JP2022504217A - 改変されたMHCクラスII DRα1ドメインを含む組換えポリペプチドおよび使用方法 - Google Patents
改変されたMHCクラスII DRα1ドメインを含む組換えポリペプチドおよび使用方法 Download PDFInfo
- Publication number
- JP2022504217A JP2022504217A JP2021518527A JP2021518527A JP2022504217A JP 2022504217 A JP2022504217 A JP 2022504217A JP 2021518527 A JP2021518527 A JP 2021518527A JP 2021518527 A JP2021518527 A JP 2021518527A JP 2022504217 A JP2022504217 A JP 2022504217A
- Authority
- JP
- Japan
- Prior art keywords
- drα1
- domain
- recombinant polypeptide
- seq
- peptide
- 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
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 253
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 184
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 151
- 102000043131 MHC class II family Human genes 0.000 title description 25
- 108091054438 MHC class II family Proteins 0.000 title description 25
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 41
- 230000000890 antigenic effect Effects 0.000 claims abstract description 38
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 30
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 27
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 21
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 150000001413 amino acids Chemical group 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 19
- 201000006417 multiple sclerosis Diseases 0.000 claims description 16
- 238000003776 cleavage reaction Methods 0.000 claims description 10
- 230000007017 scission Effects 0.000 claims description 10
- 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 claims description 9
- 108090000190 Thrombin Proteins 0.000 claims description 6
- 229960004072 thrombin Drugs 0.000 claims description 6
- 230000001363 autoimmune Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000003431 cross linking reagent Substances 0.000 claims description 3
- 238000010382 chemical cross-linking Methods 0.000 claims description 2
- 208000014644 Brain disease Diseases 0.000 claims 1
- 208000032274 Encephalopathy Diseases 0.000 claims 1
- 125000003275 alpha amino acid group Chemical group 0.000 abstract description 38
- 102100030595 HLA class II histocompatibility antigen gamma chain Human genes 0.000 description 70
- 101001082627 Homo sapiens HLA class II histocompatibility antigen gamma chain Proteins 0.000 description 70
- 230000027455 binding Effects 0.000 description 64
- 108090000623 proteins and genes Proteins 0.000 description 61
- 235000018102 proteins Nutrition 0.000 description 58
- 102000004169 proteins and genes Human genes 0.000 description 58
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 50
- 235000001014 amino acid Nutrition 0.000 description 39
- 241000699666 Mus <mouse, genus> Species 0.000 description 37
- 201000010099 disease Diseases 0.000 description 35
- 239000000427 antigen Substances 0.000 description 34
- 108091007433 antigens Proteins 0.000 description 34
- 102000036639 antigens Human genes 0.000 description 34
- 108700025073 DRhQ Proteins 0.000 description 32
- 201000002491 encephalomyelitis Diseases 0.000 description 32
- 238000002474 experimental method Methods 0.000 description 26
- 241000699670 Mus sp. Species 0.000 description 20
- 108010068647 P2 peptide Proteins 0.000 description 17
- 102220502122 Thioredoxin domain-containing protein 9_L14Q_mutation Human genes 0.000 description 17
- 238000006467 substitution reaction Methods 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 16
- 108060004872 MIF Proteins 0.000 description 15
- 102000034655 MIF Human genes 0.000 description 15
- 208000035475 disorder Diseases 0.000 description 15
- 230000004054 inflammatory process Effects 0.000 description 15
- 238000011282 treatment Methods 0.000 description 15
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 14
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 206010061218 Inflammation Diseases 0.000 description 12
- 239000012634 fragment Substances 0.000 description 12
- 208000023275 Autoimmune disease Diseases 0.000 description 11
- 125000000539 amino acid group Chemical group 0.000 description 11
- 210000001519 tissue Anatomy 0.000 description 11
- 230000002860 competitive effect Effects 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 9
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 9
- 208000017442 Retinal disease Diseases 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 230000026731 phosphorylation Effects 0.000 description 9
- 238000006366 phosphorylation reaction Methods 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 108010000123 Myelin-Oligodendrocyte Glycoprotein Proteins 0.000 description 8
- 102000002233 Myelin-Oligodendrocyte Glycoprotein Human genes 0.000 description 8
- 239000007983 Tris buffer Substances 0.000 description 8
- 239000011324 bead Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 8
- 238000001962 electrophoresis Methods 0.000 description 8
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 8
- 108020001507 fusion proteins Proteins 0.000 description 8
- 102000037865 fusion proteins Human genes 0.000 description 8
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 8
- 230000002757 inflammatory effect Effects 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 230000001105 regulatory effect Effects 0.000 description 8
- 210000004988 splenocyte Anatomy 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 7
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 230000002354 daily effect Effects 0.000 description 7
- 230000000670 limiting effect Effects 0.000 description 7
- 230000035772 mutation Effects 0.000 description 7
- 208000011580 syndromic disease Diseases 0.000 description 7
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 7
- 108091026890 Coding region Proteins 0.000 description 6
- 108010023098 DRalpha1-MOG-35-55 Proteins 0.000 description 6
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 6
- 108091028043 Nucleic acid sequence Proteins 0.000 description 6
- 210000001744 T-lymphocyte Anatomy 0.000 description 6
- 230000000903 blocking effect Effects 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 239000002502 liposome Substances 0.000 description 6
- 208000002780 macular degeneration Diseases 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000013598 vector Substances 0.000 description 6
- 108020004705 Codon Proteins 0.000 description 5
- 102000004127 Cytokines Human genes 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- 102100033133 D-dopachrome decarboxylase Human genes 0.000 description 5
- 201000004624 Dermatitis Diseases 0.000 description 5
- 238000002965 ELISA Methods 0.000 description 5
- 101000927579 Homo sapiens D-dopachrome decarboxylase Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 108700025288 RTL1000 Proteins 0.000 description 5
- 206010038923 Retinopathy Diseases 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 5
- 108010021611 acetyl-phenylalanyl-threonyl-leucyl-aspartyl-alanyl-aspartyl-phenylalanine Proteins 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 238000012217 deletion Methods 0.000 description 5
- 230000037430 deletion Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 108010026228 mRNA guanylyltransferase Proteins 0.000 description 5
- 210000001236 prokaryotic cell Anatomy 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 125000006850 spacer group Chemical group 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- 206010015150 Erythema Diseases 0.000 description 4
- 108091005904 Hemoglobin subunit beta Proteins 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- 239000004365 Protease Substances 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 208000010668 atopic eczema Diseases 0.000 description 4
- 238000002869 basic local alignment search tool Methods 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000002983 circular dichroism Methods 0.000 description 4
- 231100000321 erythema Toxicity 0.000 description 4
- 230000003053 immunization Effects 0.000 description 4
- 238000002649 immunization Methods 0.000 description 4
- 230000028709 inflammatory response Effects 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 210000004962 mammalian cell Anatomy 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 238000003032 molecular docking Methods 0.000 description 4
- 108091008146 restriction endonucleases Proteins 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 208000011117 substance-related disease Diseases 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 201000004384 Alopecia Diseases 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010016936 Folliculitis Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 102100021519 Hemoglobin subunit beta Human genes 0.000 description 3
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 3
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 3
- 208000019693 Lung disease Diseases 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 3
- 231100000360 alopecia Toxicity 0.000 description 3
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 238000004422 calculation algorithm Methods 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 210000003527 eukaryotic cell Anatomy 0.000 description 3
- 239000013604 expression vector Substances 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 230000013595 glycosylation Effects 0.000 description 3
- 238000006206 glycosylation reaction Methods 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 238000001114 immunoprecipitation Methods 0.000 description 3
- 210000003000 inclusion body Anatomy 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 210000003622 mature neutrocyte Anatomy 0.000 description 3
- 238000013508 migration Methods 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- 238000002703 mutagenesis Methods 0.000 description 3
- 231100000350 mutagenesis Toxicity 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 238000003752 polymerase chain reaction Methods 0.000 description 3
- 230000000750 progressive effect Effects 0.000 description 3
- 238000000159 protein binding assay Methods 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 238000002864 sequence alignment Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 2
- OSJPPGNTCRNQQC-UWTATZPHSA-N 3-phospho-D-glyceric acid Chemical compound OC(=O)[C@H](O)COP(O)(O)=O OSJPPGNTCRNQQC-UWTATZPHSA-N 0.000 description 2
- 239000012103 Alexa Fluor 488 Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 229920000856 Amylose Polymers 0.000 description 2
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- 206010010356 Congenital anomaly Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 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 2
- 208000016192 Demyelinating disease Diseases 0.000 description 2
- 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 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 208000010412 Glaucoma Diseases 0.000 description 2
- 206010018364 Glomerulonephritis Diseases 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 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 2
- 239000006137 Luria-Bertani broth Substances 0.000 description 2
- 208000035719 Maculopathy Diseases 0.000 description 2
- 101710175625 Maltose/maltodextrin-binding periplasmic protein Proteins 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 102000006386 Myelin Proteins Human genes 0.000 description 2
- 108010083674 Myelin Proteins Proteins 0.000 description 2
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 208000025966 Neurological disease Diseases 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- 108700025284 RTL551 Proteins 0.000 description 2
- 201000007737 Retinal degeneration Diseases 0.000 description 2
- 206010038848 Retinal detachment Diseases 0.000 description 2
- 208000025747 Rheumatic disease Diseases 0.000 description 2
- 206010039085 Rhinitis allergic Diseases 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 2
- 208000034189 Sclerosis Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 201000009594 Systemic Scleroderma Diseases 0.000 description 2
- 206010042953 Systemic sclerosis Diseases 0.000 description 2
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 201000010105 allergic rhinitis Diseases 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 210000002159 anterior chamber Anatomy 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000012875 competitive assay Methods 0.000 description 2
- 238000004590 computer program Methods 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 208000038015 macular disease Diseases 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 239000006174 pH buffer Substances 0.000 description 2
- 208000028169 periodontal disease Diseases 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 230000004481 post-translational protein modification Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000004264 retinal detachment Effects 0.000 description 2
- 230000000552 rheumatic effect Effects 0.000 description 2
- 239000012723 sample buffer Substances 0.000 description 2
- 210000003786 sclera Anatomy 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 238000002741 site-directed mutagenesis Methods 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- JKQXZKUSFCKOGQ-JLGXGRJMSA-N (3R,3'R)-beta,beta-carotene-3,3'-diol Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-JLGXGRJMSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- KISWVXRQTGLFGD-UHFFFAOYSA-N 2-[[2-[[6-amino-2-[[2-[[2-[[5-amino-2-[[2-[[1-[2-[[6-amino-2-[(2,5-diamino-5-oxopentanoyl)amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)p Chemical compound C1CCN(C(=O)C(CCCN=C(N)N)NC(=O)C(CCCCN)NC(=O)C(N)CCC(N)=O)C1C(=O)NC(CO)C(=O)NC(CCC(N)=O)C(=O)NC(CCCN=C(N)N)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 KISWVXRQTGLFGD-UHFFFAOYSA-N 0.000 description 1
- CFBILACNYSPRPM-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;2-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]acetic acid Chemical compound OCC(N)(CO)CO.OCC(CO)(CO)NCC(O)=O CFBILACNYSPRPM-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 102000007698 Alcohol dehydrogenase Human genes 0.000 description 1
- 108010021809 Alcohol dehydrogenase Proteins 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 102100038910 Alpha-enolase Human genes 0.000 description 1
- 208000024985 Alport syndrome Diseases 0.000 description 1
- 208000035939 Alveolitis allergic Diseases 0.000 description 1
- 208000033309 Analgesic asthma syndrome Diseases 0.000 description 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 1
- 102000003916 Arrestin Human genes 0.000 description 1
- 108090000328 Arrestin Proteins 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- 208000004300 Atrophic Gastritis Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 208000031212 Autoimmune polyendocrinopathy Diseases 0.000 description 1
- 206010050245 Autoimmune thrombocytopenia Diseases 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- 208000037663 Best vitelliform macular dystrophy Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102100032912 CD44 antigen Human genes 0.000 description 1
- 201000002829 CREST Syndrome Diseases 0.000 description 1
- 241000244203 Caenorhabditis elegans Species 0.000 description 1
- 208000004434 Calcinosis Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- 229920000298 Cellophane Polymers 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 208000015943 Coeliac disease 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
- 102000000503 Collagen Type II Human genes 0.000 description 1
- 108010041390 Collagen Type II Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 108010091326 Cryoglobulins Proteins 0.000 description 1
- 208000014311 Cushing syndrome Diseases 0.000 description 1
- 206010011715 Cyclitis Diseases 0.000 description 1
- 206010012305 Demyelination Diseases 0.000 description 1
- 208000001490 Dengue Diseases 0.000 description 1
- 206010012310 Dengue fever Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 102100020743 Dipeptidase 1 Human genes 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 201000001353 Doyne honeycomb retinal dystrophy Diseases 0.000 description 1
- 208000021866 Dressler syndrome Diseases 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 208000005235 Echovirus Infections Diseases 0.000 description 1
- 241000701867 Enterobacteria phage T7 Species 0.000 description 1
- 206010059284 Epidermal necrosis Diseases 0.000 description 1
- 241001198387 Escherichia coli BL21(DE3) Species 0.000 description 1
- 241000701959 Escherichia virus Lambda Species 0.000 description 1
- 208000030644 Esophageal Motility disease Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000004332 Evans syndrome Diseases 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 208000037312 Familial drusen Diseases 0.000 description 1
- 208000027445 Farmer Lung Diseases 0.000 description 1
- 201000006353 Filariasis Diseases 0.000 description 1
- 101150066516 GST gene Proteins 0.000 description 1
- 208000007465 Giant cell arteritis Diseases 0.000 description 1
- 108010072051 Glatiramer Acetate Proteins 0.000 description 1
- 108010061711 Gliadin Proteins 0.000 description 1
- 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 1
- BCCRXDTUTZHDEU-VKHMYHEASA-N Gly-Ser Chemical compound NCC(=O)N[C@@H](CO)C(O)=O BCCRXDTUTZHDEU-VKHMYHEASA-N 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 102100040505 HLA class II histocompatibility antigen, DR alpha chain Human genes 0.000 description 1
- 108010067802 HLA-DR alpha-Chains Proteins 0.000 description 1
- 208000008899 Habitual abortion Diseases 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 1
- 206010062639 Herpes dermatitis Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 101000883515 Homo sapiens Chitinase-3-like protein 1 Proteins 0.000 description 1
- 101001115699 Homo sapiens Myelin-oligodendrocyte glycoprotein Proteins 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010021263 IgA nephropathy Diseases 0.000 description 1
- 208000032578 Inherited retinal disease Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- 208000011200 Kawasaki disease Diseases 0.000 description 1
- 241000235058 Komagataella pastoris Species 0.000 description 1
- 102100031413 L-dopachrome tautomerase Human genes 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 201000010743 Lambert-Eaton myasthenic syndrome Diseases 0.000 description 1
- 206010024229 Leprosy Diseases 0.000 description 1
- 239000006142 Luria-Bertani Agar Substances 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102000043129 MHC class I family Human genes 0.000 description 1
- 108091054437 MHC class I family Proteins 0.000 description 1
- 102000009073 Macrophage Migration-Inhibitory Factors Human genes 0.000 description 1
- 108010048043 Macrophage Migration-Inhibitory Factors Proteins 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 208000003250 Mixed connective tissue disease Diseases 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 101001115695 Mus musculus Myelin-oligodendrocyte glycoprotein Proteins 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 108010021466 Mutant Proteins Proteins 0.000 description 1
- 102000008300 Mutant Proteins Human genes 0.000 description 1
- 206010028424 Myasthenic syndrome Diseases 0.000 description 1
- 241001049988 Mycobacterium tuberculosis H37Ra Species 0.000 description 1
- 208000021908 Myocardial disease Diseases 0.000 description 1
- 206010028594 Myocardial fibrosis Diseases 0.000 description 1
- 230000004988 N-glycosylation Effects 0.000 description 1
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 108091005461 Nucleic proteins Chemical group 0.000 description 1
- 208000014934 Oesophageal motility disease Diseases 0.000 description 1
- 208000003435 Optic Neuritis Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000008071 Parvoviridae Infections Diseases 0.000 description 1
- 206010057343 Parvovirus infection Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 108010081690 Pertussis Toxin Proteins 0.000 description 1
- 108010022181 Phosphopyruvate Hydratase Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 206010065159 Polychondritis Diseases 0.000 description 1
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 description 1
- 241000206607 Porphyra umbilicalis Species 0.000 description 1
- 206010036631 Presenile dementia Diseases 0.000 description 1
- 108010010974 Proteolipids Proteins 0.000 description 1
- 102000016202 Proteolipids Human genes 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- 208000006311 Pyoderma Diseases 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 208000007400 Relapsing-Remitting Multiple Sclerosis Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 208000032430 Retinal dystrophy Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 241000256248 Spodoptera Species 0.000 description 1
- 201000002661 Spondylitis Diseases 0.000 description 1
- 101000794214 Staphylococcus aureus Toxic shock syndrome toxin-1 Proteins 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 239000012505 Superdex™ Substances 0.000 description 1
- UZMAPBJVXOGOFT-UHFFFAOYSA-N Syringetin Natural products COC1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UZMAPBJVXOGOFT-UHFFFAOYSA-N 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 208000003441 Transfusion reaction Diseases 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 239000007997 Tricine buffer Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 206010047124 Vasculitis necrotising Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 102000013127 Vimentin Human genes 0.000 description 1
- 108010065472 Vimentin Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000282485 Vulpes vulpes Species 0.000 description 1
- JKQXZKUSFCKOGQ-LQFQNGICSA-N Z-zeaxanthin Natural products C([C@H](O)CC=1C)C(C)(C)C=1C=CC(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-LQFQNGICSA-N 0.000 description 1
- QOPRSMDTRDMBNK-RNUUUQFGSA-N Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCC(O)C1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C QOPRSMDTRDMBNK-RNUUUQFGSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- FHEAIOHRHQGZPC-KIWGSFCNSA-N acetic acid;(2s)-2-amino-3-(4-hydroxyphenyl)propanoic acid;(2s)-2-aminopentanedioic acid;(2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound CC(O)=O.C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 FHEAIOHRHQGZPC-KIWGSFCNSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 206010064930 age-related macular degeneration Diseases 0.000 description 1
- 206010001584 alcohol abuse Diseases 0.000 description 1
- 208000025746 alcohol use disease Diseases 0.000 description 1
- JKQXZKUSFCKOGQ-LOFNIBRQSA-N all-trans-Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C JKQXZKUSFCKOGQ-LOFNIBRQSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 238000011122 anti-angiogenic therapy Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940124691 antibody therapeutics Drugs 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 206010071578 autoimmune retinopathy Diseases 0.000 description 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 1
- 208000010928 autoimmune thyroid disease Diseases 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 238000013357 binding ELISA Methods 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 1
- 229960003669 carbenicillin Drugs 0.000 description 1
- 238000007675 cardiac surgery Methods 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000016644 chronic atrophic gastritis Diseases 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
- 238000000978 circular dichroism spectroscopy Methods 0.000 description 1
- 230000006329 citrullination Effects 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000004665 defense response Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 208000025729 dengue disease Diseases 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 230000005750 disease progression Effects 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 108010051081 dopachrome isomerase Proteins 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 201000011191 dyskinesia of esophagus Diseases 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 206010014801 endophthalmitis Diseases 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- CKSJXOVLXUMMFF-UHFFFAOYSA-N exalamide Chemical compound CCCCCCOC1=CC=CC=C1C(N)=O CKSJXOVLXUMMFF-UHFFFAOYSA-N 0.000 description 1
- 229950010333 exalamide Drugs 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 208000022195 farmer lung disease Diseases 0.000 description 1
- 208000001031 fetal erythroblastosis Diseases 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 201000006321 fundus dystrophy Diseases 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 229960003776 glatiramer acetate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000011544 gradient gel Substances 0.000 description 1
- 210000004884 grey matter Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000003215 hereditary nephritis Diseases 0.000 description 1
- 102000054350 human CHI3L1 Human genes 0.000 description 1
- 230000004727 humoral immunity Effects 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 239000012133 immunoprecipitate Substances 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 208000017532 inherited retinal dystrophy Diseases 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000002614 leucines Chemical group 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 235000012680 lutein Nutrition 0.000 description 1
- 229960005375 lutein Drugs 0.000 description 1
- KBPHJBAIARWVSC-RGZFRNHPSA-N lutein Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=C[C@H](O)CC1(C)C KBPHJBAIARWVSC-RGZFRNHPSA-N 0.000 description 1
- 239000001656 lutein Substances 0.000 description 1
- ORAKUVXRZWMARG-WZLJTJAWSA-N lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C ORAKUVXRZWMARG-WZLJTJAWSA-N 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 229940029985 mineral supplement Drugs 0.000 description 1
- 235000020786 mineral supplement Nutrition 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 208000001725 mucocutaneous lymph node syndrome Diseases 0.000 description 1
- 230000036473 myasthenia Effects 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 238000001225 nuclear magnetic resonance method Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 102000005309 phosducin Human genes 0.000 description 1
- 108010031256 phosducin Proteins 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 238000003566 phosphorylation assay Methods 0.000 description 1
- 230000000649 photocoagulation Effects 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000002516 postimmunization Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000012743 protein tagging Effects 0.000 description 1
- 238000010403 protein-protein docking Methods 0.000 description 1
- 210000001938 protoplast Anatomy 0.000 description 1
- 229960003876 ranibizumab Drugs 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 229960000160 recombinant therapeutic protein Drugs 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000004258 retinal degeneration Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 102000029752 retinol binding Human genes 0.000 description 1
- 108091000053 retinol binding Proteins 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011537 solubilization buffer Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000010421 standard material Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 108010018381 streptavidin-binding peptide Proteins 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- 210000001994 temporal artery Anatomy 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 201000004647 tinea pedis Diseases 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000009529 traumatic brain injury Effects 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
- JOPDZQBPOWAEHC-UHFFFAOYSA-H tristrontium;diphosphate Chemical compound [Sr+2].[Sr+2].[Sr+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O JOPDZQBPOWAEHC-UHFFFAOYSA-H 0.000 description 1
- LZMSXDHGHZKXJD-VJANTYMQSA-N trypanothione disulfide Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@H]1CSSC[C@H](NC(=O)CC[C@H](N)C(O)=O)C(=O)NCC(=O)NCCCNCCCCNC(=O)CNC1=O LZMSXDHGHZKXJD-VJANTYMQSA-N 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000005048 vimentin Anatomy 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019195 vitamin supplement Nutrition 0.000 description 1
- 201000007790 vitelliform macular dystrophy Diseases 0.000 description 1
- 208000020938 vitelliform macular dystrophy 2 Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 235000010930 zeaxanthin Nutrition 0.000 description 1
- 229940043269 zeaxanthin Drugs 0.000 description 1
- 239000001775 zeaxanthin Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
-
- 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
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70539—MHC-molecules, e.g. HLA-molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Cell Biology (AREA)
- Molecular Biology (AREA)
- Transplantation (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Rheumatology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Biophysics (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
本願は、2019年10月5日出願の米国仮出願第62/741,941号の利益を主張する。この仮出願は、その全体が参照により本明細書中に援用される。
本開示は、組換え治療タンパク質、特に、改変された部分的なMHC分子、および炎症性疾患の処置におけるそれらの使用に関する。
本発明は、National Institutes of Healthが授与した助成金番号R42AI122574ならびにDepartment of Veterans Affairsが授与した助成金番号5 I01 BX000226-10および1IK6BX004209の下で、政府支援を受けて行われた。米国政府は、本発明における一定の権利を有する。
多発性硬化症(MS)は、最も蔓延している、中枢神経系の白質と灰白質の両方の慢性炎症性疾患であり、世界の200万人超および米国の少なくとも40万人が罹患している(GBD 2015 Neurological Disorders Collaborator Group,Lancet Neurol.16:877-897,2017)。MSにおける炎症過程は、自己免疫主導の脱髄によって媒介され、この脱髄は神経変性損傷を伴うことが多い。現在、MSの治療法はない。したがって、MS患者は、疾患徴候のいくつかを回復させるために疾患修飾治療に頼らなければならない(Wingerchukら、Mayo Clin.Proc.89:225-240,2014)。再発寛解型のMSについては、約15種の疾患修飾薬剤が利用可能である(Reichら、N.Engl.J.Med.378:169-180,2018)。しかしながら、引き続き、MSに対する改善された治療が必要とされている。
改変された主要組織適合(MHC)クラスII DRα1ポリペプチドが、本明細書中に開示される。これらの改変されたDRα1ポリペプチドは、CD74に対する変更された親和性、およびCD74への結合についてマクロファージ遊走阻止因子(MIF)と競合する能力を、分子構造に対して明らかな影響なく示す。
本明細書中または添付の配列表に列挙されるいずれの核酸配列およびアミノ酸配列も、37C.F.R.§1.822に定義されているように、ヌクレオチド塩基およびアミノ酸に対する標準的な一文字省略形を用いて示される。少なくともいくつかの場合では、各核酸配列の一方の鎖しか示されないが、相補鎖は、示された鎖の任意の参照によって含められると理解される。
MSの動物モデルである実験的自己免疫性脳脊髄炎(EAE)とMS被験体の両方において、複数の一連のエビデンスが、その自己免疫疾患のプロセスにおける自己反応性のミエリン特異的CD4+T細胞の役割を裏付けている(Steinman,Cell 85:299-302,1996;Zamvilら、Annu.Rev.Immunol.8:579-621,1990;Chitnis,Int.Rev.Neurobiol.79:43-72,2007)。MSの初期の炎症段階を慢性的な進行性段階に押し進めると考えられている重要なサイトカインは、最初に報告されたサイトカインであるマクロファージ遊走阻止因子(MIF)およびその祖先型機能ホモログであるD-ドーパクロムトートメラーゼ(D-DT)である(Chitnis,Int.Rev.Neurobiol.79:43-72,2007)。MIFおよびD-DTのレベルは、MSでは上昇し、MSの臨床上の悪化のマーカーとして、およびEAEでは疾患進行の必要条件として、意味づけられている(Benedekら、Proc.Natl.Acad.Sci.USA 114:E8421-E8429,2017;Niinoら、J.Neurol.Sci.179(S1-2):127-131,2000;Powellら、J.Immunol.175:5611-5614,2005;Meza-Romeroら、J.Immunol.192:4164-4173,2014)。
別段述べられない限り、専門用語は、従来の使用法に従って使用される。分子生物学における一般的な用語の定義は、Benjamin Lewin,Genes V,Oxford University Pressから出版,1994(ISBN 0-19-854287-9);Kendrewら(編),The Encyclopedia of Molecular Biology,Blackwell Science Ltd.から出版,1994(ISBN 0-632-02182-9);およびRobert A.Meyers(編),Molecular Biology and Biotechnology:a Comprehensive Desk Reference,VCH Publishers,Inc.から出版,1995(ISBN 1-56081-569-8)に見られ得る。
MHCクラスII DRα1ドメインまたはそのフラグメントを含むがMHCクラスIIα2、β1またはβ2ドメインを含まず、かつ配列番号1のアミノ酸14に対応するアミノ酸位置に存在するロイシン(L)からグルタミン(Q)への置換を含む、単離された組換えポリペプチドが本明細書中に開示される。哺乳動物のMHCクラスII DRα鎖タンパク質のアミノ酸配列、ならびにこれらのタンパク質をコードする核酸は、当該分野で周知であり、GenBankをはじめとした数多くの提供元から入手可能である。例示的な配列は、参照により本明細書中に援用されるDasら(Proc.Natl.Acad.Sci.USA 80:3543-3547,1983)に提供されている(ヒトHLA DRα)。例示的なヒトDRαポリペプチドは、GenBankアクセッション番号NP_061984(2018年10月5日にGenBankに存在したものとして参照により本明細書中に援用される)である。さらなるMHCクラスII DRαポリペプチドは、例えば、IMGT/HLAデータベース(ebi.ac.uk/imgt/hla/のワールドワイドウェブにおいて利用可能)などの公的データベースから、当業者によって特定され得る。
いくつかの実施形態において、本明細書中に開示される組換えポリペプチドは、DRα1ドメインに直接またはペプチドリンカーもしくは化学リンカーを介して共有結合により連結された抗原ペプチドを含む。APCの表面上でのMHC複合体における抗原の提示は、一般に、抗原ペプチド全体が関わらない(例えば、米国特許第5,468,481号を参照のこと)。むしろ、MHC IIの場合はβ1ドメインとα1ドメインとの間の溝またはMHC Iの場合はα1ドメインとα2ドメインとの間の溝に位置するペプチドが、通常、ポリペプチド抗原全体の小さい直鎖状フラグメントとなる。Janeway & Travers(Immunobiology:The Immune System in Health and Disease,1997)に論じられているように、MHCクラスI分子のペプチド溝に位置するペプチドは、結合ポケットのサイズによって限定され、通常、8~15アミノ酸長(例えば、8、9、10、11、12、13、14または15アミノ酸)、より通常は8~10アミノ酸長である(が、考えられる例外についてはCollinsら、Nature 371:626-629,1994を参照のこと)。対照的に、MHCクラスII分子のペプチド溝に位置するペプチドは、このように限定されず、それより大きいことが多く、通常、少なくとも3~50アミノ酸長(例えば、8~30、10~25または15~23アミノ酸長)である。いくつかの例において、MHCクラスII分子のペプチド溝に位置するペプチドは、約15~23アミノ酸長である。ペプチドフラグメントは、合成ペプチド合成機を使用することなどの標準的なアプローチによって調製され得るか、または組換えポリペプチドの一部として発現され得る。
炎症性障害および/または自己免疫障害を含むがこれらに限定されない被験体における障害を処置または阻害する方法が本明細書中に開示される。開示される方法は、配列番号1のアミノ酸位置14に対応する位置にグルタミン残基を有するMHCクラスII DRα1ドメインポリペプチドを含む組換えポリペプチド(配列番号1によって例証される)、または抗原ペプチドに共有結合により連結された、配列番号1のアミノ酸位置14に対応する位置にグルタミン残基を有するMHCクラスII DRα1ドメインポリペプチドを含む組換えポリペプチド(配列番号2および3によって例証される)、またはその組換えポリペプチドをコードする核酸を被験体に投与する工程を含む。1つの非限定的な例において、その被験体は、多発性硬化症を有し、MOG-35-55ペプチドに連結された、配列番号1のアミノ酸位置14に対応する位置にグルタミン残基を有するMHCクラスII DRα1ドメインポリペプチド(例えば、配列番号2または配列番号3)を投与される。
材料および方法
Fab、抗体および他の試薬。G4は、ヒトIgGライブラリーに由来するDRα1ドメインに反応性のヒトFabであり、Dr.Yoram Reiter,Technion Israelからの厚意により供与された。抗ヒトMOG抗体は、Santa Cruz Biotechnologyから購入した。CHAPS、T20およびウシ血清アルブミンは、Sigma-Aldrichから購入した。抗CD74抗体は、Everest Biotechから購入した。UltraPure(商標)TRISは、Invitrogenから購入した。ベクターpET21d(+)は、Novagenから購入した。BL21(DE3)は、New England Biolabsから購入した。IPTGは、Inalcoから購入した。
改変されたDRα1ポリペプチドの作製および解析
DRα1-hMOG-35-55、DRα1-mMOG-35-55、DRhQおよびDRmQタンパク質の生成量は似ていたことから、L50Q置換は、転写および発現率に影響しないことが示唆された。タンパク質の収率は、一貫して約90~100mg/リットルLBブロスだった。Fab G4を用いて、精製タンパク質を検出した。以前の研究では、Fab G4が、種々の状況におけるDRα1ドメイン(独立型のドメインとして、より大きな構築物の一部として(本明細書中に記載されるものと同様)または2ドメイン組換えタンパク質の一部として(RTL1000と同様)を含む)を検出したことが示された。
Claims (19)
- 配列番号1のアミノ酸位置14に対応する位置にグルタミン残基を含むDRα1ドメインを含む、組換えポリペプチド。
- 前記DRα1ドメインが、ヒトDRα1ドメインである、請求項2に記載の組換えポリペプチド。
- 配列番号1に対して少なくとも90%の配列同一性を有するアミノ酸配列を含む、請求項1または請求項2に記載の組換えポリペプチド。
- 配列番号1のアミノ酸配列を含む、請求項3に記載の組換えポリペプチド。
- 配列番号1のアミノ酸配列からなる、請求項4に記載の組換えポリペプチド。
- 抗原ペプチドをさらに含む、請求項1に記載の組換えポリペプチド。
- リンカーをさらに含む、請求項6に記載の組換えポリペプチド。
- 前記リンカーが、ペプチドリンカーまたは化学架橋剤を含む、請求項7に記載の組換えポリペプチド。
- 前記リンカーが、第1のグリシン-セリンスペーサー、トロンビン切断部位および第2のグリシン-セリンスペーサーを含む、請求項7に記載の組換えポリペプチド。
- 前記抗原ペプチドが、MOG-35-55である、請求項6~9のいずれか1項に記載の組換えポリペプチド。
- 前記MOG-35-55が、ヒトMOG-35-55またはマウスMOG-35-55である、請求項10に記載の組換えポリペプチド。
- 前記組換えポリペプチドが、配列番号2もしくは配列番号3を含むか、または配列番号2もしくは配列番号3からなる、請求項10に記載の組換えポリペプチド。
- 請求項1~12のいずれか1項に記載の組換えポリペプチドをコードする、核酸分子。
- 請求項13に記載の核酸を含む、発現構築物。
- 請求項14に記載の発現構築物を含む、細胞株。
- 有効量の請求項1~12のいずれか1項に記載の組換えポリペプチドまたは請求項13に記載の核酸分子;および
薬学的に許容され得るキャリア
を含む、医薬組成物。 - 前記組成物が、少なくとも5mg/kgの前記組換えポリペプチドを含む、請求項16に記載の医薬組成物。
- 炎症性障害を処置する方法であって、有効量の請求項16または請求項17に記載の医薬組成物を、前記炎症性障害を有する被験体に投与する工程を含む、方法。
- 前記炎症性障害が、多発性硬化症または実験的自己免疫性脳症(EAE)である、請求項18に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862741941P | 2018-10-05 | 2018-10-05 | |
US62/741,941 | 2018-10-05 | ||
PCT/US2019/054850 WO2020072992A1 (en) | 2018-10-05 | 2019-10-04 | Recombinant polypeptides comprising modified mhc class ii drα1 domains and methods of use |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2022504217A true JP2022504217A (ja) | 2022-01-13 |
JPWO2020072992A5 JPWO2020072992A5 (ja) | 2022-10-13 |
JP7511551B2 JP7511551B2 (ja) | 2024-07-05 |
Family
ID=68296863
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021518527A Active JP7511551B2 (ja) | 2018-10-05 | 2019-10-04 | 改変されたMHCクラスII DRα1ドメインを含む組換えポリペプチドおよび使用方法 |
Country Status (8)
Country | Link |
---|---|
US (1) | US11945855B2 (ja) |
EP (1) | EP3860644A1 (ja) |
JP (1) | JP7511551B2 (ja) |
KR (1) | KR20210071019A (ja) |
CN (1) | CN113164573B (ja) |
AU (1) | AU2019355062A1 (ja) |
CA (1) | CA3114446A1 (ja) |
WO (1) | WO2020072992A1 (ja) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050142142A1 (en) * | 2003-09-05 | 2005-06-30 | Burrows Gregory G. | Monomeric recombinant MHC molecules useful for manipulation of antigen-specific T cells |
JP2015505315A (ja) * | 2012-01-06 | 2015-02-19 | オレゴン ヘルス アンド サイエンス ユニバーシティ | 部分的mhcコンストラクト及びその使用方法 |
US20150098956A1 (en) * | 2013-10-03 | 2015-04-09 | Oregon Health & Science University | RECOMBINANT POLYPEPTIDES COMPRISING MHC CLASS II a1 DOMAINS |
US20180271935A1 (en) * | 2017-03-15 | 2018-09-27 | Oregon Health & Science University | Dralpha1-mog-35-55 treatment of traumatic brain injury |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5468481A (en) | 1988-06-23 | 1995-11-21 | Amergen, Inc. | MHC class II-peptide conjugates useful in ameliorating autoimmunity |
WO2012088461A2 (en) | 2010-12-23 | 2012-06-28 | Biogen Idec Inc. | Linker peptides and polypeptides comprising same |
US20130309229A1 (en) | 2011-01-28 | 2013-11-21 | The United States Government As Represented By The Department Of Veterans Affairs | Recombinant t cell ligands and antibodies that bind b cells for the treatment of autoimmune diseases |
US9260506B2 (en) | 2011-04-07 | 2016-02-16 | Oregon Health & Science University | Treatment of retinal disorders with recombinant T cell receptor ligand (RTL) |
WO2015051328A1 (en) | 2013-10-03 | 2015-04-09 | Oregon Health & Science University | TREATMENT OF ISCHEMIC STROKE WITH DRα1-MOG-35-55 |
US10525101B2 (en) | 2015-10-23 | 2020-01-07 | Oregon Health & Science University | Methods of treating inflammatory or autoimmune disorders with compounds that bind macrophage migration inhibitory factor |
US10689446B2 (en) | 2016-06-22 | 2020-06-23 | Oregon Health & Science University | Recombinant CD74 polypeptides |
BR112019009477A2 (pt) | 2016-11-09 | 2019-07-30 | Uti Lp | moléculas de classe ii de pmhc recombinantes |
-
2019
- 2019-10-04 EP EP19791143.1A patent/EP3860644A1/en active Pending
- 2019-10-04 KR KR1020217012762A patent/KR20210071019A/ko active Search and Examination
- 2019-10-04 CN CN201980079085.8A patent/CN113164573B/zh active Active
- 2019-10-04 AU AU2019355062A patent/AU2019355062A1/en active Pending
- 2019-10-04 WO PCT/US2019/054850 patent/WO2020072992A1/en unknown
- 2019-10-04 JP JP2021518527A patent/JP7511551B2/ja active Active
- 2019-10-04 CA CA3114446A patent/CA3114446A1/en active Pending
- 2019-10-04 US US17/282,455 patent/US11945855B2/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050142142A1 (en) * | 2003-09-05 | 2005-06-30 | Burrows Gregory G. | Monomeric recombinant MHC molecules useful for manipulation of antigen-specific T cells |
JP2015505315A (ja) * | 2012-01-06 | 2015-02-19 | オレゴン ヘルス アンド サイエンス ユニバーシティ | 部分的mhcコンストラクト及びその使用方法 |
US20150098956A1 (en) * | 2013-10-03 | 2015-04-09 | Oregon Health & Science University | RECOMBINANT POLYPEPTIDES COMPRISING MHC CLASS II a1 DOMAINS |
US20180271935A1 (en) * | 2017-03-15 | 2018-09-27 | Oregon Health & Science University | Dralpha1-mog-35-55 treatment of traumatic brain injury |
Non-Patent Citations (1)
Title |
---|
J. CHEM. TECHNOL. BIOTECHNOL., vol. 80, no. 1, JPN6023038451, 2005, pages 2 - 12, ISSN: 0005155598 * |
Also Published As
Publication number | Publication date |
---|---|
WO2020072992A1 (en) | 2020-04-09 |
CA3114446A1 (en) | 2020-04-09 |
CN113164573B (zh) | 2024-05-31 |
EP3860644A1 (en) | 2021-08-11 |
CN113164573A (zh) | 2021-07-23 |
US20210380660A1 (en) | 2021-12-09 |
KR20210071019A (ko) | 2021-06-15 |
AU2019355062A1 (en) | 2021-05-06 |
JP7511551B2 (ja) | 2024-07-05 |
US11945855B2 (en) | 2024-04-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI734722B (zh) | 使用胃抑肽受體(gipr)結合蛋白與glp-1促效劑之組合來治療或改善代謝病症之方法 | |
EP1675607B1 (en) | Monomeric recombinant mhc molecules useful for manipulation of antigen-specific t cells | |
JP7357088B2 (ja) | 融合タンパク質 | |
JP6364352B2 (ja) | 部分的mhcコンストラクト及びその使用方法 | |
JP2008537736A (ja) | 抗原特異的t細胞の操作に有用な組換えmhc分子 | |
CN110896606B (zh) | 用于治疗自身免疫性水疱病的coversin | |
US10316075B2 (en) | Recombinant polypeptides comprising MHC class II α1 domains | |
US10525101B2 (en) | Methods of treating inflammatory or autoimmune disorders with compounds that bind macrophage migration inhibitory factor | |
JP7511551B2 (ja) | 改変されたMHCクラスII DRα1ドメインを含む組換えポリペプチドおよび使用方法 | |
CA3168617A1 (en) | Anti-ide antibodies and uses of same | |
BR112016006113B1 (pt) | Proteína de fusão e seu uso, molécula de ácido nucleico, vetor de expressão replicável, uso da molécula de ácido nucleico, composição farmacêutica e kit |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221004 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20221004 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230920 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20231219 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20240215 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240321 |
|
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: 20240531 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20240625 |