JP6455935B2 - 食道がんのマーカーおよびその利用 - Google Patents
食道がんのマーカーおよびその利用 Download PDFInfo
- Publication number
- JP6455935B2 JP6455935B2 JP2015554576A JP2015554576A JP6455935B2 JP 6455935 B2 JP6455935 B2 JP 6455935B2 JP 2015554576 A JP2015554576 A JP 2015554576A JP 2015554576 A JP2015554576 A JP 2015554576A JP 6455935 B2 JP6455935 B2 JP 6455935B2
- Authority
- JP
- Japan
- Prior art keywords
- antibody
- chain cdr1
- positions
- glypican
- seq
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 208000000461 Esophageal Neoplasms Diseases 0.000 title claims description 226
- 206010030155 Oesophageal carcinoma Diseases 0.000 title claims description 223
- 201000004101 esophageal cancer Diseases 0.000 title claims description 223
- 108050001154 Glypican Proteins 0.000 claims description 373
- 108050007238 Glypican-1 Proteins 0.000 claims description 372
- 102000010956 Glypican Human genes 0.000 claims description 367
- 238000000034 method Methods 0.000 claims description 211
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 176
- 108090000623 proteins and genes Proteins 0.000 claims description 173
- 230000014509 gene expression Effects 0.000 claims description 148
- 150000007523 nucleic acids Chemical class 0.000 claims description 132
- 102000039446 nucleic acids Human genes 0.000 claims description 103
- 108020004707 nucleic acids Proteins 0.000 claims description 103
- 239000000126 substance Substances 0.000 claims description 102
- 238000001514 detection method Methods 0.000 claims description 97
- 239000003795 chemical substances by application Substances 0.000 claims description 94
- 239000000523 sample Substances 0.000 claims description 85
- 239000012634 fragment Substances 0.000 claims description 52
- 150000001413 amino acids Chemical group 0.000 claims description 51
- 230000027455 binding Effects 0.000 claims description 51
- 238000009739 binding Methods 0.000 claims description 47
- 239000000427 antigen Substances 0.000 claims description 40
- 108091007433 antigens Proteins 0.000 claims description 40
- 102000036639 antigens Human genes 0.000 claims description 40
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 32
- 230000000295 complement effect Effects 0.000 claims description 27
- 238000006467 substitution reaction Methods 0.000 claims description 23
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 22
- 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 19
- 238000012217 deletion Methods 0.000 claims description 19
- 230000037430 deletion Effects 0.000 claims description 19
- 230000035772 mutation Effects 0.000 claims description 18
- 208000007433 Lymphatic Metastasis Diseases 0.000 claims description 16
- 238000007792 addition Methods 0.000 claims description 15
- 208000009956 adenocarcinoma Diseases 0.000 claims description 13
- 239000012491 analyte Substances 0.000 claims 2
- 210000004027 cell Anatomy 0.000 description 215
- 239000002773 nucleotide Substances 0.000 description 109
- 125000003729 nucleotide group Chemical group 0.000 description 109
- 239000004055 small Interfering RNA Substances 0.000 description 107
- 102000004169 proteins and genes Human genes 0.000 description 105
- 235000018102 proteins Nutrition 0.000 description 95
- 108090000765 processed proteins & peptides Proteins 0.000 description 94
- 108020004459 Small interfering RNA Proteins 0.000 description 91
- 102000004196 processed proteins & peptides Human genes 0.000 description 78
- 239000003814 drug Substances 0.000 description 74
- 239000003550 marker Substances 0.000 description 73
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 68
- 230000009368 gene silencing by RNA Effects 0.000 description 68
- 102000040430 polynucleotide Human genes 0.000 description 68
- 108091033319 polynucleotide Proteins 0.000 description 68
- 239000002157 polynucleotide Substances 0.000 description 68
- 229920001184 polypeptide Polymers 0.000 description 63
- 241000282414 Homo sapiens Species 0.000 description 60
- 230000000694 effects Effects 0.000 description 59
- 229920002477 rna polymer Polymers 0.000 description 56
- 235000001014 amino acid Nutrition 0.000 description 54
- 229940024606 amino acid Drugs 0.000 description 51
- 108020004999 messenger RNA Proteins 0.000 description 51
- 238000012360 testing method Methods 0.000 description 50
- 108020004414 DNA Proteins 0.000 description 47
- 102000053602 DNA Human genes 0.000 description 46
- 238000003745 diagnosis Methods 0.000 description 46
- 206010028980 Neoplasm Diseases 0.000 description 43
- 239000000047 product Substances 0.000 description 40
- 201000011510 cancer Diseases 0.000 description 39
- 229940124597 therapeutic agent Drugs 0.000 description 36
- 238000011282 treatment Methods 0.000 description 36
- 108091034117 Oligonucleotide Proteins 0.000 description 33
- 230000006870 function Effects 0.000 description 33
- 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 description 32
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 description 32
- 230000000692 anti-sense effect Effects 0.000 description 31
- 101150030514 GPC1 gene Proteins 0.000 description 30
- 239000000032 diagnostic agent Substances 0.000 description 30
- 229940039227 diagnostic agent Drugs 0.000 description 30
- 239000000203 mixture Substances 0.000 description 30
- 210000001519 tissue Anatomy 0.000 description 30
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 27
- 238000009396 hybridization Methods 0.000 description 27
- 239000003112 inhibitor Substances 0.000 description 26
- 210000002966 serum Anatomy 0.000 description 26
- 230000003993 interaction Effects 0.000 description 25
- 230000001225 therapeutic effect Effects 0.000 description 25
- 239000013598 vector Substances 0.000 description 25
- 238000004458 analytical method Methods 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 23
- 241000699666 Mus <mouse, genus> Species 0.000 description 22
- 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 description 21
- 108091027967 Small hairpin RNA Proteins 0.000 description 21
- 238000004519 manufacturing process Methods 0.000 description 21
- 239000000758 substrate Substances 0.000 description 21
- 229940079593 drug Drugs 0.000 description 20
- 239000005557 antagonist Substances 0.000 description 18
- 239000011230 binding agent Substances 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 238000001262 western blot Methods 0.000 description 18
- 108020004635 Complementary DNA Proteins 0.000 description 17
- 201000010099 disease Diseases 0.000 description 17
- 238000003199 nucleic acid amplification method Methods 0.000 description 17
- 230000000069 prophylactic effect Effects 0.000 description 17
- 241000287828 Gallus gallus Species 0.000 description 16
- 230000000259 anti-tumor effect Effects 0.000 description 16
- 238000010804 cDNA synthesis Methods 0.000 description 16
- 239000002299 complementary DNA Substances 0.000 description 16
- 150000003839 salts Chemical class 0.000 description 16
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 15
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 15
- 230000004071 biological effect Effects 0.000 description 15
- 235000013330 chicken meat Nutrition 0.000 description 15
- 238000002474 experimental method Methods 0.000 description 15
- 108020001507 fusion proteins Proteins 0.000 description 15
- 102000037865 fusion proteins Human genes 0.000 description 15
- 238000001727 in vivo Methods 0.000 description 15
- 230000002401 inhibitory effect Effects 0.000 description 15
- 238000002965 ELISA Methods 0.000 description 14
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 14
- 210000004369 blood Anatomy 0.000 description 14
- 239000008280 blood Substances 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 13
- 108090000790 Enzymes Proteins 0.000 description 13
- 229940088598 enzyme Drugs 0.000 description 13
- 238000011532 immunohistochemical staining Methods 0.000 description 13
- 238000002347 injection Methods 0.000 description 13
- 239000007924 injection Substances 0.000 description 13
- 239000012528 membrane Substances 0.000 description 13
- 230000002265 prevention Effects 0.000 description 13
- 239000011780 sodium chloride Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 230000009471 action Effects 0.000 description 12
- 239000003446 ligand Substances 0.000 description 12
- 210000004379 membrane Anatomy 0.000 description 12
- 230000004048 modification Effects 0.000 description 12
- 238000012986 modification Methods 0.000 description 12
- 239000013642 negative control Substances 0.000 description 12
- 230000001629 suppression Effects 0.000 description 12
- 101001070736 Homo sapiens Glypican-1 Proteins 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 11
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 11
- 239000003124 biologic agent Substances 0.000 description 11
- 230000022534 cell killing Effects 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 11
- 239000013604 expression vector Substances 0.000 description 11
- 102000050168 human GPC1 Human genes 0.000 description 11
- 238000003018 immunoassay Methods 0.000 description 11
- 229920000642 polymer Polymers 0.000 description 11
- 230000009257 reactivity Effects 0.000 description 11
- 239000003139 biocide Substances 0.000 description 10
- 208000035475 disorder Diseases 0.000 description 10
- 230000012010 growth Effects 0.000 description 10
- 230000002452 interceptive effect Effects 0.000 description 10
- 238000005259 measurement Methods 0.000 description 10
- 230000007423 decrease Effects 0.000 description 9
- 230000002209 hydrophobic effect Effects 0.000 description 9
- 230000003053 immunization Effects 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- 150000002632 lipids Chemical class 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 239000000872 buffer Substances 0.000 description 8
- 239000000969 carrier Substances 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 238000004949 mass spectrometry Methods 0.000 description 8
- 239000002679 microRNA Substances 0.000 description 8
- 238000011002 quantification Methods 0.000 description 8
- 238000003753 real-time PCR Methods 0.000 description 8
- -1 t-butyloxycarbonyl Chemical group 0.000 description 8
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 7
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 7
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 7
- 108700011259 MicroRNAs Proteins 0.000 description 7
- 239000006180 TBST buffer Substances 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 125000000539 amino acid group Chemical group 0.000 description 7
- 230000008827 biological function Effects 0.000 description 7
- 229940098773 bovine serum albumin Drugs 0.000 description 7
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 7
- 125000005647 linker group Chemical group 0.000 description 7
- 238000000691 measurement method Methods 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 230000026731 phosphorylation Effects 0.000 description 7
- 238000006366 phosphorylation reaction Methods 0.000 description 7
- 230000003449 preventive effect Effects 0.000 description 7
- 230000002441 reversible effect Effects 0.000 description 7
- 239000012453 solvate Substances 0.000 description 7
- 125000006850 spacer group Chemical group 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 102000007469 Actins Human genes 0.000 description 6
- 108010085238 Actins Proteins 0.000 description 6
- 238000001061 Dunnett's test Methods 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 239000002033 PVDF binder Substances 0.000 description 6
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 6
- 108091081021 Sense strand Proteins 0.000 description 6
- 150000001450 anions Chemical class 0.000 description 6
- 230000006907 apoptotic process Effects 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- 238000001962 electrophoresis Methods 0.000 description 6
- 210000003238 esophagus Anatomy 0.000 description 6
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 6
- 230000001900 immune effect Effects 0.000 description 6
- 238000002372 labelling Methods 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 238000001543 one-way ANOVA Methods 0.000 description 6
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 6
- 239000001509 sodium citrate Substances 0.000 description 6
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- 230000008685 targeting Effects 0.000 description 6
- 238000001890 transfection Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 102000010565 Apoptosis Regulatory Proteins Human genes 0.000 description 5
- 108010063104 Apoptosis Regulatory Proteins Proteins 0.000 description 5
- 102000003952 Caspase 3 Human genes 0.000 description 5
- 108090000397 Caspase 3 Proteins 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 230000003321 amplification Effects 0.000 description 5
- 238000013459 approach Methods 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 150000001768 cations Chemical class 0.000 description 5
- 230000010261 cell growth Effects 0.000 description 5
- 210000000170 cell membrane Anatomy 0.000 description 5
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 5
- 238000002405 diagnostic procedure Methods 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 238000010195 expression analysis Methods 0.000 description 5
- 239000003966 growth inhibitor Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 210000004698 lymphocyte Anatomy 0.000 description 5
- 238000010369 molecular cloning Methods 0.000 description 5
- 238000003127 radioimmunoassay Methods 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 238000003757 reverse transcription PCR Methods 0.000 description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 238000002560 therapeutic procedure 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
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 4
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 4
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 4
- 108091032955 Bacterial small RNA Proteins 0.000 description 4
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 4
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 4
- 241000282693 Cercopithecidae Species 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 102100032530 Glypican-3 Human genes 0.000 description 4
- 101001014668 Homo sapiens Glypican-3 Proteins 0.000 description 4
- 108010038807 Oligopeptides Proteins 0.000 description 4
- 102000015636 Oligopeptides Human genes 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 102000000574 RNA-Induced Silencing Complex Human genes 0.000 description 4
- 108010016790 RNA-Induced Silencing Complex Proteins 0.000 description 4
- 238000011579 SCID mouse model Methods 0.000 description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 230000031018 biological processes and functions Effects 0.000 description 4
- 238000007385 chemical modification Methods 0.000 description 4
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 4
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 230000002708 enhancing effect Effects 0.000 description 4
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 125000001165 hydrophobic group Chemical group 0.000 description 4
- 238000002649 immunization Methods 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 4
- 238000004091 panning Methods 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000002336 ribonucleotide Substances 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- 210000000952 spleen Anatomy 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000013518 transcription Methods 0.000 description 4
- 230000035897 transcription Effects 0.000 description 4
- 238000002054 transplantation Methods 0.000 description 4
- 239000000439 tumor marker Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108020005544 Antisense RNA Proteins 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 108090000994 Catalytic RNA Proteins 0.000 description 3
- 102000053642 Catalytic RNA Human genes 0.000 description 3
- 108020004705 Codon Proteins 0.000 description 3
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- 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 3
- 241000282412 Homo Species 0.000 description 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- 239000012097 Lipofectamine 2000 Substances 0.000 description 3
- 108060004795 Methyltransferase Proteins 0.000 description 3
- 101001070735 Mus musculus Glypican-1 Proteins 0.000 description 3
- 101100449210 Mus musculus Gpc1 gene Proteins 0.000 description 3
- 238000000636 Northern blotting Methods 0.000 description 3
- 108091005461 Nucleic proteins Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 108091028664 Ribonucleotide Proteins 0.000 description 3
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000002105 Southern blotting Methods 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000021736 acetylation Effects 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 3
- 238000005349 anion exchange Methods 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 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 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- VYXSBFYARXAAKO-WTKGSRSZSA-N chembl402140 Chemical compound Cl.C1=2C=C(C)C(NCC)=CC=2OC2=C\C(=N/CC)C(C)=CC2=C1C1=CC=CC=C1C(=O)OCC VYXSBFYARXAAKO-WTKGSRSZSA-N 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000010367 cloning Methods 0.000 description 3
- 239000003184 complementary RNA Substances 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 239000010432 diamond Substances 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 239000007850 fluorescent dye Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 229930004094 glycosylphosphatidylinositol Natural products 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 210000004408 hybridoma Anatomy 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 230000016784 immunoglobulin production Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 238000001325 log-rank test Methods 0.000 description 3
- 210000004962 mammalian cell Anatomy 0.000 description 3
- 229910021645 metal ion Inorganic materials 0.000 description 3
- 238000002493 microarray Methods 0.000 description 3
- 239000011859 microparticle Substances 0.000 description 3
- 230000011278 mitosis Effects 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 238000002823 phage display Methods 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000002652 ribonucleotide group Chemical group 0.000 description 3
- 108091092562 ribozyme Proteins 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000002741 site-directed mutagenesis Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 230000009870 specific binding Effects 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- QGKMIGUHVLGJBR-UHFFFAOYSA-M (4z)-1-(3-methylbutyl)-4-[[1-(3-methylbutyl)quinolin-1-ium-4-yl]methylidene]quinoline;iodide Chemical compound [I-].C12=CC=CC=C2N(CCC(C)C)C=CC1=CC1=CC=[N+](CCC(C)C)C2=CC=CC=C12 QGKMIGUHVLGJBR-UHFFFAOYSA-M 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- CZIHNRWJTSTCEX-UHFFFAOYSA-N 2 Acetylaminofluorene Chemical compound C1=CC=C2C3=CC=C(NC(=O)C)C=C3CC2=C1 CZIHNRWJTSTCEX-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 2
- 108010082126 Alanine transaminase Proteins 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 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
- 108091023037 Aptamer Proteins 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- 101100180402 Caenorhabditis elegans jun-1 gene Proteins 0.000 description 2
- 241000282836 Camelus dromedarius Species 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 102000014914 Carrier Proteins Human genes 0.000 description 2
- 241000700199 Cavia porcellus Species 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
- 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
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 229920002971 Heparan sulfate Polymers 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- 238000007397 LAMP assay Methods 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
- 241000282560 Macaca mulatta Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 238000000585 Mann–Whitney U test Methods 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 241000282577 Pan troglodytes Species 0.000 description 2
- 108090000526 Papain Proteins 0.000 description 2
- 102000057297 Pepsin A Human genes 0.000 description 2
- 108090000284 Pepsin A Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 101710137500 T7 RNA polymerase Proteins 0.000 description 2
- 238000008050 Total Bilirubin Reagent Methods 0.000 description 2
- 101710120037 Toxin CcdB Proteins 0.000 description 2
- 238000005411 Van der Waals force Methods 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003149 assay kit Methods 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 108091008324 binding proteins Proteins 0.000 description 2
- 239000003181 biological factor Substances 0.000 description 2
- 238000001574 biopsy Methods 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
- 210000000601 blood cell Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 229930195731 calicheamicin Natural products 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 238000005341 cation exchange Methods 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 238000001516 cell proliferation assay Methods 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000011651 chromium Substances 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 238000004590 computer program Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000009260 cross reactivity Effects 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 229940104302 cytosine Drugs 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000003795 desorption Methods 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 210000001808 exosome Anatomy 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 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 2
- 238000002795 fluorescence method Methods 0.000 description 2
- 235000013355 food flavoring agent Nutrition 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
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 150000004676 glycans Polymers 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 108010083213 heparitinsulfate lyase Proteins 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000001114 immunoprecipitation Methods 0.000 description 2
- 238000007901 in situ hybridization Methods 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 230000010468 interferon response Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000001155 isoelectric focusing Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 230000002101 lytic effect Effects 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
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 108010082117 matrigel Proteins 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 238000002515 oligonucleotide synthesis Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000000816 peptidomimetic Substances 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000032361 posttranscriptional gene silencing Effects 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000003498 protein array Methods 0.000 description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- 230000006798 recombination Effects 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000001177 retroviral effect Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- IBKZNJXGCYVTBZ-IDBHZBAZSA-M sodium;1-[3-[2-[5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]ethyldisulfanyl]propanoyloxy]-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].O=C1C(S(=O)(=O)[O-])CC(=O)N1OC(=O)CCSSCCNC(=O)CCCC[C@H]1[C@H]2NC(=O)N[C@H]2CS1 IBKZNJXGCYVTBZ-IDBHZBAZSA-M 0.000 description 2
- VSIVTUIKYVGDCX-UHFFFAOYSA-M sodium;4-[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].COC1=CC([N+]([O-])=O)=CC=C1[N+]1=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=NN1C1=CC=C([N+]([O-])=O)C=C1 VSIVTUIKYVGDCX-UHFFFAOYSA-M 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000010381 tandem affinity purification Methods 0.000 description 2
- 239000013076 target substance Substances 0.000 description 2
- 238000011191 terminal modification Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000011830 transgenic mouse model Methods 0.000 description 2
- 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 2
- 238000000539 two dimensional gel electrophoresis Methods 0.000 description 2
- 229940035893 uracil Drugs 0.000 description 2
- 238000012784 weak cation exchange Methods 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- ASWBNKHCZGQVJV-UHFFFAOYSA-N (3-hexadecanoyloxy-2-hydroxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C ASWBNKHCZGQVJV-UHFFFAOYSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- FVPXJPVSJNSJBL-UHFFFAOYSA-N 1h-pyrimidine-2,4-dione;1,3-thiazole Chemical compound C1=CSC=N1.O=C1C=CNC(=O)N1 FVPXJPVSJNSJBL-UHFFFAOYSA-N 0.000 description 1
- VGONTNSXDCQUGY-RRKCRQDMSA-N 2'-deoxyinosine Chemical group C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC2=O)=C2N=C1 VGONTNSXDCQUGY-RRKCRQDMSA-N 0.000 description 1
- MIJDSYMOBYNHOT-UHFFFAOYSA-N 2-(ethylamino)ethanol Chemical compound CCNCCO MIJDSYMOBYNHOT-UHFFFAOYSA-N 0.000 description 1
- 125000000134 2-(methylsulfanyl)ethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])[*] 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- GOLORTLGFDVFDW-UHFFFAOYSA-N 3-(1h-benzimidazol-2-yl)-7-(diethylamino)chromen-2-one Chemical compound C1=CC=C2NC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 GOLORTLGFDVFDW-UHFFFAOYSA-N 0.000 description 1
- UJBCLAXPPIDQEE-UHFFFAOYSA-N 5-prop-1-ynyl-1h-pyrimidine-2,4-dione Chemical class CC#CC1=CNC(=O)NC1=O UJBCLAXPPIDQEE-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 102100031680 Beta-catenin-interacting protein 1 Human genes 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 101710094648 Coat protein Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 238000000018 DNA microarray Methods 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000009007 Diagnostic Kit Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 241000701959 Escherichia virus Lambda Species 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 1
- 108090000385 Fibroblast growth factor 7 Proteins 0.000 description 1
- 102100028071 Fibroblast growth factor 7 Human genes 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- 241000724791 Filamentous phage Species 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000001989 Glypican-6 Human genes 0.000 description 1
- 108050009385 Glypican-6 Proteins 0.000 description 1
- 102100021181 Golgi phosphoprotein 3 Human genes 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 101000993469 Homo sapiens Beta-catenin-interacting protein 1 Proteins 0.000 description 1
- 101000935587 Homo sapiens Flavin reductase (NADPH) Proteins 0.000 description 1
- 101000808011 Homo sapiens Vascular endothelial growth factor A Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 101000829171 Hypocrea virens (strain Gv29-8 / FGSC 10586) Effector TSP1 Proteins 0.000 description 1
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 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
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-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
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 101710125418 Major capsid protein Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 229940121849 Mitotic inhibitor Drugs 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 101710141454 Nucleoprotein Proteins 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 101710149632 Pectinesterase A Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108010043958 Peptoids Proteins 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 1
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 101710083689 Probable capsid protein Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 108010026552 Proteome Proteins 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 108020004518 RNA Probes Proteins 0.000 description 1
- 239000003391 RNA probe Substances 0.000 description 1
- 238000011530 RNeasy Mini Kit Methods 0.000 description 1
- 244000097202 Rathbunia alamosensis Species 0.000 description 1
- 235000009776 Rathbunia alamosensis Nutrition 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 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
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 101100082060 Xenopus laevis pou5f1.1 gene Proteins 0.000 description 1
- 108010084455 Zeocin Proteins 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 102000005840 alpha-Galactosidase Human genes 0.000 description 1
- 108010030291 alpha-Galactosidase Proteins 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 238000011091 antibody purification Methods 0.000 description 1
- 230000009831 antigen interaction Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 108010045569 atelocollagen Proteins 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 238000004422 calculation algorithm Methods 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229950008138 carmellose Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000005277 cation exchange chromatography Methods 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000000006 cell growth inhibition assay Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000005289 controlled pore glass Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 231100000409 cytocidal Toxicity 0.000 description 1
- 230000000445 cytocidal effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960000633 dextran sulfate Drugs 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- CRVGKGJPQYZRPT-UHFFFAOYSA-N diethylamino acetate Chemical compound CCN(CC)OC(C)=O CRVGKGJPQYZRPT-UHFFFAOYSA-N 0.000 description 1
- 238000002349 difference gel electrophoresis Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000012869 ethanol precipitation Methods 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000013861 fat-free Nutrition 0.000 description 1
- 229960004887 ferric hydroxide Drugs 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000001641 gel filtration chromatography Methods 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 238000012226 gene silencing method Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000011544 gradient gel Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 102000058223 human VEGFA Human genes 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000012872 hydroxylapatite chromatography Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229940124452 immunizing agent Drugs 0.000 description 1
- 230000000951 immunodiffusion Effects 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 238000007850 in situ PCR Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 150000002496 iodine Chemical class 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 238000000752 ionisation method Methods 0.000 description 1
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 238000001948 isotopic labelling Methods 0.000 description 1
- 238000001001 laser micro-dissection Methods 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 230000029226 lipidation Effects 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 230000008604 lipoprotein metabolism Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 241001515942 marmosets Species 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 150000004667 medium chain fatty acids Chemical class 0.000 description 1
- 229960005558 mertansine Drugs 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 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
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 230000007498 myristoylation Effects 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229940043515 other immunoglobulins in atc Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000013610 patient sample Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 229940080469 phosphocellulose Drugs 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000010399 physical interaction Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 210000002706 plastid Anatomy 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000000941 radioactive substance Substances 0.000 description 1
- 238000002708 random mutagenesis Methods 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000009711 regulatory function Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 235000009566 rice Nutrition 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
- 238000011076 safety test Methods 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 239000012723 sample buffer Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000002924 silencing RNA Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 108010088201 squamous cell carcinoma-related antigen Proteins 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000012799 strong cation exchange Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000000672 surface-enhanced laser desorption--ionisation Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000006491 synthase reaction Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 238000001269 time-of-flight mass spectrometry Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000009752 translational inhibition Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000004879 turbidimetry Methods 0.000 description 1
- 238000010396 two-hybrid screening Methods 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
-
- 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
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
-
- 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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/23—Immunoglobulins specific features characterized by taxonomic origin from birds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
- G01N2400/10—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- G01N2400/38—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence, e.g. gluco- or galactomannans, Konjac gum, Locust bean gum or Guar gum
- G01N2400/40—Glycosaminoglycans, i.e. GAG or mucopolysaccharides, e.g. chondroitin sulfate, dermatan sulfate, hyaluronic acid, heparin, heparan sulfate, and related sulfated polysaccharides
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biomedical Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Biophysics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- Pathology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Cell Biology (AREA)
- Plant Pathology (AREA)
- General Physics & Mathematics (AREA)
- Food Science & Technology (AREA)
- Epidemiology (AREA)
- Peptides Or Proteins (AREA)
Description
からなる群から選ばれる抗体、またはそのフラグメントもしくは機能的等価物を提供する。これらの抗体は、配列番号2の33〜61位、または、339〜358位および/もしくは388〜421位、または430〜530位をエピトープとして有していてもよい。これらの抗体は、モノクローナル抗体、ポリクローナル抗体、キメラ抗体、ヒト化抗体、ヒト抗体、多機能抗体、二重特異性またはオリゴ特異性(oligospecific)抗体、単鎖抗体、scFV、ダイアボディー、sc(Fv)2(single chain(Fv)2)、およびscFv−Fcから選択される抗体であってもよい。
(a)配列番号1に記載の塩基配列またはそのフラグメント配列を有するポリヌクレオチド;
(b)配列番号2に記載のアミノ酸配列からなるポリペプチドまたはそのフラグメントをコードするポリヌクレオチド;
(c)配列番号2に記載のアミノ酸配列において、1以上のアミノ酸が、置換、付加および欠失からなる群より選択される1つの変異を有する改変体ポリペプチドまたはそのフラグメントであって、生物学的活性を有する改変体ポリペプチドをコードする、ポリヌクレオチド;
(d)配列番号1に記載の塩基配列のスプライス変異体もしくは対立遺伝子変異体またはそのフラグメントである、ポリヌクレオチド;
(e)配列番号2に記載のアミノ酸配列からなるポリペプチドの種相同体またはそのフラグメントをコードする、ポリヌクレオチド;
(f)(a)〜(e)のいずれか1つのポリヌクレオチドにストリンジェント条件下でハイブリダイズし、かつ生物学的活性を有するポリペプチドをコードするポリヌクレオチド;または
(g)(a)〜(e)のいずれか1つのポリヌクレオチドまたはその相補配列に対する同一性が少なくとも70%、少なくとも80%、少なくとも90%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、または少なくとも99%である塩基配列からなり、かつ、生物学的活性を有するポリペプチドをコードするポリヌクレオチドであり得る。ここで、生物学的活性とは、代表的に、Glypican-1の有する活性またはマーカーとして同じ生物内に存在する他のタンパク質から識別し得ることをいう。
Glypican-1のアミノ酸配列としては、
(a)配列番号2に記載のアミノ酸配列またはそのフラグメントからなる、ポリペプチド;
(b)配列番号2に記載のアミノ酸配列において、1以上のアミノ酸が置換、付加および欠失からなる群より選択される1つの変異を有し、かつ、生物学的活性を有する、ポリペプチド;
(c)配列番号1に記載の塩基配列のスプライス変異体または対立遺伝子変異体によってコードされる、ポリペプチド;
(d)配列番号2に記載のアミノ酸配列の種相同体である、ポリペプチド;または
(e)(a)〜(d)のいずれか1つのポリペプチドに対する同一性が少なくとも70%、少なくとも80%、少なくとも90%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、または少なくとも99%であるアミノ酸配列を有し、かつ、生物学的活性を有する、ポリペプチド、であり得る。ここで、生物学的活性とは、代表的に、Glypican-1の有する活性またはマーカーとして同じ生物内に存在する他のタンパク質から識別し得ること(例えば、抗原として用いられる場合特異的エピトープとして機能し得る領域を含むこと)をいう。
以下に本発明の好ましい実施形態を説明する。以下に提供される実施形態は、本発明のよりよい理解のために提供されるものであり、本発明の範囲は以下の記載に限定されるべきでないことが理解される。従って、当業者は、本明細書中の記載を参酌して、本発明の範囲内で適宜改変を行うことができることは明らかである。また、本発明の以下の実施形態は単独でも使用されあるいはそれらを組み合わせて使用することができることが理解される。
1つの局面において、本発明は、Glypican-1またはその発現産物あるいはそのフラグメントまたは誘導体を含む、食道がんを識別するためのマーカーを提供する。Glypican-1は生体内に存在するものであり、健常人またはその由来試料では、発現が少なく、食道がんにおいて発現が顕著に高いことから、食道がんの有効な指標マーカーとして用いることができることが本発明において見出された。
からなる群から選ばれる抗体、またはそのフラグメントもしくは機能的等価物を提供する。これらの抗体は、配列番号2の33〜61位、または、339〜358位および/もしくは388〜421位、または430〜530位をエピトープとして有していてもよい。これらの抗体は、モノクローナル抗体、ポリクローナル抗体、キメラ抗体、ヒト化抗体、ヒト抗体、多機能抗体、二重特異性またはオリゴ特異性(oligospecific)抗体、単鎖抗体、scFV、ダイアボディー、sc(Fv)2(single chain(Fv)2)、およびscFv−Fcから選択される抗体であってもよい。これらの抗体は、本明細書に記載される任意の用途で用いられ得る。
1つの局面において、本発明によれば、本発明による検出、検査および/または診断のための方法を実施するための検出、検査および/または診断のためのキットが提供される。このキットは、本発明の検出剤、検査剤および/または診断剤を含む。その実施形態としては、本明細書において記載された任意の実施形態を単独または組み合わせ用いることができる。
1つの局面では、本発明は、Glypican-1の抑制剤を含む、食道がんを予防または治療するための組成物または医薬(治療薬または予防薬)を提供する。この治療または予防薬を用いれば、食道がんを治療または予防することができる。またこの治療または予防薬は、抗体を使用するため、安全性の観点から優れている。
本明細書において用いられる分子生物学的手法、生化学的手法、微生物学的手法は、当該分野において周知であり慣用されるものであり、例えば、Sambrook J. et al.(1989). Molecular Cloning: A Laboratory Manual,Cold Spring Harborおよびその3rd Ed.(2001); Ausubel, F.M.(1987).Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience; Ausubel,F.M.(1989). Short Protocols inMolecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology,Greene Pub. Associates and Wiley-Interscience;Innis,M.A.(1990).PCR Protocols: A Guide to Methods and Applications, Academic Press; Ausubel,F.M.(1992).Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates;Ausubel,F.M. (1995).Short Protocols in MolecularBiology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates;Innis,M.A. et al.(1995).PCR Strategies, Academic Press; Ausubel,F.M.(1999).Short Protocols in Molecular Biology: A Compendium of Methods fromCurrent Protocols in Molecular Biology,Wiley, and annual updates; Sninsky, J.J.et al.(1999). PCR Applications: Protocols for Functional Genomics, Academic Press、別冊実験医学「遺伝子導入&発現解析実験法」羊土社、1997などに記載されており、これらは本明細書において関連する部分(全部であり得る)が参考として援用される。
食道がん手術組織は大阪大学医学部附属病院にてインフォームドコンセントについて同意を得た患者より提供していただいた。
本実施例では、ウェスタンブロットによるGlypican-1の各種細胞における発現を調べた。
正常食道上皮細胞HEEpic, Het1A、食道扁平上皮癌細胞株TE1,TE5, TE6, TE8, TE9, TE10, TE11, TE14, TE15について、氷冷PBS(-)で洗浄後、cell scraperではがし、遠心分離により細胞を回収した。細胞はLysisbuffer(20mM Tris-HCl, pH 7.5, 150 mM NaCl, 1% Triton X-100, 1 x protease inhibitorcocktail (ナカライテスク), 1 x phosphatase inhibitor cocktail (ナカライテスク)) により溶解し、遠心分離(13,200rpm,4℃、15min)により上清をタンパク質抽出液として回収した。タンパク質濃度はタンパク質定量キット(DCProtein Assay kit (Bio-Rad Laboratories社))を用いてウシ血清アルブミン(BSA)
をスタンダードとして定量した。
その結果を図1に示す。Glypican-1について、特異的な抗体を用いてWestern blot法にて解析を行った。その結果、Glypican-1がHEEpicとHet1Aで発現しておらず、食道扁平上皮癌細胞株で発現していることを確認した。
本実施例では、Glypican-1(Accession No. P35052)の正常細胞および各種食道がん細胞株における相対発現量を調べた。
正常食道上皮細胞HEEpic,Het1Aに対して食道扁平上皮癌細胞株TE1, TE6, TE8, TE9, TE10, TE14におけるGlypican-1の発現量を相対的に評価した。
その結果を図2に示す。図2に示すように、正常株では、1.2台であったのに対して、食道がん細胞株では、TE6、TE9、TE10およびTE14では2倍以上、TE1およびTE8でも1.6〜1.7と高い相対比率を示し、6種類の食道扁平上皮癌細胞株の内、4種類の癌細胞株にて2倍以上に高発現することが分かった。したがって、Glypican-1は食道がんのマーカーとして有用であることが示された。
次に、本実施例では、Glypican-1は食道がん細胞の細胞表面に発現することをFACSにて確認した。
細胞はPBS(Nacalai Tesque)で2回洗浄し、0.02% EDTA solution (Nacalai Tesque)でdishよりはがした。細胞をFACSstaining buffer (PBS supplemented with 1% FBS and 0.1% sodium azide)で2回洗浄し、5倍希釈したgoat anti-human Glypican-1 antibody (R&D Systems, Minneapolis, MN) で染色し、続いて50倍希釈したPE-labeled anti-goat IgG antibodyで染色した。染色した細胞はFACSCanto II (Becton Dickinson, Mountain View, CA, USA)で測定し、FlowJo software (TreeStar, Stanford, CA, USA)を用いてデータ解析した。
結果を図3に示す。示されるように、正常細胞では、Glypican-1の発現はバックグラウンド程度であったのに対して、いずれの食道がん細胞株においてもGlypican-1は有意に発現が増大していることが示された。
本実施例では、食道扁平上皮癌症例の組織(原発およびリンパ節転移)におけるGlypican-1を免疫組織化学染色により確認した。
パラフィン包埋組織の薄切は脱パラフィン処理、アルコールによる脱水を行った。Glypican-1に対する免疫組織化学染色はABC法により抗GPC-1抗体(Atlasantibodies:HPA030571)を用いて行った。
図4Aにその結果を示す。また、さらに別のシリーズで行った結果を図4Bに示す。いずれのシリーズにおいても、Glypican-1について、手術組織に対し免疫組織化学染色法を行うことで、細胞株でなく、癌組織における、癌抗原候補分子の発現について評価した。示されるように、免疫組織化学染色によっても、Glypican-1の食道がん細胞株における有意な発現増強が観察された。この実験の結果、Glypican-1が、食道扁平上皮癌組織の細胞膜において高発現することが判明した。
ヒトの各種正常組織由来RNAはHuman Total RNA Master Panel II (Clontech, Palo Alto, CA, USA)を用いた。食道扁平上皮癌細胞株TE11について、RNeasyminikit(QIAGEN)によりRNAを精製した。QuantiTect Reverse Transcription Kit(Qiagen)を用いてトータルRNAをcDNAへ逆転写した。
・GPC-1, forward primer 5’- GCCAGATCTACGGAGCCAAG-3’(配列番号27;NM_002046.3)
・GPC-1,reverse primer 5’- AGGTTCTCCTCCATCTCGCT-3’ (配列番号28;NM_002046.3)
・GAPDH, forward primer ’-AGCAATGCCTCCTGCACCACCAAC-3’(配列番号29;NM_002081.2)
・GAPDH, reverse primer 5’-CCGGAGGGGCCATCCACAGTCT-3’ (配列番号30;NM_002081.2)
・β-actin,forward primer ’-AGCCTCGCCTTTGCCGA-3’(配列番号31;NM_001101.3)
・β-actin, reverse primer 5’-CTGGTGCCTGGGGCG-3’ (配列番号32;NM_001101.3)。
結果を図5Aに示す。図に示すように、市販の各種ヒト正常組織由来RNAを用いて、リアルタイムPCR解析による各種正常組織におけるglypican-1の発現解析を行い、GAPDH発現に対する相対値としてglypican-1の発現量を調べたところ、正常組織での発現は低いことが確認された。いずれの組織においても、Glypican-1の有意な発現は見られなかったのに対して、食道癌細胞株では、顕著な発現増加がみられた。(図5A)。食道癌組織、非癌部位、TE14を加えた場合でも同様の傾向が見られた。図5BリアルタイムPCR解析による同一患者の食道癌組織および非癌部位におけるGlypican-1の発現解析を行った結果を示す。β-actin発現に対する相対値としてGlypican-1の発現量を調べたところ、食道癌組織では非癌部位と比較して有意な発現レベルの上昇が認められた。したがって、これらの結果からも、本発明のglypican-1は食道がんのマーカーとして有用であることが理解される。
健常人血清(N=5)、及び、食道がん患者血清(N=9)をPBSで2倍希釈し、USCNLife ScienceINC社のhuman ELISAキットで定量を行った。その結果、食道がん患者9例中6例において、健常人血清よりも血清中Glypican-1の濃度が高値を示すことが判明した(図6〜図7)。
本実施例では、Glypican-1が食道扁平上皮癌細胞株の増殖と関係しているかどうかについて明らかにするため、Glypican-1に対するsiRNAを用いたGlypican-1の発現抑制を用いて、invitroでの抗腫瘍効果を検討した。
食道がん細胞は96ウェルプレートに2,000cells/wellまき、lipofectamine2000を用いたsiRNAトランスフェクション後72時間後にWST-8アッセイ法によって細胞増殖アッセイを行った。Glypican-1に対するsiRNAおよび、negative control siRNAはQIAGEN社より入手した。
lipofectamine2000を用いてTE6, TE8, TE14 細胞にsiRNAトランスフェクションした72時間後に、PBSで細胞を洗浄し、caspase-3fluorometric assay キット(R&D systems)を用いて測定した。
TE6,TE8, TE14について、氷冷PBS(-)で洗浄後、cell scraperではがし、遠心分離により細胞を回収した。細胞はRIPA buffer(10 mMTris-HCl, pH 7.5, 150 mM NaCl, 1% Nonidet P-40, 0.1% sodium deoxycholate, 0.1%SDS, phosphatase ,1 x protease inhibitor (ナカライテスク)cocktail (ナカライテスク)) により溶解し、遠心分離(13,200rpm,4℃、15min)により上清をタンパク質抽出液として回収した。タンパク質濃度はタンパク質定量キット(DC Protein Assay kit (Bio-RadLaboratories社))を用いてウシ血清アルブミン(BSA)をスタンダードとして定量した。
その結果を図8、9、10A、10Bおよび10Cに示す。Glypican-1に対するsiRNA はGlypican-1陽性食道扁平上皮癌細胞(TE5、TE6、TE8、TE14およびTE15)に対して抗腫瘍効果を示した。このとき、Glypican-1のsiRNAによるGlypican-1の発現抑制により、TE6,TE8, TE14においてcaspase-3活性の上昇が認められたことから、アポトーシスが誘導されていることが明らかになった。また、TE6、TE8およびTE14においてGlypican-1の発現抑制はAKTのリン酸化レベルの低下を引き起こすことが明らかとなった。TE8細胞において、Glypican-1のsiRNAによるGlypican-1の発現抑制により、アポトーシス促進性のタンパク質(pro-apoptotic protein)であるPuma, Bik, Bimの発現増加と抗アポトーシス性のタンパク質(Anti-apoptotic protein)であるBcl-wの発現減少が認められ、さらにEGFRのリン酸化レベルの減少も認められた。
本実施例では、GPC-1ニワトリ抗体を作製し、特徴づけを行った。以下にプロトコールを示す。
ヒトGlypican-1のcDNAをほ乳動物発現ベクター(pcDNA3.1-V5/His-TOPO)にライゲーションし、C末端にV5/Hisタグ融合タンパク質となるようにクローニングした。次に、発現ベクターをニワトリリンパ芽球様細胞株にエレクトロポレーション法でトランスフェクトした後、2mg/mlのG418を添加して発現細胞の選択をおこなった。得られたLSR発現細胞株をニワトリに過免疫した。抗体価の測定はcell-ELISAにて実施した。細胞株はGlypican-1発現ニワトリリンパ芽球様細胞株を4×105cells/wellで使用した。
免疫をおこなったニワトリから脾臓を摘出した後、リンパ球を分離した。得られたリンパ球からRNAを抽出してcDNAの合成を行いscFv ファージ抗体ライブラリーを作製した。ファージ抗体ライブラリーの作製に関しては、[nakamuraet al., J Vet Med Sci. 2004 Jul;66(7):807-14]に記載の一般的な手法に従った。
scFv ファージライブラリーを用いてcell panningを行いGlypican-1特異的なファージの濃縮を行った。Glypican-1非発現細胞株に添加して非特異ファージの吸収操作をおこなった後、ヒトGlypican-1発現細胞株と反応させた。細胞株はリンパ芽球様細胞株を用いた。有機溶媒で洗浄後、Glypican-1発現細胞株に特異的に結合したファージを回収し、大腸菌に感染させた。4回パニングをおこなった後、ライブラリーの反応性をGlypican-1発現細胞株を用いたcell-ELISA、及びFACS解析で確認した。反応性が上昇し始めていたライブラリーからファージのクローニングを行いcell-ELISA、及びFACS解析にて反応性を確認した。陽性クローンを選択した後、配列を決定した。Cell panningに関しては、[Giordano et al., Nat Med. 2001 Nov;7(11):1249-53.]に記載の方法に従った。
抗体を用いたFACS解析を行うにあたり、Glypican-1陰性細胞として、ニワトリTリンパ芽球様細胞株(CT01細胞)、Glypican-1陽性細胞としてヒトGlypican-1を強制発現させたCT01細胞(CT01-GPC-1#42)を用いた。開発した抗体の各種クローンを一次抗体として用い、2次抗体としてはFITC標識GoatAnti-Mouse IgG(H+L chain specific)(southern biothech社)を用い、FACS CantoII (BD社)を用いて測定し、測定データはFlowJo(Tree Star社)を用いて解析した。その結果、Glypican-1をFACSで染色出来る抗体として、20種類のクローンを開発することに成功した。
結果を図11に示す。示されるように、いずれの抗体も反応性の結果から、これらの抗体は、診断薬・治療薬として使用される可能性があることが理解される。
Scidマウス(6週齢、メス)皮下に食道がん細胞株TE-8を2x106cells/100μl (PBS:マトリゲル=1:1)で移植する。移植後14日目にマウスを2群に分け、抗Glypican-1抗体あるいはisotype control抗体(MouseIgG2a、M7769、Sigma)を10mg/kg週2回の頻度で計6回、腹腔内に投与した。TE-8移植マウスは抗体投与開始後25日目に解剖し、腫瘍重量も計測する。腫瘍体積=長径x短径x高さより計算する。これにより抗腫瘍効果を確認することができる。
抗Glypican-1抗体の親和性解析はBiacore3000を用いて測定した。CM5 sensor tipにMouse Antibody Capture Kitウサギ抗マウスIgGポリクローナル抗体を固相化し、各種抗Glypican1抗体クローンをキャプチャーし、リガンドとしてリコンビナントGlypican-1(R&D systems 4519-GP-050)を各種濃度で添加し、結合と解離をモニターした。得られたセンサーグラムはBIAevaluation 4.1 softwareを用いて解析し、KD値を算出した(図12)。その結果抗GPC1抗体(#1-12)はKD値が2.61nMと高親和性を示す事が明らかとなった。
293細胞にマウスGlypican-1発現ベクターあるいは空ベクターを、lipofectamine2000を用いてトランスフェクションし、抗Glypican-1抗体各種クローンとの反応性をFACSにて解析した。その結果、#18(2-63)以外のクローンにおいてマウスGlypican-1と交差反応を示すことが明らかとなった(図13)。
TE14細胞を96ウェルプレートに2000cells/wellまき、37℃のCO2インキュベーターにて一晩インキュベートした。96ウェルプレートの細胞上清を捨て、抗Glypican-1抗体の希釈液(0μg/ml、1μg/ml、10μg/ml、100μg/ml)を100μL/wellずつ加えた。72時間後にWST-8アッセイ法によって細胞増殖アッセイを行った。また、コントロールとして、非抗LSR抗体であるマウスIgG2(biolegend社、400224、MOPC-173)を使用した。結果を図14に示す。抗Glypican-1抗体#19(2-70)を接触させることによって、食道癌細胞(TE14)の増殖が抑制された。
各種抗Glypican-1抗体のエピトープ解析を実施した。ヒトGlypican-1の全長の発現ベクターより33-61番目のアミノ酸を欠失させたtruncate mutantを作成した。この発現ベクターを293細胞にトランスフェクションし、各種抗Glypican-1抗体との反応性をFACSにより解析した。その結果、#7(1-28)と#19(2-70)の2クローンにおいて、FACSでの反応性が消失していたことから、#7(1-28)と#19(2-70)のエピトープは33-61番目の領域に存在すると考えられた(図16A、図16B)。
SCIDマウス(6週齢、メス)皮下に食道扁平上皮癌細胞株E14を2x106cells/100μl(PBS:マトリゲル=1:1)で移植した。移植後14日目にマウスを2群に分け、抗GPC1抗体#4(1-12)、抗GPC1抗体#19(2-70)あるいはisotypecontrol抗体(MouseIgG2a、M7769、Sigma)を10mg/kg週2回の頻度で計6回、腹腔内に投与した(図18)。TE14移植マウスは抗体投与開始後24日目に解剖し、腫瘍重量も計測した。腫瘍体積=長径x短径x短径x0.5より計算した。
NOD/SCIDマウス(6週齢、メス)皮下に食道扁平上皮癌細胞株TE14を2x106cells/100μl (PBS:マトリゲル=1:1)で移植した。移植後14日目にマウスを2群に分け、抗GPC1抗体#4(1-12)、抗GPC1抗体#19(2-70)あるいはisotypecontrol抗体(MouseIgG2a、M7769、Sigma)を10mg/kg週2回の頻度で計6回、腹腔内に投与した。TE14移植マウスは抗体投与開始後24日目に解剖し、腫瘍重量も計測した。腫瘍体積=長径x短径x短径x0.5より計算した。
SCIDマウス(6週齢、メス)皮下にGPC1陰性の肺扁平上皮癌細胞株であるLK2に2×106cells/100μl(PBS:マトリゲル=1:1)で移植した。移植後14日目にマウスを2群に分け、抗GPC1抗体(#1-12)あるいはisotype control抗体(MouseIgG2a、M7769、Sigma)を1週2回の頻度で計6回、腹腔内に投与した(図23)。マウスは抗体投与開始後24目に解剖し、腫瘍重量も計測した。腫瘍体積=長径x短径x短径x0.5より計算した。
抗Glypican-1抗体#4(1-12)はマウスGlypican-1とも交差反応を示すため、マウスに投与したときの急性毒性試験を実施した。C57BL/6J(8w)マウスの雄、雌それぞれにマウスIgG2a(Sigma,M7769)あるいは抗Glypican-1抗体 #4(1-12)を1mg腹腔内投与し、7日目にマウスを解剖し、脳、心臓、腎臓、肝臓、肺、脾臓を摘出しHE染色による病理解析を実施した。また、採血を行い、自動血球計測装置(VetScanHMII)、動物用生化学血液分析器(VetScanVS2)を用いて解析した(図26)。その結果、血球数のデータにおいて両者に有意な変化は認められなかった(図27、図28)。同様に血液生化学データにおいても両者に有意な変化は認められなかった(図29、図30)。このことから抗LSR抗体#1-25は毒性が少なく安全性が高いことが示唆された。
配列番号2:ヒトGlypican-1タンパク質配列(P35052)
配列番号3:抗GPC−1抗体1−4配列
配列番号4:抗GPC−1抗体1−5配列
配列番号5:抗GPC−1抗体1−10配列
配列番号6:抗GPC−1抗体1−12配列
配列番号7:抗GPC−1抗体1−18配列
配列番号8:抗GPC−1抗体1−27配列
配列番号9:抗GPC−1抗体1−28配列
配列番号10:抗GPC−1抗体1−30配列
配列番号11:抗GPC−1抗体1−50配列
配列番号12:抗GPC−1抗体1−57配列
配列番号13:抗GPC−1抗体1−66配列
配列番号14:抗GPC−1抗体1−77配列
配列番号15:抗GPC−1抗体1−91配列
配列番号16:抗GPC−1抗体2−11配列
配列番号17:抗GPC−1抗体2−14配列
配列番号18:抗GPC−1抗体2−57配列
配列番号19:抗GPC−1抗体2−60配列
配列番号20:抗GPC−1抗体2−63配列
配列番号21:抗GPC−1抗体2−70配列
配列番号22:抗GPC−1抗体2−77配列
配列番号23:Glypican-1 siRNAコア配列(ガイド配列)のセンス鎖配列
配列番号24:Glypican-1 siRNAコア配列(ガイド配列)のアンチセンス鎖配列
配列番号25:Glypican-1 siRNAセンス鎖全長配列
配列番号26:Glypican-1 siRNAアンチセンス鎖全長配列
配列番号27:GPC−1フォワードプライマー配列
配列番号28:GPC−1リバースプライマー配列
配列番号29:GAPDHフォワードプライマー配列
配列番号30:GAPDHリバースプライマー配列
配列番号31:βアクチンフォワードプライマー配列
配列番号32:βアクチンリバースプライマー配列
Claims (11)
- Glypican-1遺伝子またはその発現産物に結合する物質を含む、食道がんを識別するための検出剤であって、該物質は、配列番号2の33〜61位、または、339〜358位および388〜421位、または430〜530位をエピトープとして有する抗Glypican-1抗体またはその抗原結合フラグメント、あるいはGlypican-1をコードする核酸にハイブリダイズする核酸である、検出剤。
- 前記物質は、標識されたものである、請求項1に記載の検出剤。
- 前記Glypican−1遺伝子またはその発現産物は、配列番号1(核酸配列)または配列番号2(アミノ酸配列)である、請求項1または2に記載の検出剤。
- 前記物質は、抗体またはそのフラグメントであり、該抗体は以下:
(a)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号3の31〜35位、50〜65位、98〜114位、163〜170位、187〜193位、および226〜235位で示されるアミノ酸配列を含む抗体、
(b)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号4の31〜35位、50〜66位、99〜110位、159〜166位、183〜187位、および222〜231位で示されるアミノ酸配列を含む抗体、
(c)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号5の31〜35位、50〜66位、99〜113位、162〜170位、187〜193位、および226〜237位で示されるアミノ酸配列を含む抗体、
(d)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号6の31〜35位、51〜66位、99〜112位、160〜170位、187〜193位、および226〜236位で示されるアミノ酸配列を含む抗体、
(e)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号7の31〜35位、50〜66位、99〜120位、169〜176位、193〜199位、および232〜242位で示されるアミノ酸配列を含む抗体、
(f)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号8の31〜35位、50〜65位、98〜114位、163〜170位、187〜193位、および226〜235位で示されるアミノ酸配列を含む抗体、
(g)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号9の31〜35位、50〜66位、99〜120位、169〜176位、193〜199位、および232〜241位で示されるアミノ酸配列を含む抗体、
(h)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号10の31〜35位、50〜65位、98〜113位、162〜171位、188〜194位、および227〜237位で示されるアミノ酸配列を含む抗体、
(i)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号11の31〜35位、50〜65位、98〜114位、163〜170位、187〜193位、および226〜235位で示されるアミノ酸配列を含む抗体、
(j)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号12の31〜35位、50〜66位、99〜113位、162〜169位、186〜192位、および225〜234位で示されるアミノ酸配列を含む抗体、
(k)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号13の31〜35位、50〜66位、99〜116位、165〜174位、191〜197位、および230〜240位で示されるアミノ酸配列を含む抗体、
(l)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号14の31〜35位、50〜66位、99〜113位、162〜169位、186〜192位、および225〜235位で示されるアミノ酸配列を含む抗体、
(m)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号15の31〜35位、50〜66位、99〜113位、162〜170位、187〜193位、および226〜236位で示されるアミノ酸配列を含む抗体、
(n)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号16の31〜35位、50〜66位、99〜110位、159〜166位、183〜189位、および222〜237で示されるアミノ酸配列を含む抗体、
(o)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号17の31〜35位、50〜65位、98〜113位、162〜171位、188〜194位、および227〜237位で示されるアミノ酸配列を含む抗体、
(p)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号18の31〜35位、50〜66位、99〜116位、165〜174位、191〜197位、および230〜240位で示されるアミノ酸配列を含む抗体、
(q)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号19の31〜35位、50〜66位、99〜115位、164〜175位、193〜199位、および232〜241位で示されるアミノ酸配列を含む抗体、
(r)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号20の31〜35位、50〜66位、99〜117位、166〜177位、194〜200位、および233〜242位で示されるアミノ酸配列を含む抗体、
(s)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号21の32〜36位、51〜67位、100〜114位、163〜171位、188〜194位、および227〜236位で示されるアミノ酸配列を含む抗体、および
(t)重鎖CDR1、2、3、軽鎖CDR1、2、および3が、それぞれ配列番号22の31〜35位、50〜65位、98〜114位、163〜170位、187〜193位、および226〜235位で示されるアミノ酸配列を含む抗体、
からなる群から選ばれる1種以上の抗体、あるいは該抗体の変異体であって、該変異体において該抗体のフレームワークに1または数個の置換、付加もしくは欠失を含むが、該CDRには変異を含まない、変異体を有することを特徴とする、請求項1〜3のいずれか一項に記載の検出剤。 - 前記物質は、核酸であり、該核酸はプローブまたはプライマーである、請求項1〜4のいずれか一項に記載の検出剤。
- 前記プローブまたはプライマーは、配列番号1に記載の核酸配列またはその相補鎖あるいはその変異体の断片である、請求項5に記載の検出剤。
- 前記プローブまたはプライマーは、配列番号25および/または26を有することを特徴とする、請求項6に記載の検出剤。
- 前記食道がんはリンパ節転移部位のもの、扁平上皮癌および/または腺癌を含む、請求項1〜7のいずれか一項に記載の検出剤。
- Glypican-1遺伝子またはその発現産物を、食道がんを識別する指標とする方法であって、該方法は、請求項1〜8のいずれか一項に記載の検出剤を用いて、該Glypican-1遺伝子またはその発現産物を検出する工程を含む、方法。
- 前記食道がんはリンパ節転移部位のもの、扁平上皮癌および/または腺癌を含む、請求項9に記載の方法。
- 対象検体のGlypican-1遺伝子の発現が正常検体のものに比べて上昇している場合、該対象検体は食道がんを有することを示す、請求項9または10に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2013272085 | 2013-12-27 | ||
JP2013272085 | 2013-12-27 | ||
PCT/JP2014/006455 WO2015098112A1 (ja) | 2013-12-27 | 2014-12-25 | 食道がんのマーカーおよびその利用 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017088418A Division JP6500933B2 (ja) | 2013-12-27 | 2017-04-27 | 食道がんのマーカーおよびその利用 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPWO2015098112A1 JPWO2015098112A1 (ja) | 2017-03-23 |
JP6455935B2 true JP6455935B2 (ja) | 2019-01-23 |
Family
ID=53478008
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015554576A Active JP6455935B2 (ja) | 2013-12-27 | 2014-12-25 | 食道がんのマーカーおよびその利用 |
JP2017088418A Active JP6500933B2 (ja) | 2013-12-27 | 2017-04-27 | 食道がんのマーカーおよびその利用 |
JP2018038672A Active JP6606793B2 (ja) | 2013-12-27 | 2018-03-05 | 食道がんのマーカーおよびその利用 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017088418A Active JP6500933B2 (ja) | 2013-12-27 | 2017-04-27 | 食道がんのマーカーおよびその利用 |
JP2018038672A Active JP6606793B2 (ja) | 2013-12-27 | 2018-03-05 | 食道がんのマーカーおよびその利用 |
Country Status (3)
Country | Link |
---|---|
US (3) | US10077316B2 (ja) |
JP (3) | JP6455935B2 (ja) |
WO (1) | WO2015098112A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023022090A1 (ja) | 2021-08-17 | 2023-02-23 | 慶應義塾 | 遺伝子改変t細胞集団の製造方法 |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016208754A1 (ja) * | 2015-06-24 | 2016-12-29 | 学校法人慶應義塾 | 抗グリピカン-1-免疫抗原受容体 |
WO2017023138A1 (ko) * | 2015-08-05 | 2017-02-09 | 주식회사 유영제약 | 키메라 항원 수용체 및 키메라 항원 수용체가 발현된 t 세포 |
KR101657033B1 (ko) * | 2016-03-25 | 2016-09-13 | 성균관대학교산학협력단 | V-ATPase subunit V1E1의 단백질 발현 수준을 측정하여 식도암 환자의 생존율과 예후를 예측하는 방법 |
KR101926834B1 (ko) * | 2017-03-21 | 2018-12-07 | 동아에스티 주식회사 | 항-dr5 항체 및 그의 용도 |
US20200308299A1 (en) * | 2017-04-28 | 2020-10-01 | National University Corporation Kochi University | Anti-gpc-1 antibody |
EP3883971A1 (en) * | 2019-01-22 | 2021-09-29 | The United States of America, as represented by the Secretary, Department of Health and Human Services | High affinity monoclonal antibodies targeting glypican-1 and methods of use |
WO2021019944A1 (ja) | 2019-07-29 | 2021-02-04 | 公立大学法人名古屋市立大学 | 食道癌バイオマーカー及びその用途 |
AU2021246922A1 (en) * | 2020-03-30 | 2022-10-20 | Crystal Bioscience Inc. | Anti-GIPR antibody and methods of use thereof |
WO2021251459A1 (ja) | 2020-06-11 | 2021-12-16 | 国立大学法人高知大学 | ヒト化抗gpc-1抗体 |
CN114213532B (zh) * | 2021-12-13 | 2023-06-13 | 东北农业大学 | 高亲和力的抗鸡传染性法氏囊病毒的scFv抗体的制备及其应用 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7108986B2 (en) * | 1998-10-16 | 2006-09-19 | The Regents Of The University Of California | Glypican-1 in human breast cancer |
US20040226056A1 (en) * | 1998-12-22 | 2004-11-11 | Myriad Genetics, Incorporated | Compositions and methods for treating neurological disorders and diseases |
US20070054332A1 (en) * | 2005-08-10 | 2007-03-08 | Alan Rapraeger | Syndecan 1 ectodomain inhibits cancer |
CN101616684A (zh) | 2007-02-02 | 2009-12-30 | 诺瓦提斯公司 | 用于治疗骨相关病症的硬化蛋白结合配偶体调节剂 |
US20100291091A1 (en) * | 2007-07-30 | 2010-11-18 | ONCOTHERAPY SCIENCE ,inc. | Cancer associated gene ly6k |
US8168586B1 (en) * | 2007-11-21 | 2012-05-01 | Celera Corporation | Cancer targets and uses thereof |
JP5403534B2 (ja) * | 2008-10-29 | 2014-01-29 | インフォコム株式会社 | 食道癌の予後予測のための情報を提供する方法 |
WO2010074049A1 (ja) * | 2008-12-22 | 2010-07-01 | 株式会社 未来創薬研究所 | 抗hs6st2抗体及びその用途 |
JP2014515759A (ja) * | 2011-04-29 | 2014-07-03 | ノバルティス アーゲー | 扁平上皮がんを治療する方法関連出願 |
-
2014
- 2014-12-25 WO PCT/JP2014/006455 patent/WO2015098112A1/ja active Application Filing
- 2014-12-25 JP JP2015554576A patent/JP6455935B2/ja active Active
- 2014-12-25 US US15/108,251 patent/US10077316B2/en active Active
-
2017
- 2017-04-27 JP JP2017088418A patent/JP6500933B2/ja active Active
-
2018
- 2018-03-05 JP JP2018038672A patent/JP6606793B2/ja active Active
- 2018-08-14 US US16/103,840 patent/US20180362658A1/en not_active Abandoned
-
2021
- 2021-06-30 US US17/364,531 patent/US20210340275A1/en not_active Abandoned
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023022090A1 (ja) | 2021-08-17 | 2023-02-23 | 慶應義塾 | 遺伝子改変t細胞集団の製造方法 |
Also Published As
Publication number | Publication date |
---|---|
JP2017186343A (ja) | 2017-10-12 |
JPWO2015098112A1 (ja) | 2017-03-23 |
WO2015098112A1 (ja) | 2015-07-02 |
US20210340275A1 (en) | 2021-11-04 |
JP6606793B2 (ja) | 2019-11-20 |
JP2018123136A (ja) | 2018-08-09 |
US10077316B2 (en) | 2018-09-18 |
US20170066836A1 (en) | 2017-03-09 |
JP6500933B2 (ja) | 2019-04-17 |
US20180362658A1 (en) | 2018-12-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6606793B2 (ja) | 食道がんのマーカーおよびその利用 | |
JP6564408B2 (ja) | S100a4抗体およびその治療上の使用 | |
JP2022174167A (ja) | Ror1癌の治療および転移の阻害に使用するための抗体およびワクチン | |
US9316654B2 (en) | TAZ/WWTR1 for diagnosis and treatment of cancer | |
US20200308299A1 (en) | Anti-gpc-1 antibody | |
US20190023781A1 (en) | Therapeutic drug for malignant tumors | |
EP2682475A1 (en) | Antibody and antigen recognizing tumor-initiating cells and use thereof | |
AU2005248351A1 (en) | Methods for treating cancer using anti-Wnt2 monoclonal antibodies and siRNA | |
US20090010931A1 (en) | Compositions and methods for restoring sensitivity to treatment with her2 antagonists | |
JP2011530283A (ja) | がんの診断および治療のためのvhz | |
KR101906558B1 (ko) | Tspan8에 특이적인 신규 항체 및 이의 용도 | |
WO2006123829A1 (ja) | PAP2aに対する抗体ならびにその診断的および治療的使用 | |
WO2005121338A1 (ja) | 抗perp抗体 | |
KR102264305B1 (ko) | 인산화된 베타-카테닌에 특이적으로 결합하는 항체 및 이의 용도 | |
KR20210126057A (ko) | 암세포에 존재하는 케라틴 14(krt14)의 세포외 부분을 표적화함으로써 암을 치료하거나 예방하는 방법 | |
WO2024101382A1 (ja) | 免疫チェックポイントの調節に用いるための組成物 | |
US20210164982A1 (en) | Pharmaceutical use of actinin-4 involved in induction of cervical cancer |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160616 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20160616 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20170302 |
|
A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20170424 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170427 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20170905 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20171117 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20171117 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20171128 |
|
C21 | Notice of transfer of a case for reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C21 Effective date: 20171129 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20180112 |
|
C211 | Notice of termination of reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C211 Effective date: 20180116 |
|
C22 | Notice of designation (change) of administrative judge |
Free format text: JAPANESE INTERMEDIATE CODE: C22 Effective date: 20180423 |
|
C13 | Notice of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: C13 Effective date: 20180831 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20181026 |
|
C23 | Notice of termination of proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C23 Effective date: 20181106 |
|
C03 | Trial/appeal decision taken |
Free format text: JAPANESE INTERMEDIATE CODE: C03 Effective date: 20181129 |
|
C30A | Notification sent |
Free format text: JAPANESE INTERMEDIATE CODE: C3012 Effective date: 20181129 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20181214 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6455935 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 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: R3D04 |
|
RD03 | Notification of appointment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: R3D03 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: R3D04 |