRNA expression of various chemokines (IL-8, MIP-3, MIP-1 ⁇ ) and GAPDH was increased by control (instead of untreated cells and activated ASK 1) 3-galactosidase (/ 3- FIG. 9 is a diagram quantified by using the RNase protection assay in comparison with (Cells expressing Gal)). The vertical axis shows the names of the detected genes, that is, the names of various cytokins and chemokines, and GAPDH as a negative control, and the horizontal axis shows the group names.
  • Fig. 2 shows the actual status of IL-18 when activated ASK1 (ASK1- ⁇ ) was overexpressed in cultured normal human skin keratinocytes by the adenovirus vector method.
  • the expression level of the protein was compared with the control (untreated cells and cells expressing 3-galactosidase (] 3-Ga 1) instead of active ASK 1) in a graph quantified by ELISA. is there.
  • the vertical axis indicates the concentration (pg / mL) of IL-8 secreted into the culture supernatant, and the horizontal axis indicates the group name.
  • the error number indicates the standard deviation.
  • FIG. 3 shows the actual protein expression level of MIP-1 when activated ASK 1 (ASK 1 - ⁇ ) was overexpressed in cultured normal human skin keratinocytes by the adenovirus vector method.
  • FIG. 4 is a graph quantified by an ELISA method as compared with a control (untreated cells and cells expressing i3-galactosidase (3-Gal) instead of active ASK1).
  • the vertical axis indicates the concentration (pg / mL) of MlP-1 ⁇ secreted into the culture supernatant, and the horizontal axis indicates the group name.
  • the error bar represents the standard deviation.
  • FIG. 4 shows the actual protein expression level of MIP-1 / 3 when activated ASK1 (ASK1- ⁇ ) was overexpressed in cultured normal human skin keratinocytes by the adenovirus vector method.
  • FIG. 4 is a graph quantified by ELISA in comparison with a control (untreated cells and cells expressing 3-galactosidase (instead of activated ASK1) 3-galactosidase).
  • the vertical axis indicates the concentration (pgZmL) of MlP_l secreted into the culture supernatant, and the horizontal axis indicates the group name. Error bars indicate standard deviation.
  • FIG. 5 shows the actual protein expression level of MIP-3 when activated ASK1 (ASK1- ⁇ ) was overexpressed in normal human cultured skin keratinocytes by the adenovirus vector method.
  • FIG. 4 is a graph quantified by an ELISA method as compared with a control (untreated cells and cells expressing / 3-galactosidase (/ 3-Gal) instead of active ASK1).
  • the vertical axis indicates the concentration (pgZmL) of MlP-3 secreted into the culture supernatant, and the horizontal axis indicates the group name.
  • the error bar indicates the standard deviation.
  • Fig. 6 shows the expression level of IL-16 protein induced by LPS using fetal fibroblasts (MEFs) as cells derived from ASK1 knockout mice.
  • MESFs fetal fibroblasts
  • the time-dependent changes were determined by ELISA using MESK s cells (ASK1 ⁇ / ⁇ ; open bar) and wild-type MEF s cells (ASK 1 + / +; black bar) derived from ASK1 knockout mice. It is a graph.
  • the vertical axis shows the concentration (pgZmL) of IL-16 protein secreted into the culture supernatant, and the horizontal axis shows time (hour).
  • the error number indicates the standard deviation.
  • FIG. 7 shows the dose dependence of LPS-stimulated IL-6 protein expression on LPS using fetal fibroblasts (MEFs) as cells derived from ASK1 knockout mice.
  • FIG. 4 is a graph comparing and quantifying MEF s cells (ASK 1 ⁇ / ⁇ ; white bars) and wild type MEF s cells (ASK 1 + / +; black bars) by the ELISA method.
  • the vertical axis shows the concentration (pg / mL) of IL-6 protein secreted into the culture supernatant, and the horizontal axis shows the concentration of LPS (/ mL).
  • the error number indicates the standard deviation.
  • FIG. 8 shows the temporal change in the expression level of IL_1] 3 protein induced by LPS using spleen cells (sp1e no cytes) derived from ASK1 knockout mice.
  • This is a graph showing comparative quantification of sp 1 enocytes (ASK1-no-; open circle) derived from wild-type sp 1 enocytes (ASK 1 + / +; black circle) by ELISA.
  • the vertical axis indicates the concentration (pg / mL) of IL-1 / 3 protein secreted into the culture supernatant, and the horizontal axis indicates time (hour). Error bars represent standard deviation.
  • Fig. 9 shows the time-dependent changes in the expression level of IL-6 protein induced by LPS using spleen cells (sp 1 e no cytes) derived from ASK1 knockout mice.
  • This is a graph of comparative quantification of eno cytes (ASK1—Z_; open circle) and wild-type sp 1 enocytes (ASK 1 + / +; black circle) by the ELISA method.
  • the vertical axis shows the concentration (pgZmL) of IL-6 protein secreted into the culture supernatant, and the horizontal axis shows time (hours). Error bars represent standard deviation.
  • FIG. 10 shows the expression level of MIP-1 ⁇ protein stimulated by LPS using spleen cells (sp 1 enocytes) derived from ASK1 knockout mice.
  • the temporal changes were determined by ELISA using sp1 enocytes (ASK1——; open circles) and wild-type sp1 enocytes (ASK1 +++; black circles) derived from ASK1 knockout mice.
  • ASK1—— sp1 enocytes
  • ASK1 +++ wild-type sp1 enocytes
  • Fig. 11 is a graph comparing the survival rates of ASK1 knockout mice (ASK1-/-; open circles) and wild-type mice (ASKl + 10; black circles) with respect to the sepsis model over time.
  • the vertical axis shows the survival rate (%), and the horizontal axis shows the group name.
  • Fig. 12 shows the blood TNF- ⁇ concentration 2 hours after LPS induction in a sepsis model in ASK1 knockout mice (ASK1 ⁇ / ⁇ ; open circles) and wild-type mouse (ASK1 + Z +; black circles). It is the graph which compared. The vertical axis shows blood TNF-serum concentration (ngZmL), and the horizontal axis shows group names. The error bar represents the standard deviation. BEST MODE FOR CARRYING OUT THE INVENTION
  • the present inventors have conducted intensive studies to find drugs useful for the prevention or treatment of immune diseases.As a result, ASK 1 is involved in the development and progression of immune diseases, and ASK 1 inhibitors are useful for immune diseases. The knowledge was obtained, and the present invention was achieved.
  • the present inventors established normal cultured human skin keratinocytes overexpressing activated ASK1, and established various types of cytokines, chemokines. The expression level was measured. As a result, in activated ASK1 overexpressing cells, IL-1 and IL-6 cytodynamics, IL-8, MIP-1 ⁇ , MI ⁇ -1) 3 and MIP_3 ⁇ chemokines were highly expressed. I confirmed that These facts indicate that ASK1 is involved in enhancing the expression of these cytokines, chemokines, which are deeply involved in the development and progression of immune diseases.
  • the present inventors produced ASK1 knockout mice by the method described below. Made. Fetal fibroblasts and spleen cells were collected from the prepared ASK1 knockout mice, and the amounts of production of IL-1, IL-6 and MIP-1 ⁇ induced by LPS (lipopolysaccharide) stimulation were measured. As a result, fetal fibroblasts and spleen cells of ASK1 knockout mice were significantly different from those of wild type (normal) mouse fetal fibroblasts and spleen cells. The production of spikes was suppressed. From these facts, it was revealed that reducing the activity of ASK1 can actually suppress the production of the cytokine ⁇ chemokine. Therefore, the above experimental results indicate that ASK1 inhibitors are extremely useful for prevention and treatment of various immune diseases.
  • the present inventors have found that in an in vivo test using a sepsis model, the survival rate of ASK1 knockout mice is significantly improved as compared with wild-type mice, and that the ASK1 knockout mice Observed that there was little increase in blood TNF concentration. From these facts, it was found that reducing the activity of ASK1 can remarkably improve the pathology of various immune diseases such as sepsis. These are nothing less than further supporting that ASK1 inhibitors are extremely useful for prevention and treatment of various immune diseases.
  • an ASK1 inhibitor as an active ingredient, a drug useful for prevention or treatment of an immune disease can be provided.
  • Use of an effective amount of an ASK1 inhibitor can provide a useful method for preventing or treating an immune disease.
  • ⁇ ++ '' indicates that two ASK1 loci present on a pair of homologous chromosomes in a mouse or mouse-derived cells are both normal, that is, wild-type
  • “One Z—” is a homozygote in which a mutation has been introduced into both of the two ASK1 loci present on each of a pair of homologous chromosomes and has no ASK1 protein expression, ie, ASK1 Indicates that the mouse or mouse-derived cell has been knocked out.
  • the term “immune disease” refers to a disease that develops or develops due to the breakdown of the immune system due to abnormal functions of various cells, such as rheumatoid arthritis, Surin dependence) Diabetes, systemic lupus erythematosus (SLE), psoriasis, inflammatory bowel disease, multiple sclerosis, systemic sclerosis, hemolytic anemia, thrombocytopenia, neutropenia, siedalen syndrome, IgA kidney Disease, lupus nephritis, mesangial proliferative nephritis, polymyositis, Hashimoto's disease, Graves' disease, Addison's disease, primary biliary cirrhosis (PBC), ankylosing myelitis, autoimmune hepatitis, pemphigus vulgaris, severe Autoimmune diseases such as myasthenia, anti-glomerular basement membrane disease, Casteman disease, celiac disease
  • the pharmaceutical composition of the present invention is particularly useful for treating rheumatoid arthritis, type I (insulin-dependent) diabetes, systemic lupus erythematosus (SLE), psoriasis, inflammatory bowel disease, multiple sclerosis, thrombocytopenia, siedalen syndrome, etc. It is suitable for allergic diseases such as autoimmune disease, bronchial asthma, atopic dermatitis, and sepsis.
  • the ASK1 inhibitor is not limited to a substance having an ASK1 inhibitory action per se, but produces an ASK1 inhibitory substance in vivo or in a culture system.
  • a derivative in which one or more amino acids are added, inserted, substituted, and Z or deleted (for example, deletion of the alanine residue at position 960) in the amino acid sequence see, for example, Reference 29 below)
  • Dominant negative for human ASK1 eg, K709R, K709M; hereinafter, referred to as ASK1 dominant negative
  • antisense oligonucleotide for human ASK1 hereinafter, referred to as ASK1 antisense oligonucleotide
  • AS Chemicals with K1 inhibitory activity eg, Daryuthion S-transferase (Mu 1 -1 etc.), Nef (Ne f), 14—3—3 White matter, thioredoxin, heat shock protein Hsp72, protein phosphat
  • a recombinant vector capable of replicating and expressing the dominant negative or antisense oligonucleotide in a target tissue or host cell hereinafter, referred to as a “recombinant vector”.
  • ASK1 dominant negative body expression recombinant vector or ASK1 antisense oligonucleotide expression recombinant vector which expresses a chemical substance having ASK1 inhibitory activity or its sense oligonucleotide in target tissues or host cells (Hereinafter referred to as a recombinant vector expressing a chemical substance having an ASK1 inhibitory action or a recombinant oligonucleotide vector expressing a sense oligonucleotide having a chemical substance having an ASK1 inhibitory action).
  • C a host cell transformed with an ASK1 dominant-negative expression recombinant vector, a host cell transformed with an ASK1 antisense oligonucleotide-expressing recombinant vector , ASK1 inhibitory chemical expression vector And a host cell transformed with a recombinant vector expressing a sense oligonucleotide which expresses a chemical substance having an ASK1 inhibitory action).
  • the method of using the ASK1 inhibitor of the present invention includes ASK1 dominant negative expression recombinant vector, ASK1 antisense oligonucleotide expression recombinant vector, chemical expression recombinant vector having ASK1 inhibitory activity, and Introduces a recombinant vector expressing senseoligonucleotide of a chemical substance having ASK1 inhibitory activity or a host cell transformed by the recombinant vector into a target tissue in a living body by an appropriate method, and ASK1 dominant negative, ASK1 antisense nucleotide, use as a genetic preventive or therapeutic agent by expressing a chemical substance having ASK1 inhibitory activity or its sense oligonucleotide, or ASK1 dominant negative, ASK1 antisense oligonucleotide, ASK1 inhibitory chemical, or ASK (1)
  • ASK1 The lysine residue at position 709 of ASK 1 is an ATP-binding site, which can be inactivated by substituting it with arginine or methionine. Therefore, dominant negative ( A dominant-negative type) ASK1 (K709R, K709M), which functions as a mutant, is inserted into an expression vector, and the vector is transfected or infused into cells by the lipofection method or adenovirus infection method. Thus, overexpression in cells can be exemplified. The ASK1 overexpressing cells transformed in this way can remarkably suppress the production of cytokinetic chemokines.
  • the vector examples include a plasmid vector, a virus vector (for example, a retrovirus vector, an adenovirus vector, a herpes virus vector, a Sendai virus vector, and a vaccinia virus vector), and a ribosome vector (for example, a click). Ribosome vector).
  • a virus vector for example, a retrovirus vector, an adenovirus vector, a herpes virus vector, a Sendai virus vector, and a vaccinia virus vector
  • a ribosome vector for example, a click.
  • a nucleotide sequence that controls its expression eg, a promoter sequence, a terminator sequence, an enhancer sequence
  • ⁇ ⁇ ⁇ a gene marker for selecting a microorganism, insect cell, animal cultured cell, etc. for example, , Neomycin resistance gene, kanamycin resistance gene
  • Host cells include, for example, E. coli, yeast, insect cells, and CH ⁇ cells, Examples include animal cells such as COS cells, mink lung epithelial cells (eg, MvI Lu), lymphocytes, fibroblasts, blood cells, and tumor cells.
  • animal cells such as COS cells, mink lung epithelial cells (eg, MvI Lu), lymphocytes, fibroblasts, blood cells, and tumor cells.
  • Methods for introducing a recombinant vector into a target tissue or host cell include the HVJ liposome method (see References 38 and 39 below), the method of directly administering an ASK1 inhibitor by injection, the calcium phosphate method, and the DEAE-dextran method.
  • a method using a gene gun see Reference 40 below
  • a method using a ribofection method see Reference 41 below
  • a vector for example, a retrovirus vector, an adenovirus vector, a herpes virus vector, Vaccinia virus vector.
  • preparation forms are used depending on the usage.
  • the formulation form include tablets, capsules, granules, powders, pills, fine granules, troches, injections, rectal administration, suppositories, and the like. Is administered.
  • preparations containing an ASK1 inhibitor contain the above-mentioned ASK1 inhibitor as an active ingredient, and are commonly used as excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents. It can be produced by appropriately mixing, diluting or dissolving with pharmaceutical additives such as agents, preservatives, wetting agents, emulsifiers, dispersing agents, stabilizers, and solubilizing agents, and dispensing according to a conventional method.
  • pharmaceutical additives such as agents, preservatives, wetting agents, emulsifiers, dispersing agents, stabilizers, and solubilizing agents, and dispensing according to a conventional method.
  • the dose of an ASK1 inhibitor for pharmacological prophylaxis or treatment of immune disease is determined as appropriate, taking into account usage, patient age, gender, severity of symptoms, type of disease, etc.
  • the dose may be 0.1 to 50 Omg, preferably about 0.5 to 10 Omg, and may be administered once or several times a day.
  • the dose of the ASK1 inhibitor in the genetic prevention or treatment of an immune disease can also be appropriately determined according to the above.
  • an ASK1 dominant negative, an ASK1 antisense oligonucleotide, a chemical substance having ASK1 inhibitory activity, a nucleotide sequence encoding the sense oligonucleotide thereof, a vector containing the same, or a By introducing into a target tissue using a host cell transformed by a vector, the onset or progression of an immune disease can be suppressed.
  • the administration of ASK1 dominant negative, ASK1 antisense oligonucleotide, a chemical substance having ASK1 inhibitory activity, or a preparation containing its senseoligonucleotide, orally or parenterally causes the onset or development of an immune disease. Progress can be restrained.
  • Reference 31 Romas Geleziunas et al., Ature, Vol. 410, pp. 834-838 (2001)
  • Reference 32 FASEB Journal, Vol. 15, No. 4, pp. A235 (2001)
  • Bunnan Inu 37 Xianghong Zou et al., Molecular and Cellular Biology, Vol. 21, No. 14, pp. 4818-4828 (2001)
  • Test example 1 The content of the present invention will be described in more detail by the following test examples, but the present invention is not limited to the content.
  • Test example 1 The content of the present invention will be described in more detail by the following test examples, but the present invention is not limited to the content.
  • Activated ASK1 (ASK1- ⁇ ; see Reference 42 below), a molecule that is permanently activated by deleting the N-terminal activity suppression region of the ASK1 molecule, is overexpressed in cells, and the physiology of ASK1
  • the target function was amplified and detected by the following method. First, an adenovirus vector (Ad-ASK1- ⁇ ) incorporating this active ASK1 was prepared, and the active human ASK1 was overexpressed in cultured normal human skin keratinocytes by the adenovirus method.
  • the recombinant virus is infected with 3 x 10 6 eel 1 s / we 11 normal human cultured skin keratinocytes at an efficiency of about 5 and the cells and culture supernatant 5 mL was collected.
  • the increase in mRNA expression levels of various cytokins and chemokines was quantified using the RNase protection assay, and the protein concentration released into the culture supernatant as the actual protein expression level was determined by ELISA. It was quantified using.
  • untreated cells and cells expressing) 3-galactosidase instead of active ASK1 were compared.
  • GAPDH a gene whose mRNA level did not change with stimulation, was used as a negative control.
  • Fig. 1 For the mRNA expression levels of various cytokines and chemokines, and for the protein expression levels in Fig. 2 (IL-18), Fig. 3 (MIP-la), and Fig. 3 respectively. This is shown in Fig. 4 ( ⁇ ⁇ ⁇ _1; 3) and Fig. 5 ( ⁇ ⁇ ⁇ —3a).
  • ASK1 activation of ASK1 causes cytokines such as IL-1 and IL-1 / 3, as well as IL-8, ⁇ ⁇ ⁇ _1 (3 ⁇ 4, ⁇ ⁇ ⁇ — 1/3, MI ⁇ -3 This indicates that the expression of mRNA or various proteins of chemokines such as a is induced.
  • chromosomal DNA fragments including the first exon of ASK1 were cloned from the chromosome (genomic) DNA library of 129ZS VJ mice (Strategene). Using one of the clones, 10 kb upstream and 2 kb downstream of the first exon were used as the homologous recombination region, and the first exon and the adjacent intron region were converted to GFP (greenflourescence protein) and neomycin for positive selection. A targeting vector replaced with a resistance gene was constructed. As a targeting vector, pBluescript SK (Strategene) containing DT-A (diphtheria toxin ⁇ chain) for negative selection was used.
  • GFP greenflourescence protein
  • the evening vector was introduced into J1 ES cells (embryon icst emce11) by the electoporation method. After selecting neomycin-resistant ES cell colonies, homologous recombination cells were further confirmed by Southern blotting. Heterozygous mutant ES cells were introduced into C57BL / 6J blastocysts by microinjection. Backcrossing of the born chimeric mice to C57BLZ6J mice resulted in F1 (first generation) heterozygous mice. After confirming whether or not the gene mutation was introduced into germ cells by Southern blotting, ASK1 knockout mice, which are homozygotes of ASK1, were established from the crossing of these F1 heterozygous mice. . Test example 3
  • Inflammatory cytokine IL-1 ⁇ stimulated by LPS using fetal fibroblasts (mouse embryon icfibrob 1 asts; ME F s) and spleen cells (sp 1 e no cytes) from ASK 1 knockout mice Then, it was examined whether ASK1 is involved in the induction of the expression of IL-16 and the chemokine MI ⁇ -1 ⁇ .
  • fetal fibroblasts MEFs
  • 10 g / mL LPS was added to cells seeded at a concentration of 1 ⁇ 10 5 ce 11 s / we 11
  • the temporal change in the secretion amount of IL-16 protein into the culture supernatant at 12, 24 hours was measured.
  • ILs were added to cells seeded at a concentration of 1 ⁇ 10 5 ce 11 s Zwe 11 by adding 10 Z gZmL of LPS to about 0.5 mL of medium.
  • 1) Induce the expression of 3, IL-6 and MIP-1 ⁇ , and 1-1,3, IL-6 and MIP in the culture supernatant at 6, 12, and 24 hours after LPS stimulation. -The amount of secreted protein was measured.
  • the expression levels of each of the cytokines and chemokines were determined using the ELISA method, as in Test Example 1.
  • Figures 6 and 7 show the results for fetal fibroblasts (MEFs), and Figures 8, 9 and 10 show the results for spleen cells (sple no cytes).
  • MEFs fetal fibroblasts
  • Figures 8, 9 and 10 show the results for spleen cells (sple no cytes).
  • spleen cells derived from ASK1 knockout mice splenenocytes
  • IL-13 Fig. 8
  • IL-6 Fig. 9
  • MIP-1 ⁇ Fig. 10
  • the survival rates of the ASK1 knockout mouse and the wild-type mouse in the sepsis model were compared. Sepsis was induced by injecting LPS into mice intraperitoneally at a dose of 18.7 mg Zkg body weight. In sepsis, a sharp rise in cytokines has been observed, which has been shown to cause subsequent shock death. Therefore, the TNF- ⁇ concentration in the blood 2 hours after the induction was measured, and thereafter the survival rate of the individual was observed over time. In addition, 10 knockout mice and 10 wild-type mice were used.
  • FIG. 11 shows the change over time in the survival rate of the individual
  • FIG. 12 shows the TNF- ⁇ concentration in the blood 2 hours after the induction in the ASK1 knockout mouse and the wild type mouse, respectively.
  • FIG. 12 shows the survival rate in the ASK1 knockout mice.
  • the present invention relates to the prevention or treatment of an immune disease using an ASK1 inhibitor as an active ingredient.
  • various immune diseases such as rheumatoid arthritis, type I diabetes, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, multiple sclerosis, thrombocytopenia, siedalen syndrome, bronchial asthma, atopic dermatitis, and sepsis Of the present invention can be provided.

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Abstract

L'invention concerne des médicaments préventifs ou des remèdes pour des maladies immunologiques telles que la polyarthrite rhumatoïde, les diabètes de type I, le lupus érythémateux systémique, le psoriasis, la maladie inflammatoire du colon, la sclérose en plaques, la thrombocytopénie, le syndrome de Sjögren, l'asthme bronchique, le sepsis et la dermatite atopique, caractérisés par le fait qu'ils contiennent une substance chimique présentant un effet d'inhibition de ASK1 (par exemple, un composé négatif dominant de ASK1, un oligonucléotide antisens de ASK1, du glutathion, une S-transférase (Mul-1, etc.), Nef, la protéine 14-3-3 ou de la thiorédoxine), un oligonucléotide sens de ces composés, un vecteur d'expression de ces composés ou des cellules hôtes transformées par ce vecteur d'expression, et présentent un effet d'inhibition de la production de cytokines ou de chimiokines variées.
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JP2006151861A (ja) * 2004-11-29 2006-06-15 Redox Bioscience Inc 喫煙によって引き起こされる臓器障害の予防乃至治療剤
WO2006090849A1 (fr) * 2005-02-25 2006-08-31 Redox Bioscience Inc. Therapie et prophylaxie de conjonctivites inflammatoires
JP2007269671A (ja) * 2006-03-30 2007-10-18 Redox Bioscience Inc アレルギー性皮膚炎の予防ないし治療剤
JP2007531789A (ja) * 2004-04-05 2007-11-08 エイムスコ・リミテッド 疾患の治療法
JP2008501772A (ja) * 2004-06-11 2008-01-24 シンジェンタ リミテッド 炎症性皮膚状態を寛解するための方法
US7390625B2 (en) 2002-11-22 2008-06-24 Takeda Pharmaceutical Company Limited Apoptosis-associated protein and use thereof
CN102229655B (zh) * 2009-10-23 2012-05-23 山东省医药生物技术研究中心 抗类风湿性关节炎的多肽及其在制药中的应用
CN102229656B (zh) * 2009-10-23 2012-05-23 山东省医药生物技术研究中心 抗类风湿性关节炎的多肽及其在制药中的应用
CN102229658B (zh) * 2009-10-23 2012-05-23 山东省医药生物技术研究中心 抗类风湿性关节炎的多肽及其在制药中的应用
CN102229654B (zh) * 2009-10-23 2012-05-23 山东省医药生物技术研究中心 抗类风湿性关节炎的多肽及其在制药中的应用
CN102229657B (zh) * 2009-10-23 2012-05-23 山东省医药生物技术研究中心 抗类风湿性关节炎的多肽及其在制药中的应用
CN102229653B (zh) * 2009-10-23 2012-05-23 山东省医药生物技术研究中心 抗类风湿性关节炎的多肽及其在制药中的应用
CN111265662A (zh) * 2020-02-11 2020-06-12 中山大学附属第五医院 干预14-3-3在治疗脓毒症中的应用
WO2020213913A1 (fr) * 2019-04-16 2020-10-22 연세대학교 산학협력단 Composition comprenant une protéine gstt1 ou un gène la codant comme principe actif

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Publication number Priority date Publication date Assignee Title
US7390625B2 (en) 2002-11-22 2008-06-24 Takeda Pharmaceutical Company Limited Apoptosis-associated protein and use thereof
JP2007531789A (ja) * 2004-04-05 2007-11-08 エイムスコ・リミテッド 疾患の治療法
JP2008501772A (ja) * 2004-06-11 2008-01-24 シンジェンタ リミテッド 炎症性皮膚状態を寛解するための方法
JP2006151861A (ja) * 2004-11-29 2006-06-15 Redox Bioscience Inc 喫煙によって引き起こされる臓器障害の予防乃至治療剤
JP2012167121A (ja) * 2005-02-25 2012-09-06 Redox Bioscience Inc 炎症性眼表面疾患の予防ないし治療剤
WO2006090849A1 (fr) * 2005-02-25 2006-08-31 Redox Bioscience Inc. Therapie et prophylaxie de conjonctivites inflammatoires
JP5043644B2 (ja) * 2005-02-25 2012-10-10 レドックス・バイオサイエンス株式会社 炎症性眼表面疾患の予防ないし治療剤
JP2007269671A (ja) * 2006-03-30 2007-10-18 Redox Bioscience Inc アレルギー性皮膚炎の予防ないし治療剤
CN102229655B (zh) * 2009-10-23 2012-05-23 山东省医药生物技术研究中心 抗类风湿性关节炎的多肽及其在制药中的应用
CN102229656B (zh) * 2009-10-23 2012-05-23 山东省医药生物技术研究中心 抗类风湿性关节炎的多肽及其在制药中的应用
CN102229658B (zh) * 2009-10-23 2012-05-23 山东省医药生物技术研究中心 抗类风湿性关节炎的多肽及其在制药中的应用
CN102229654B (zh) * 2009-10-23 2012-05-23 山东省医药生物技术研究中心 抗类风湿性关节炎的多肽及其在制药中的应用
CN102229657B (zh) * 2009-10-23 2012-05-23 山东省医药生物技术研究中心 抗类风湿性关节炎的多肽及其在制药中的应用
CN102229653B (zh) * 2009-10-23 2012-05-23 山东省医药生物技术研究中心 抗类风湿性关节炎的多肽及其在制药中的应用
WO2020213913A1 (fr) * 2019-04-16 2020-10-22 연세대학교 산학협력단 Composition comprenant une protéine gstt1 ou un gène la codant comme principe actif
CN111265662A (zh) * 2020-02-11 2020-06-12 中山大学附属第五医院 干预14-3-3在治疗脓毒症中的应用

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