JP4961559B2 - インターロイキン18阻害剤を有効成分とする疾患の予防又は治療剤 - Google Patents
インターロイキン18阻害剤を有効成分とする疾患の予防又は治療剤 Download PDFInfo
- Publication number
- JP4961559B2 JP4961559B2 JP2007112157A JP2007112157A JP4961559B2 JP 4961559 B2 JP4961559 B2 JP 4961559B2 JP 2007112157 A JP2007112157 A JP 2007112157A JP 2007112157 A JP2007112157 A JP 2007112157A JP 4961559 B2 JP4961559 B2 JP 4961559B2
- Authority
- JP
- Japan
- Prior art keywords
- gene
- inhibitor
- copd
- therapeutic agent
- inhibitors
- 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.)
- Active
Links
- 108090000171 Interleukin-18 Proteins 0.000 title claims description 72
- 102000003810 Interleukin-18 Human genes 0.000 title claims description 65
- 239000003814 drug Substances 0.000 title claims description 33
- 229940124597 therapeutic agent Drugs 0.000 title claims description 27
- 230000003449 preventive effect Effects 0.000 title claims description 14
- 239000003112 inhibitor Substances 0.000 title description 34
- 201000010099 disease Diseases 0.000 title description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 20
- 239000004480 active ingredient Substances 0.000 title description 6
- 108090000623 proteins and genes Proteins 0.000 claims description 72
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 48
- 150000001413 amino acids Chemical class 0.000 claims description 24
- 102000004169 proteins and genes Human genes 0.000 claims description 21
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 11
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 8
- 229920001184 polypeptide Polymers 0.000 claims description 6
- 125000003275 alpha amino acid group Chemical group 0.000 claims 2
- 238000000034 method Methods 0.000 description 30
- 210000004072 lung Anatomy 0.000 description 25
- 238000010171 animal model Methods 0.000 description 24
- 241000699666 Mus <mouse, genus> Species 0.000 description 22
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 18
- 108090000426 Caspase-1 Proteins 0.000 description 17
- 235000018102 proteins Nutrition 0.000 description 16
- 102000035195 Peptidases Human genes 0.000 description 14
- 108091005804 Peptidases Proteins 0.000 description 14
- 239000004365 Protease Substances 0.000 description 14
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 14
- 230000014509 gene expression Effects 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 102000004557 Interleukin-18 Receptors Human genes 0.000 description 11
- 108010017537 Interleukin-18 Receptors Proteins 0.000 description 11
- 108010076504 Protein Sorting Signals Proteins 0.000 description 11
- 102100035904 Caspase-1 Human genes 0.000 description 10
- 206010014561 Emphysema Diseases 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- 108010067372 Pancreatic elastase Proteins 0.000 description 9
- 102000016387 Pancreatic elastase Human genes 0.000 description 9
- 235000019419 proteases Nutrition 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 8
- 208000024172 Cardiovascular disease Diseases 0.000 description 7
- 239000002299 complementary DNA Substances 0.000 description 7
- 239000002243 precursor Substances 0.000 description 7
- 230000000069 prophylactic effect Effects 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 241000700605 Viruses Species 0.000 description 6
- 230000034994 death Effects 0.000 description 6
- 231100000517 death Toxicity 0.000 description 6
- 210000002216 heart Anatomy 0.000 description 6
- 238000011532 immunohistochemical staining Methods 0.000 description 6
- -1 CP80633 Chemical compound 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
- 208000019693 Lung disease Diseases 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 102000044166 interleukin-18 binding protein Human genes 0.000 description 5
- 108010070145 interleukin-18 binding protein Proteins 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 230000000241 respiratory effect Effects 0.000 description 5
- 206010001881 Alveolar proteinosis Diseases 0.000 description 4
- 108020004705 Codon Proteins 0.000 description 4
- 206010019280 Heart failures Diseases 0.000 description 4
- 206010019663 Hepatic failure Diseases 0.000 description 4
- 241000725303 Human immunodeficiency virus Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229940124446 critical care medicine Drugs 0.000 description 4
- 230000007812 deficiency Effects 0.000 description 4
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 208000007903 liver failure Diseases 0.000 description 4
- 231100000835 liver failure Toxicity 0.000 description 4
- 230000002093 peripheral effect Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 230000002685 pulmonary effect Effects 0.000 description 4
- 208000002815 pulmonary hypertension Diseases 0.000 description 4
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 239000013598 vector Substances 0.000 description 4
- 108010076667 Caspases Proteins 0.000 description 3
- 102000011727 Caspases Human genes 0.000 description 3
- 108010074328 Interferon-gamma Proteins 0.000 description 3
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 3
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 3
- 108010006035 Metalloproteases Proteins 0.000 description 3
- 102000005741 Metalloproteases Human genes 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- 108091081024 Start codon Proteins 0.000 description 3
- 108090000203 Uteroglobin Proteins 0.000 description 3
- 102100031083 Uteroglobin Human genes 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 230000002554 disease preventive effect Effects 0.000 description 3
- 208000033065 inborn errors of immunity Diseases 0.000 description 3
- 229940066294 lung surfactant Drugs 0.000 description 3
- 239000003580 lung surfactant Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000000414 obstructive effect Effects 0.000 description 3
- 208000028529 primary immunodeficiency disease Diseases 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 241000701161 unidentified adenovirus Species 0.000 description 3
- 239000013603 viral vector Substances 0.000 description 3
- 229960002555 zidovudine Drugs 0.000 description 3
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 3
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- 239000005541 ACE inhibitor Substances 0.000 description 2
- 102000035101 Aspartic proteases Human genes 0.000 description 2
- 108091005502 Aspartic proteases Proteins 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 206010065929 Cardiovascular insufficiency Diseases 0.000 description 2
- 206010009192 Circulatory collapse Diseases 0.000 description 2
- 102000005927 Cysteine Proteases Human genes 0.000 description 2
- 108010005843 Cysteine Proteases Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 241000702421 Dependoparvovirus Species 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000016942 Elastin Human genes 0.000 description 2
- 108010014258 Elastin Proteins 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 108060006678 I-kappa-B kinase Proteins 0.000 description 2
- 102000001284 I-kappa-B kinase Human genes 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 108010072621 Interleukin-1 Receptor-Associated Kinases Proteins 0.000 description 2
- 102000006940 Interleukin-1 Receptor-Associated Kinases Human genes 0.000 description 2
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 2
- 239000004909 Moisturizer Substances 0.000 description 2
- 108010014632 NF-kappa B kinase Proteins 0.000 description 2
- 102000019148 NF-kappaB-inducing kinase activity proteins Human genes 0.000 description 2
- 108090000526 Papain Proteins 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 2
- 102000008889 TNF receptor-associated factor TRAF Human genes 0.000 description 2
- 108050000808 TNF receptor-associated factor TRAF Proteins 0.000 description 2
- 108700019146 Transgenes Proteins 0.000 description 2
- 241000700618 Vaccinia virus Species 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000011225 antiretroviral therapy Methods 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 210000000233 bronchiolar non-ciliated Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 210000004177 elastic tissue Anatomy 0.000 description 2
- 239000003063 flame retardant Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000000520 microinjection Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000001333 moisturizer Effects 0.000 description 2
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 2
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 2
- 235000019834 papain Nutrition 0.000 description 2
- 229940055729 papain Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 206010040560 shock Diseases 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- ZEYYDOLCHFETHQ-JOCHJYFZSA-N (2r)-2-cyclopentyl-2-[4-(quinolin-2-ylmethoxy)phenyl]acetic acid Chemical compound C1([C@@H](C(=O)O)C=2C=CC(OCC=3N=C4C=CC=CC4=CC=3)=CC=2)CCCC1 ZEYYDOLCHFETHQ-JOCHJYFZSA-N 0.000 description 1
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- RNFJDJUURJAICM-UHFFFAOYSA-N 2,2,4,4,6,6-hexaphenoxy-1,3,5-triaza-2$l^{5},4$l^{5},6$l^{5}-triphosphacyclohexa-1,3,5-triene Chemical compound N=1P(OC=2C=CC=CC=2)(OC=2C=CC=CC=2)=NP(OC=2C=CC=CC=2)(OC=2C=CC=CC=2)=NP=1(OC=1C=CC=CC=1)OC1=CC=CC=C1 RNFJDJUURJAICM-UHFFFAOYSA-N 0.000 description 1
- NOIRDLRUNWIUMX-UHFFFAOYSA-N 2-amino-3,7-dihydropurin-6-one;6-amino-1h-pyrimidin-2-one Chemical compound NC=1C=CNC(=O)N=1.O=C1NC(N)=NC2=C1NC=N2 NOIRDLRUNWIUMX-UHFFFAOYSA-N 0.000 description 1
- UTUUPXBCDMQYRR-HSZRJFAPSA-N 4-[(2r)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine Chemical compound COC1=CC=C([C@H](CC=2C=CN=CC=2)C=2C=CC=CC=2)C=C1OC1CCCC1 UTUUPXBCDMQYRR-HSZRJFAPSA-N 0.000 description 1
- QSUSKMBNZQHHPA-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-pyridin-4-ylimidazol-2-yl]but-3-yn-1-ol Chemical compound C=1C=CC=CC=1CCCN1C(C#CCCO)=NC(C=2C=CC(F)=CC=2)=C1C1=CC=NC=C1 QSUSKMBNZQHHPA-UHFFFAOYSA-N 0.000 description 1
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 238000011814 C57BL/6N mouse Methods 0.000 description 1
- 229940124803 CXCR2 antagonist Drugs 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- 102100029855 Caspase-3 Human genes 0.000 description 1
- 108090000566 Caspase-9 Proteins 0.000 description 1
- 102100026550 Caspase-9 Human genes 0.000 description 1
- 102000003908 Cathepsin D Human genes 0.000 description 1
- 108090000258 Cathepsin D Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 108091062157 Cis-regulatory element Proteins 0.000 description 1
- 108010041986 DNA Vaccines Proteins 0.000 description 1
- 229940021995 DNA vaccine Drugs 0.000 description 1
- 108010024212 E-Selectin Proteins 0.000 description 1
- 102100023471 E-selectin Human genes 0.000 description 1
- 102000002149 Elafin Human genes 0.000 description 1
- 108010015972 Elafin Proteins 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 108060003393 Granulin Proteins 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 1
- 101000618525 Homo sapiens Membrane transport protein XK Proteins 0.000 description 1
- 101001109463 Homo sapiens NACHT, LRR and PYD domains-containing protein 1 Proteins 0.000 description 1
- 101000612671 Homo sapiens Pulmonary surfactant-associated protein C Proteins 0.000 description 1
- 101000777301 Homo sapiens Uteroglobin Proteins 0.000 description 1
- 108010049328 ICI 200355 Proteins 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102100025390 Integrin beta-2 Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 229940124761 MMP inhibitor Drugs 0.000 description 1
- 101150053046 MYD88 gene Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 1
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 1
- 241000711408 Murine respirovirus Species 0.000 description 1
- 101000960949 Mus musculus Interleukin-18 Proteins 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 108700023220 N-acetylneuraminate lyases Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 1
- 101710089543 Nitric oxide synthase, inducible Proteins 0.000 description 1
- 238000010222 PCR analysis Methods 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000002200 Respiratory Hypersensitivity Diseases 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- 206010039203 Road traffic accident Diseases 0.000 description 1
- 108010000303 Secretory Proteinase Inhibitory Proteins Proteins 0.000 description 1
- 102000002255 Secretory Proteinase Inhibitory Proteins Human genes 0.000 description 1
- 108090000787 Subtilisin Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- 108090001109 Thermolysin Proteins 0.000 description 1
- HMNZFMSWFCAGGW-XPWSMXQVSA-N [3-[hydroxy(2-hydroxyethoxy)phosphoryl]oxy-2-[(e)-octadec-9-enoyl]oxypropyl] (e)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(COP(O)(=O)OCCO)OC(=O)CCCCCCC\C=C\CCCCCCCC HMNZFMSWFCAGGW-XPWSMXQVSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 102000015395 alpha 1-Antitrypsin Human genes 0.000 description 1
- 108010050122 alpha 1-Antitrypsin Proteins 0.000 description 1
- 229940024142 alpha 1-antitrypsin Drugs 0.000 description 1
- 210000002821 alveolar epithelial cell Anatomy 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- XFILPEOLDIKJHX-QYZOEREBSA-N batimastat Chemical compound C([C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)[C@H](CSC=1SC=CC=1)C(=O)NO)C1=CC=CC=C1 XFILPEOLDIKJHX-QYZOEREBSA-N 0.000 description 1
- 229950001858 batimastat Drugs 0.000 description 1
- 102000016966 beta-2 Adrenergic Receptors Human genes 0.000 description 1
- 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 229950008654 butaprost Drugs 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000032341 cell morphogenesis Effects 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 239000002852 cysteine proteinase inhibitor Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical class CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- MDCUNMLZLNGCQA-HWOAGHQOSA-N elafin Chemical compound N([C@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H]1C(=O)N2CCC[C@H]2C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H]2CSSC[C@H]3C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(=O)N[C@@H](CSSC[C@H]4C(=O)N5CCC[C@H]5C(=O)NCC(=O)N[C@H](C(N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H]5N(CCC5)C(=O)[C@H]5N(CCC5)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCSC)NC(=O)[C@H](C)NC2=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N4)C(=O)N[C@@H](CSSC1)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N3)=O)[C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)C(C)C)C(C)C)C(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)N MDCUNMLZLNGCQA-HWOAGHQOSA-N 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000004030 hiv protease inhibitor Substances 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000008011 inorganic excipient Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 102000008625 interleukin-18 receptor activity proteins Human genes 0.000 description 1
- 108040002014 interleukin-18 receptor activity proteins Proteins 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 150000002535 isoprostanes Chemical class 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000003591 leukocyte elastase inhibitor Substances 0.000 description 1
- VNYSSYRCGWBHLG-AMOLWHMGSA-N leukotriene B4 Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC(O)=O VNYSSYRCGWBHLG-AMOLWHMGSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229940083747 low-ceiling diuretics xanthine derivative Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 229950008959 marimastat Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 description 1
- XRISENIKJUKIHD-LHQZMKCDSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(e,4r)-4-hydroxy-4-(1-propylcyclobutyl)but-1-enyl]-5-oxocyclopentyl]heptanoate Chemical compound CCCC1([C@H](O)C\C=C\[C@@H]2[C@H](C(=O)C[C@H]2O)CCCCCCC(=O)OC)CCC1 XRISENIKJUKIHD-LHQZMKCDSA-N 0.000 description 1
- 229960005249 misoprostol Drugs 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000017128 negative regulation of NF-kappaB transcription factor activity Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000008012 organic excipient Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 210000003101 oviduct Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229940127293 prostanoid Drugs 0.000 description 1
- 150000003814 prostanoids Chemical class 0.000 description 1
- 201000003489 pulmonary alveolar proteinosis Diseases 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960005224 roxithromycin Drugs 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- BTGNGJJLZOIYID-UHFFFAOYSA-N sivelestat Chemical compound C1=CC(OC(=O)C(C)(C)C)=CC=C1S(=O)(=O)NC1=CC=CC=C1C(=O)NCC(O)=O BTGNGJJLZOIYID-UHFFFAOYSA-N 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 229960005314 suramin Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- MQLXPRBEAHBZTK-SEINRUQRSA-M tiotropium bromide hydrate Chemical compound O.[Br-].C[N+]1(C)[C@H]2C[C@@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 MQLXPRBEAHBZTK-SEINRUQRSA-M 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 description 1
- 108010087967 type I signal peptidase Proteins 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000003519 ventilatory effect Effects 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- JPZXHKDZASGCLU-LBPRGKRZSA-N β-(2-naphthyl)-alanine Chemical compound C1=CC=CC2=CC(C[C@H](N)C(O)=O)=CC=C21 JPZXHKDZASGCLU-LBPRGKRZSA-N 0.000 description 1
Images
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
(2)(1)のうち、ポリペプチドであるもののアミノ酸配列のうち、1若しくは数個のアミノ酸が欠失,置換若しくは付加されたアミノ酸配列からなりかつインターロイキン18阻害活性を有するタンパク質
(3)(1)のうち、ポリペプチドであるものをコードする遺伝子
(4)(2)をコードする遺伝子
プロテアーゼとは、蛋白質分解酵素のことであるが、例えば、メタロプロテアーゼ,システインプロテアーゼ,セリンプロテアーゼ,アスパラギン酸プロテアーゼ(酸性プロテアーゼ)等が挙げられる。
MMPとは、動物細胞の細胞間の接着性マトリックス・タンパク質を加水分解し、細胞分裂や形態形成、さらにはガン転移に関与している亜鉛含有プロテアーゼである。MMPとしては、MMP−1,2,・・・28等30種類近くが同定されている。
本発明のCOPDの予防又は治療剤の有効成分として用いられるものとしては、下記(1)乃至(4)単独の他、これらの組み合わせ等が挙げられる。
(1)インターロイキン18阻害剤(レドックス活性蛋白質を除く)
(2)インターロイキン18阻害剤(レドックス活性蛋白質を除く)のアミノ酸配列のうち、1若しくは数個のアミノ酸が欠失,置換若しくは付加されたアミノ酸配列からなりかつインターロイキン18阻害活性を有するタンパク質
(3)(1)をコードする遺伝子
(4)(2)をコードする遺伝子
尚、上記(1)および(2)に於けるインターロイキン18阻害剤のアミノ酸配列は、後述するIL−18阻害剤として、一般に知られるアミノ酸配列であれば、特に限定されるものではないが、レドックス活性蛋白質は除くものとする。
阻害剤である、I-κBinhibitor,I-κBαgene transfer(American Journal of Respiratory and Critical Care Medicine vol.160 pp S72-S79, 1999)やPS-341(Proc.Natl.Acad.Sci.USA vol.95 PP.15671-15676, December 1998 Medical Sciences)等が挙げられる。
例えば、LTB4 antagonists (例えばLY29311, SC-53228, CP-105,696, SB201146, BIIL284)、5'-Lipxygenase inhibitors (例えばzileutin, Bayx1005)、Chemokine inhibitors、IL-8 antagonists (例えばSB225002; CXCR2 antagonists)、TNF inhibitors (例えばmonoclonal Ab, soluble receptors, MMP inhibitors)、Antioxydants (例えばNAC, NAL, グルタチオン,スーパーオキシドジスムターゼ等)、Prostanoid inhibitors (例えばCOX-2 inhibitors, thromboxane antagonists、isoprostane receptor antagonists)、iNOS inhibitor 等
例えば、Phosphodiesterase 4 inhibitors (例えばSB207499, CP80633, CDP-840)、Adhesion inhibitors (例えばanti-CD11/CD18, anti-ICAM1, E-selectin inhibitors)、Prostaglandin E analogs (例えばmisoprostil, butaprost)、サイトカイン(例えばIL-10)、Colchicine、Macrolide antibiotics (例えばerythromycin, clarithromycin, roxithromycin)等
例えば、Neutrophil elastase inhibitors (例えばICI200355, ONO-5046, MR-889, L658,758)、Cathepsin inhibitors (例えばsuramin)、Matrix metalloprotease inhibitors (例えばbatimastat, marimastat、KBR7785)、alpha1-antitrypsin (例えばpurified, human recombinant, gene transfer)、Secretory leukoprotease inhibitor、Elafin等
例えば免疫抑制剤FK506等
テオフィリン等のキサンチン誘導体,β2受容体刺激剤,抗コリン剤,抗アレルギー用剤,副腎皮質ホルモン剤及び吸入ステロイド等のステロイド剤等。
ウイルスの中では、レトロウイルス、アデノウイルス、アデノ関連ウイルス、ワクシニアウイルス等が好ましく、特にアデノウイルスが好ましい。
本発明のプロテアーゼ阻害剤やCOPD又は免疫不全症候群の予防又は治療剤を、上記のような様々な形態で投与すること、あるいは、本発明のプロテアーゼ阻害剤やCOPD、免疫不全症候群の予防又は治療剤である遺伝子を、遺伝子治療によって用いることによって、予防又は治療することができる。
[伝統的COPD動物モデル]
本発明において、COPD抑制効果の確認のために用いる肺気腫動物モデルは、文献記載の方法を用いることができるが(Shapiro, S. D. Animal models for COPD. Chest, 117: 223S-227S, 2000)、具体的には、例えば清潔PBSに懸濁した豚エラスターゼを、シリンジで気管内投与すること等によって作製することができる。
本発明において、COPD抑制効果の確認のために用いる疾患動物モデルとしては、本発明者(星野,特願2004−069835)によって開発された、新たなCOPD動物モデルも用いることができる。この動物モデルは、COPDの他、肺胞蛋白症や循環器疾患の動物モデルとしても使用可能であるが、下記の説明におていは、便宜上、COPD動物モデルと記載することがある。その作製方法を以下に記載する。
(X1)インターロイキン−18遺伝子
(X2)インターロイキン−18のアミノ酸配列のうち、1若しくは数個のアミノ酸が欠失,置換若しくは付加されたアミノ酸配列からなりかつインターロイキン18と同等の活性を有するタンパク質をコードする遺伝子
(Y1)カスパーゼ−1遺伝子
(Y2)カスパーゼ−1のアミノ酸配列のうち、1若しくは数個のアミノ酸が欠失,置換若しくは付加されたアミノ酸配列からなりかつカスパーゼ−1と同等の活性を有するタンパク質をコードする遺伝子
この動物モデルに導入する組換遺伝子は、下記(X1)又は(X2)遺伝子(以下、併せて「IL-18遺伝子類」と記載することがある。),あるいは下記(Y1)又は(Y2)遺伝子(以下、併せて「カスパーゼ1遺伝子類」と記載することがある。)を、肺特異的に発現するプロモーターの制御下に置くことによって、得ることができる。肺特異的に発現するプロモーターとしては、肺構成細胞由来プロモーター等が挙げられ、例えば肺サーファクタントプロモーター又はクララ細胞プロモーター等が挙げられる。
(X2)IL-18のアミノ酸配列のうち、1若しくは数個のアミノ酸が欠失,置換若しくは付加されたアミノ酸配列からなりかつIL-18と同等の活性を有するタンパク質をコードする遺伝子
(Y1)カスパーゼ−1遺伝子
(Y2)カスパーゼ−1のアミノ酸配列のうち、1若しくは数個のアミノ酸が欠失,置換若しくは付加されたアミノ酸配列からなりかつカスパーゼ−1と同等の活性を有するタンパク質をコードする遺伝子
シグナルペプチドとしては、例えばマウスの免疫グロブリン(以下「Ig」と記載する。)κ−チェーン・シグナルペプチド等が挙げられる。
マウスのIgκ−チェーン・シグナルペプチドは、例えば、Carroll, W. L., E. Mendel, S. Levy. 1985. Hybridoma fusion cell lines contain an aberrant kappa transcript. Mol. Immunol. 25:991.等に記載されている。
例えば、Nucleic Acids Res. 1984 Jan 25;12(2):857-72. Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. に記載されている。
ポリA配列としては、牛由来のポリA配列等が挙げられる。例えば、Goldman, L. A., E. C. Cutrone, S. V. Kotenko, C. D. Krause, J. A. Langer. 1996. Modifications of vectors pEF-BOS, pcDNA1 and pcDNA3 result in improved convenience and expression. BioTechniques 21:1013.等に記載されている。
疾患動物モデルは、例えば次のような方法で、作成することができる。
COPD患者10人の外科手術で得た組織及び交通事故等で亡くなった人等の6人の肺組織をホルマリン固定し、パラフィン切片を作製した。抗ヒトIL-18抗体(clone8)で免疫組織染色を行った。
「Kitasato, Y., Hoshino, T., Okamoto, M., Kato, S., Koda, Y., Nagata, N., Kinoshita, M., Koga, H., Yoon, D. Y., Asao, H., Ohmoto, H., Koga, T., Rikimaru, T., and Aizawa, H. Enhanced expression of interleukin-18 and its receptor in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol, 31: 619-625, 2004.」に報告してあるように、健常人の肺にはほとんど発現していない(図1)。
このことは、肺でのIL-18の過剰発現が、COPDの病因であることを裏付けるものである。
Claims (1)
- 下記(1)乃至(4)から選択される、少なくとも一種以上を含むことを特徴とする、慢性閉塞性肺疾患の予防又は治療剤。
(1)レドックス活性タンパク質を除く、抗IL−18抗体
(2)(1)のうち、ポリペプチドであるもののアミノ酸配列のうち、1若しくは数個のアミノ酸が欠失,置換若しくは付加されたアミノ酸配列からなりかつインターロイキン18阻害活性を有するタンパク質
(3)(1)のうち、ポリペプチドであるものをコードする遺伝子
(4)(2)をコードする遺伝子
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2007112157A JP4961559B2 (ja) | 2004-03-11 | 2007-04-20 | インターロイキン18阻害剤を有効成分とする疾患の予防又は治療剤 |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004069835 | 2004-03-11 | ||
JP2004069835 | 2004-03-11 | ||
JP2004094065 | 2004-03-29 | ||
JP2004094065 | 2004-03-29 | ||
JP2007112157A JP4961559B2 (ja) | 2004-03-11 | 2007-04-20 | インターロイキン18阻害剤を有効成分とする疾患の予防又は治療剤 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2006510996A Division JP4160615B2 (ja) | 2004-03-11 | 2005-03-11 | プロテアーゼ阻害剤 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2011262938A Division JP2012087136A (ja) | 2004-03-11 | 2011-11-30 | インターロイキン18阻害剤を有効成分とする疾患の予防又は治療剤 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2007246529A JP2007246529A (ja) | 2007-09-27 |
JP4961559B2 true JP4961559B2 (ja) | 2012-06-27 |
Family
ID=38591187
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007112157A Active JP4961559B2 (ja) | 2004-03-11 | 2007-04-20 | インターロイキン18阻害剤を有効成分とする疾患の予防又は治療剤 |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP4961559B2 (ja) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ME00549B (me) * | 2001-01-29 | 2011-10-10 | Serono Lab | Upotreba inhibitora il-18 za liječenje i/ili prevenciju srčanih oboljenja |
-
2007
- 2007-04-20 JP JP2007112157A patent/JP4961559B2/ja active Active
Also Published As
Publication number | Publication date |
---|---|
JP2007246529A (ja) | 2007-09-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7332157B2 (ja) | アンジオテンシン変換酵素2(ace2)の活性な低分子量変異体 | |
Suemori et al. | Identification and characterization of rat intestinal trefoil factor: tissue-and cell-specific member of the trefoil protein family. | |
CN105008397B (zh) | 作为治疗试剂的Gla结构域 | |
US20040266686A1 (en) | Methods of treating inflammatory skin diseases | |
JP4669512B2 (ja) | Fgf2を有効成分として含む喘息および慢性閉塞性肺疾患の予防または治療剤 | |
JP2001512417A (ja) | Ob融合タンパク質組成物および方法 | |
HU226419B1 (en) | Human bikunin | |
JP2001515360A (ja) | ▲II▼型TGF−βレセプター/免疫グロブリン定常領域融合タンパク質 | |
JP4823389B2 (ja) | 慢性閉塞性肺疾患の治療剤又は予防剤 | |
JP6307080B2 (ja) | 骨髄細胞に発現する誘発性受容体1(trem−1)trem様転写産物1(tlt−1)に由来する阻害ペプチドおよびその使用 | |
KR100798545B1 (ko) | 죽상경화증의 치료 또는 예방을 위한 il-18 저해물질의용도 | |
JP2023510864A (ja) | グルカゴン、glp-1及びgip受容体の全てに対して活性を有する三重活性体の持続型結合体の肺疾患の治療的使用 | |
AU2002352119B2 (en) | Human cDNAs and proteins and uses thereof | |
US20080090766A1 (en) | Preventive or therapeutic agents for diseases including interleukin-18 inhibitor as an active ingredient | |
JP4961559B2 (ja) | インターロイキン18阻害剤を有効成分とする疾患の予防又は治療剤 | |
AU714536B2 (en) | Novel gene up-regulated in regenerating liver | |
TW202237634A (zh) | 用於治療covid-19之dsg2組成物和方法 | |
JP2001072607A (ja) | 新規血管内皮機能改善法 | |
WO2005087925A1 (ja) | 組換遺伝子,疾患動物モデル,及び被験物の評価方法 | |
WO2013156771A1 (en) | Anti-atherogenic peptides | |
JP2004307427A (ja) | 腎虚血再灌流傷害の治療・改善・予防剤 | |
JP3648547B2 (ja) | 血液凝固阻害活性を有するフタトゲチマダニ由来のHl−1蛋白質 | |
JP2007297279A (ja) | ダニグループ1アレルゲンの改変体 | |
JP2007262027A (ja) | At−iiiによる内因性igf−1の産生誘導剤 | |
JPWO2004016784A1 (ja) | プロテアーゼ阻害剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20080306 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20080306 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20110228 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20110425 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20110506 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110518 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20110518 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110622 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20110920 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20111130 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20111213 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20120116 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20120229 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20120301 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20120229 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20120301 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 4961559 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20150406 Year of fee payment: 3 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |