JP2017528115A - N末端切断型インターロイキン−38 - Google Patents
N末端切断型インターロイキン−38 Download PDFInfo
- Publication number
- JP2017528115A JP2017528115A JP2016574256A JP2016574256A JP2017528115A JP 2017528115 A JP2017528115 A JP 2017528115A JP 2016574256 A JP2016574256 A JP 2016574256A JP 2016574256 A JP2016574256 A JP 2016574256A JP 2017528115 A JP2017528115 A JP 2017528115A
- Authority
- JP
- Japan
- Prior art keywords
- truncated
- protein
- cell
- cells
- 1rapl1
- 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.)
- Granted
Links
- 101001076386 Homo sapiens Interleukin-1 family member 10 Proteins 0.000 title claims abstract description 187
- 102100026015 Interleukin-1 family member 10 Human genes 0.000 title claims abstract description 185
- 210000004027 cell Anatomy 0.000 claims abstract description 127
- 238000000034 method Methods 0.000 claims abstract description 34
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 26
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 25
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 25
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 24
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 24
- 239000013598 vector Substances 0.000 claims abstract description 20
- 238000011282 treatment Methods 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 230000002265 prevention Effects 0.000 claims abstract description 8
- 238000012216 screening Methods 0.000 claims abstract description 6
- 239000005557 antagonist Substances 0.000 claims abstract description 5
- 230000000694 effects Effects 0.000 claims description 33
- 108090001005 Interleukin-6 Proteins 0.000 claims description 26
- 150000001413 amino acids Chemical group 0.000 claims description 21
- 230000001640 apoptogenic effect Effects 0.000 claims description 21
- 239000006228 supernatant Substances 0.000 claims description 21
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 19
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 18
- 230000004913 activation Effects 0.000 claims description 17
- 229920001184 polypeptide Polymers 0.000 claims description 17
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 8
- 230000028993 immune response Effects 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 208000027866 inflammatory disease Diseases 0.000 claims description 5
- 230000005764 inhibitory process Effects 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 244000005700 microbiome Species 0.000 claims description 4
- 230000011664 signaling Effects 0.000 claims description 4
- 238000003776 cleavage reaction Methods 0.000 claims description 3
- 208000026278 immune system disease Diseases 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- 239000000556 agonist Substances 0.000 claims description 2
- 238000000338 in vitro Methods 0.000 claims description 2
- 244000052769 pathogen Species 0.000 claims description 2
- 230000001717 pathogenic effect Effects 0.000 claims description 2
- 101100286700 Homo sapiens IL1F10 gene Proteins 0.000 claims 1
- 210000002540 macrophage Anatomy 0.000 abstract description 52
- 102000004127 Cytokines Human genes 0.000 abstract description 25
- 108090000695 Cytokines Proteins 0.000 abstract description 25
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 10
- 102000015696 Interleukins Human genes 0.000 abstract description 5
- 108010063738 Interleukins Proteins 0.000 abstract description 5
- 230000005934 immune activation Effects 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 25
- 150000001875 compounds Chemical class 0.000 description 23
- 239000000203 mixture Substances 0.000 description 21
- 230000014509 gene expression Effects 0.000 description 20
- 230000016396 cytokine production Effects 0.000 description 19
- 230000000638 stimulation Effects 0.000 description 19
- 101000979342 Homo sapiens Nuclear factor NF-kappa-B p105 subunit Proteins 0.000 description 18
- 102100023050 Nuclear factor NF-kappa-B p105 subunit Human genes 0.000 description 18
- 230000006698 induction Effects 0.000 description 16
- 239000002158 endotoxin Substances 0.000 description 12
- 229920006008 lipopolysaccharide Polymers 0.000 description 12
- 102000039996 IL-1 family Human genes 0.000 description 10
- 108091069196 IL-1 family Proteins 0.000 description 10
- 206010061218 Inflammation Diseases 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 230000004054 inflammatory process Effects 0.000 description 9
- 230000017306 interleukin-6 production Effects 0.000 description 9
- 230000001575 pathological effect Effects 0.000 description 9
- 230000001105 regulatory effect Effects 0.000 description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 description 9
- 238000000540 analysis of variance Methods 0.000 description 8
- 239000011324 bead Substances 0.000 description 8
- 230000001419 dependent effect Effects 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 230000002018 overexpression Effects 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 102000001708 Protein Isoforms Human genes 0.000 description 7
- 108010029485 Protein Isoforms Proteins 0.000 description 7
- 108020004459 Small interfering RNA Proteins 0.000 description 7
- 210000001744 T-lymphocyte Anatomy 0.000 description 7
- 230000006907 apoptotic process Effects 0.000 description 7
- 230000003247 decreasing effect Effects 0.000 description 7
- 239000013612 plasmid Substances 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 230000028327 secretion Effects 0.000 description 7
- 101000994815 Homo sapiens Interleukin-1 receptor accessory protein-like 1 Proteins 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000013604 expression vector Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 102100034413 Interleukin-1 receptor accessory protein-like 1 Human genes 0.000 description 5
- 108091007973 Interleukin-36 Proteins 0.000 description 5
- 108060001084 Luciferase Proteins 0.000 description 5
- 239000005089 Luciferase Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 239000003018 immunosuppressive agent Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 101000599048 Homo sapiens Interleukin-6 receptor subunit alpha Proteins 0.000 description 4
- 102000019223 Interleukin-1 receptor Human genes 0.000 description 4
- 108050006617 Interleukin-1 receptor Proteins 0.000 description 4
- 102000003814 Interleukin-10 Human genes 0.000 description 4
- 108090000174 Interleukin-10 Proteins 0.000 description 4
- 102100037792 Interleukin-6 receptor subunit alpha Human genes 0.000 description 4
- 102000004890 Interleukin-8 Human genes 0.000 description 4
- 108090001007 Interleukin-8 Proteins 0.000 description 4
- 102000016978 Orphan receptors Human genes 0.000 description 4
- 108070000031 Orphan receptors Proteins 0.000 description 4
- 102100030929 Single Ig IL-1-related receptor Human genes 0.000 description 4
- 230000006052 T cell proliferation Effects 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 229940099539 IL-36 receptor antagonist Drugs 0.000 description 3
- 102100037850 Interferon gamma Human genes 0.000 description 3
- 108010074328 Interferon-gamma Proteins 0.000 description 3
- 102000013691 Interleukin-17 Human genes 0.000 description 3
- 108050003558 Interleukin-17 Proteins 0.000 description 3
- 101710089409 Interleukin-36 receptor antagonist protein Proteins 0.000 description 3
- 102100021150 Interleukin-36 receptor antagonist protein Human genes 0.000 description 3
- 231100000111 LD50 Toxicity 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 108010018242 Transcription Factor AP-1 Proteins 0.000 description 3
- 102100023118 Transcription factor JunD Human genes 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 210000000845 cartilage Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 239000002612 dispersion medium Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 102000048090 human IL-38 Human genes 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 230000021995 interleukin-8 production Effects 0.000 description 3
- 230000028958 macrophage cytokine production Effects 0.000 description 3
- 210000004962 mammalian cell Anatomy 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000003753 real-time PCR Methods 0.000 description 3
- 238000001525 receptor binding assay Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 201000005671 spondyloarthropathy Diseases 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 108091026890 Coding region Proteins 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 101000652846 Homo sapiens Single Ig IL-1-related receptor Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 102000044594 Interleukin-1 Receptor Accessory Human genes 0.000 description 2
- 101710180389 Interleukin-1 receptor accessory protein Proteins 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 102400000108 N-terminal peptide Human genes 0.000 description 2
- 101800000597 N-terminal peptide Proteins 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
- 101710107435 Single Ig IL-1-related receptor Proteins 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 102100034412 X-linked interleukin-1 receptor accessory protein-like 2 Human genes 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 102000003675 cytokine receptors Human genes 0.000 description 2
- 108010057085 cytokine receptors Proteins 0.000 description 2
- 238000004163 cytometry Methods 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 239000012737 fresh medium Substances 0.000 description 2
- 238000001502 gel electrophoresis Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- 229940125721 immunosuppressive agent Drugs 0.000 description 2
- 229940124589 immunosuppressive drug Drugs 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000010212 intracellular staining Methods 0.000 description 2
- 210000001503 joint Anatomy 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 230000001338 necrotic effect Effects 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 230000034190 positive regulation of NF-kappaB transcription factor activity Effects 0.000 description 2
- 230000004481 post-translational protein modification Effects 0.000 description 2
- 210000001236 prokaryotic cell Anatomy 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108091032955 Bacterial small RNA Proteins 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 206010051728 Bone erosion Diseases 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 108010045171 Cyclic AMP Response Element-Binding Protein Proteins 0.000 description 1
- 102000005636 Cyclic AMP Response Element-Binding Protein Human genes 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 208000010975 Dystrophic epidermolysis bullosa Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010053776 Eosinophilic cellulitis Diseases 0.000 description 1
- 206010016207 Familial Mediterranean fever Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 108010040721 Flagellin Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108700007698 Genetic Terminator Regions Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 208000003807 Graves Disease Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 208000032456 Hemorrhagic Shock Diseases 0.000 description 1
- 101001033249 Homo sapiens Interleukin-1 beta Proteins 0.000 description 1
- 101001019615 Homo sapiens Interleukin-18 receptor accessory protein Proteins 0.000 description 1
- 101000998122 Homo sapiens Interleukin-37 Proteins 0.000 description 1
- 101000994810 Homo sapiens X-linked interleukin-1 receptor accessory protein-like 2 Proteins 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 108010034143 Inflammasomes Proteins 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 102100026018 Interleukin-1 receptor antagonist protein Human genes 0.000 description 1
- 101710144554 Interleukin-1 receptor antagonist protein Proteins 0.000 description 1
- 102100035010 Interleukin-18 receptor accessory protein Human genes 0.000 description 1
- 102100033502 Interleukin-37 Human genes 0.000 description 1
- 206010023203 Joint destruction Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000254158 Lampyridae Species 0.000 description 1
- 108010047357 Luminescent Proteins Proteins 0.000 description 1
- 102000006830 Luminescent Proteins Human genes 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 208000036626 Mental retardation Diseases 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- MSFSPUZXLOGKHJ-UHFFFAOYSA-N Muraminsaeure Natural products OC(=O)C(C)OC1C(N)C(O)OC(CO)C1O MSFSPUZXLOGKHJ-UHFFFAOYSA-N 0.000 description 1
- 102000008300 Mutant Proteins Human genes 0.000 description 1
- 108010021466 Mutant Proteins Proteins 0.000 description 1
- 206010028665 Myxoedema Diseases 0.000 description 1
- 102100022691 NACHT, LRR and PYD domains-containing protein 3 Human genes 0.000 description 1
- 101710126825 NACHT, LRR and PYD domains-containing protein 3 Proteins 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 102000014413 Neuregulin Human genes 0.000 description 1
- 108050003475 Neuregulin Proteins 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 206010034038 Parotitis Diseases 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 108010013639 Peptidoglycan Proteins 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 206010049771 Shock haemorrhagic Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 208000006045 Spondylarthropathies Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 108010087660 TIGIRR-1 receptor Proteins 0.000 description 1
- 210000000068 Th17 cell Anatomy 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 208000008526 Wells syndrome Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000013564 activation of immune response Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 208000037979 autoimmune inflammatory disease Diseases 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 208000027710 cyclic fever Diseases 0.000 description 1
- 239000000409 cytokine receptor agonist Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 210000001671 embryonic stem cell Anatomy 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 208000004298 epidermolysis bullosa dystrophica Diseases 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 239000006277 exogenous ligand Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical class O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 102000052105 human IL1RAPL1 Human genes 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000031261 interleukin-10 production Effects 0.000 description 1
- 230000024949 interleukin-17 production Effects 0.000 description 1
- 229940100601 interleukin-6 Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001155 isoelectric focusing Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 229940051866 mouthwash Drugs 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 208000003786 myxedema Diseases 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000006218 nasal suppository Substances 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003762 quantitative reverse transcription PCR Methods 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 108700015048 receptor decoy activity proteins Proteins 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000012121 regulation of immune response Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000008409 synovial inflammation Effects 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
-
- 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
- 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
-
- 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
- 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
- A61P39/00—General protective or antinoxious 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
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
- G01N33/5041—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects involving analysis of members of signalling pathways
-
- 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
- G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
- G01N33/6869—Interleukin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
- G01N2333/52—Assays involving cytokines
- G01N2333/54—Interleukins [IL]
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/91—Transferases (2.)
- G01N2333/912—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/10—Screening for compounds of potential therapeutic value involving cells
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Urology & Nephrology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Cell Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Pathology (AREA)
- General Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Physics & Mathematics (AREA)
- Food Science & Technology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Rheumatology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Epidemiology (AREA)
Abstract
Description
a.細胞を得る工程と、
b.前記細胞を微生物関連分子パターン(MAMP)、病原体関連分子パターン(PAMP)又はアポトーシス細胞上清(ACM)と接触させる工程と、
c.前記細胞を本発明の切断型IL-38タンパク質及び候補調節因子と更に接触させる工程と、
d.前記細胞のJNK活性化を求める工程と、
を含み、
対照細胞又は参照値と比べ、前記細胞のJNK活性化の増大により、前記候補調節因子が切断型IL-38のアンタゴニストであることが示され、対照細胞又は参照値と比べ、JNK活性化の低下により、前記候補調節因子が切断型IL-38のアゴニストであることが示される、方法に関する。
本発明は、種々の疾患の治療又は予防の治療薬として使用することができる切断型IL-38タンパク質を提供する。本発明によれば、化合物及び組成物は、病的に活性化した免疫応答又は炎症応答を特徴とする病態の治療及び/又は予防に特に有用である。特に、本発明は、広範囲の一連の慢性炎症障害及び自己免疫障害に関与することが示された、インターロイキン-6及びインターロイキン-17等のサイトカインの病的活性を特徴とする病態を治療しようと試みている。
本出願の別の態様は、自己免疫疾患又は炎症性疾患の治療又は予防のための組成物及びキットに関する。1つの実施の形態において、組成物は、場合により薬学的に許容される担体と合わせて本明細書に記載のタンパク質、核酸又は組換え細胞等の化合物を含む。
MCSLPMARYYIIKYADQKALYTRDGQLLVGDPVADNCCAEKICILPNRGLARTKVPI
FLGIQGGSRCLACVETEEGPSLQLEDVNIEELYKGGEEATRFTFFQSSSGSAFRLEAAA
WPGWFLCGPAEPQQPVQLTKESEPSARTKFYFEQSW
配列番号2
LYTRDGQLLVGDPVADNCCAEKICILPNRGLARTKVPIFLGIQGGSRCLACVETEEGP
SLQLEDVNIEELYKGGEEATRFTFFQSSSGSAFRLEAAAWPGWFLCGPAEPQQPVQLT
KESEPSARTKFYFEQSW
インハウスELISA(in-house ELISA)を行い、腫瘍細胞株により産生されたIL-38のレベルを求めるとき、本発明者らは、アポトーシス細胞死の誘導により上清内のIL-38分泌が著しく増大していることに気づいた。生存A549肺癌又はMDA.231乳癌細胞の上清(VCM)に比べ、壊死細胞上清(NCM)ではないアポトーシス細胞上清(ACM)はおよそ10倍高いIL-38のレベルが含まれていた(図1A)。これはまた初代ヒト好中球又はPBMCでも同様あったが、アポトーシス中のIL-38の放出の増加はそれほど大きくはなかった(図1A)。IL-38分泌の動態を分析するため、A549細胞上清のIL-38濃度をアポトーシス誘導時の様々な時間点において測定した。IL-38分泌の上昇がアポトーシス誘導の12時間後に観察され(図1B)、同時にA549細胞内にアポトーシスマーカーの発生を観察した(データは示さず)。
アポトーシス細胞由来のメディエーターは、サイトカイン産生を含む食細胞応答を調節する能力を有する(26)。本発明者らはLPSによるマクロファージ活性化時に又はアポトーシス細胞と相互作用する際に産生される一群のサイトカインの産生におけるIL-38の役割を分析した(27)。これらのうち、IL-6及びIL-8産生は、IL-38によって調節された。LPSのみに比べ、LPS刺激マクロファージに組換えIL-38を加えることにより、IL-6及びIL-8の産生が増大した(図2A)。興味深いことに、ヒトマクロファージを、A549細胞のACMのみ又は組換えヒトIL-38と組み合わせたACMで刺激したとき、反対の作用が観察された(図2B)。IL-38は、マクロファージ由来のACM誘導性IL-6及びIL-8の分泌を抑制した。ACMが既にIL-38を含有していることから、本発明者らは、内因性IL-38がマクロファージのサイトカイン産生(macrophage cytokine production)に影響を及ぼしているかについて考えた。この疑問を解決するため、IL-38をA549細胞において過剰発現させ、又はノックアウトさせた後ACMを作製した。実際に、ヒトマクロファージを、IL-38を過剰発現させたA549細胞から作製したACMで刺激することにより、IL-6及びIL-8の分泌が減少したが、IL-38ノックダウンA549細胞のACMで刺激することにより、高濃度のIL-6及びIL-8が得られた(図2C)。顕著な転写因子のうち、サイトカイン産生を調節し、IL-1ファミリーにより調節される因子は、NFκB及びAP1である。マクロファージとアポトーシス細胞とが相互作用した後、NFκBが遮断されるため(28)、本発明者らは、内因性IL-38がACMに応答してAP1の活性化を調節するかどうかを考えた。対照ACMに比べ、IL-38ノックダウンA549細胞のACMを、AP1ルシフェラーゼレポーター構築物をトランスフェクトしたマクロファージと作用させるとき、本発明者らは、IL-38のレベルが低いACMがより著名なAP1活性化を誘導することに気づいた(図2D)。結論として、内因性IL-38は、アポトーシス細胞上清に応答した炎症によるマクロファージ活性化を制限していた。
本発明者らは、IL-38が受容体アンタゴニストとして作用することによりACM誘導性サイトカイン産生を阻害するという仮説を立てた。それゆえ、本発明者らは、IL-38に関連したIL-1受容体ファミリーの候補物質を分析した。IL-38がIL-1R6に結合することが示され(19)、本発明者らは、オーファン受容体のIL-1RAPL1がACM刺激後にマクロファージのサイトカイン産生を調節することを観察した(16)。本発明者らははじめにIL1R6の発現を求め、マクロファージのIL-1RAPL1におけるmRNAレベルを、qPCRを用いて(図3A)及びACM又はLPS刺激後の細胞表面アベイラビリティのレベルをFACSにより(図3B)求めた。IL1R6発現は概ね低く(図3C)、ACM又はLPS刺激後のmRNAレベルを更に下方調節したにも関わらず、これは細胞表面の発現レベルでは明らかではなかった。これに対して、IL-1RAPL1の発現は増大し(図3C)、LPS処理の6時間後並びにACM処理の6時間後及び24時間後(図3A、B)のmRNAレベルにおいて及び細胞表面においての両方で更に誘導された。さらに、細胞表面のIL-1RAPL1発現は、LPSで24時間刺激した後に減少した。これらの実験は、少なくともIL-38の作用に対する更なる候補物質としてのIL-1RAPL1を示唆した。次に、本発明者らは、競合アッセイ及び受容体結合アッセイの両方を行うことによりIL-38がIL-1RAPL1に結合するか否かを分析した。競合アッセイにおいて、ヒトマクロファージを組換えヒトIL-38とインキュベーションした後、IL-1R6又はIL-1RAPL1の表面発現を分析した。IL-1R6の表面発現レベルが低いことから、IL-38のプレインキュベーションによる細胞表面の発現の差を観察することを確かめることが困難であった(図3C、D)。しかし、IL-1RAPL1において、本発明者らはIL-38がFACS染色に用いた抗体と競合した(図3C、D)ことを観察し、IL-38がIL-1RAPL1に結合する可能性があることが示された。これらの結果を立証するため、直接受容体結合アッセイを行った。プレートをIL-1R6-Fc及びIL-1RAPL1-Fcキメラを用いてコーティングし、様々な濃度のIL-38をウェルに添加し、IL-38の結合を視覚化した。最近報告したように(19)、実際にIL-38はIL-1R6に結合した(図3E)。さらに、IL-38はIL-1RAPL1にも結合した(図3E)。これらの結果によりIL-38がIL-1RAPL1に結合することによってサイトカイン産生を調節し得ることが示唆されたとして、本発明者らはACM誘導性サイトカイン産生におけるIL-1RAPL1の役割について考えた。ヒトマクロファージのIL-1R6又はIL-1RAPL1の一時的なノックダウンを行い、ACM刺激後のマクロファージ培養上清中のIL-6及びIL-8のレベルを測定した。ACM刺激後のIL-6及びIL-8の産生は、IL-1RAPL1依存性であった(図4A)が、IL-1R6は、本発明者らのモデルにおけるサイトカイン産生に関与しなかった(図4B)。
次に、本発明者らは、T細胞活性化に対するマクロファージ上清の影響を分析することによって、マクロファージのサイトカイン産生に対するIL-38依存性抑制の下流の結果について考えた。本発明者らは初代ヒトT細胞を単離し、抗CD3/抗CD28ビーズを用いてこれらの細胞を刺激し、ACM及びIL-38ノックダウンA549細胞のACMを用いて予め刺激したマクロファージ上清と繰り返しこれらの細胞をインキュベーションした。培養7日後にT細胞上清のIL-10、IL-17及びIFN-γのレベルを測定した。マクロファージをACMで刺激すると、マクロファージ上清により、T細胞によるIFN-γ及びIL-10の産生が減少し、IL-17レベルが僅かに上昇した(図5A)。それにも関わらず、マクロファージをIL-38切断ACMで刺激すると、マクロファージ上清により、T細胞によるIL-17産生が大きく上昇し、IL-10濃度が更に低下した(図5A)。これらの作用は、T細胞増殖の差とは関連のないものであった。ACM処理はT細胞の増殖数に影響を及ぼさなかった(図5B)が、分裂前T細胞が分裂する数に影響を及ぼしており、これはIFN-γ及びIL-10のレベルの減少で説明することができた(図5C)。しかし、T細胞増殖における、ACMがIL-38を含有するか否かについての差はなかった(図5B、C)。これらのデータは、アポトーシス細胞由来のIL-38がマクロファージ依存性のTh17細胞の産生を制限し、IL-10発現を維持することを示す。
IL-1Raを除くIL-1ファミリーの全てのメンバーは前駆体として産生され、この前駆体のN末端が切断されて完全な活性が得られる。最近では、N末端のプロドメインの大きさに従って、IL-38はIL-36のサブファミリーに分類されていた(4、19)。このIL-36のサブファミリーの一メンバーとしてのIL-38はコンセンサスモチーフを保持するが、これによりN末端の切断部位が決定されると推定されている(図6A)。アポトーシスがIL-38プロセシングを誘導するか否かを求めるために、C末端をmycタグ化したIL-38を腫瘍細胞において過剰発現させ、これらの細胞からACMを作製した。免疫沈降後、IL-38の2Dゲル電気泳動を行い、IL-38アイソフォームを視覚化した。2つのIL-38アイソフォームをゲル内で同定することに成功し、IL-38が実際にアポトーシス中にプロセシングされることが示された(図6B)。推定上のIL-38アイソフォームを表す2つのスポットを選定し、質量分析法(MS)により分析した。完全長のIL-38と予測された、分子量の大きいスポットにおいて、2つのN末端ペプチドがMS分析において認められ、1つは9個〜18個のアミノ酸であり、もう1つは24個〜41個のアミノ酸であり、一方、分子量の小さいサンプルでは、24個〜41個のアミノ酸のペプチドのみが認められた(図6C)。したがって、アポトーシス細胞のIL-38はN末端プロセシングされている。
完全長及び切断型のIL-38が異なる生物学的活性を有するか否かを求めるため、IL-1βのみ又は様々な濃度の完全長IL-38(IL-38aa1-152)若しくは切断型IL-38(IL-38aa20-152)と組み合わせて刺激したヒトマクロファージ上清中のIL-6濃度を求めた。IL-β刺激後、高濃度のIL-38aa1-152(20 ng/ml、10 ng/ml)はIL-6産生を顕著に増大させたが、IL-38aa20-152は低濃度で行ったときでもIL-6産生を低下させた(図7A)。ACM中のIL-38がIL-1RAPL1と相互作用することによってIL-6産生を調節することから、本発明者らはサイトカイン産生において相反する役割を有する両方のIL-38アイソフォームがIL-1RAPL1に結合するか否かを考えた。本発明者らは、上記で説明したように受容体結合アッセイを行った。このアッセイでは、両方のIL-38アイソフォームがIL-1RAPL1に結合した(図7B)。しかし、結合動態は僅かに異なるようであった。IL-38aa1-152及びIL-38aa20-152がサイトカイン産生に対して相反する役割を発揮するが、これらはともにIL-1RAPL1に結合することができると考えるとき、IL-6産生に対する作用がともにIL-1RAPL1依存性であるか否かが分析の更なるキーポイントとなった。これを実現するため、マクロファージにおいて一時的なIL-1RAPL1ノックダウンを行い、その上清のIL-6濃度をIL-1βのみ又はIL-38aa1-152若しくはIL-38aa20-152と組み合わせて刺激した後に測定した。マクロファージのIL-1RAPL1ノックダウンにより、完全長のIL-38によるIL-6誘導及び切断型IL-38によるIL-6抑制の両方が無効となった(図7C)。
本発明者らはアポトーシス細胞と相互作用する際にIL-38がマクロファージのAP1を調節する証拠を得た(図2D)。IL-38がIL-1RAPL1との相互作用に対して影響を及ぼすシグナル伝達経路を分析するため、本発明者らははじめにHEK293T細胞の受容体過剰発現モデルを利用した。細胞にIL-1RAPL1の過剰発現構築物及びAP1又はNFκBレポーター構築物を共トランスフェクトした。レポーター構築物をトランスフェクトしたがIL-1RAPL1を過剰発現しないHEK細胞を対照として使用した。はじめに、IL-1RAPL1過剰発現細胞モデル及び対照細胞を特徴付けるため、これらの細胞をIL-1βで刺激し、AP1(図8A)又はNFκB(図8B)活性を測定した。IL-1βをオーファン受容体IL-1RAPL1の低親和性リガンドとして使用した(14)。IL-1β刺激後、対照細胞においてNFκBの顕著な誘導が観察されたが、AP1活性は観察されなかった。それにも関わらず、IL-1RAPL1が過剰発現すると、AP1の活性化及びNFκB活性の上昇が観察された。したがって、IL-1βのみではIL-1RAPL1に非依存的にNFκB活性化を誘導するが、AP1を活性化させず、AP1活性化にはIL-1RAPL1を必要とした。興味深いことに、何らかの刺激がなくても、対照細胞に対してAP1及びNFκB活性を増大させるには、IL-1RAPL1があれば十分であった(図8A、B)。それゆえ、HEK細胞をIL-1β刺激後のIL-1RAPL1はAP1を活性化させるがNFκBを活性化させず、また外因性リガンドを添加することなく過剰発現させるとAP1及びNFκBの活性化を誘導する。これを確認するため、様々な転写因子結合部位において点変異を含む、又は含まないIL-6プロモーター構築物(AP1、NFκB、CREB及びCEBPβ)を使用した。HEK細胞に、IL1RAPL1過剰発現プラスミド及びIL-6レポーター構築物を共トランスフェクトした(29)。また、この条件において、IL-1RAPL1の過剰発現は、HEK対照細胞と比べIL-6プロモーターを活性化させた。このIL-6プロモーター誘導は、AP1及びNFκB結合部位が変異したとき無効となった(図8C)。これはHEK細胞により産生されたIL-1RAPL1に対する内因性リガンドが存在することを示唆する。次に、本発明者らは、IL-38aa1-152及びIL-38aa20-152がIL-1RAPL1の下流にてAP1及びNFκBの活性に影響を及ぼすか否かについて考えた。この条件におけるNFκBプロモーター活性はIL-38により調節されなかった(図8D)が、AP1誘導は両方のIL-38アイソフォームにより負の方向に調節された(図3E)。IL-38aa20-152が完全長のタンパク質に比べ低濃度にてAP1誘導を調節することができたことは重要なことであった。IL-1RAPLにより誘導されたAP1活性をIL-38依存的に抑制するシグナル伝達を分析するため、対照HEK細胞に対するIL-1RAPL1過剰発現細胞のリン酸化JNK及びp38の細胞内染色を行った。IL-1RAPL1の過剰発現後、リン酸化JNKにおいて誘導が観察されたが、p38においては観察されなかった。この誘導は、IL-38aa20-152によって顕著に減少したが、IL-38aa1-152によっては減少せず、切断型IL-38の調節の役割が大きいことを確認した。
次に、本発明者らは、本発明者らのHEKモデルのデータをマクロファージ条件に移行させた。ヒトマクロファージにAP1又はNFκBレポーター構築物をトランスフェクトし、ヒトマクロファージをIL-1βのみ又はIL-38aa20-152若しくはIL-38aa1-152と組み合わせて刺激した。HEK細胞と同じく、IL-38aa20-152はマクロファージのAP1活性を低下させたが、NFκB活性は低下させず、その一方で、IL-38aa1-152は効果がなかった(図9)。したがって、切断型IL-38のみがマクロファージのAP-1活性を抑制し、このことはIL-38を欠失するアポトーシス細胞上清で刺激したマクロファージが高いAP1活性レベルを示した(図2D)本発明者らの発見と一致するものである。最後に本発明者らは、IL-38aa1-152がマクロファージをIL-1β刺激した後にIL-6産生を増大させるかについての疑問に取り組んだ(図7A)が、HEK細胞モデルでは、IL-38aa1-152はAP1及びNFκBのどちらの活性化も増大させなかった。この矛盾を検討するため、マクロファージにIL-6レポーター構築物をトランスフェクトし、マクロファージをIL-1βのみ、又は両方のIL-38アイソフォームと組み合わせて刺激した。予想した通り、IL-38aa20-152はIL-6プロモーター活性を減少させるが、IL-38aa1-152はIL-6プロモーター誘導に全く影響を与えず(図9)、IL-38aa1-152が介在したIL-6産生の増大は、転写により調節されなかったことが示唆された。
1. Sims, J. E. & Smith, D. E. (2010) Nat RevImmunol 10, 89-102.
2. Dinarello, C. A. (2009) Annu Rev Immunol 27,519-50.
3. Dinarello, C. A. (2013) Seminars inimmunology.
4. Garlanda, C., Dinarello, C. A. & Mantovani,A. (2013) Immunity 39, 1003-18.
5. Towne, J. E., Renshaw, B. R., Douangpanya,J., Lipsky, B. P., Shen, M., Gabel, C. A. & Sims, J. E. (2011) J Biol Chem286, 42594-602.
6. Latz, E., Xiao, T. S. & Stutz, A. (2013)Nat Rev Immunol 13, 397-411.
7. Boraschi, D. & Tagliabue, A. (2013)Seminars in immunology.
8. Pavlowsky, A., Gianfelice, A., Pallotto, M.,Zanchi, A., Vara, H., Khelfaoui, M., Valnegri, P., Rezai, X., Bassani, S.,Brambilla, D., Kumpost, J., Blahos, J., Roux, M. J., Humeau, Y., Chelly, J.,Passafaro, M., Giustetto, M., Billuart, P. & Sala, C. (2010) Currentbiology : CB 20, 103-15.
9. Gambino, F., Kneib, M., Pavlowsky, A., Skala,H., Heitz, S., Vitale, N., Poulain, B., Khelfaoui, M., Chelly, J., Billuart, P.& Humeau, Y. (2009) The European journal of neuroscience 30, 1476-86.
10. Jin, H., Gardner, R. J., Viswesvaraiah, R.,Muntoni, F. & Roberts, R. G. (2000) European journal of human genetics :EJHG 8, 87-94.
11. Born, T. L., Smith, D. E., Garka, K. E.,Renshaw, B. R., Bertles, J. S. & Sims, J. E. (2000) The Journal ofbiological chemistry 275, 29946-54.
12. Carrie, A., Jun, L., Bienvenu, T., Vinet, M.C., McDonell, N., Couvert, P., Zemni, R., Cardona, A., Van Buggenhout, G.,Frints, S., Hamel, B., Moraine, C., Ropers, H. H., Strom, T., Howell, G. R.,Whittaker, A., Ross, M. T., Kahn, A., Fryns, J. P., Beldjord, C., Marynen, P.& Chelly, J. (1999) Nature genetics 23, 25-31.
13. Khan, J. A., Brint, E. K., O'Neill, L. A.& Tong, L. (2004) The Journal of biological chemistry 279, 31664-70.
14. Pavlowsky, A., Zanchi, A., Pallotto, M.,Giustetto, M., Chelly, J., Sala, C. & Billuart, P. (2010) Commun IntegrBiol 3, 245-7.
15. Arthur, J. S. & Ley, S. C. (2013) NatRev Immunol 13, 679-92.
16. Ley, S., Weigert, A., Heriche, J. K.,Mille-Baker, B., Janssen, R. A. & Brune, B. (2013) Immunobiology 218,40-51.
17. Lin, H., Ho, A. S., Haley-Vicente, D.,Zhang, J., Bernal-Fussell, J., Pace, A. M., Hansen, D., Schweighofer, K., Mize,N. K. & Ford, J. E. (2001) The Journal of biological chemistry 276, 20597-602.
18. Bensen, J. T., Dawson, P. A., Mychaleckyj,J. C. & Bowden, D. W. (2001) Journal of interferon & cytokine research: the official journal of the International Society for Interferon and CytokineResearch 21, 899-904.
19. van de Veerdonk, F. L., Stoeckman, A. K.,Wu, G., Boeckermann, A. N., Azam, T., Netea, M. G., Joosten, L. A., van derMeer, J. W., Hao, R., Kalabokis, V. & Dinarello, C. A. (2012) Proc NatlAcad Sci U S A 109, 3001-5.
20. Jung, M. Y., Kang, S. W., Kim, S. K., Kim,H. J., Yun, D. H., Yim, S. V., Hong, S. J. & Chung, J. H. (2010)Scandinavian journal of rheumatology 39, 190-6.
21. Guo, Z. S., Li, C., Lin, Z. M., Huang, J.X., Wei, Q. J., Wang, X. W., Xie, Y. Y., Liao, Z. T., Chao, S. Y. & Gu, J.R. (2010) International journal of immunogenetics 37, 33-7.
22. Chou, C. T., Timms, A. E., Wei, J. C., Tsai,W. C., Wordsworth, B. P. & Brown, M. A. (2006) Annals of the rheumaticdiseases 65, 1106-9.
23. Monnet, D., Kadi, A., Izac, B., Lebrun, N.,Letourneur, F., Zinovieva, E., Said-Nahal, R., Chiocchia, G. & Breban, M.(2012) Annals of the rheumatic diseases 71, 885-90.
24. Rahman, P., Sun, S., Peddle, L., Snelgrove,T., Melay, W., Greenwood, C. & Gladman, D. (2006) Arthritis and rheumatism54, 2321-5.
25. Dehghan, A., , et al. (2011) Circulation123, 731-8.
26. Zitvogel, L., Kepp, O. & Kroemer, G.(2010) Cell 140, 798-804.
27. Ley, S., Weigert, A., Weichand, B., Henke,N., Mille-Baker, B., Janssen, R. A. & Brune, B. (2013) Oncogene 32, 631-40.
28. Weigert, A., Tzieply, N., von Knethen, A.,Johann, A. M., Schmidt, H., Geisslinger, G. & Brune, B. (2007) Mol BiolCell 18, 3810-9.
29. Xiao, W., Hodge, D. R., Wang, L., Yang, X.,Zhang, X. & Farrar, W. L. (2004) Prostate 61, 354-70.
Claims (15)
- 単離された切断型IL-38タンパク質又はその機能的変異体であって、該切断型IL-38タンパク質が配列番号1によるアミノ酸配列に対してN末端切断型であり、該切断が配列番号1の1位〜30位の少なくとも10個の隣接するアミノ酸を含む、切断型IL-38タンパク質又はその機能的変異体。
- 前記切断型IL-38タンパク質は野生型IL-38タンパク質(配列番号1)に対しN末端にて2個〜50個のアミノ酸が切断されている、請求項1に記載の単離された切断型IL-38タンパク質。
- 前記切断型IL-38タンパク質は配列番号1に示すタンパク質に対して、N末端にて11個、12個、13個、14個、15個、16個、17個、18個、19個又は20個のアミノ酸が切断されている、請求項2に記載の単離された切断型IL38タンパク質。
- 配列番号1の最初の100個、50個、30個、20個又は19個のアミノ酸と同一でないN末端を有する、請求項1〜3のいずれか一項に記載の切断型IL-38タンパク質。
- 請求項1〜4のいずれか一項に記載の切断型IL-38タンパク質をコードする配列を含む核酸。
- 発現したときに請求項1〜4のいずれか一項に記載の前記切断型IL-38タンパク質からなるポリペプチドを産生するが、配列番号1による完全長のIL-38タンパク質でない、配列を含む、請求項5に記載の核酸。
- 請求項5又は6に記載の核酸を含むベクター。
- 発現可能な配列がプロモーターに操作可能に結合する、請求項7に記載のベクター。
- 請求項5若しくは6に記載の核酸又は請求項7若しくは8に記載のベクターを含む組換え細胞。
- 医療において使用するための、免疫疾患又は炎症性疾患の治療又は予防に使用するための、請求項1〜4のいずれか一項に記載の切断型IL-38タンパク質又は請求項5若しくは6に記載の核酸又は請求項7若しくは8に記載のベクター又は請求項9に記載の組換え細胞を含む医薬組成物。
- 細胞の免疫応答を調節するin-vitroの方法であって、該細胞と請求項1〜4のいずれか一項に記載の切断型IL-38タンパク質とを接触させること、又は該細胞において請求項5若しくは6に記載の核酸を発現させることを含む、方法。
- 前記免疫応答の調節は、JNKシグナル伝達の阻害、又はIL-6放出及びTH17産生の阻害である、請求項11に記載の方法。
- 切断型IL-38の活性の調節因子をスクリーニングする方法であって、
a.細胞を得る工程と、
b.前記細胞を微生物関連分子パターン(MAMP)、病原体関連分子パターン(PAMP)又はアポトーシス細胞上清(ACM)と接触させる工程と、
c.前記細胞を請求項1〜4のいずれか一項に記載の切断型IL-38タンパク質及び候補調節因子と更に接触させる工程と、
d.前記細胞のJNK活性化を求める工程と、
を含み、
対照細胞又は参照値と比べ、前記細胞のJNK活性化の増大により、前記候補調節因子が切断型IL-38のアンタゴニストであることが示され、対照細胞又は参照値と比べ、JNK活性化の低下により、前記候補調節因子が切断型IL-38のアゴニストであることが示される、方法。 - 例えば、前記細胞においてIL-1RAPL1を異所的に発現させることにより、該細胞が細胞表面に切断型IL-38の受容体を発現する、請求項13に記載の方法。
- 前記JNK活性化がAP-1レポーター構築物を用いて求められる、請求項13又は14に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14178478.5 | 2014-07-25 | ||
EP14178478.5A EP2977384A1 (en) | 2014-07-25 | 2014-07-25 | N-terminally truncated interleukin-38 |
PCT/EP2015/066084 WO2016012312A1 (en) | 2014-07-25 | 2015-07-14 | N-terminally truncated interleukin-38 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019121045A Division JP2019216717A (ja) | 2014-07-25 | 2019-06-28 | N末端切断型インターロイキン−38 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2017528115A true JP2017528115A (ja) | 2017-09-28 |
JP6678600B2 JP6678600B2 (ja) | 2020-04-08 |
Family
ID=51220485
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016574256A Active JP6678600B2 (ja) | 2014-07-25 | 2015-07-14 | N末端切断型インターロイキン−38 |
JP2019121045A Pending JP2019216717A (ja) | 2014-07-25 | 2019-06-28 | N末端切断型インターロイキン−38 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019121045A Pending JP2019216717A (ja) | 2014-07-25 | 2019-06-28 | N末端切断型インターロイキン−38 |
Country Status (8)
Country | Link |
---|---|
US (2) | US10618946B2 (ja) |
EP (2) | EP2977384A1 (ja) |
JP (2) | JP6678600B2 (ja) |
KR (1) | KR20170038854A (ja) |
CN (2) | CN106661095B (ja) |
CA (1) | CA2951840C (ja) |
ES (1) | ES2730050T3 (ja) |
WO (1) | WO2016012312A1 (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2977384A1 (en) * | 2014-07-25 | 2016-01-27 | Fraunhofer Gesellschaft zur Förderung der angewandten Forschung e.V. | N-terminally truncated interleukin-38 |
CN107007821B (zh) * | 2017-05-04 | 2020-08-04 | 宁波大学 | 白细胞介素-38在制备防治肥胖症及代谢综合征产品中的应用 |
EP3400962A1 (en) | 2017-05-09 | 2018-11-14 | Fraunhofer Gesellschaft zur Förderung der angewandten Forschung e.V. | Inhibitors of il-38 for use in treating and/or preventing cancer in a subject |
CN110314225A (zh) * | 2018-03-29 | 2019-10-11 | 瑞阳(苏州)生物科技有限公司 | 含有白细胞介素-38重组蛋白的药物组合物及其应用 |
CN110564849B (zh) * | 2019-04-15 | 2020-07-14 | 上海市同仁医院 | 白介素-38在制备结直肠癌预后产品中的应用 |
CN111012899A (zh) * | 2020-01-08 | 2020-04-17 | 重庆医科大学 | Il-38的新用途 |
WO2022006588A1 (en) * | 2020-06-29 | 2022-01-06 | Trustees Of Tufts College | Il-38 and analogues thereof for treatment of neuro-inflammatory and neurodegenerative diseases |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001040291A2 (en) * | 1999-12-06 | 2001-06-07 | Curagen Corporation | Proteins and nucleic acids encoding the same |
JP2003523209A (ja) * | 2000-01-27 | 2003-08-05 | イミュネックス・コーポレーション | Fil−1シータdnaおよびポリペプチド |
JP2009533062A (ja) * | 2006-04-10 | 2009-09-17 | ザ・クイーンズ・メディカル・センター | Cracモジュレーターおよび創薬のためのその使用 |
JP2010131026A (ja) * | 2010-01-19 | 2010-06-17 | Kunihiro Matsumoto | 新規tab2蛋白質 |
JP2012167017A (ja) * | 2009-06-15 | 2012-09-06 | National Cerebral & Cardiovascular Center | ペプチドおよびその用途 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6339141B1 (en) * | 1999-05-20 | 2002-01-15 | Hycey Inc. | Interleukin-1 Hy2 materials and methods |
IL131242A0 (en) * | 1999-08-04 | 2001-01-28 | Given Imaging Ltd | A method for temperature sensing |
US20020156009A1 (en) * | 2000-11-02 | 2002-10-24 | Dennis Ballinger | Novel interleukin - 1 Hy2 materials and methods |
EP1390404A2 (en) * | 2000-12-21 | 2004-02-25 | Novartis AG | Interleukin-1 related gene and protein |
WO2003048376A2 (en) * | 2001-11-29 | 2003-06-12 | Nuvelo, Inc. | Modulation of immune-cell related disorders using il-1hy2 |
WO2011025128A2 (ko) * | 2009-08-31 | 2011-03-03 | 포항공과대학교 산학협력단 | 혈관내피세포성장인자 수용체 저해를 통한 Th17 염증질환 치료 방법 및 이를 위한 약학적 조성물 |
JP2015222174A (ja) * | 2012-09-13 | 2015-12-10 | 学校法人 久留米大学 | 炎症性疾患を処置するため薬剤のスクリーニング方法 |
CN103397038B (zh) * | 2013-07-29 | 2015-05-20 | 宁波大学 | 一种人白细胞介素-38的生产方法 |
EP2977384A1 (en) * | 2014-07-25 | 2016-01-27 | Fraunhofer Gesellschaft zur Förderung der angewandten Forschung e.V. | N-terminally truncated interleukin-38 |
-
2014
- 2014-07-25 EP EP14178478.5A patent/EP2977384A1/en not_active Withdrawn
-
2015
- 2015-07-14 ES ES15735977T patent/ES2730050T3/es active Active
- 2015-07-14 KR KR1020177004992A patent/KR20170038854A/ko not_active Application Discontinuation
- 2015-07-14 US US15/328,690 patent/US10618946B2/en active Active
- 2015-07-14 EP EP15735977.9A patent/EP3194431B1/en active Active
- 2015-07-14 CN CN201580036071.XA patent/CN106661095B/zh active Active
- 2015-07-14 CN CN202111415790.6A patent/CN114369151A/zh active Pending
- 2015-07-14 WO PCT/EP2015/066084 patent/WO2016012312A1/en active Application Filing
- 2015-07-14 JP JP2016574256A patent/JP6678600B2/ja active Active
- 2015-07-14 CA CA2951840A patent/CA2951840C/en active Active
-
2019
- 2019-06-28 JP JP2019121045A patent/JP2019216717A/ja active Pending
-
2020
- 2020-03-02 US US16/806,620 patent/US20200277349A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001040291A2 (en) * | 1999-12-06 | 2001-06-07 | Curagen Corporation | Proteins and nucleic acids encoding the same |
JP2003523209A (ja) * | 2000-01-27 | 2003-08-05 | イミュネックス・コーポレーション | Fil−1シータdnaおよびポリペプチド |
JP2009533062A (ja) * | 2006-04-10 | 2009-09-17 | ザ・クイーンズ・メディカル・センター | Cracモジュレーターおよび創薬のためのその使用 |
JP2012167017A (ja) * | 2009-06-15 | 2012-09-06 | National Cerebral & Cardiovascular Center | ペプチドおよびその用途 |
JP2010131026A (ja) * | 2010-01-19 | 2010-06-17 | Kunihiro Matsumoto | 新規tab2蛋白質 |
Non-Patent Citations (2)
Title |
---|
DATABASE GENBANK [ONLINE], ACCEESSION NO. GL193421, 2009-12-17 UPLOADED, [RETRIEVED ON 2018-10-10],, JPN7018003541 * |
DATABASE GENBANK [ONLINE], ACCEESSION NO. KB112867, 2012-12-20 UPLOADED, [RETRIEVED ON 2018-10-10],, JPN6018040675 * |
Also Published As
Publication number | Publication date |
---|---|
JP6678600B2 (ja) | 2020-04-08 |
US20200277349A1 (en) | 2020-09-03 |
JP2019216717A (ja) | 2019-12-26 |
US10618946B2 (en) | 2020-04-14 |
CN114369151A (zh) | 2022-04-19 |
EP3194431B1 (en) | 2019-03-13 |
US20170218039A1 (en) | 2017-08-03 |
EP3194431A1 (en) | 2017-07-26 |
EP2977384A1 (en) | 2016-01-27 |
CA2951840A1 (en) | 2016-01-28 |
CN106661095A (zh) | 2017-05-10 |
CN106661095B (zh) | 2021-11-02 |
WO2016012312A1 (en) | 2016-01-28 |
ES2730050T3 (es) | 2019-11-07 |
KR20170038854A (ko) | 2017-04-07 |
CA2951840C (en) | 2024-01-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20200277349A1 (en) | N-terminally truncated interleukin-38 | |
Trivella et al. | Structure and function of interleukin-22 and other members of the interleukin-10 family | |
De Souza et al. | SH2 domains from suppressor of cytokine signaling-3 and protein tyrosine phosphatase SHP-2 have similar binding specificities | |
US20220332834A2 (en) | Antibodies and polypeptides directed against cd127 | |
BR112020009920A2 (pt) | Agonistas parciais de interleucina-2 | |
US9815883B2 (en) | Inhibiting peptides derived from TREM-like transcript 1 (TLT-1) and uses thereof | |
Takada et al. | Molecular mechanism of apoptosis by amyloid β-protein fibrils formed on neuronal cells | |
US11149071B2 (en) | Fusion protein Slit2D2(C386S)-HSA and use thereof in prevention and/or treatment of lung inflammation | |
EP3720493A1 (en) | Combinations of ripk1- and ikk-inhibitors for the prevention or treatment of immune diseases | |
US20200164032A1 (en) | Chemokine decoy receptors of rodent gammaherpesviruses and uses thereof | |
EP0634935A4 (en) | A NEW THERAPY OF SEPSIS BY MEANS OF A SOLUBLE FORM OF RECOMBINANT CD14 MYELOMONOCYTIC ANTIGEN. | |
WO2022244341A1 (ja) | ペプチド及び医薬用組成物 | |
US9611295B2 (en) | Treatment of IL-17 mediated disease by blocking SEFIR-SEFIR interactions | |
US10738095B2 (en) | Engineered CCL20 locked dimer polypeptide | |
WO2018196743A1 (zh) | 人血清淀粉样蛋白a1功能性短肽及其制备方法和应用 | |
WO2014095977A1 (en) | Novel pellino peptide | |
US10400027B2 (en) | Protein and use thereof in treating multiple sclerosis | |
JP2021523892A (ja) | Oca−bペプチドコンジュゲート及び処置方法 | |
Qiu | Functional and molecular aspects of ion channels in macrophages | |
AU2015202354A1 (en) | Inhibiting peptides derived from TREM-like transcript 1 (TLT-1) and uses thereof | |
WO2005118637A1 (en) | Treatment of inflammatory conditions |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20171218 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20181018 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190118 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20190228 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190628 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20190724 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20190820 |
|
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: 20200218 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200317 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6678600 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |