JP2017524337A - 急性骨髄性白血病(aml)などの血液のいくつかの腫瘍に対する新規免疫療法 - Google Patents
急性骨髄性白血病(aml)などの血液のいくつかの腫瘍に対する新規免疫療法 Download PDFInfo
- Publication number
- JP2017524337A JP2017524337A JP2016567242A JP2016567242A JP2017524337A JP 2017524337 A JP2017524337 A JP 2017524337A JP 2016567242 A JP2016567242 A JP 2016567242A JP 2016567242 A JP2016567242 A JP 2016567242A JP 2017524337 A JP2017524337 A JP 2017524337A
- Authority
- JP
- Japan
- Prior art keywords
- seq
- peptide
- cells
- tumor
- hla
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 203
- 208000031261 Acute myeloid leukaemia Diseases 0.000 title claims description 137
- 238000009169 immunotherapy Methods 0.000 title abstract description 12
- 210000004369 blood Anatomy 0.000 title description 8
- 239000008280 blood Substances 0.000 title description 8
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 565
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 272
- 210000004027 cell Anatomy 0.000 claims abstract description 193
- 241000282414 Homo sapiens Species 0.000 claims abstract description 79
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 claims abstract description 66
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 51
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 48
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 48
- 229960005486 vaccine Drugs 0.000 claims abstract description 33
- 108090000623 proteins and genes Proteins 0.000 claims description 150
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 129
- 102000004169 proteins and genes Human genes 0.000 claims description 114
- 238000000034 method Methods 0.000 claims description 112
- 108091007433 antigens Proteins 0.000 claims description 107
- 102000036639 antigens Human genes 0.000 claims description 107
- 239000000427 antigen Substances 0.000 claims description 106
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 claims description 105
- 108700018351 Major Histocompatibility Complex Proteins 0.000 claims description 104
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 89
- 230000014509 gene expression Effects 0.000 claims description 70
- 239000003446 ligand Substances 0.000 claims description 63
- 230000027455 binding Effects 0.000 claims description 62
- 150000001413 amino acids Chemical class 0.000 claims description 60
- 201000011510 cancer Diseases 0.000 claims description 49
- 108020004414 DNA Proteins 0.000 claims description 45
- 108091008874 T cell receptors Proteins 0.000 claims description 42
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 40
- 238000000338 in vitro Methods 0.000 claims description 40
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 claims description 36
- 210000000612 antigen-presenting cell Anatomy 0.000 claims description 34
- 239000013604 expression vector Substances 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 28
- 238000004519 manufacturing process Methods 0.000 claims description 28
- 230000005847 immunogenicity Effects 0.000 claims description 23
- 230000005867 T cell response Effects 0.000 claims description 21
- 108010058597 HLA-DR Antigens Proteins 0.000 claims description 20
- 102000006354 HLA-DR Antigens Human genes 0.000 claims description 20
- -1 MYCH2 Proteins 0.000 claims description 19
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 17
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 17
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 17
- 108020001507 fusion proteins Proteins 0.000 claims description 17
- 102000037865 fusion proteins Human genes 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 210000004443 dendritic cell Anatomy 0.000 claims description 14
- 229940079593 drug Drugs 0.000 claims description 13
- 102000004127 Cytokines Human genes 0.000 claims description 11
- 108090000695 Cytokines Proteins 0.000 claims description 11
- 238000011510 Elispot assay Methods 0.000 claims description 11
- 238000003114 enzyme-linked immunosorbent spot assay Methods 0.000 claims description 11
- 238000001727 in vivo Methods 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 238000010186 staining Methods 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000002299 complementary DNA Substances 0.000 claims description 10
- 230000035772 mutation Effects 0.000 claims description 10
- 238000004949 mass spectrometry Methods 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 230000002018 overexpression Effects 0.000 claims description 9
- 229940023041 peptide vaccine Drugs 0.000 claims description 8
- 102100027279 FAS-associated factor 1 Human genes 0.000 claims description 7
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 claims description 7
- 230000003834 intracellular effect Effects 0.000 claims description 7
- 238000003556 assay Methods 0.000 claims description 6
- 230000002147 killing effect Effects 0.000 claims description 6
- 102100028796 Chromosome transmission fidelity protein 18 homolog Human genes 0.000 claims description 5
- 102100040792 DNA primase small subunit Human genes 0.000 claims description 5
- 102100023526 Deubiquitinating protein VCPIP1 Human genes 0.000 claims description 5
- 101000916387 Homo sapiens Chromosome transmission fidelity protein 18 homolog Proteins 0.000 claims description 5
- 101000611567 Homo sapiens DNA primase small subunit Proteins 0.000 claims description 5
- 101000622317 Homo sapiens Deubiquitinating protein VCPIP1 Proteins 0.000 claims description 5
- 230000006698 induction Effects 0.000 claims description 5
- 108010028930 invariant chain Proteins 0.000 claims description 5
- 102100033568 Acyl-CoA-binding domain-containing protein 6 Human genes 0.000 claims description 4
- 101000801610 Homo sapiens Acyl-CoA-binding domain-containing protein 6 Proteins 0.000 claims description 4
- 101000788412 Homo sapiens Probable methyltransferase TARBP1 Proteins 0.000 claims description 4
- 102100025214 Probable methyltransferase TARBP1 Human genes 0.000 claims description 4
- 230000004913 activation Effects 0.000 claims description 4
- 238000012258 culturing Methods 0.000 claims description 4
- 238000010195 expression analysis Methods 0.000 claims description 4
- 239000001963 growth medium Substances 0.000 claims description 4
- 238000002493 microarray Methods 0.000 claims description 4
- 125000001433 C-terminal amino-acid group Chemical group 0.000 claims description 3
- 102100023571 Zinc finger protein 131 Human genes 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 210000004899 c-terminal region Anatomy 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000012163 sequencing technique Methods 0.000 claims description 3
- 102100028801 Calsyntenin-1 Human genes 0.000 claims description 2
- 102100039607 Erlin-1 Human genes 0.000 claims description 2
- 101000799853 Homo sapiens Alpha-1B-glycoprotein Proteins 0.000 claims description 2
- 101000916423 Homo sapiens Calsyntenin-1 Proteins 0.000 claims description 2
- 101000814010 Homo sapiens Erlin-1 Proteins 0.000 claims description 2
- 101001030591 Homo sapiens Mitochondrial ubiquitin ligase activator of NFKB 1 Proteins 0.000 claims description 2
- 101000640231 Homo sapiens Protein SDA1 homolog Proteins 0.000 claims description 2
- 101000607829 Homo sapiens Queuine tRNA-ribosyltransferase accessory subunit 2 Proteins 0.000 claims description 2
- 101000976574 Homo sapiens Zinc finger protein 131 Proteins 0.000 claims description 2
- 102100038531 Mitochondrial ubiquitin ligase activator of NFKB 1 Human genes 0.000 claims description 2
- 102100033960 Protein SDA1 homolog Human genes 0.000 claims description 2
- 102100039899 Queuine tRNA-ribosyltransferase accessory subunit 2 Human genes 0.000 claims description 2
- 108010055623 S-Phase Kinase-Associated Proteins Proteins 0.000 claims description 2
- 102000000341 S-Phase Kinase-Associated Proteins Human genes 0.000 claims description 2
- 230000003213 activating effect Effects 0.000 claims description 2
- 229920002477 rna polymer Polymers 0.000 claims description 2
- 238000012070 whole genome sequencing analysis Methods 0.000 claims description 2
- 102100021283 1-aminocyclopropane-1-carboxylate synthase-like protein 1 Human genes 0.000 claims 1
- 102100023779 40S ribosomal protein S5 Human genes 0.000 claims 1
- 102100027787 ATP synthase subunit g, mitochondrial Human genes 0.000 claims 1
- 102100022423 ATP-dependent RNA helicase DHX33 Human genes 0.000 claims 1
- 102100029457 Adenine phosphoribosyltransferase Human genes 0.000 claims 1
- 108010024223 Adenine phosphoribosyltransferase Proteins 0.000 claims 1
- 102100033326 Alpha-1B-glycoprotein Human genes 0.000 claims 1
- 102100033658 Alpha-globin transcription factor CP2 Human genes 0.000 claims 1
- 102100040038 Amyloid beta precursor like protein 2 Human genes 0.000 claims 1
- 102100027139 Ankyrin repeat and SAM domain-containing protein 1A Human genes 0.000 claims 1
- 102100026444 Arrestin domain-containing protein 1 Human genes 0.000 claims 1
- 102100030009 Azurocidin Human genes 0.000 claims 1
- 102100036597 Basement membrane-specific heparan sulfate proteoglycan core protein Human genes 0.000 claims 1
- 102100026349 Beta-1,4-galactosyltransferase 1 Human genes 0.000 claims 1
- 102100032487 Beta-mannosidase Human genes 0.000 claims 1
- 101000891022 Borrelia burgdorferi (strain ATCC 35210 / B31 / CIP 102532 / DSM 4680) Flagellar filament 41 kDa core protein Proteins 0.000 claims 1
- 102100026094 C-type lectin domain family 12 member A Human genes 0.000 claims 1
- 102100021703 C3a anaphylatoxin chemotactic receptor Human genes 0.000 claims 1
- 102100029876 Capping protein, Arp2/3 and myosin-I linker protein 2 Human genes 0.000 claims 1
- 102100026679 Carboxypeptidase Q Human genes 0.000 claims 1
- 102100032920 Chromobox protein homolog 2 Human genes 0.000 claims 1
- 102100031239 Chromodomain-helicase-DNA-binding protein 1-like Human genes 0.000 claims 1
- 102100023661 Coiled-coil domain-containing protein 115 Human genes 0.000 claims 1
- 102100033601 Collagen alpha-1(I) chain Human genes 0.000 claims 1
- 102100033855 Complex I assembly factor TMEM126B, mitochondrial Human genes 0.000 claims 1
- 102100028233 Coronin-1A Human genes 0.000 claims 1
- 102100038252 Cyclin-G1 Human genes 0.000 claims 1
- 102100035186 DNA excision repair protein ERCC-1 Human genes 0.000 claims 1
- 102100031230 DNA topoisomerase I, mitochondrial Human genes 0.000 claims 1
- 101100214821 Danio rerio abhd2a gene Proteins 0.000 claims 1
- 102100036727 Deformed epidermal autoregulatory factor 1 homolog Human genes 0.000 claims 1
- 102100030220 Diacylglycerol kinase zeta Human genes 0.000 claims 1
- 102100024108 Dystrophin Human genes 0.000 claims 1
- 102100027414 E3 ubiquitin-protein ligase RNF19B Human genes 0.000 claims 1
- 102100032064 EMILIN-2 Human genes 0.000 claims 1
- 102100021799 ER degradation-enhancing alpha-mannosidase-like protein 2 Human genes 0.000 claims 1
- 102100035074 Elongator complex protein 3 Human genes 0.000 claims 1
- 102100031862 Endoplasmic reticulum-Golgi intermediate compartment protein 1 Human genes 0.000 claims 1
- 102100039328 Endoplasmin Human genes 0.000 claims 1
- 102100036089 Fascin Human genes 0.000 claims 1
- 102100026545 Fibronectin type III domain-containing protein 3B Human genes 0.000 claims 1
- 102100039956 Geminin Human genes 0.000 claims 1
- 102100034158 Golgin subfamily A member 7B Human genes 0.000 claims 1
- 102100039622 Granulocyte colony-stimulating factor receptor Human genes 0.000 claims 1
- 102100027490 H2.0-like homeobox protein Human genes 0.000 claims 1
- 102100033079 HLA class II histocompatibility antigen, DM alpha chain Human genes 0.000 claims 1
- 108010050568 HLA-DM antigens Proteins 0.000 claims 1
- 102100022695 Histidine ammonia-lyase Human genes 0.000 claims 1
- 101000675558 Homo sapiens 1-aminocyclopropane-1-carboxylate synthase-like protein 1 Proteins 0.000 claims 1
- 101000622644 Homo sapiens 40S ribosomal protein S5 Proteins 0.000 claims 1
- 101000936950 Homo sapiens ATP synthase subunit g, mitochondrial Proteins 0.000 claims 1
- 101000901934 Homo sapiens ATP-dependent RNA helicase DHX33 Proteins 0.000 claims 1
- 101000800875 Homo sapiens Alpha-globin transcription factor CP2 Proteins 0.000 claims 1
- 101000890401 Homo sapiens Amyloid beta precursor like protein 2 Proteins 0.000 claims 1
- 101000694621 Homo sapiens Ankyrin repeat and SAM domain-containing protein 1A Proteins 0.000 claims 1
- 101000785762 Homo sapiens Arrestin domain-containing protein 1 Proteins 0.000 claims 1
- 101000785776 Homo sapiens Artemin Proteins 0.000 claims 1
- 101000793686 Homo sapiens Azurocidin Proteins 0.000 claims 1
- 101001000001 Homo sapiens Basement membrane-specific heparan sulfate proteoglycan core protein Proteins 0.000 claims 1
- 101000766145 Homo sapiens Beta-1,4-galactosyltransferase 1 Proteins 0.000 claims 1
- 101001016707 Homo sapiens Beta-mannosidase Proteins 0.000 claims 1
- 101000912622 Homo sapiens C-type lectin domain family 12 member A Proteins 0.000 claims 1
- 101000896583 Homo sapiens C3a anaphylatoxin chemotactic receptor Proteins 0.000 claims 1
- 101000793825 Homo sapiens Capping protein, Arp2/3 and myosin-I linker protein 2 Proteins 0.000 claims 1
- 101000910846 Homo sapiens Carboxypeptidase Q Proteins 0.000 claims 1
- 101000797586 Homo sapiens Chromobox protein homolog 2 Proteins 0.000 claims 1
- 101000777053 Homo sapiens Chromodomain-helicase-DNA-binding protein 1-like Proteins 0.000 claims 1
- 101000978267 Homo sapiens Coiled-coil domain-containing protein 115 Proteins 0.000 claims 1
- 101000640719 Homo sapiens Complex I assembly factor TMEM126B, mitochondrial Proteins 0.000 claims 1
- 101000860852 Homo sapiens Coronin-1A Proteins 0.000 claims 1
- 101000884191 Homo sapiens Cyclin-G1 Proteins 0.000 claims 1
- 101000876529 Homo sapiens DNA excision repair protein ERCC-1 Proteins 0.000 claims 1
- 101000929421 Homo sapiens Deformed epidermal autoregulatory factor 1 homolog Proteins 0.000 claims 1
- 101000864576 Homo sapiens Diacylglycerol kinase zeta Proteins 0.000 claims 1
- 101001053946 Homo sapiens Dystrophin Proteins 0.000 claims 1
- 101000921278 Homo sapiens EMILIN-2 Proteins 0.000 claims 1
- 101000895713 Homo sapiens ER degradation-enhancing alpha-mannosidase-like protein 2 Proteins 0.000 claims 1
- 101000877382 Homo sapiens Elongator complex protein 3 Proteins 0.000 claims 1
- 101000920804 Homo sapiens Endoplasmic reticulum-Golgi intermediate compartment protein 1 Proteins 0.000 claims 1
- 101000812663 Homo sapiens Endoplasmin Proteins 0.000 claims 1
- 101000914654 Homo sapiens FAS-associated factor 1 Proteins 0.000 claims 1
- 101001021925 Homo sapiens Fascin Proteins 0.000 claims 1
- 101000913642 Homo sapiens Fibronectin type III domain-containing protein 3B Proteins 0.000 claims 1
- 101000886596 Homo sapiens Geminin Proteins 0.000 claims 1
- 101001070504 Homo sapiens Golgin subfamily A member 7B Proteins 0.000 claims 1
- 101000746364 Homo sapiens Granulocyte colony-stimulating factor receptor Proteins 0.000 claims 1
- 101001081101 Homo sapiens H2.0-like homeobox protein Proteins 0.000 claims 1
- 101001044626 Homo sapiens Histidine ammonia-lyase Proteins 0.000 claims 1
- 101000994369 Homo sapiens Integrin alpha-5 Proteins 0.000 claims 1
- 101001027631 Homo sapiens Kinesin-like protein KIF20B Proteins 0.000 claims 1
- 101001050567 Homo sapiens Kinesin-like protein KIF2C Proteins 0.000 claims 1
- 101001139146 Homo sapiens Krueppel-like factor 2 Proteins 0.000 claims 1
- 101001090713 Homo sapiens L-lactate dehydrogenase A chain Proteins 0.000 claims 1
- 101001065536 Homo sapiens LYR motif-containing protein 1 Proteins 0.000 claims 1
- 101001138062 Homo sapiens Leukocyte-associated immunoglobulin-like receptor 1 Proteins 0.000 claims 1
- 101000608935 Homo sapiens Leukosialin Proteins 0.000 claims 1
- 101001059429 Homo sapiens MAP/microtubule affinity-regulating kinase 3 Proteins 0.000 claims 1
- 101000958390 Homo sapiens Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA Proteins 0.000 claims 1
- 101000578830 Homo sapiens Methionine aminopeptidase 1 Proteins 0.000 claims 1
- 101000869796 Homo sapiens Microprocessor complex subunit DGCR8 Proteins 0.000 claims 1
- 101000929655 Homo sapiens Monoacylglycerol lipase ABHD2 Proteins 0.000 claims 1
- 101001128431 Homo sapiens Myeloid-derived growth factor Proteins 0.000 claims 1
- 101000886220 Homo sapiens N-acetylgalactosaminyltransferase 7 Proteins 0.000 claims 1
- 101001090919 Homo sapiens N-acylglucosamine 2-epimerase Proteins 0.000 claims 1
- 101000973439 Homo sapiens NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial Proteins 0.000 claims 1
- 101001072765 Homo sapiens Neutral alpha-glucosidase AB Proteins 0.000 claims 1
- 101000981336 Homo sapiens Nibrin Proteins 0.000 claims 1
- 101001007862 Homo sapiens Nuclear pore complex protein Nup85 Proteins 0.000 claims 1
- 101000578361 Homo sapiens Nucleolar complex protein 4 homolog Proteins 0.000 claims 1
- 101000981502 Homo sapiens Pantothenate kinase 2, mitochondrial Proteins 0.000 claims 1
- 101000603761 Homo sapiens Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase Proteins 0.000 claims 1
- 101000728117 Homo sapiens Plasma membrane calcium-transporting ATPase 4 Proteins 0.000 claims 1
- 101001094868 Homo sapiens Plexin-D1 Proteins 0.000 claims 1
- 101000829538 Homo sapiens Polypeptide N-acetylgalactosaminyltransferase 15 Proteins 0.000 claims 1
- 101000610110 Homo sapiens Pre-B-cell leukemia transcription factor 2 Proteins 0.000 claims 1
- 101000874142 Homo sapiens Probable ATP-dependent RNA helicase DDX46 Proteins 0.000 claims 1
- 101000859935 Homo sapiens Protein CREG1 Proteins 0.000 claims 1
- 101000653788 Homo sapiens Protein S100-A11 Proteins 0.000 claims 1
- 101000864298 Homo sapiens Protein SLX4IP Proteins 0.000 claims 1
- 101000981715 Homo sapiens Protein lifeguard 4 Proteins 0.000 claims 1
- 101001122471 Homo sapiens Protein orai-3 Proteins 0.000 claims 1
- 101000920560 Homo sapiens Putative endoplasmin-like protein Proteins 0.000 claims 1
- 101001019136 Homo sapiens Putative methyltransferase-like protein 7A Proteins 0.000 claims 1
- 101000717459 Homo sapiens RCC1 and BTB domain-containing protein 2 Proteins 0.000 claims 1
- 101000725943 Homo sapiens RNA polymerase II subunit A C-terminal domain phosphatase Proteins 0.000 claims 1
- 101000687317 Homo sapiens RNA-binding motif protein, X chromosome Proteins 0.000 claims 1
- 101000945093 Homo sapiens Ribosomal protein S6 kinase alpha-4 Proteins 0.000 claims 1
- 101000880431 Homo sapiens Serine/threonine-protein kinase 4 Proteins 0.000 claims 1
- 101000987297 Homo sapiens Serine/threonine-protein kinase PAK 4 Proteins 0.000 claims 1
- 101000618118 Homo sapiens Speriolin-like protein Proteins 0.000 claims 1
- 101001131204 Homo sapiens Sulfhydryl oxidase 1 Proteins 0.000 claims 1
- 101000654486 Homo sapiens Suppressor of IKBKE 1 Proteins 0.000 claims 1
- 101000638745 Homo sapiens THO complex subunit 7 homolog Proteins 0.000 claims 1
- 101000715159 Homo sapiens Transcription initiation factor TFIID subunit 9 Proteins 0.000 claims 1
- 101000655536 Homo sapiens Transforming growth factor-beta receptor-associated protein 1 Proteins 0.000 claims 1
- 101000645417 Homo sapiens Transmembrane protein 164 Proteins 0.000 claims 1
- 101000830781 Homo sapiens Tropomyosin alpha-4 chain Proteins 0.000 claims 1
- 101000641003 Homo sapiens Tyrosine-tRNA ligase, cytoplasmic Proteins 0.000 claims 1
- 101000809513 Homo sapiens Ubiquitin recognition factor in ER-associated degradation protein 1 Proteins 0.000 claims 1
- 101000841505 Homo sapiens Uridine-cytidine kinase 2 Proteins 0.000 claims 1
- 101000854707 Homo sapiens VPS35 endosomal protein-sorting factor-like Proteins 0.000 claims 1
- 101000965705 Homo sapiens Volume-regulated anion channel subunit LRRC8D Proteins 0.000 claims 1
- 101000818806 Homo sapiens Zinc finger protein 264 Proteins 0.000 claims 1
- 101000802337 Homo sapiens Zinc finger protein 543 Proteins 0.000 claims 1
- 101000782294 Homo sapiens Zinc finger protein 638 Proteins 0.000 claims 1
- 101000976457 Homo sapiens Zinc finger protein 805 Proteins 0.000 claims 1
- 101000599046 Homo sapiens Zinc finger protein Eos Proteins 0.000 claims 1
- 101000723957 Homo sapiens Zinc finger protein with KRAB and SCAN domains 8 Proteins 0.000 claims 1
- 101000680450 Homo sapiens tRNA (adenine(37)-N6)-methyltransferase Proteins 0.000 claims 1
- 102100032817 Integrin alpha-5 Human genes 0.000 claims 1
- 102100037691 Kinesin-like protein KIF20B Human genes 0.000 claims 1
- 102100023424 Kinesin-like protein KIF2C Human genes 0.000 claims 1
- 102100020675 Krueppel-like factor 2 Human genes 0.000 claims 1
- 102100034671 L-lactate dehydrogenase A chain Human genes 0.000 claims 1
- 102100032135 LYR motif-containing protein 1 Human genes 0.000 claims 1
- 102100020943 Leukocyte-associated immunoglobulin-like receptor 1 Human genes 0.000 claims 1
- 102100028920 MAP/microtubule affinity-regulating kinase 3 Human genes 0.000 claims 1
- 102100038245 Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA Human genes 0.000 claims 1
- 102100030612 Mast cell carboxypeptidase A Human genes 0.000 claims 1
- 102100028379 Methionine aminopeptidase 1 Human genes 0.000 claims 1
- 102100032459 Microprocessor complex subunit DGCR8 Human genes 0.000 claims 1
- 102100036617 Monoacylglycerol lipase ABHD2 Human genes 0.000 claims 1
- 108091006676 Monovalent cation:proton antiporter-3 Proteins 0.000 claims 1
- 102100031789 Myeloid-derived growth factor Human genes 0.000 claims 1
- 102100034977 N-acylglucosamine 2-epimerase Human genes 0.000 claims 1
- 102100022195 NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial Human genes 0.000 claims 1
- 102100036592 Neutral alpha-glucosidase AB Human genes 0.000 claims 1
- 102100024403 Nibrin Human genes 0.000 claims 1
- 102100027582 Nuclear pore complex protein Nup85 Human genes 0.000 claims 1
- 102100027986 Nucleolar complex protein 4 homolog Human genes 0.000 claims 1
- 102100024127 Pantothenate kinase 2, mitochondrial Human genes 0.000 claims 1
- 102100038551 Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase Human genes 0.000 claims 1
- 108010068633 Perilipin-3 Proteins 0.000 claims 1
- 102000001486 Perilipin-3 Human genes 0.000 claims 1
- 102100029743 Plasma membrane calcium-transporting ATPase 4 Human genes 0.000 claims 1
- 102100035380 Plexin-D1 Human genes 0.000 claims 1
- 102100023229 Polypeptide N-acetylgalactosaminyltransferase 15 Human genes 0.000 claims 1
- 102100040168 Pre-B-cell leukemia transcription factor 2 Human genes 0.000 claims 1
- 102100035725 Probable ATP-dependent RNA helicase DDX46 Human genes 0.000 claims 1
- 102100031145 Probable low affinity copper uptake protein 2 Human genes 0.000 claims 1
- 102100027796 Protein CREG1 Human genes 0.000 claims 1
- 102100029811 Protein S100-A11 Human genes 0.000 claims 1
- 102100029920 Protein SLX4IP Human genes 0.000 claims 1
- 102100024094 Protein lifeguard 4 Human genes 0.000 claims 1
- 102100027135 Protein orai-3 Human genes 0.000 claims 1
- 102100031916 Putative endoplasmin-like protein Human genes 0.000 claims 1
- 102100034758 Putative methyltransferase-like protein 7A Human genes 0.000 claims 1
- 102100020834 RCC1 and BTB domain-containing protein 2 Human genes 0.000 claims 1
- 102100027669 RNA polymerase II subunit A C-terminal domain phosphatase Human genes 0.000 claims 1
- 102100024939 RNA-binding motif protein, X chromosome Human genes 0.000 claims 1
- 108091007336 RNF19B Proteins 0.000 claims 1
- 102100033644 Ribosomal protein S6 kinase alpha-4 Human genes 0.000 claims 1
- 102100030681 SH3 and multiple ankyrin repeat domains protein 3 Human genes 0.000 claims 1
- 101710101741 SH3 and multiple ankyrin repeat domains protein 3 Proteins 0.000 claims 1
- 108091006567 SLC31A2 Proteins 0.000 claims 1
- 101001053942 Saccharolobus solfataricus (strain ATCC 35092 / DSM 1617 / JCM 11322 / P2) Diphosphomevalonate decarboxylase Proteins 0.000 claims 1
- 102100037629 Serine/threonine-protein kinase 4 Human genes 0.000 claims 1
- 102100027940 Serine/threonine-protein kinase PAK 4 Human genes 0.000 claims 1
- 102100021914 Speriolin-like protein Human genes 0.000 claims 1
- 102100034371 Sulfhydryl oxidase 1 Human genes 0.000 claims 1
- 101000930762 Sulfolobus acidocaldarius (strain ATCC 33909 / DSM 639 / JCM 8929 / NBRC 15157 / NCIMB 11770) Signal recognition particle receptor FtsY Proteins 0.000 claims 1
- 102100031446 Suppressor of IKBKE 1 Human genes 0.000 claims 1
- 102100031291 THO complex subunit 7 homolog Human genes 0.000 claims 1
- 101150106297 Top1mt gene Proteins 0.000 claims 1
- 102100036651 Transcription initiation factor TFIID subunit 9 Human genes 0.000 claims 1
- 102100032349 Transforming growth factor-beta receptor-associated protein 1 Human genes 0.000 claims 1
- 102100025765 Transmembrane protein 164 Human genes 0.000 claims 1
- 102100024944 Tropomyosin alpha-4 chain Human genes 0.000 claims 1
- 102100034298 Tyrosine-tRNA ligase, cytoplasmic Human genes 0.000 claims 1
- 102100038833 Ubiquitin recognition factor in ER-associated degradation protein 1 Human genes 0.000 claims 1
- 102100037111 Uracil-DNA glycosylase Human genes 0.000 claims 1
- 101710160987 Uracil-DNA glycosylase Proteins 0.000 claims 1
- 102100029150 Uridine-cytidine kinase 2 Human genes 0.000 claims 1
- 102100020777 VPS35 endosomal protein-sorting factor-like Human genes 0.000 claims 1
- 102100040987 Volume-regulated anion channel subunit LRRC8D Human genes 0.000 claims 1
- 102100021367 Zinc finger protein 264 Human genes 0.000 claims 1
- 102100034658 Zinc finger protein 543 Human genes 0.000 claims 1
- 102100035806 Zinc finger protein 638 Human genes 0.000 claims 1
- 102100023624 Zinc finger protein 805 Human genes 0.000 claims 1
- 102100037793 Zinc finger protein Eos Human genes 0.000 claims 1
- 102100028346 Zinc finger protein with KRAB and SCAN domains 8 Human genes 0.000 claims 1
- 108010029483 alpha 1 Chain Collagen Type I Proteins 0.000 claims 1
- 239000013256 coordination polymer Substances 0.000 claims 1
- 230000001747 exhibiting effect Effects 0.000 claims 1
- 238000011502 immune monitoring Methods 0.000 claims 1
- 102100022110 tRNA (adenine(37)-N6)-methyltransferase Human genes 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 37
- 210000004881 tumor cell Anatomy 0.000 abstract description 22
- 230000005975 antitumor immune response Effects 0.000 abstract description 6
- 238000002619 cancer immunotherapy Methods 0.000 abstract description 5
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 3
- 235000018102 proteins Nutrition 0.000 description 109
- 210000001519 tissue Anatomy 0.000 description 67
- 235000001014 amino acid Nutrition 0.000 description 56
- 229940024606 amino acid Drugs 0.000 description 55
- 229920001184 polypeptide Polymers 0.000 description 55
- 239000000523 sample Substances 0.000 description 44
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 40
- 239000013598 vector Substances 0.000 description 40
- 239000012634 fragment Substances 0.000 description 38
- 238000004458 analytical method Methods 0.000 description 35
- 108091054437 MHC class I family Proteins 0.000 description 30
- 238000011282 treatment Methods 0.000 description 28
- 230000000638 stimulation Effects 0.000 description 22
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 21
- 102100037850 Interferon gamma Human genes 0.000 description 21
- 108010074328 Interferon-gamma Proteins 0.000 description 21
- 102000043129 MHC class I family Human genes 0.000 description 21
- 125000000539 amino acid group Chemical group 0.000 description 21
- 238000006467 substitution reaction Methods 0.000 description 21
- 239000002671 adjuvant Substances 0.000 description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 20
- 201000010099 disease Diseases 0.000 description 19
- 230000028993 immune response Effects 0.000 description 19
- 108091054438 MHC class II family Proteins 0.000 description 18
- 238000009472 formulation Methods 0.000 description 18
- 208000020816 lung neoplasm Diseases 0.000 description 18
- 230000006870 function Effects 0.000 description 17
- 238000012986 modification Methods 0.000 description 17
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 16
- 201000005202 lung cancer Diseases 0.000 description 16
- 230000004048 modification Effects 0.000 description 16
- 102000040430 polynucleotide Human genes 0.000 description 16
- 108091033319 polynucleotide Proteins 0.000 description 16
- 239000002157 polynucleotide Substances 0.000 description 16
- 230000004044 response Effects 0.000 description 16
- 102100028972 HLA class I histocompatibility antigen, A alpha chain Human genes 0.000 description 15
- 108010075704 HLA-A Antigens Proteins 0.000 description 15
- 238000013459 approach Methods 0.000 description 15
- 230000002062 proliferating effect Effects 0.000 description 15
- 102000054766 genetic haplotypes Human genes 0.000 description 14
- 210000000987 immune system Anatomy 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 102000043131 MHC class II family Human genes 0.000 description 12
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 12
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 108010026552 Proteome Proteins 0.000 description 11
- 230000000692 anti-sense effect Effects 0.000 description 11
- 238000001514 detection method Methods 0.000 description 11
- 210000004698 lymphocyte Anatomy 0.000 description 11
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 10
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 10
- 108010038807 Oligopeptides Proteins 0.000 description 10
- 210000000265 leukocyte Anatomy 0.000 description 10
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 230000001105 regulatory effect Effects 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 239000000439 tumor marker Substances 0.000 description 10
- 102100036618 ATP-binding cassette sub-family A member 13 Human genes 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 102100035248 Alpha-(1,3)-fucosyltransferase 4 Human genes 0.000 description 9
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 9
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 9
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 9
- 101000929660 Homo sapiens ATP-binding cassette sub-family A member 13 Proteins 0.000 description 9
- 101001022185 Homo sapiens Alpha-(1,3)-fucosyltransferase 4 Proteins 0.000 description 9
- 101000577881 Homo sapiens Macrophage metalloelastase Proteins 0.000 description 9
- 108060003951 Immunoglobulin Proteins 0.000 description 9
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 9
- 108091028043 Nucleic acid sequence Proteins 0.000 description 9
- 108091034117 Oligonucleotide Proteins 0.000 description 9
- 102000015636 Oligopeptides Human genes 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 238000011161 development Methods 0.000 description 9
- 230000018109 developmental process Effects 0.000 description 9
- 238000003745 diagnosis Methods 0.000 description 9
- 239000012636 effector Substances 0.000 description 9
- 230000002163 immunogen Effects 0.000 description 9
- 102000018358 immunoglobulin Human genes 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 238000011002 quantification Methods 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 230000028327 secretion Effects 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- 238000002560 therapeutic procedure Methods 0.000 description 9
- 108700028369 Alleles Proteins 0.000 description 8
- 206010006187 Breast cancer Diseases 0.000 description 8
- 208000026310 Breast neoplasm Diseases 0.000 description 8
- 102000053602 DNA Human genes 0.000 description 8
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 8
- 108010002350 Interleukin-2 Proteins 0.000 description 8
- 102000000588 Interleukin-2 Human genes 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 206010020718 hyperplasia Diseases 0.000 description 8
- 210000001616 monocyte Anatomy 0.000 description 8
- 239000013642 negative control Substances 0.000 description 8
- 239000013641 positive control Substances 0.000 description 8
- 238000012552 review Methods 0.000 description 8
- 230000003393 splenic effect Effects 0.000 description 8
- 238000013518 transcription Methods 0.000 description 8
- 230000035897 transcription Effects 0.000 description 8
- 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 7
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 7
- 241000238631 Hexapoda Species 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000012512 characterization method Methods 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 230000000295 complement effect Effects 0.000 description 7
- 206010016629 fibroma Diseases 0.000 description 7
- 210000002443 helper t lymphocyte Anatomy 0.000 description 7
- 230000001939 inductive effect Effects 0.000 description 7
- 239000002502 liposome Substances 0.000 description 7
- 201000005249 lung adenocarcinoma Diseases 0.000 description 7
- 210000001165 lymph node Anatomy 0.000 description 7
- 238000010647 peptide synthesis reaction Methods 0.000 description 7
- 238000012545 processing Methods 0.000 description 7
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 108091026890 Coding region Proteins 0.000 description 6
- 101710187301 FAS-associated factor 1 Proteins 0.000 description 6
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 6
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 6
- 102100027998 Macrophage metalloelastase Human genes 0.000 description 6
- 208000034254 Squamous cell carcinoma of the cervix uteri Diseases 0.000 description 6
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 6
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 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 6
- 239000002253 acid Substances 0.000 description 6
- 208000009956 adenocarcinoma Diseases 0.000 description 6
- 239000011324 bead Substances 0.000 description 6
- 201000006612 cervical squamous cell carcinoma Diseases 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 6
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 6
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 210000004962 mammalian cell Anatomy 0.000 description 6
- 239000003550 marker Substances 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 238000002823 phage display Methods 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 229950010550 resiquimod Drugs 0.000 description 6
- BXNMTOQRYBFHNZ-UHFFFAOYSA-N resiquimod Chemical compound C1=CC=CC2=C(N(C(COCC)=N3)CC(C)(C)O)C3=C(N)N=C21 BXNMTOQRYBFHNZ-UHFFFAOYSA-N 0.000 description 6
- 230000001177 retroviral effect Effects 0.000 description 6
- 238000007920 subcutaneous administration Methods 0.000 description 6
- 230000009258 tissue cross reactivity Effects 0.000 description 6
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 5
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 5
- 102100028389 Melanoma antigen recognized by T-cells 1 Human genes 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 206010060862 Prostate cancer Diseases 0.000 description 5
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 description 5
- 102100033117 Toll-like receptor 9 Human genes 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 230000000890 antigenic effect Effects 0.000 description 5
- 230000001580 bacterial effect Effects 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 229960004397 cyclophosphamide Drugs 0.000 description 5
- 238000000684 flow cytometry Methods 0.000 description 5
- 210000004602 germ cell Anatomy 0.000 description 5
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 5
- 229960002751 imiquimod Drugs 0.000 description 5
- 230000003308 immunostimulating effect Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- 230000003211 malignant effect Effects 0.000 description 5
- 201000001441 melanoma Diseases 0.000 description 5
- 230000001394 metastastic effect Effects 0.000 description 5
- 206010061289 metastatic neoplasm Diseases 0.000 description 5
- 239000000178 monomer Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000007790 solid phase Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- 230000009466 transformation Effects 0.000 description 5
- 238000002255 vaccination Methods 0.000 description 5
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 description 4
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- 241000701022 Cytomegalovirus Species 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 4
- 102100028976 HLA class I histocompatibility antigen, B alpha chain Human genes 0.000 description 4
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 description 4
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 description 4
- 101001008951 Homo sapiens Kinesin-like protein KIF15 Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 108010002586 Interleukin-7 Proteins 0.000 description 4
- 102100027630 Kinesin-like protein KIF15 Human genes 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 4
- 108020004511 Recombinant DNA Proteins 0.000 description 4
- 206010038019 Rectal adenocarcinoma Diseases 0.000 description 4
- 108010090804 Streptavidin Proteins 0.000 description 4
- 230000024932 T cell mediated immunity Effects 0.000 description 4
- 208000024770 Thyroid neoplasm Diseases 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229960002685 biotin Drugs 0.000 description 4
- 235000020958 biotin Nutrition 0.000 description 4
- 239000011616 biotin Substances 0.000 description 4
- 210000003995 blood forming stem cell Anatomy 0.000 description 4
- 210000000988 bone and bone Anatomy 0.000 description 4
- 210000001185 bone marrow Anatomy 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 231100000504 carcinogenesis Toxicity 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 230000036755 cellular response Effects 0.000 description 4
- 238000010367 cloning Methods 0.000 description 4
- 210000001072 colon Anatomy 0.000 description 4
- 208000029742 colonic neoplasm Diseases 0.000 description 4
- 235000018417 cysteine Nutrition 0.000 description 4
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
- 201000003908 endometrial adenocarcinoma Diseases 0.000 description 4
- 208000029382 endometrium adenocarcinoma Diseases 0.000 description 4
- 238000007918 intramuscular administration Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 201000010260 leiomyoma Diseases 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- 239000012931 lyophilized formulation Substances 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 239000011859 microparticle Substances 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 4
- 230000037452 priming Effects 0.000 description 4
- 238000000159 protein binding assay Methods 0.000 description 4
- 201000001281 rectum adenocarcinoma Diseases 0.000 description 4
- 238000004007 reversed phase HPLC Methods 0.000 description 4
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 230000004936 stimulating effect Effects 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- NHJVRSWLHSJWIN-UHFFFAOYSA-N 2,4,6-trinitrobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O NHJVRSWLHSJWIN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 101710159080 Aconitate hydratase A Proteins 0.000 description 3
- 101710159078 Aconitate hydratase B Proteins 0.000 description 3
- 208000036832 Adenocarcinoma of ovary Diseases 0.000 description 3
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 3
- 210000003359 CD4-positive helper T lymphocyte Anatomy 0.000 description 3
- 208000005623 Carcinogenesis Diseases 0.000 description 3
- 108010078791 Carrier Proteins Proteins 0.000 description 3
- 102100031584 Cell division cycle-associated 7-like protein Human genes 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 3
- 230000004543 DNA replication Effects 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 108010058607 HLA-B Antigens Proteins 0.000 description 3
- 108010093013 HLA-DR1 Antigen Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 101000777638 Homo sapiens Cell division cycle-associated 7-like protein Proteins 0.000 description 3
- 101000604155 Homo sapiens Nucleolar protein 14 Proteins 0.000 description 3
- 101001109282 Homo sapiens NudC domain-containing protein 1 Proteins 0.000 description 3
- 108010047761 Interferon-alpha Proteins 0.000 description 3
- 102000006992 Interferon-alpha Human genes 0.000 description 3
- 108010065805 Interleukin-12 Proteins 0.000 description 3
- 102000013462 Interleukin-12 Human genes 0.000 description 3
- 108090000978 Interleukin-4 Proteins 0.000 description 3
- 102000004388 Interleukin-4 Human genes 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- 206010024612 Lipoma Diseases 0.000 description 3
- 108010010995 MART-1 Antigen Proteins 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 206010050513 Metastatic renal cell carcinoma Diseases 0.000 description 3
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 3
- 102100038789 Nucleolar protein 14 Human genes 0.000 description 3
- 102100022475 NudC domain-containing protein 1 Human genes 0.000 description 3
- 108700026244 Open Reading Frames Proteins 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 206010061328 Ovarian epithelial cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 108090000526 Papain Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 102100035703 Prostatic acid phosphatase Human genes 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 3
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 3
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 3
- 108020004682 Single-Stranded DNA Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000033133 Testicular seminomatous germ cell tumor Diseases 0.000 description 3
- 102000002689 Toll-like receptor Human genes 0.000 description 3
- 108020000411 Toll-like receptor Proteins 0.000 description 3
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 229960000397 bevacizumab Drugs 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 239000000090 biomarker Substances 0.000 description 3
- 230000036952 cancer formation Effects 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000022131 cell cycle Effects 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 201000010897 colon adenocarcinoma Diseases 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- 230000000139 costimulatory effect Effects 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 238000013467 fragmentation Methods 0.000 description 3
- 238000006062 fragmentation reaction Methods 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 3
- 238000001415 gene therapy Methods 0.000 description 3
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 3
- 230000011132 hemopoiesis Effects 0.000 description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 230000006058 immune tolerance Effects 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 230000016784 immunoglobulin production Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 201000007785 kidney angiomyolipoma Diseases 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 238000013507 mapping Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 210000000754 myometrium Anatomy 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 230000002611 ovarian Effects 0.000 description 3
- 208000013371 ovarian adenocarcinoma Diseases 0.000 description 3
- 201000006588 ovary adenocarcinoma Diseases 0.000 description 3
- 229940055729 papain Drugs 0.000 description 3
- 235000019834 papain Nutrition 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 210000005259 peripheral blood Anatomy 0.000 description 3
- 239000011886 peripheral blood Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 210000002826 placenta Anatomy 0.000 description 3
- 208000004333 pleomorphic adenoma Diseases 0.000 description 3
- 108700002563 poly ICLC Proteins 0.000 description 3
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000004393 prognosis Methods 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 108010043671 prostatic acid phosphatase Proteins 0.000 description 3
- 230000006337 proteolytic cleavage Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 108091008146 restriction endonucleases Proteins 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 230000003595 spectral effect Effects 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 208000024662 testicular seminoma Diseases 0.000 description 3
- 208000008732 thymoma Diseases 0.000 description 3
- 239000003053 toxin Substances 0.000 description 3
- 231100000765 toxin Toxicity 0.000 description 3
- 108700012359 toxins Proteins 0.000 description 3
- 230000001131 transforming effect Effects 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- 238000011870 unpaired t-test Methods 0.000 description 3
- 238000010200 validation analysis Methods 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- JVJFIQYAHPMBBX-UHFFFAOYSA-N 4-hydroxynonenal Chemical compound CCCCCC(O)C=CC=O JVJFIQYAHPMBBX-UHFFFAOYSA-N 0.000 description 2
- 206010069754 Acquired gene mutation Diseases 0.000 description 2
- 206010000830 Acute leukaemia Diseases 0.000 description 2
- 108020005544 Antisense RNA Proteins 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- 108700020463 BRCA1 Proteins 0.000 description 2
- 102000036365 BRCA1 Human genes 0.000 description 2
- 101150072950 BRCA1 gene Proteins 0.000 description 2
- 102100033680 Bombesin receptor-activated protein C6orf89 Human genes 0.000 description 2
- 101100180402 Caenorhabditis elegans jun-1 gene Proteins 0.000 description 2
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 208000030808 Clear cell renal carcinoma Diseases 0.000 description 2
- 206010048832 Colon adenoma Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 2
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 2
- 241000723655 Cowpea mosaic virus Species 0.000 description 2
- 102000036364 Cullin Ring E3 Ligases Human genes 0.000 description 2
- 108091007045 Cullin Ring E3 Ligases Proteins 0.000 description 2
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical compound CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 108010040721 Flagellin Proteins 0.000 description 2
- 208000004057 Focal Nodular Hyperplasia Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010051066 Gastrointestinal stromal tumour Diseases 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
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 102100028971 HLA class I histocompatibility antigen, C alpha chain Human genes 0.000 description 2
- 108010052199 HLA-C Antigens Proteins 0.000 description 2
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 2
- 101000984746 Homo sapiens BRCA1-associated protein Proteins 0.000 description 2
- 101000944524 Homo sapiens Bombesin receptor-activated protein C6orf89 Proteins 0.000 description 2
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 description 2
- 101000578784 Homo sapiens Melanoma antigen recognized by T-cells 1 Proteins 0.000 description 2
- 101000952113 Homo sapiens Probable ATP-dependent RNA helicase DDX5 Proteins 0.000 description 2
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 2
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 2
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 108091092195 Intron Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 150000008575 L-amino acids Chemical class 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 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
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- AIJULSRZWUXGPQ-UHFFFAOYSA-N Methylglyoxal Chemical compound CC(=O)C=O AIJULSRZWUXGPQ-UHFFFAOYSA-N 0.000 description 2
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 2
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 2
- 102100038610 Myeloperoxidase Human genes 0.000 description 2
- 108090000235 Myeloperoxidases Proteins 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 108010077850 Nuclear Localization Signals Proteins 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010073260 Ovarian granulosa cell tumour Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 2
- 206010033964 Parathyroid tumour benign Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 102100037434 Probable ATP-dependent RNA helicase DDX5 Human genes 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 239000013614 RNA sample Substances 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 102000018779 Replication Protein C Human genes 0.000 description 2
- 108010027647 Replication Protein C Proteins 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 102000004584 Somatomedin Receptors Human genes 0.000 description 2
- 108010017622 Somatomedin Receptors Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000037453 T cell priming Effects 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 150000008043 acidic salts Chemical class 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000003044 adaptive effect Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000005875 antibody response Effects 0.000 description 2
- 210000000628 antibody-producing cell Anatomy 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 108010081355 beta 2-Microglobulin Proteins 0.000 description 2
- 102000015736 beta 2-Microglobulin Human genes 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 210000000601 blood cell Anatomy 0.000 description 2
- 201000007980 brain meningioma Diseases 0.000 description 2
- 239000008364 bulk solution Substances 0.000 description 2
- 238000004422 calculation algorithm Methods 0.000 description 2
- 229940022399 cancer vaccine Drugs 0.000 description 2
- 230000021235 carbamoylation Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 206010073251 clear cell renal cell carcinoma Diseases 0.000 description 2
- 238000001360 collision-induced dissociation Methods 0.000 description 2
- 230000005757 colony formation Effects 0.000 description 2
- 229940047120 colony stimulating factors Drugs 0.000 description 2
- 239000003184 complementary RNA Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- XVOYSCVBGLVSOL-UHFFFAOYSA-N cysteic acid Chemical compound OC(=O)C(N)CS(O)(=O)=O XVOYSCVBGLVSOL-UHFFFAOYSA-N 0.000 description 2
- 210000000172 cytosol Anatomy 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 239000005547 deoxyribonucleotide Substances 0.000 description 2
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- OQALFHMKVSJFRR-UHFFFAOYSA-N dityrosine Chemical compound OC(=O)C(N)CC1=CC=C(O)C(C=2C(=CC=C(CC(N)C(O)=O)C=2)O)=C1 OQALFHMKVSJFRR-UHFFFAOYSA-N 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 230000012202 endocytosis Effects 0.000 description 2
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 206010049444 fibromatosis Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000003500 gene array Methods 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 201000005787 hematologic cancer Diseases 0.000 description 2
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 2
- 229920001519 homopolymer Polymers 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 125000001165 hydrophobic group Chemical group 0.000 description 2
- 230000007124 immune defense Effects 0.000 description 2
- 229940124452 immunizing agent Drugs 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 208000030776 invasive breast carcinoma Diseases 0.000 description 2
- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 201000009546 lung large cell carcinoma Diseases 0.000 description 2
- 201000005243 lung squamous cell carcinoma Diseases 0.000 description 2
- 208000037841 lung tumor Diseases 0.000 description 2
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 210000002752 melanocyte Anatomy 0.000 description 2
- 239000011325 microbead Substances 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 201000010225 mixed cell type cancer Diseases 0.000 description 2
- 208000029638 mixed neoplasm Diseases 0.000 description 2
- 238000002703 mutagenesis Methods 0.000 description 2
- 231100000350 mutagenesis Toxicity 0.000 description 2
- 201000002120 neuroendocrine carcinoma Diseases 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- 210000002747 omentum Anatomy 0.000 description 2
- 208000029749 ovarian granulosa cell tumor Diseases 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 201000003686 parathyroid adenoma Diseases 0.000 description 2
- 208000014643 parathyroid gland adenoma Diseases 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- OJUGVDODNPJEEC-UHFFFAOYSA-N phenylglyoxal Chemical compound O=CC(=O)C1=CC=CC=C1 OJUGVDODNPJEEC-UHFFFAOYSA-N 0.000 description 2
- 239000013600 plasmid vector Substances 0.000 description 2
- 229940115272 polyinosinic:polycytidylic acid Drugs 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 230000004481 post-translational protein modification Effects 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 150000003254 radicals Chemical group 0.000 description 2
- 238000004725 rapid separation liquid chromatography Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 229960003310 sildenafil Drugs 0.000 description 2
- 201000010106 skin squamous cell carcinoma Diseases 0.000 description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 230000037439 somatic mutation Effects 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 229960001796 sunitinib Drugs 0.000 description 2
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 206010042863 synovial sarcoma Diseases 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 230000002381 testicular Effects 0.000 description 2
- 210000001550 testis Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 108010060175 trypsinogen activation peptide Proteins 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 230000003827 upregulation Effects 0.000 description 2
- 239000000277 virosome Substances 0.000 description 2
- 210000005253 yeast cell Anatomy 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- OPCHFPHZPIURNA-MFERNQICSA-N (2s)-2,5-bis(3-aminopropylamino)-n-[2-(dioctadecylamino)acetyl]pentanamide Chemical compound CCCCCCCCCCCCCCCCCCN(CC(=O)NC(=O)[C@H](CCCNCCCN)NCCCN)CCCCCCCCCCCCCCCCCC OPCHFPHZPIURNA-MFERNQICSA-N 0.000 description 1
- FYGDTMLNYKFZSV-URKRLVJHSA-N (2s,3r,4s,5s,6r)-2-[(2r,4r,5r,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5r,6s)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1[C@@H](CO)O[C@@H](OC2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-URKRLVJHSA-N 0.000 description 1
- DMQYDVBIPXAAJA-VHXPQNKSSA-N (3z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)-(5-methyl-1h-imidazol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1CN(CC)CCC1NC1=CC=C(NC(=O)\C2=C(/C=3NC=C(C)N=3)C=3C=C(F)C=CC=3)C2=C1 DMQYDVBIPXAAJA-VHXPQNKSSA-N 0.000 description 1
- POVNCJSPYFCWJR-USZUGGBUSA-N (4s)-4-[[(2s)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-5-[(2s)-2-[[2-[(2s)-2-[[(2s)-1-[[(2s,3r)-1-[[(1s)-1-carboxy-2-methylpropyl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1- Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O)C1=CC=C(O)C=C1 POVNCJSPYFCWJR-USZUGGBUSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 108020004463 18S ribosomal RNA Proteins 0.000 description 1
- 101150028074 2 gene Proteins 0.000 description 1
- GVJXGCIPWAVXJP-UHFFFAOYSA-N 2,5-dioxo-1-oxoniopyrrolidine-3-sulfonate Chemical compound ON1C(=O)CC(S(O)(=O)=O)C1=O GVJXGCIPWAVXJP-UHFFFAOYSA-N 0.000 description 1
- KFDPCYZHENQOBV-UHFFFAOYSA-N 2-(bromomethyl)-4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1CBr KFDPCYZHENQOBV-UHFFFAOYSA-N 0.000 description 1
- VUCNQOPCYRJCGQ-UHFFFAOYSA-N 2-[4-(hydroxymethyl)phenoxy]acetic acid Chemical class OCC1=CC=C(OCC(O)=O)C=C1 VUCNQOPCYRJCGQ-UHFFFAOYSA-N 0.000 description 1
- IOJUJUOXKXMJNF-UHFFFAOYSA-N 2-acetyloxybenzoic acid [3-(nitrooxymethyl)phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)OC1=CC=CC(CO[N+]([O-])=O)=C1 IOJUJUOXKXMJNF-UHFFFAOYSA-N 0.000 description 1
- JRYMOPZHXMVHTA-DAGMQNCNSA-N 2-amino-7-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1h-pyrrolo[2,3-d]pyrimidin-4-one Chemical compound C1=CC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O JRYMOPZHXMVHTA-DAGMQNCNSA-N 0.000 description 1
- IZQAUUVBKYXMET-UHFFFAOYSA-N 2-bromoethanamine Chemical compound NCCBr IZQAUUVBKYXMET-UHFFFAOYSA-N 0.000 description 1
- JQPFYXFVUKHERX-UHFFFAOYSA-N 2-hydroxy-2-cyclohexen-1-one Natural products OC1=CCCCC1=O JQPFYXFVUKHERX-UHFFFAOYSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- HXHAJRMTJXHJJZ-UHFFFAOYSA-N 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=CC(Br)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1CCCC1 HXHAJRMTJXHJJZ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WHNPOQXWAMXPTA-UHFFFAOYSA-N 3-methylbut-2-enamide Chemical compound CC(C)=CC(N)=O WHNPOQXWAMXPTA-UHFFFAOYSA-N 0.000 description 1
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 206010001150 Adenocarcinoma gastric Diseases 0.000 description 1
- 208000036764 Adenocarcinoma of the esophagus Diseases 0.000 description 1
- 208000006468 Adrenal Cortex Neoplasms Diseases 0.000 description 1
- 208000009888 Adrenocortical Adenoma Diseases 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- 229940122450 Altered peptide ligand Drugs 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 108091093088 Amplicon Proteins 0.000 description 1
- 108010049777 Ankyrins Proteins 0.000 description 1
- 102000008102 Ankyrins Human genes 0.000 description 1
- 241000272478 Aquila Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 244000186140 Asperula odorata Species 0.000 description 1
- 102000004000 Aurora Kinase A Human genes 0.000 description 1
- 108090000461 Aurora Kinase A Proteins 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- BXTVQNYQYUTQAZ-UHFFFAOYSA-N BNPS-skatole Chemical compound N=1C2=CC=CC=C2C(C)(Br)C=1SC1=CC=CC=C1[N+]([O-])=O BXTVQNYQYUTQAZ-UHFFFAOYSA-N 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- 108020004513 Bacterial RNA Proteins 0.000 description 1
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 229920002498 Beta-glucan Polymers 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- 210000001239 CD8-positive, alpha-beta cytotoxic T lymphocyte Anatomy 0.000 description 1
- 241000244203 Caenorhabditis elegans Species 0.000 description 1
- 101100421200 Caenorhabditis elegans sep-1 gene Proteins 0.000 description 1
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 1
- 101100507655 Canis lupus familiaris HSPA1 gene Proteins 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 206010008805 Chromosomal abnormalities Diseases 0.000 description 1
- 208000031404 Chromosome Aberrations Diseases 0.000 description 1
- 102100025590 Chromosome transmission fidelity protein 8 homolog Human genes 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 102100040901 Circadian clock protein PASD1 Human genes 0.000 description 1
- 101100007328 Cocos nucifera COS-1 gene Proteins 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 208000037845 Cutaneous squamous cell carcinoma Diseases 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 102100025176 Cyclin-A1 Human genes 0.000 description 1
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 1
- 206010011732 Cyst Diseases 0.000 description 1
- 208000026292 Cystic Kidney disease Diseases 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- YVGGHNCTFXOJCH-UHFFFAOYSA-N DDT Chemical compound C1=CC(Cl)=CC=C1C(C(Cl)(Cl)Cl)C1=CC=C(Cl)C=C1 YVGGHNCTFXOJCH-UHFFFAOYSA-N 0.000 description 1
- 102000004594 DNA Polymerase I Human genes 0.000 description 1
- 108010017826 DNA Polymerase I Proteins 0.000 description 1
- 108010092681 DNA Primase Proteins 0.000 description 1
- 102000016559 DNA Primase Human genes 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 108010093668 Deubiquitinating Enzymes Proteins 0.000 description 1
- 102000001477 Deubiquitinating Enzymes Human genes 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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 102100031780 Endonuclease Human genes 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 108010059378 Endopeptidases Proteins 0.000 description 1
- 102000005593 Endopeptidases Human genes 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 108010007005 Estrogen Receptor alpha Proteins 0.000 description 1
- 102100038595 Estrogen receptor Human genes 0.000 description 1
- 108091029865 Exogenous DNA Proteins 0.000 description 1
- 102100026561 Filamin-A Human genes 0.000 description 1
- 102100020715 Fms-related tyrosine kinase 3 ligand protein Human genes 0.000 description 1
- 101710162577 Fms-related tyrosine kinase 3 ligand protein Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- 235000008526 Galium odoratum Nutrition 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 208000002966 Giant Cell Tumor of Bone Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 206010018498 Goitre Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 108060005986 Granzyme Proteins 0.000 description 1
- 102000001398 Granzyme Human genes 0.000 description 1
- 101150009006 HIS3 gene Proteins 0.000 description 1
- 108010064885 HLA-DR3 Antigen Proteins 0.000 description 1
- 108010046732 HLA-DR4 Antigen Proteins 0.000 description 1
- 108010086031 HLA-DR6 Antigen Proteins 0.000 description 1
- 102000012215 HSC70 Heat-Shock Proteins Human genes 0.000 description 1
- 108010036652 HSC70 Heat-Shock Proteins Proteins 0.000 description 1
- 206010066476 Haematological malignancy Diseases 0.000 description 1
- 206010019629 Hepatic adenoma Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 102100021090 Homeobox protein Hox-A9 Human genes 0.000 description 1
- 102100029279 Homeobox protein SIX1 Human genes 0.000 description 1
- 101100382122 Homo sapiens CIITA gene Proteins 0.000 description 1
- 101000856249 Homo sapiens Chromosome transmission fidelity protein 8 homolog Proteins 0.000 description 1
- 101000613559 Homo sapiens Circadian clock protein PASD1 Proteins 0.000 description 1
- 101000934314 Homo sapiens Cyclin-A1 Proteins 0.000 description 1
- 101000913549 Homo sapiens Filamin-A Proteins 0.000 description 1
- 101100395311 Homo sapiens HLA-B gene Proteins 0.000 description 1
- 101000634171 Homo sapiens Homeobox protein SIX1 Proteins 0.000 description 1
- 101001063392 Homo sapiens Lymphocyte function-associated antigen 3 Proteins 0.000 description 1
- 101001056128 Homo sapiens Mannose-binding protein C Proteins 0.000 description 1
- 101001028136 Homo sapiens Methyltransferase-like 26 Proteins 0.000 description 1
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 1
- 101000938702 Homo sapiens N-acetyltransferase ESCO1 Proteins 0.000 description 1
- 101001100327 Homo sapiens RNA-binding protein 45 Proteins 0.000 description 1
- 101000911790 Homo sapiens Sister chromatid cohesion protein DCC1 Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 101000669460 Homo sapiens Toll-like receptor 5 Proteins 0.000 description 1
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 description 1
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 description 1
- 206010062904 Hormone-refractory prostate cancer Diseases 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 1
- 102000012745 Immunoglobulin Subunits Human genes 0.000 description 1
- 108010079585 Immunoglobulin Subunits Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 102000003816 Interleukin-13 Human genes 0.000 description 1
- 108090000176 Interleukin-13 Proteins 0.000 description 1
- 108090000172 Interleukin-15 Proteins 0.000 description 1
- 102100030703 Interleukin-22 Human genes 0.000 description 1
- 108010065637 Interleukin-23 Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 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
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 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
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 1
- 206010023774 Large cell lung cancer Diseases 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 108700005090 Lethal Genes Proteins 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 102100030984 Lymphocyte function-associated antigen 3 Human genes 0.000 description 1
- 102100026371 MHC class II transactivator Human genes 0.000 description 1
- 108700002010 MHC class II transactivator Proteins 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229920000057 Mannan Polymers 0.000 description 1
- 102100026553 Mannose-binding protein C Human genes 0.000 description 1
- 206010063916 Metastatic gastric cancer Diseases 0.000 description 1
- 102100037543 Methyltransferase-like 26 Human genes 0.000 description 1
- 102100034256 Mucin-1 Human genes 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- GUVMFDICMFQHSZ-UHFFFAOYSA-N N-(1-aminoethenyl)-1-[4-[[5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[hydroxy-[[3-[hydroxy-[[3-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]phosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]phosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(2-amino-6-oxo-1H-purin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(2-amino-6-oxo-1H-purin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-[[[2-[[[2-[[[5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[5-(4-amino-2-oxopyrimidin-1-yl)-2-[[hydroxy-[2-(hydroxymethyl)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxyphosphinothioyl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphinothioyl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphinothioyl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphinothioyl]oxymethyl]-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphinothioyl]oxymethyl]oxolan-2-yl]-5-methylimidazole-4-carboxamide Chemical compound CC1=C(C(=O)NC(N)=C)N=CN1C1OC(COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)CO)C(OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)O)C1 GUVMFDICMFQHSZ-UHFFFAOYSA-N 0.000 description 1
- VIHYIVKEECZGOU-UHFFFAOYSA-N N-acetylimidazole Chemical compound CC(=O)N1C=CN=C1 VIHYIVKEECZGOU-UHFFFAOYSA-N 0.000 description 1
- 102100030815 N-acetyltransferase ESCO1 Human genes 0.000 description 1
- 108010084333 N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine Proteins 0.000 description 1
- 101150076367 NOP14 gene Proteins 0.000 description 1
- 108091061960 Naked DNA Proteins 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 208000009869 Neu-Laxova syndrome Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 102000007999 Nuclear Proteins Human genes 0.000 description 1
- 108010089610 Nuclear Proteins Proteins 0.000 description 1
- 108700001237 Nucleic Acid-Based Vaccines Proteins 0.000 description 1
- 206010030137 Oesophageal adenocarcinoma Diseases 0.000 description 1
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 108700006640 OspA Proteins 0.000 description 1
- 239000012648 POLY-ICLC Substances 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 101800001442 Peptide pr Proteins 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 101710093543 Probable non-specific lipid-transfer protein Proteins 0.000 description 1
- 102100036691 Proliferating cell nuclear antigen Human genes 0.000 description 1
- 102100039156 Queuine tRNA-ribosyltransferase catalytic subunit 1 Human genes 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 102000009572 RNA Polymerase II Human genes 0.000 description 1
- 108010009460 RNA Polymerase II Proteins 0.000 description 1
- 102000044126 RNA-Binding Proteins Human genes 0.000 description 1
- 108700020471 RNA-Binding Proteins Proteins 0.000 description 1
- 230000004570 RNA-binding Effects 0.000 description 1
- 102100038823 RNA-binding protein 45 Human genes 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000035977 Rare disease Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000036284 Rhinitis seasonal Diseases 0.000 description 1
- 101100394989 Rhodopseudomonas palustris (strain ATCC BAA-98 / CGA009) hisI gene Proteins 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 208000018020 Sickle cell-beta-thalassemia disease syndrome Diseases 0.000 description 1
- 102100027040 Sister chromatid cohesion protein DCC1 Human genes 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 108010002687 Survivin Proteins 0.000 description 1
- 108700005078 Synthetic Genes Proteins 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 239000012163 TRI reagent Substances 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
- 108010017842 Telomerase Proteins 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- NYTOUQBROMCLBJ-UHFFFAOYSA-N Tetranitromethane Chemical compound [O-][N+](=O)C([N+]([O-])=O)([N+]([O-])=O)[N+]([O-])=O NYTOUQBROMCLBJ-UHFFFAOYSA-N 0.000 description 1
- 206010043391 Thalassaemia beta Diseases 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical group OP(O)(S)=O RYYWUUFWQRZTIU-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
- 102100039357 Toll-like receptor 5 Human genes 0.000 description 1
- 102100039390 Toll-like receptor 7 Human genes 0.000 description 1
- 102100033110 Toll-like receptor 8 Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 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
- 102100039094 Tyrosinase Human genes 0.000 description 1
- 108060008724 Tyrosinase Proteins 0.000 description 1
- 108010005705 Ubiquitinated Proteins Proteins 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- 108010027273 Valosin Containing Protein Proteins 0.000 description 1
- 102000018709 Valosin Containing Protein Human genes 0.000 description 1
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- 108700020467 WT1 Proteins 0.000 description 1
- 101150084041 WT1 gene Proteins 0.000 description 1
- 101710145570 Zinc finger protein 131 Proteins 0.000 description 1
- HMNZFMSWFCAGGW-XPWSMXQVSA-N [3-[hydroxy(2-hydroxyethoxy)phosphoryl]oxy-2-[(e)-octadec-9-enoyl]oxypropyl] (e)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(COP(O)(=O)OCCO)OC(=O)CCCCCCC\C=C\CCCCCCCC HMNZFMSWFCAGGW-XPWSMXQVSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- KRHYYFGTRYWZRS-BJUDXGSMSA-N ac1l2y5h Chemical compound [18FH] KRHYYFGTRYWZRS-BJUDXGSMSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 208000002517 adenoid cystic carcinoma Diseases 0.000 description 1
- 230000000240 adjuvant effect Effects 0.000 description 1
- 238000011467 adoptive cell therapy Methods 0.000 description 1
- 208000015234 adrenal cortex adenoma Diseases 0.000 description 1
- 201000003354 adrenal cortical adenoma Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229940060265 aldara Drugs 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 102000006707 alpha-beta T-Cell Antigen Receptors Human genes 0.000 description 1
- 108010087408 alpha-beta T-Cell Antigen Receptors Proteins 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229940037003 alum Drugs 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000002870 angiogenesis inducing agent Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 230000006023 anti-tumor response Effects 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 230000014102 antigen processing and presentation of exogenous peptide antigen via MHC class I Effects 0.000 description 1
- 230000008349 antigen-specific humoral response Effects 0.000 description 1
- 239000002257 antimetastatic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000008346 aqueous phase 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
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 201000010878 atypical lipomatous tumor Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 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
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000005422 blasting Methods 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 201000011143 bone giant cell tumor Diseases 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 201000003714 breast lobular carcinoma Diseases 0.000 description 1
- KQNZDYYTLMIZCT-KQPMLPITSA-N brefeldin A Chemical compound O[C@@H]1\C=C\C(=O)O[C@@H](C)CCC\C=C\[C@@H]2C[C@H](O)C[C@H]21 KQNZDYYTLMIZCT-KQPMLPITSA-N 0.000 description 1
- JUMGSHROWPPKFX-UHFFFAOYSA-N brefeldin-A Natural products CC1CCCC=CC2(C)CC(O)CC2(C)C(O)C=CC(=O)O1 JUMGSHROWPPKFX-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 208000002458 carcinoid tumor Diseases 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 229920006317 cationic polymer Polymers 0.000 description 1
- 229960002412 cediranib Drugs 0.000 description 1
- 229940047495 celebrex Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000005859 cell recognition Effects 0.000 description 1
- 230000006041 cell recruitment Effects 0.000 description 1
- 229940030156 cell vaccine Drugs 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 210000002230 centromere Anatomy 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 230000002925 chemical effect Effects 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 230000006328 chemical modification of amino acids Effects 0.000 description 1
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 238000011220 combination immunotherapy Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910001431 copper ion Inorganic materials 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical group BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- OILAIQUEIWYQPH-UHFFFAOYSA-N cyclohexane-1,2-dione Chemical compound O=C1CCCCC1=O OILAIQUEIWYQPH-UHFFFAOYSA-N 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000004163 cytometry Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 125000001295 dansyl group Chemical group [H]C1=C([H])C(N(C([H])([H])[H])C([H])([H])[H])=C2C([H])=C([H])C([H])=C(C2=C1[H])S(*)(=O)=O 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000007418 data mining Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000004041 dendritic cell maturation Effects 0.000 description 1
- 229940029030 dendritic cell vaccine Drugs 0.000 description 1
- 108010017271 denileukin diftitox Proteins 0.000 description 1
- 238000000432 density-gradient centrifugation Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 201000002893 dermoid cyst of ovary Diseases 0.000 description 1
- 125000004386 diacrylate group Chemical group 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 125000004989 dicarbonyl group Chemical group 0.000 description 1
- FFYPMLJYZAEMQB-UHFFFAOYSA-N diethyl pyrocarbonate Chemical compound CCOC(=O)OC(=O)OCC FFYPMLJYZAEMQB-UHFFFAOYSA-N 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000006334 disulfide bridging Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 208000018529 duodenal adenocarcinoma Diseases 0.000 description 1
- 201000005839 duodenum adenocarcinoma Diseases 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 229940056913 eftilagimod alfa Drugs 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000001437 electrospray ionisation time-of-flight quadrupole detection Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 208000023965 endometrium neoplasm Diseases 0.000 description 1
- 101150007166 ensa gene Proteins 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 208000028653 esophageal adenocarcinoma Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 238000010265 fast atom bombardment Methods 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 108700014844 flt3 ligand Proteins 0.000 description 1
- 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 1
- 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 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000002594 fluoroscopy Methods 0.000 description 1
- 108010003374 fms-Like Tyrosine Kinase 3 Proteins 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000012520 frozen sample Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 238000010230 functional analysis Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000011223 gene expression profiling Methods 0.000 description 1
- 238000003208 gene overexpression Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 201000003872 goiter Diseases 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 210000002288 golgi apparatus Anatomy 0.000 description 1
- 230000036449 good health Effects 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 229920000140 heteropolymer Polymers 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 108010027263 homeobox protein HOXA9 Proteins 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000037451 immune surveillance Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000002998 immunogenetic effect Effects 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 239000000568 immunological adjuvant Substances 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 238000013394 immunophenotyping Methods 0.000 description 1
- 230000000091 immunopotentiator Effects 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 230000002637 immunotoxin Effects 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 229940051026 immunotoxin Drugs 0.000 description 1
- 231100000608 immunotoxin Toxicity 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000011078 in-house production Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 201000008600 infiltrating lipoma Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229940117681 interleukin-12 Drugs 0.000 description 1
- 108010074108 interleukin-21 Proteins 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 238000010212 intracellular staining Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- PGHMRUGBZOYCAA-UHFFFAOYSA-N ionomycin Natural products O1C(CC(O)C(C)C(O)C(C)C=CCC(C)CC(C)C(O)=CC(=O)C(C)CC(C)CC(CCC(O)=O)C)CCC1(C)C1OC(C)(C(C)O)CC1 PGHMRUGBZOYCAA-UHFFFAOYSA-N 0.000 description 1
- PGHMRUGBZOYCAA-ADZNBVRBSA-N ionomycin Chemical compound O1[C@H](C[C@H](O)[C@H](C)[C@H](O)[C@H](C)/C=C/C[C@@H](C)C[C@@H](C)C(/O)=C/C(=O)[C@@H](C)C[C@@H](C)C[C@@H](CCC(O)=O)C)CC[C@@]1(C)[C@@H]1O[C@](C)([C@@H](C)O)CC1 PGHMRUGBZOYCAA-ADZNBVRBSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 208000022013 kidney Wilms tumor Diseases 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 208000024596 kidney oncocytoma Diseases 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 125000001909 leucine group Chemical class [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002960 lipid emulsion Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000001142 lung small cell carcinoma Diseases 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 108010051618 macrophage stimulatory lipopeptide 2 Proteins 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000008099 melanin synthesis Effects 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 150000002730 mercury Chemical class 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- ZCQGVFNHUATAJY-UHFFFAOYSA-N methyl 2-[methyl(prop-2-enoyl)amino]acetate Chemical compound COC(=O)CN(C)C(=O)C=C ZCQGVFNHUATAJY-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000004005 microsphere Substances 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
- 238000005065 mining Methods 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- 229940035032 monophosphoryl lipid a Drugs 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 229940035036 multi-peptide vaccine Drugs 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 230000002632 myometrial effect Effects 0.000 description 1
- CMWYAOXYQATXSI-UHFFFAOYSA-N n,n-dimethylformamide;piperidine Chemical compound CN(C)C=O.C1CCNCC1 CMWYAOXYQATXSI-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000014399 negative regulation of angiogenesis Effects 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 230000010309 neoplastic transformation Effects 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- VXAPDXVBDZRZKP-UHFFFAOYSA-N nitric acid phosphoric acid Chemical compound O[N+]([O-])=O.OP(O)(O)=O VXAPDXVBDZRZKP-UHFFFAOYSA-N 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 101150087140 nudC gene Proteins 0.000 description 1
- 239000002751 oligonucleotide probe Substances 0.000 description 1
- 230000006548 oncogenic transformation Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229940100027 ontak Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 208000004971 ovarian teratoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 208000003154 papilloma Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 210000003681 parotid gland Anatomy 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000013610 patient sample Substances 0.000 description 1
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 1
- 229960000639 pazopanib Drugs 0.000 description 1
- 201000008785 pediatric osteosarcoma Diseases 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 230000016446 peptide cross-linking Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 229940125667 peptide vaccine candidate Drugs 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 229930192851 perforin Natural products 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229940115270 poly iclc Drugs 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 210000001978 pro-t lymphocyte Anatomy 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229940021993 prophylactic vaccine Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- 230000016434 protein splicing Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 229940034080 provenge Drugs 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 108010061997 queuine tRNA-ribosyltransferase Proteins 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000007347 radical substitution reaction Methods 0.000 description 1
- 239000000941 radioactive substance Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 208000005039 renal oncocytoma Diseases 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography 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
- 230000028710 ribosome assembly Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 210000004116 schwann cell Anatomy 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 101150110594 sdad1 gene Proteins 0.000 description 1
- 208000017022 seasonal allergic rhinitis Diseases 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 208000007056 sickle cell anemia Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229960000714 sipuleucel-t Drugs 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 229940074386 skatole Drugs 0.000 description 1
- 208000020352 skin basal cell carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 210000001812 small ribosome subunit Anatomy 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000014626 tRNA modification Effects 0.000 description 1
- 229960000835 tadalafil Drugs 0.000 description 1
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 1
- 108010010186 talactoferrin alfa Proteins 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- 229940021747 therapeutic vaccine Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000002992 thymic effect Effects 0.000 description 1
- 230000005029 transcription elongation Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 210000003171 tumor-infiltrating lymphocyte Anatomy 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
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 239000012646 vaccine adjuvant Substances 0.000 description 1
- 229940124931 vaccine adjuvant Drugs 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
- 230000006459 vascular development Effects 0.000 description 1
- 210000000605 viral structure Anatomy 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 208000022752 well-differentiated liposarcoma Diseases 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- 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
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/1025—Acyltransferases (2.3)
- C12N9/1029—Acyltransferases (2.3) transferring groups other than amino-acyl groups (2.3.1)
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/90—Isomerases (5.)
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y203/00—Acyltransferases (2.3)
- C12Y203/01—Acyltransferases (2.3) transferring groups other than amino-acyl groups (2.3.1)
- C12Y203/01048—Histone acetyltransferase (2.3.1.48)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y306/00—Hydrolases acting on acid anhydrides (3.6)
- C12Y306/04—Hydrolases acting on acid anhydrides (3.6) acting on acid anhydrides; involved in cellular and subcellular movement (3.6.4)
- C12Y306/04004—Plus-end-directed kinesin ATPase (3.6.4.4)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y599/00—Other isomerases (5.99)
- C12Y599/01—Other isomerases (5.99.1)
- C12Y599/01002—DNA topoisomerase (5.99.1.2)
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
- G01N33/5047—Cells of the immune system
- G01N33/505—Cells of the immune system involving T-cells
-
- 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
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5156—Animal cells expressing foreign proteins
-
- 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
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5158—Antigen-pulsed cells, e.g. T-cells
-
- 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
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
- A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
-
- 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
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
- C12N5/0638—Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]
-
- 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
- C12Q2600/136—Screening for pharmacological compounds
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Wood Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cell Biology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
- Hematology (AREA)
- Toxicology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Gastroenterology & Hepatology (AREA)
- Analytical Chemistry (AREA)
- Pathology (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Physics & Mathematics (AREA)
- Mycology (AREA)
- Developmental Biology & Embryology (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Abstract
Description
非定型脂肪腫;
脳腫瘍、そして腎オンコサイトーマおよびリンパ節悪性黒色腫から選択される増殖性疾患;神経膠芽腫、そして骨非骨化性線維腫、髄膜腫、乳がん、子宮内膜腺がん、大網平滑筋肉腫、耳下腺多形性腺腫、皮膚扁平上皮がん、甲状腺腺結節性過形成、および子宮頸部扁平上皮がんから選択される増殖性疾患;
乳小葉がん;
乳管内がん;
結腸または直腸がん、そして腺がん、副腎皮質がん、乳粘液がん、腺がん、子宮内膜ミュラー管混合腫瘍、線維腫症、腎がん、肝臓限局性結節性過形成、肝細胞がん、肺小細胞がん、肺扁平上皮がん、乳がん、リンパ節非ホジキンリンパ腫、転移性腎細胞がん、子宮筋層平滑筋腫、卵巣奇形腫、卵巣莢膜腫−線維腫、副甲状腺腫、前立腺良性結節性過形成、直腸腺がん、脾臓慢性骨髄性白血病、脾臓髄外造血、胃腺がん、滑膜肉腫、精巣セミノーマ、胸線胸腺腫、および子宮頸部扁平上皮がんから選択される増殖性疾患;
結腸腺腫;
子宮内膜腺がん;
食道腺がん;
腎血管筋脂肪腫;
腎明細胞がん、そして骨非骨化性線維腫、脳髄膜腫、結腸腺がん、結腸腺腫、結腸非ホジキンリンパ腫から選択される増殖性疾患;
腎明細胞がん、そして子宮内膜腺がん、腎血管筋脂肪腫、多発性嚢胞腎、腎移行上皮がん、脂肪腫非ホジキンリンパ腫、卵巣腺がん、耳下腺多形性腺腫、前立腺がん、脾臓非ホジキンリンパ腫、胃消化管間質腫瘍(GIST)、滑膜肉腫、および甲状腺結節性過形成から選択される増殖性疾患;
腎臓、腎細胞がん;例えば非明細胞型;
脂肪肉腫;
肝限局性結節性過形成;
肝臓、肝細胞がん、そして副腎皮質腺腫、乳がん、腺様嚢胞がん、結腸腺がん、肝限局性結節性過形成、肝細胞がん、肺腺がん、膵臓腺がん、耳下腺多形性腺腫、小腸消化管間質腫瘍、甲状腺結節性過形成、線維腫症、腎血管筋脂肪腫、腎細胞がん、肝限局性結節性過形成、肺大細胞がん、子宮筋層平滑筋腫、および子宮頸部扁平上皮がんから選択される増殖性疾患;肺腺がん;
肺非小細胞肺がん、そして骨非骨化性線維腫、腎がん、肝細胞がん、肺腺がん、肺神経内分泌がん、大網、腺がん、シュワン細胞腫、脾臓慢性骨髄性白血病、脾臓髄外造血、胃腺がん、精巣セミノーマ、胸腺腫、および子宮頸部扁平上皮がんから選択される増殖性疾患;
リンパ節浸潤性乳がん;
リンパ節非ホジキンリンパ腫;
悪性線維性組織球腫;
転移性浸潤性乳がん;
転移性腎細胞がん;
大網腺がん;
明細胞型卵巣腺がん;
卵巣顆粒膜細胞腫瘍;
膵臓腺がん、そして骨巨細胞腫、骨肉腫、乳がん、軟骨肉腫、筋肉内脂肪腫、脂肪腫、肺腺がん、リンパ節ホジキン病、子宮筋層、平滑筋腫、卵巣粘液性嚢胞腺がん、胃腺がん、および胸腺腫から選択される増殖性疾患;
副甲状腺腫;
前立腺がん;
直腸腺がん;
小腸消化管間質腫瘍;
脾臓慢性骨髄性白血病;
脾臓髄外造血;
扁平上皮がん;
胃腺がん、そして、脳髄膜腫、転移性肝臓カルチノイド腫瘍、前立腺がん、および脾臓慢性骨髄性白血病から選択される増殖性疾患;
胃分化型腺がん、そして結腸腺がん、結腸非ホジキンリンパ腫、子宮内膜腺がん、腎ウィルムス腫瘍、肺腺がん、肺小細胞がん、リンパ節非ホジキンリンパ腫、悪性線維性組織球腫、転移性浸潤性乳小葉がん、副甲状腺腫、直腸腺がん、胃腺がん、精巣セミノーマ、および子宮子宮頸部扁平上皮がんから選択される増殖性疾患;
胃腺がん、そして肺腺がん、転移性腎細胞がん、子宮筋層平滑筋腫、非ホジキンリンパ腫、菌状息肉腫、卵巣腺がん、膵臓腺がん、および白血球細胞慢性リンパ球性白血病から選択される増殖性疾患;
胃子宮内膜、腺がん;
転移性胃がん、そして腺がん、骨非骨化性線維腫、乳がん、十二指腸腺がん、肝腺腫、肺大細胞がん、肺神経内分泌がん、肺扁平上皮がん、リンパ節非ホジキンリンパ腫、卵巣顆粒膜細胞腫瘍、卵巣ミュラー管混合腫瘍、膵臓腺がん、前立腺結節性過形成、直腸腺がん、および基底細胞がんから選択される増殖性疾患;
甲状腺結節性過形成;
および子宮頸部扁平上皮がん。
a)がん精巣抗原:T細胞によって認識され得る、これまでに同定された最初の腫瘍関連抗原(TAA)はこのクラスに属し、最初はがん精巣(CT)抗原と称されたが、それは、そのメンバーが組織学的に異なるヒト腫瘍で発現し、正常組織では、精巣の精母細胞/精原細胞のみに存在し、時として胎盤に存在するためであった。精巣の細胞は、クラスIおよびII HLA分子を発現しないので、これらの抗原は正常組織のT細胞によって認識され得ず、したがって免疫学的に腫瘍特異的と見なされる。CT抗原の周知の例は、MAGEファミリーメンバーまたはNY−ESO−1である。
b)分化抗原:これらのTAAは、腫瘍と、それから腫瘍が生じる正常組織との間で共有され;大多数は、メラノーマおよび正常なメラノサイトに見られる。これらのメラノサイト系関連タンパク質の多くはメラニン生合成に関与し、したがって腫瘍特異的でないが、それでもなおがん免疫療法のために広く利用されている。例としては、黒色腫に対するチロシナーゼおよびMelan−A/MART−1、または前立腺がんに対するPSAが挙げられるが、これに限定されるものではない。
c)過剰発現されるTAA:広範に発現されるTAAをエンコードする遺伝子は、組織学的に異なるタイプの腫瘍で、ならびに多数の正常組織で、概してより低い発現レベルで検出されている。正常組織によってプロセシングされ、潜在的に提示されるエピトープの多くは、T細胞認識閾値レベルに満たない可能性がある一方で、腫瘍細胞におけるそれらの過剰発現は、先に確立された免疫寛容を破壊することで抗がん応答を引き起こし得る。このクラスのTAAの顕著な例は、Her−2/neu、サバイビン、テロメラーゼまたはWT1である。
d)腫瘍特異的抗原:これらのユニークなTAAは、正常な遺伝子(β−カテニン、CDK4など)の変異から生じる。これらの分子変化のいくつかは、腫瘍性形質転換および/または進行に関連する。腫瘍特異的抗原は、通常、正常組織に対する自己免疫反応のリスクなしに、強力な免疫応答を誘導できる。他方、これらのTAAは、ほとんどの場合、その上でそれらが同定されたまさにその腫瘍のみと関係があり、通常は、多くの個々の腫瘍間で共有されない。
e)異常な翻訳後修飾から生じるTAA:このようなTAAは、腫瘍中で特異的でなく過剰発現もされないタンパク質から生じてもよいが、それでもなお、主に腫瘍中で活性の翻訳後プロセスによって、腫瘍関連抗原になる。このクラスの例は、腫瘍でMUC1のような新規エピトープをもたらす改変グリコシル化パターンから、または腫瘍特異的であってもなくてもよい分解中のタンパク質スプライシング事象から生じる。
f)腫瘍ウイルスタンパク質:これらのTAAは、発がん過程で重要な役割を果たしてもよいウイルスタンパク質であり、それらは外来性である(ヒト由来でない)ため、T細胞応答を誘起し得る。このようなタンパク質の例は、子宮頸がんで発現される、ヒト乳頭腫16型ウイルスタンパク質E6およびE7である。
同一性百分率=100[1−(C/R)]
式中、Cは、参照配列と比較される配列との間のアライメント長にわたる、参照配列と比較配列の間の差異の数であり、
(i)比較配列中に対応する整列塩基またはアミノ酸を有しない参照配列中の各塩基またはアミノ酸、および
(ii)参照配列中の各ギャップ、および
(iii)比較配列中の整列塩基またはアミノ酸と異なる参照配列中の各整列塩基またはアミノ酸が、差異を構成して、
(iiii)アライメントは、整合配列の1位から開始しなくてはならず;
Rは、比較配列とのアライメント長にわたる参照配列中の塩基またはアミノ酸の数であり、参照配列中に生じるあらゆるギャップも塩基またはアミノ酸として数えられる。
(a)溶液中のまたは凍結乾燥形態の上述の医薬組成物を含有する容器;
(b)任意選択的に、凍結乾燥製剤のための希釈剤または再構成溶液を含有する第2の容器;および
(c)任意選択的に、(i)溶液の使用、または(ii)凍結乾燥製剤の再構成および/または使用のための取扱説明書
を含んでなるキットをさらに目的とする。
1.悪性物質からのHLAリガンドが、質量分析法によって同定された。
2.マイクロアレイによるゲノム規模メッセンジャーリボ核酸(mRNA)発現解析を使用して、一連の正常器官および組織と比較して悪性組織(AML)中の遺伝子過剰発現が同定された。
3.同定されたHLAリガンドは、遺伝子発現データと比較された。ステップ2で検出された、選択的にまたは過剰に発現された遺伝子によってコードされるペプチドは、多重ペプチドワクチンのための適切なTUMAP候補と見なされた。
4.同定されたペプチドのTUMAPとしての妥当性を支持する追加的な証拠を同定するために、文献調査が実施された。
5.mRNAレベルでの過剰発現の関連性は、ステップ3からの選択されたTUMAPの腫瘍組織上における再検出と、健常組織における検出の欠如(またはまれな)検出によって確認された。
6.選択されたペプチドによる生体内T細胞応答の誘導が可能かどうかを評価するために、健常ドナーならびにAML患者からのヒトT細胞を使用して、生体外免疫原性アッセイが実施された。
細胞表面に提示される腫瘍関連ペプチドの同定および定量化
組織サンプル
患者の腫瘍サンプルは、University of Tubingen,Tubingen,Germanyによって提供された。全ての患者の告知に基づく同意書が与えられた。組織サンプルは、外科手術直後に液体窒素中で衝撃凍結され、TUMAPの単離まで−80℃で保存された。リガンドーム分析では、治療前の診断時または再発時における、AML患者からのPBMC(>80%の血中AML BLASTカウント)、ならびに健常ドナーのPBMCおよびBMNCが、密度勾配遠心分離によって単離された。
HLAクラスIおよびII分子は、以前記載されたような標準イムノアフィニティー精製を用いて単離された。手短に述べると、スナップ凍結細胞ペレットが、1×プロテアーゼ阻害剤(Complete,Roche,Basel,Switzerland)を含有する、10 mMの CHAPS/PBS(AppliChem,St.Louis,MO,USA/Gibco,Carlsbad,CA,USA)中で溶解された。HLA分子は、それぞれCNBr活性化セファロースに共有結合する、汎HLAクラスI特異的mAb W6/32および汎HLAクラスII特異的mAb Tu39を使用して、シングルステップで精製された(GE Healthcare,Chalfont St Giles,UK)。HLA:ペプチド複合体は、0.2%トリフルオロ酢酸(TFA、Merck,Whitehouse Station,NJ,USA)の反復添加によって溶出された。溶出画分E1〜E8は貯留され、遠心分離濾過ユニット(Amicon,Millipore,Billerica,MA,USA)を使用して、限外濾過によって遊離HLAリガンドが単離された。HLAリガンドは、ZipTip C18ピペット(Millipore)先端を使用して、濾液から抽出されて脱塩された。抽出されたペプチドは、35μlの80%アセトニトリル(ACN、Merck)/0.2%TFA中で溶出され、完全に乾燥するまで遠心分離され、25μlの1%ACN/0.05%TFAに再懸濁された。サンプルは、LC−MS/MSによる分析まで−20℃で保存された。
ペプチドサンプルは、逆相液体クロマトグラフィー(nanoUHPLC,UltiMate 3000 RSLCnano,ThermoFisher,Waltham,MA,USA)によって分離され、引き続いてオンライン接続されたLTQ Orbitrap XLハイブリッド質量分光計(ThermoFiher)中で分析された。サンプルは、5回の技術的反復試験中で分析された。5μl(サンプルの20%に相当する)のサンプル容積が、75μm×2cm捕捉カラム(Acclaim PepMap RSLC、ThermoFisher)に、4μl/分で5.75分間にわたり注入された。引き続いてペプチド分離が、50μm×50cm分離カラム(Acclaim PepMap RSLC,ThermoFisher)上で、2.4から32.0%に及ぶACN勾配を適用して、50℃および175nl/分の流速で140分間にわたり実施された。溶出ペプチドは、ナノスプレーイオン化によってイオン化され、調査スキャンで最も豊富な5つの前駆イオンのフラグメントスペクトルを生成する、トップ5CID(衝突誘起解離)法を実装する質量分光計内で分析された。分解能は、60,00に設定された。HLAクラスIリガンドでは、質量範囲は400〜650m/zに限定され、電荷状態2および3が断片化を許された。HLAクラスIIでは、300〜1,500m/zの質量範囲が分析されて、電荷状態≧2が断片化を許された。
AML患者および健常ボランティアからのPBMCが、10%貯留ヒト型血清(PHS、社内製造)、100mMのβ−メルカプトエタノール(Roth,Karlsruhe,Germany)、および1%ペニシリン/ストレプトマイシン(GE)が添加されたRPMI1640培地(Gibco)中で培養された。CD8+T細胞刺激では、PBMCが解凍されて、1μg/mlペプチドでパルス処理された。ペプチドパルス処理PBMC(5〜6×106細胞/ml)は、37℃および5%CO2で12日間培養された。0日目および1日目に、5ng/mlのIL−4(R&D Systems,Minneapolis,MN,USA)および5ng/mlのIL−7(Promokine,Heidelberg,Germany)が、培養液に追加された。3、5、7、および9日目に、2ng/mlのIL−2(R&D Systems)が培養液に追加された。ペプチド刺激PBMCは、12日目にELISPOTアッセイによって、13日目に細胞内サイトカイン染色によって、それぞれ機能解析された。CD4+T細胞刺激では、培養は、次の2つの修正を加えて、CD8+T細胞について記載されたようにして実施された:パルス処理は10μg/mlのHLAクラスIIペプチドを用いて実施され、IL−4およびIL−7は添加されなかった。
IFN−γELISPOTアッセイは、以前記載されたようにして実施された(Widenmeyer M,Griesemann H,Stevanovic S,Feyerabend S,Klein R,Attig S,et al.Promiscuous survivin peptide induces robust CD4+ T−cell responses in the majority of vaccinated cancer patients.Int J Cancer.2012 Jul 1;131(1):140−9)。手短に述べると、96ウェルニトロセルロースプレート(Millipore)が、1mg/mlのIFN−γmAb(Mabtech,Cincinnati,OH,USA)で被覆され、4℃で一晩培養された。プレートは、10%PHSによって37℃で2時間ブロックされた。5×105個の細胞/ウェルの予備刺激PBMCが、1μg/ml(HLAクラスI)または2.5μg/ml(HLAクラスII)ペプチドでパルス処理されて、24〜26時間培養された。読み取りは、製造会社の使用説明書に従って実施された。スポットは、ImmunoSpot S5分析器(CTL,Shaker Heights,OH,USA)を使用して計数された。>15スポット/ウェルカウントされ、ウェルあたりの平均スポットカウントが、陰性対照ウェルの平均スポット数よりも少なくとも3倍高ければ、T細胞応答は陽性と見なされた(がんイムノガイディングプログラム(CIP)ガイドラインに準拠する)。
ペプチド特異的CD8+T細胞の発生頻度および機能性が、細胞内IFN−γおよびTNF−α染色によって分析された。PBMCは、1μg/mlの個々のペプチドでパルス処理されて、10μg/mlのBrefeldin A(Sigma,St.Louis,MO,USA)および10μg/mlのGolgiStop(BD)の存在下で6〜8時間培養された。細胞は、Cytofix/Cytoperm(BD)、CD8−PECy7(Beckman Coulter,Fullerton,CA,USA)、CD4−APC(BD Bioscience)、TNF−α−PE(Beckman Coulter)、およびIFN−γ−FITC(BD)を使用して標識された。サンプルは、FACS Canto II上で分析された。
健康な単球との比較を可能にするために、免疫表現型検査が定義するようにCD15−AML芽球と少なくとも5%の正常なCD15+単球とを含有する、追加的な患者サンプル中で、HLA表面発現の定量化が実施された。HLA表面発現は、QIFIKIT(登録商標)定量的フローサイトメトリーアッセイキット(Dako,Glostrup,Denmark)を使用して、製造会社の使用説明書に従って分析された。手短に述べると、各三つ組み試験サンプルが、汎HLAクラスI特異的モノクローナル抗体(mAb)W6/32、HLA−DR特異的mAbL243(どちらも社内で作成)またはIgGアイソタイプ対照(BioLegend,SanDiego,CA,USA)で、それぞれ染色された。FITC−コンジュゲートウサギ抗マウスF(ab’)2フラグメント(Dako)による二次染色が、引き続いてPBMC、BMNCならびにQIFIKIT(登録商標)定量化ビーズ上で実施された。表面マーカー染色が、直接標識CD34(BD,Franklin Lakes,NJ,USA)、CD15(BD)、CD45(BD)、およびCD38(BD)を用いて実施された。LSR Fortessa細胞分析器(BD)上のフローサイトメトリー分析の直前に、7AAD(BioLegend)が生存マーカーとして添加された。
原発性AMLサンプルは、自己由来良性白血球と比較してHLA発現の損失または下方制御を示さない
対応する良性白血球と比較したAML芽球上のHLA発現レベルが、判定された。この目的を達成するために、CD15−AMLがある5人の患者と、5人の健康なBMNCドナーのパネルにおいて、HLA表面レベルがフローサイトメトリーによって定量化された。AML芽球はCD34+としてゲートされ、CD45med生存細胞およびそれらのHLA発現が、自己由来CD15+正常顆粒球および単球と比された。HLAレベルは不均一であり、全HLAクラスI分子カウントは、AML芽球上の45,189〜261,647分子/細胞から、CD15+細胞上の75,344〜239,496分子/細胞に及ぶことが分かった。3つ組みの患者個別分析におけるHLA表面発現は、3/5の患者で軽微ながらも有意な過剰発現を明らかにした(不対t検定、P≦0.001)。HLA−DR発現は、AML芽球上で1,476〜45,150分子/細胞、CD15+細胞で上で0〜3,252の範囲であり、全ての分析された患者においてAML芽球上で有意により高かった(P≦0.001)。対照のために、5人の健常BMNCドナーの造血幹細胞(HSC、CD34+CD38−)上で、HLA表面分子カウントが分析された。正常な単球と比較した、AML上の HLA表面発現の包括的統計解析は、平均HLAクラスIおよびII発現に有意差がないことを明らかにした。正常なHSC(248,587±35,351分子/細胞)上の平均HLAクラスIカウントは、AML芽球(116,445±37,855分子/細胞、P=0.034、図1c)よりも有意に高いことが分かった。正常なHSC(38,373±5,159分子/細胞)上の平均HLAクラスIIカウントは、AML芽球(17,103±7,604分子/細胞、P=0.053)と比較して有意に高いレベルを示した。
15人のAML患者(表1)のHLAクラスIリガンドームをマッピングすることで、6,104個の起源タンパク質に相当する合計13,238個の異なるペプチドが同定された。患者あたりの同定された(がん)固有のペプチド数は、563〜2,733個(平均1,299個のペプチド)の範囲であった。健常コホート(30人のPBMCドナー、5BMNC人のドナー)では、合計17,940個の固有ペプチドが同定された(PBMC上では17,322ペプチド/7,207起源タンパク;BMNC上では1,738ペプチド/1,384起源タンパク質、補足)。12人のAML患者におけるHLAクラスIIリガンドームの分析は、885個の起源タンパク質に相当する、合計2,816個の固有ペプチド(104〜753個のペプチド/患者の範囲、平均332個のペプチド)をもたらした。HLAクラスII健常対照コホート(13人のPBMC、2人のBMNCドナー)は、2,202個の異なるペプチドをもたらした(PBMC上では2,046個のペプチド/756個の起源タンパク質、BMNC上では317個のペプチド/164個の起源タンパク質)。HLAクラスI(スピアマンR=0.27、P=0.33)、またはHLAクラスII(R=0.31、P=0.33)のどちらについても、分析された細胞数とペプチド同定数の間に相関は見られなかった。
ペプチドワクチン接種の新規標的をAML中で同定するために、AML、PBMCmおよびBMNCコホートのHLAリガンド起源タンパク質が、比較されマッピングされた。HLA起源タンパク質の重複分析は、1,435個のタンパク質(マッピングされたAML起源プロテオームの3.6%)が、AML患者のHLAリガンドームで排他的に表示されることを明らかにした。AMLは、そのHLA起源タンパク質の75.5%(4,588個のタンパク質)をPBMCと共有し、19.3%(1,173個のタンパク質)をBMNCと共有することが分かった。BMNCのHLAリガンド起源タンパク質は、PBMCの起源プロテオームの89.9%(1,173個のタンパク質)との重複を示した。この無数の可能な標的から、本発明者らは、汎用ワクチン設計のために最も妥当で幅広く適用できる候補を選択することを目指した。したがって、本発明者らは、本発明者らのプラットフォーム上で抗原を選択するための最重要基準として、AMLリガンドーム中のAMLの排他的かつ高頻度の表示を定義した。これらの基準に従ったHLAリガンド起源タンパク質の格付けは、≧20%のAMLリガンドームで排他的に表示される、132個のタンパク質(AML起源プロテオームの2.2%)のサブセットを同定した。これらの2つの基準によって定義されるLiTAA(リガンドーム由来腫瘍関連抗原)中に、本発明者らは、患者リガンドームの8/15(53.3%)で検出されて、6つの異なるHLAリガンド(AEQFRLEQI(配列番号1)(B*44)、FTAEFSSRY(配列番号2)(A*03)、HHDESVLTNVF(配列番号3)(B*38:01)、REQDEAYRL(配列番号4)(B*44:25)、RPVMPSRQI(配列番号5)(B*07)、VQREYNLNF(配列番号6)(B*15)によって表示される、FAS随伴因子1(FAF1)を最上位として同定した。≧33%のAMLリガンドームにおける表示を示した最上位の15個のLiTAAの概要は、表2に示される。要約すると、最上位の132個の最も頻度の高いLiTAAのみが、幅広く適用できるAML特異的ペプチドワクチンの開発に適する25を超える異なるHLA拘束性がある、341個の異なる天然に提示されるHLAリガンド(LiTAP、リガンドーム由来腫瘍関連ペプチド)のパネルを提供する。さらに、1,727個の異なるHLAリガンドによって表示される、<20%の表示頻度があるさらなる1,389個のAML限定的起源タンパク質が、より個別化されたワクチン設計アプローチのリポジトリの役割を果たしてもよい。
二次データマイニングアプローチは、天然に提示されるHLAリガンドのデータセット中における、(Anguille S,Van Tendeloo VF,Berneman ZN.Leukemia−associated antigens and their relevance to the immunotherapy of acute myeloid leukemia.Leukemia.2012 Oct;26(10):2186−96で概説されるような)確立されたAML関連抗原の同定および格付けに焦点を合わせた。これらの既報の抗原の29個を表示する、122個の異なるHLAリガンドが同定された。著しいことに、これらの抗原の>80%(24/29)は、良性PBMCおよび/またはBMNC上でもまた表示され、したがってAML特異的でないことが発見された。
異なるAMLサブセットにわたる、本発明者らの新規標的の適用性を評価するために、FMS様チロシンキナーゼ3遺伝子内縦列重複(FLT3−ITD、n=8)およびFLT3野性型(FLT3−WT、n=7)患者サブセット中における、LiTAAの表示が特性決定された。HLAクラスIリガンドームの類似性インデクシングは、FLT3−WTサブセットが、FLT3−TIDサブセット(平均1687.0±156.5、n=21、P<0.0001、図6)よりも有意に低い、内部不均一性(平均916.2±70.6、n=21)を提示することを明らかにした。AML限定的HLA起源タンパク質(FLT3−WT:748個のタンパク質、FLT3−ITD:926個のタンパク質)の重複分析は、それぞれ32.0%(FLT3−WT/FLT3−ITD)および25.6%(FLT3−ITD/FLT3−WT)の重複を明らかにした(図3d)。注目すべきことに、高位のLiTAAの42/46(91.3%)は、双方のサブセットで表示されることが分かった(図3E)。FLT3−ITDサブセット中で排他的に同定された、3つのHLAリガンド起源タンパク質SKP1(5/8)、C16orf13(5/8)、およびERLIN1(4/8)は、表示頻度が≧50%に達した。FLT3−WT特異的LiTAA MUL1は、FLT3−WTリガンドームの4/7(57.1%)で表示される。総合すると、これらのデータは、高度に頻繁なサブセット特異的標的のごく一部を指摘する一方で、標的選択するための考案されたHLAリガンドームのコホート構成分析ストラテジーを支持する。
本発明者らのHLA−A*03LiTAPの免疫原性および特異性を評価するために、本発明者らは、次に、12日間免疫復活IFN−γELISPOTアッセイを実施した。6人のAML患者ならびに8人の健常人から得られたPBMCが、最高位のHLA−A*03LiTAPの異なる貯留(PI 1およびPI 2)で刺激された。2/6のAMLサンプルでは、用いられたペプチド貯留の双方について、有意なIFN−γ分泌が観察された(図4a)。これらの知見を立証するために、12日間刺激前PBMC(図4b)を使用して、IFN−γおよびTNF−αのための細胞内サイトカイン染色およびフローサイトメトリーが実施された。PI 1およびPI 2特異的CD8+T細胞応答は、IFN−γ(PI 1:1.6%、PI 2:1.7%のCD8+T細胞)およびTNF−α(PI 1:2.6%、PI 2:2.4%のCD8+T細胞)分泌によって機能的に特徴付けられることが確認された。PI 1およびPI 2で刺激されたA*03陽性健常ドナーPBMCを使用した検証ELISPOTアッセイは、有意なIFN−γ分泌がないことを示した(0/8、図4c)。これらの最初の特性決定は、本明細書で定義されるLiTAPが、AML特異的T細胞エピトープとして潜在的に機能することを示す。
HLAクラスII起源プロテオームの重複分析は、1,079個の異なるHLAリガンドによって表示される396個のタンパク質(44.7%)が、AMLのHLAリガンドーム中で排他的に表示されることを同定した。AMLは、それぞれPBMCおよびBMNCと、その起源プロテオームの53.3%(472個のタンパク質)および15.1%(134個のタンパク質)を共有することが分かった。BMNCは、PBMCとの88.2%(127個のタンパク質)の起源プロテオーム重複を示した。HLAクラスIについて上述されるような比較HLA起源プロテオームプロファイリングを実施することで、本発明者らは、≧20%の表示頻度がある36個のLiTAA(152個の異なるHLAクラスIIリガンドによって表示される)を同定できた。最高位クラスII LiTAA(A1BG)は6/12(50%)の患者で同定されて、5個の異なるリガンドによって表示される。HLAクラスIおよびクラスIIリガンドームの双方で提示されるLiTAAを同定するために、本発明者らは、引き続いて、それぞれのAML限定的起源プロテオームを比較した。これは、43個の共通起源タンパク質(それぞれ3.0%/10.4%のHLAクラスI/HLAクラスII起源プロテオーム)のみのパネルを明らかにした。それぞれのクラスI対クラスIIリガンドマッピングは、完全な包埋HLAクラスIリガンドを含有する、3つのHLAクラスIIペプチドを同定した。
本発明のペプチドをコードする遺伝子発現プロファイリング
MHC分子によって腫瘍細胞の表面に提示されるとAML中で同定された全てのペプチドが、免疫療法に適するとは限らないが、それはこれらのペプチドの大多数が、多数の細胞型によって発現される正常な細胞タンパク質に由来するためである。これらのペプチドのごく少数のみが腫瘍関連であり、それらが由来する腫瘍を高特異性で認識するT細胞を誘導できると思われる。このようなペプチドを同定し、ワクチン接種によって誘導される自己免疫リスクを最小化するために、本発明者らは、大多数の正常組織と比較して腫瘍細胞上で過剰発現される、タンパク質に由来するペプチドに焦点を合わせた。
外科的に除去された組織標本は、告知に基づく同意書を各患者から得た後に、University of Heidelberg,Heidelberg,Germanyによって提供された(実施例1を参照されたい)。腫瘍組織標本は、外科手術直後に液体窒素中でスナップ凍結され、その後、液体窒素下で乳鉢と乳棒によって均質化された。全RNAは、TRI試薬(Ambion,Darmstadt,Germany)を使用してこれらのサンプルから調製され、RNeasy(QIAGEN,Hilden,Germany)による精製がそれに続き;どちらの方法も製造業者のプロトコルに従って実施された。
全ての腫瘍および正常組織RNAサンプルの遺伝子発現解析は、Affymetrix Human Genome(HG)U133AまたはHG−U133 Plus 2.0オリゴヌクレオチドマイクロアレイ(Affymetrix,Santa Clara,CA,USA)によって実施された。全てのステップは、Affymetrixマニュアルに従って実施された。簡単に述べると、マニュアルに記載されるようにして、SuperScript RTII(Invitrogen)およびオリゴdT−T7プライマー(MWG Biotech,Ebersberg,Germany)を使用して、二本鎖cDNAが5〜8μgの全RNAから合成された。生体外転写は、U133AアレイのためのBioArray High Yield RNA Transcript Labelling Kit(ENZO Diagnostics,Inc.,Farmingdale,NY,USA)、またはU133 Plus 2.0のためのGeneChip IVT標識キット(Affymetrix)によって実施され、cRNA断片化、ハイブリダイゼーション、およびストレプトアビジン−フィコエリトリンとビオチン化抗ストレプトアビジン抗体(Molecular Probes,Leiden,Netherlands)による染色がそれに続いた。画像は、Agilent 2500A GeneArray Scanner(U133A)またはAffymetrix Gene−Chip Scanner 3000(U133 Plus 2.0)でスキャンされ、全てのパラメータについてデフォルト設定を使用して、GCOSソフトウェア(Affymetrix)によってデータ解析された。正規化のために、Affymetrixによって提供される100個のハウスキーピング遺伝子が使用された。相対的発現値は、ソフトウェアによって与えられるシグナルlog比から計算され、正常な腎臓サンプルが自由裁量で1.0に設定された。
AML MHCクラスI提示ペプチドの生体外免疫原性
本発明のTUMAPの免疫原性に関する情報を得るために、本発明者らは、ペプチド/MHC複合体および抗CD28抗体を負荷した人工抗原提示細胞(aAPC)によるCD8+T細胞の反復刺激に基づく、生体外T細胞プライミングアッセイを用いて調査を実施した。このようにして、本発明者らは、これまでに本発明の9個のHLA−A*0201拘束性TUMAPの免疫原性を示し得て、これらのペプチドが、それに対するCD8+前駆T細胞がヒトに存在する、T細胞エピトープであることを実証した。
ペプチドMHC複合体(pMHC)および抗CD28抗体を負荷した、人工抗原提示細胞による生体外刺激を実施するために、本発明者らは、最初に、告知に基づく同意後に、Transfusion Medicine Tuebingen,Germanyから得られた健常ドナーのCD8ミクロビーズ(Miltenyi Biotec,Bergisch−Gladbach,Germany)を使用した正の選択を通じて、新鮮HLA−A*02白血球除去生成物からCD8+T細胞を単離した。
試験されたHLAクラスIペプチドでは、ペプチド特異的T細胞系の生成によって、生体外免疫原性が実証され得る。本発明の2種のペプチドのTUMAP特異的多量体染色後の代表的フローサイトメトリー結果が、対応する陰性対照と共に図4に示される。
ペプチドの合成
全てのペプチドは、Fmocストラテジーを使用する、標準的な十分に確立された固相ペプチド合成を使用して合成された。分取RP−HPLCによる精製後、イオン交換法を実施して、生理学的適合性カウンターイオン(例えばトリフルオロ酢酸、酢酸、アンモニウムまたは塩化物)が組み込まれた。
MHC結合アッセイ−MHCクラスI
本発明によるT細胞ベースの治療法のための候補ペプチドは、それらのMHC結合能力(親和性)についてさらに試験された。個々のペプチドMHC複合体は、分析された関心のあるペプチドで交換することによって生成された。ペプチド受容性MHC分子を効果的に結合して安定化し得るペプチド候補のみが、MHC複合体の分離を防止する。交換反応の収率を判定するために、安定化MHC複合体の軽鎖(β2m)の検出に基づくELISAが実施された。アッセイは、概して、Rodenko et al.(Rodenko,B.et al.,Nat Protoc.1(2006):1120−1132)に記載されるようにして実施された。
MHC結合アッセイ−MHCクラスII
HLAクラスIIタンパク質は、多数のハプロタイプによってコードされる、3つの主要なアイソタイプHLA−DR、−DP、−DQに分類される。様々なαおよびβ鎖の組み合わせは、任意の母集団に見られるHLAクラスIIタンパク質の多様性を増大させる。したがって、選択されたHLAクラスII TUMAPは、かなりの割合の患者で、効果的なT細胞応答に寄与するために、数種の異なるHLA−DR分子に結合しなくてはならない(すなわち乱交雑結合能力を示す)。
Babbio, F. et al., Cell Cycle 3 (2004): 486-490
Bidkhori, G. et al., PLoS.One. 8 (2013): e67552
Enesa, K. etal., Adv.Exp.Med.Biol. 809 (2014):33-48
Greiner, J. et al., Int.J Cancer 106 (2003): 224-231
Huang, A. et al., Cancer Res. 65 (2005): 5607-5619
Isaksson, H. S. et al.,Oncotarget. 5 (2014): 4040-4049
Kuznetsova, E. B. et al.,Mol.Biol.(Mosk) 41 (2007): 624-633
Liu, D. et al., Int.J Oncol. 45 (2014): 1232-1240
McLellan, J. et al.,Mol.Biol.Cell 20 (2009): 5306-5313
Oh, Y. et al., J Biol.Chem 287 (2012): 17517-17529
Price, J. C. et al., PLoS.One. 8 (2014): e63313
Rao, W. et al., Carcinogenesis 35 (2014a): 1573-1581
Rao, W. et al., PLoS.One. 9 (2014b): e85705
RefSeq, The NCBI handbook [Internet], Chapter 18(2002)
Sand, M. et al., Mol.Carcinog. 51 (2012): 916-922
Scanlan, M. J. et al., CancerImmun. 1 (2001): 4
Soupene, E. et al., J Lipid Res. 49 (2008): 1103-1112
Tian, Y. et al., Int.J Oncol. 43 (2013): 2082-2090
Uchiyama, K. etal., J Cell Biol. 159 (2002):855-866
Vanneste, D. etal., Curr.Biol. 19 (2009): 1712-1717
Yotov, W. V. etal., Genes Chromosomes.Cancer 26(1999): 62-69
Zhang, J. etal., J Allergy Clin.Immunol. 115(2005): 548-554
Zhou, B. et al., Cancer Biol.Ther13 (2012a): 871-879
Zhou, B. et al., Cancer Lett. 322 (2012b): 195-203
Claims (48)
- 配列番号1〜配列番号325、配列番号326〜配列番号447または配列番号448〜配列番号605から選択される配列と少なくとも80%同一であるアミノ酸配列を含んでなる、9〜100アミノ酸長のペプチド、またはその薬学的に許容可能な塩。
- ヒト主要組織適合性複合体(MHC)クラスI分子および/またはヒト主要組織適合性複合体(MHC)クラスII分子に結合する能力を有する、請求項1に記載のペプチド。
- 9〜30アミノ酸長である、請求項1に記載のペプチド。
- 10アミノ酸長以下のN末端および/またはC末端アミノ酸伸長を含んでなる、請求項1に記載のペプチド。
- (a)配列番号1〜配列番号325、配列番号326〜配列番号447または配列番号448〜配列番号605と少なくとも80%同一であるアミノ酸配列からなるペプチド;
(b)10アミノ酸長以下のコア配列のN末端伸長を有する(a)のペプチド;および
(c)10アミノ酸長以下のC末端伸長を有する(a)または(b)のペプチド
からなる群から選択される、請求項1〜3のいずれか一項に記載のペプチド。 - 前記アミノ酸配列が、配列番号1〜配列番号325、配列番号326〜配列番号447または配列番号448〜配列番号605と少なくとも90%同一である、請求項1〜5のいずれか一項に記載のペプチド。
- 前記アミノ酸配列が、配列番号1〜配列番号325、配列番号326〜配列番号447または配列番号448〜配列番号605と少なくとも95%同一である、請求項1〜6のいずれか一項に記載のペプチド。
- 前記アミノ酸配列が、配列番号1〜配列番号325、配列番号326〜配列番号447または配列番号448〜配列番号605のいずれかを含んでなる、請求項1〜6のいずれか一項に記載のペプチド。
- 前記アミノ酸配列が、配列番号1〜配列番号325、配列番号326〜配列番号447または配列番号448〜配列番号605のいずれかからなる、請求項1または2に記載のペプチド。
- 前記ペプチドが、修飾されおよび/または非ペプチド結合を含む、請求項1〜9のいずれか一項に記載のペプチド。
- 配列番号1〜配列番号325、配列番号326〜配列番号447または配列番号448〜配列番号605からなる群から選択されるアミノ酸配列と少なくとも80%の同一性を有するHLAリガンドと、反応性のT細胞受容体。
- 前記アミノ酸配列が、配列番号1〜配列番号325または配列番号448〜配列番号605と少なくとも90%、または少なくとも95%同一である、請求項11に記載のT細胞受容体。
- 前記アミノ酸配列が、配列番号1〜配列番号325または配列番号448〜配列番号605のいずれかを含んでなる、請求項11または12に記載のT細胞受容体。
- 前記アミノ酸配列が、配列番号1〜配列番号325、配列番号326〜配列番号447または配列番号448〜配列番号605のいずれかからなる、請求項11〜13のいずれか一項に記載のT細胞受容体。
- (a)配列番号1〜配列番号325または配列番号448〜配列番号605と少なくとも80%と同一であるアミノ酸;および
(b)HLA−DR抗原関連不変鎖(Ii)のN末端アミノ酸1〜80
を含んでなる、融合タンパク質。 - 前記(a)のアミノ酸配列が、配列番号1〜配列番号325または配列番号448〜配列番号605と少なくとも90%、好ましくは少なくとも95%同一である、請求項15に記載の融合タンパク質。
- 前記(a)のアミノ酸配列が、配列番号1〜配列番号325または配列番号448〜配列番号605を含んでなる、請求項16に記載の融合タンパク質。
- (a)請求項1〜10のいずれか一項に記載のペプチド;
(b)請求項11〜14のいずれか一項に記載のT細胞受容体;または
(c)請求項15〜17のいずれか一項に記載の融合タンパク質
をエンコードする核酸。 - DNA、cDNA、PNA、RNAまたはそれらの組み合わせである、請求項に18記載の核酸。
- 請求項18または19に記載の核酸を含んでなる、発現ベクター。
- 請求項18または19に記載の核酸、または請求項20に記載の発現ベクターを含んでなる、宿主細胞。
- 例えば、樹状細胞などの抗原提示細胞である、請求項21に記載の宿主細胞。
- 請求項1〜10のいずれか一項に記載のペプチド、請求項12〜14のいずれか一項に記載のT細胞受容体、または請求項15〜17のいずれか一項に記載の融合タンパク質を製造する方法であって、請求項21に記載の宿主細胞を培養するステップと、前記宿主細胞および/またはその培養液から前記ペプチド、前記T細胞受容体、または前記融合タンパク質を単離するステップとを含んでなる、方法。
- CTLを適切な抗原提示細胞の表面に発現される抗原負荷ヒトクラスIまたはII MHC分子に、前記CTLが抗原特異的様式で活性化するのに十分な時間にわたり、生体外で接触させるステップを含んでなり、前記抗原が請求項1〜10のいずれか一項に記載のペプチドである、活性化細胞傷害性Tリンパ球(CTL)を製造するためのインビトロ法。
- 前記抗原が、十分な量の前記抗原を抗原提示細胞に接触させることで、適切な抗原提示細胞の表面に発現されるクラスIまたはII MHC分子上に負荷される、請求項24に記載の方法。
- 前記抗原提示細胞が、請求項1〜9のいずれか一項に記載の前記ペプチドを発現する能力がある発現ベクターを含んでなる、請求項25に記載の方法。
- 請求項24〜26のいずれか一項に記載の方法によって製造される、活性化細胞毒性Tリンパ球(CTL)。
- 請求項27に記載の細胞傷害性Tリンパ球(CTL)の有効数を患者に投与するステップを含んでなる、患者において標的がん細胞を死滅させる方法。
- 請求項1〜10のいずれか一項に記載のペプチド、請求項12〜14のいずれか一項に記載のT細胞受容体、請求項15〜17のいずれか一項に記載の融合タンパク質、請求項18または19に記載の核酸、請求項20に記載の発現ベクター、請求項22または23に記載の宿主細胞、または請求項27に記載の活性化細胞傷害性Tリンパ球の薬剤としての、または薬剤の製造における使用。
- 前記薬剤がワクチンである、請求項29に記載の使用。
- 前記薬剤ががんに対して有効である、請求項29または30に記載の使用。
- 前記がんが、急性骨髄性白血病および/または慢性リンパ管白血病である、請求項29〜31のいずれか一項に記載の使用。
- 請求項1〜10のいずれか一項に記載のペプチドからなる群から選択される少なくとも1つの活性成分、請求項12〜14のいずれか一項に記載のT細胞受容体、請求項15〜17のいずれか一項に記載の融合タンパク質、請求項18または19に記載の核酸、請求項20に記載の発現ベクター、請求項22または23に記載の宿主細胞、および請求項27に記載の活性化細胞毒性Tリンパ球、および薬学的に許容可能な担体を含んでなる、医薬組成物。
- a)FAF1、PLXND1、GMNN、CPQ、ATP5L、ITGA5、SKP1、CHD1L、TGFBRAP1、NGLY1、APLP2、KIF2C、ELP3、DGKZ、MYCH2、SLC31A2、ERLIN1、SERPINB2、ABHD2、GAA、OPRL1、WDR45B、TUFM、MFAP1、ZNF543、STK4、ZKSCAN8、FNDC3B、TMEM164、THOC7、KLF2、TMEM126B、UFD1L、MUL1、VCPIP1、KIF20B、CSF3R、NOC4L、EMILIN2、SHANK3、UCK2、PHPT1、KIF15、SLC12A6、DOLK、EEF2K、PIK3R2、TMEM194A、CCS、ZNF264、LYRM1、NBN、TIPRLTIP41、RPS6KA4、RCBTB2、PAK4、ERCC1、DMD、UNG、CPA3、AZU1、ATP2B4、MARK3、HLA−DMA、NDUFS1、S100A11、HAL、PRIM1、RENBP、CCNG1、ZNF131、HRSP12、EIF6、TMPRSS3、UBE2G2、NOP14、TFCP2、TARBP1、TTL12、HLX、CBX2、ZNF638、C3AR1、TAF9、FSCN1、ZNF805、CLEC12A、SLX4IP、RLTPR、RNF19B、DDX46、LRRC8D、C16orf62、GOLGA7、RHOT1、BBS1、CEP76、GANC、ATP8B4、PPIL4、HPT1、CHTF18、DGCR8、ANKS1A、TOP1MT、PHACTR3、CCDC115、SORCS2、ACCS、ACBD6、ORAI3、SIKE1、C9orf156、EDEM2、NUP85、PANK2、SPATC1L、IKZF4、DHX33、METTL7A、QTRTD1、TMBIM4、RAVER2、SDAD1、UCKL1、STMN3、CHIC2、ODF2L、PRR12、FARSA、CTDP1、A1BG、CORO1A、RPS5、C19orf10、PLIN3、CLSTN1、HSP90B1、B4GALT1、SPN、METAP1、HSPG2、QSOX1、MANBA、CREG1、LDHA、CP、COL1A1、CRP、APRT、MBL2、IFI30、LBP、RAB5A、ICAM3、MAN1A1、RBMX、PBX2、YARS、TPM4、RBL36A、GANAB、HSP90B2P、LAIR1、GALNT7、ARRDC1、およびERGIC1からなる群から選択されるタンパク質に由来して、ヒト主要組織適合性複合体(MHC)クラスI分子および/またはヒト主要組織適合性複合体(MHC)クラスII分子に結合する能力を有するペプチド;
b)(a)に記載のペプチドと反応性のT細胞受容体;
c)(a)に記載のペプチドと、HLA−DR抗原関連不変鎖(Ii)のN末端アミノ酸1〜80とを含んでなる融合タンパク質;
d)a)〜c)のいずれかをコードする核酸、または前記核酸を含んでなる発現ベクター;
e)dの発現ベクターを含んでなる宿主細胞;および
f)CTLを適切な抗原提示細胞の表面に発現されるa)に記載のペプチドと、前記CTLを抗原特異的様式で活性化するのに十分な時間にわたり、生体外で接触させるステップを含んでなる方法によって得られる、活性化細胞毒性Tリンパ球(CTL)
からなる群から選択される、少なくとも1つの活性成分;および
薬学的に許容可能な担体
を含んでなる医薬組成物。 - 請求項34に記載の医薬組成物の有効量を患者に投与するステップを含んでなる、患者において標的細胞を死滅させる方法。
- (a)少なくとも1つの原発性腫瘍サンプルから、そして少なくとも1つの対応する正常な組織サンプルから、天然に提示されるHLAリガンドを溶出して同定するステップと;
(b)同定された前記HLAリガンドに基づいて、前記少なくとも腫瘍サンプルおよび前記少なくとも正常な組織サンプルのリガンドームを生成するステップと;
(c)a)前記少なくとも1つの腫瘍サンプルの細胞によって排他的に提示される抗原に由来し、b)前記少なくとも1つの腫瘍サンプルの前記リガンドーム中で高頻度の提示を示す、包含に適する少なくとも1つのHLAリガンドを選択するステップと
を含んでなる、ペプチドベースのワクチンへの包含に適する腫瘍関連ペプチドを同定する方法。 - 前記提示頻度が、少なくとも5%、少なくとも10%、および少なくとも20%から選択される、請求項36に記載の方法。
- 複数のサンプルが使用されて、複数のリガンドームが生成される、請求項36または37に記載の方法。
- 個々の患者からの腫瘍サンプルがステップ(a)で使用される、個別化ペプチドベースワクチンへの包含に適する腫瘍関連ペプチドを同定する方法。
- ステップ(c)の前記選択するステップが、前記リガンドームと、対応する非腫瘍組織との比較で腫瘍中の免疫原性および過剰提示について予備選別されたペプチドのデータベースとを比較するステップを含んでなる、請求項36〜39のいずれか一項に記載の方法。
- 前記同定するステップが、前記腫瘍サンプルに由来するMHC分子から結合ペプチドを溶出させるステップと、前記溶出ペプチドを配列決定するステップとを含んでなる、請求項36〜40のいずれか一項に記載の方法。
- 前記少なくとも正常な組織サンプルが、患者からの腫瘍サンプルと組織型が一致する、請求項36〜41のいずれか一項に記載の方法。
- データベースに含まれる前記ペプチドが、
1)前記腫瘍材料からのHLAリガンドを質量分析法によって同定するステップと;
2)マイクロアレイを使用するゲノム規模メッセンジャーリボ核酸(mRNA)発現解析を使用して、一連の正常組織と比較することで、前記腫瘍材料中で過剰発現される遺伝子を同定するステップと;
3)遺伝子発現データによって同定された前記HLAリガンドを比較するステップと;
4)ステップb)で検出された特異的発現または過剰発現される遺伝子によってコードされるペプチドを選択するテップと;
5)ステップc)からの選択されたHLAリガンドを正常組織と対比して腫瘍組織上で再検出することで、mRNAレベルにおける過剰発現の関連性を確認するステップと;
6)選択されたペプチドによって、生体内T細胞応答誘導が達成され得るかどうかを評価するために、患者または健常ドナーからのヒトT細胞を使用して生体外免疫原性アッセイを実施するステップと
を含んでなる方法によって同定される、請求項39〜42のいずれか一項に記載の方法。 - 前記データベースに含まれるペプチドの免疫原性が、生体外免疫原性アッセイ、個々のHLA結合に対する患者免疫モニタリング、MHC多量体染色、ELISPOTアッセイ、および細胞内サイトカイン染色の群から選択される方法によって判定される、請求項40〜43のいずれか一項に記載の方法。
- 前記データベースが、配列番号1〜配列番号605のペプチドを含んでなる、請求項40〜44のいずれか一項に記載の方法。
- 前記個々の患者からの正常な対応する組織と比較して、前記腫瘍サンプルに固有の少なくとも1つの変異を有する、少なくとも1つのペプチドを同定するステップと、任意選択的に、前記ペプチドをワクチンへの包含のために選択するステップとをさらに含んでなる、請求項40〜43のいずれか一項に記載の方法。
- 前記少なくとも1つの変異が、全ゲノム配列決定によって同定される、請求項46に記載の方法。
- (c)に従って選択された少なくとも1つの腫瘍関連ペプチドを含んでなるペプチドベースのワクチンを製造するステップをさらに含んでなり、前記ペプチドベースのワクチンが好ましくは個別化される、請求項36〜47のいずれか一項に記載の方法。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201461990980P | 2014-05-09 | 2014-05-09 | |
GBGB1408255.6A GB201408255D0 (en) | 2014-05-09 | 2014-05-09 | Novel immunotherapy against several tumours of the blood, such as acute myeloid leukemia (AML) |
GB1408255.6 | 2014-05-09 | ||
US61/990,980 | 2014-05-09 | ||
PCT/EP2015/060168 WO2015169945A2 (en) | 2014-05-09 | 2015-05-08 | Novel immunotherapy against several tumors of the blood, such as acute myeloid leukemia (aml) |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2017524337A true JP2017524337A (ja) | 2017-08-31 |
JP2017524337A5 JP2017524337A5 (ja) | 2019-10-03 |
JP6659582B2 JP6659582B2 (ja) | 2020-03-04 |
Family
ID=51032516
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016567242A Expired - Fee Related JP6659582B2 (ja) | 2014-05-09 | 2015-05-08 | 急性骨髄性白血病(aml)などの血液のいくつかの腫瘍に対する新規免疫療法 |
Country Status (25)
Country | Link |
---|---|
US (2) | US10064924B2 (ja) |
EP (3) | EP3140319B1 (ja) |
JP (1) | JP6659582B2 (ja) |
KR (1) | KR20170003976A (ja) |
CN (1) | CN106459167A (ja) |
AU (2) | AU2015257652B2 (ja) |
BR (1) | BR112016025035A2 (ja) |
CA (1) | CA2946349A1 (ja) |
CR (1) | CR20160531A (ja) |
DK (1) | DK3140319T3 (ja) |
EA (2) | EA035456B1 (ja) |
ES (1) | ES2747734T3 (ja) |
GB (1) | GB201408255D0 (ja) |
HU (1) | HUE045177T2 (ja) |
LT (1) | LT3140319T (ja) |
MA (3) | MA49280A (ja) |
ME (1) | ME03565B (ja) |
MX (1) | MX2016014711A (ja) |
PL (1) | PL3140319T3 (ja) |
PT (1) | PT3140319T (ja) |
RS (1) | RS59471B1 (ja) |
SG (1) | SG11201608332SA (ja) |
SI (1) | SI3140319T1 (ja) |
TW (2) | TW201920246A (ja) |
WO (1) | WO2015169945A2 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019102710A1 (ja) * | 2017-11-21 | 2019-05-31 | 尚史 三輪 | ヒト癌細胞転移阻害薬およびヒト癌細胞判定薬 |
Families Citing this family (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10704021B2 (en) | 2012-03-15 | 2020-07-07 | Flodesign Sonics, Inc. | Acoustic perfusion devices |
US10000533B2 (en) | 2014-06-20 | 2018-06-19 | Immatics Biotechnologies Gmbh | Immunotherapy against several tumors of the blood, in particular chronic lymphoid leukemia (CLL) |
US11708572B2 (en) | 2015-04-29 | 2023-07-25 | Flodesign Sonics, Inc. | Acoustic cell separation techniques and processes |
MA42420A (fr) | 2015-05-13 | 2018-05-23 | Agenus Inc | Vaccins pour le traitement et la prévention du cancer |
GB201521746D0 (en) | 2015-12-10 | 2016-01-27 | Immatics Biotechnologies Gmbh | Novel peptides and combination of peptides for use in immunotherapy against CLL and other cancers |
GB201521894D0 (en) * | 2015-12-11 | 2016-01-27 | Immatics Biotechnologies Gmbh | Novel peptides and combination of peptides for use in immunotherapy against various cancers |
PE20181535A1 (es) | 2015-12-16 | 2018-09-26 | Gritstone Oncology Inc | Identificacion, fabricacion y uso de neoantigeno |
SG10202111399YA (en) | 2015-12-22 | 2021-11-29 | Immatics Biotechnologies Gmbh | Peptides and combination of peptides for use in immunotherapy against breast cancer and other cancers |
EP4219524A3 (en) * | 2016-04-06 | 2023-10-18 | immatics biotechnologies GmbH | Novel peptides and combination of peptides for use in immunotherapy against aml and other cancers |
WO2017174645A1 (en) * | 2016-04-06 | 2017-10-12 | Immatics Biotechnologies Gmbh | Novel peptides and combination of peptides for use in immunotherapy against aml and other cancers |
JP2019513752A (ja) * | 2016-04-07 | 2019-05-30 | ケース ウエスタン リザーブ ユニバーシティ | 神経変性疾患を治療するためのtdp−43のミトコンドリア局在化阻害剤 |
US11214789B2 (en) | 2016-05-03 | 2022-01-04 | Flodesign Sonics, Inc. | Concentration and washing of particles with acoustics |
JP7075125B2 (ja) * | 2016-05-25 | 2022-05-25 | イマティクス バイオテクノロジーズ ゲーエムベーハー | 標的としてのおよび胆嚢がんおよび胆管がんおよびその他のがんに対する免疫療法で使用するための新規ペプチド、ペプチド組み合わせ |
MA45491A (fr) * | 2016-06-27 | 2019-05-01 | Juno Therapeutics Inc | Épitopes à restriction cmh-e, molécules de liaison et procédés et utilisations associés |
EP3504230A1 (en) * | 2016-08-23 | 2019-07-03 | GlaxoSmithKline Biologicals SA | Fusion peptides with antigens linked to short fragments of invariant chain (cd74) |
TWI796299B (zh) | 2016-08-26 | 2023-03-21 | 德商英麥提克生物技術股份有限公司 | 用於頭頸鱗狀細胞癌和其他癌症免疫治療的新型肽和支架 |
KR102639592B1 (ko) | 2016-12-08 | 2024-02-21 | 이매틱스 바이오테크놀로지스 게엠베하 | 짝짓기가 향상된 t 세포 수용체 |
DE102016123893A1 (de) | 2016-12-08 | 2018-06-14 | Immatics Biotechnologies Gmbh | T-Zellrezeptoren mit verbesserter Bindung |
WO2018189152A2 (en) | 2017-04-10 | 2018-10-18 | Immatics Biotechnologies Gmbh | Peptides and combination of peptides for use in immunotherapy against leukemias and other cancers |
EP3609522A4 (en) * | 2017-04-10 | 2021-05-05 | Yoram Palti | METHODS AND COMPOUNDS FOR THE TREATMENT OF DIABETES |
CN112521478A (zh) | 2017-04-10 | 2021-03-19 | 伊玛提克斯生物技术有限公司 | 用于白血病和其他癌症免疫治疗的肽和肽组合物 |
JP7227237B2 (ja) | 2017-10-10 | 2023-02-21 | グリットストーン バイオ インコーポレイテッド | ホットスポットを利用した新生抗原の特定 |
AU2018373154A1 (en) | 2017-11-22 | 2020-07-02 | Gritstone Bio, Inc. | Reducing junction epitope presentation for neoantigens |
WO2019210055A2 (en) | 2018-04-26 | 2019-10-31 | Agenus Inc. | Heat shock protein-binding peptide compositions and methods of use thereof |
CN108707666B (zh) * | 2018-05-28 | 2021-04-09 | 陕西中医药大学第二附属医院 | Dgkz基因作为白血病检测的生物标志物的应用 |
CN109663128A (zh) * | 2018-11-21 | 2019-04-23 | 中国农业大学 | 一种肺动脉高压标志物及其作为治疗靶点的应用 |
CN112409449B (zh) * | 2019-08-19 | 2023-12-15 | 辽宁中健医药科技有限公司 | Hla-a0201限定性kif15特异性抗肿瘤ctl优势表位肽及应用 |
CN112980955A (zh) * | 2021-03-05 | 2021-06-18 | 南昌大学第二附属医院 | Emilin2作为胶质瘤替莫唑胺耐药检测、治疗及预后分子靶点的应用 |
CN113130001B (zh) * | 2021-03-31 | 2023-07-18 | 甘肃中医药大学 | 一种天然化合物与抗肿瘤化合物配伍的筛选方法 |
US20240197919A1 (en) * | 2021-05-04 | 2024-06-20 | California Institute Of Technology | Recombinant aavs for delivery to central nervous system and brain vasculature |
EP4392441A1 (en) * | 2021-08-24 | 2024-07-03 | Immatics US, Inc. | Selection of immune cells using peptide mhc complexes generated by conditional ligand exchange |
CN114703274B (zh) * | 2022-04-01 | 2023-08-15 | 中国人民解放军总医院 | Phpt1在预警和/或治疗高原病中的应用 |
CN117586344A (zh) * | 2022-08-12 | 2024-02-23 | 上海交通大学医学院附属瑞金医院 | 靶向flt3-d835突变的抗原肽及其在肿瘤免疫治疗中的应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003530083A (ja) * | 1999-12-10 | 2003-10-14 | エピミューン インコーポレイテッド | ペプチドおよび核酸組成物を使用する、HER2/neuに対する細胞性免疫応答の誘導 |
JP2005514029A (ja) * | 2001-11-07 | 2005-05-19 | マンカインド コーポレイション | 抗原提示細胞におけるエピトープ同調 |
Family Cites Families (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4440859A (en) | 1977-05-27 | 1984-04-03 | The Regents Of The University Of California | Method for producing recombinant bacterial plasmids containing the coding sequences of higher organisms |
US4704362A (en) | 1977-11-08 | 1987-11-03 | Genentech, Inc. | Recombinant cloning vehicle microbial polypeptide expression |
DK171727B1 (da) | 1978-12-22 | 1997-04-14 | Biogen Inc | Rekombinante hepatitis B virus DNA-molekyler, værtsorganismer transformeret hermed, HBV-antigenspecifikke polypeptider, DNA-sekvenser kodende for HBV-antigenspecifikke polypeptider, metoder til påvisning af hepatitis B virus-antistoffer, metoder til fremstilling af nævnte DNA-molekyler, fremgangsmåder til fremstilling af nævnte polypeptider og midler til påvisning af HBV-infektion |
US4530901A (en) | 1980-01-08 | 1985-07-23 | Biogen N.V. | Recombinant DNA molecules and their use in producing human interferon-like polypeptides |
US4342566A (en) | 1980-02-22 | 1982-08-03 | Scripps Clinic & Research Foundation | Solid phase anti-C3 assay for detection of immune complexes |
US4678751A (en) | 1981-09-25 | 1987-07-07 | Genentech, Inc. | Hybrid human leukocyte interferons |
US4766075A (en) | 1982-07-14 | 1988-08-23 | Genentech, Inc. | Human tissue plasminogen activator |
US4582800A (en) | 1982-07-12 | 1986-04-15 | Hoffmann-La Roche Inc. | Novel vectors and method for controlling interferon expression |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4757006A (en) | 1983-10-28 | 1988-07-12 | Genetics Institute, Inc. | Human factor VIII:C gene and recombinant methods for production |
US4677063A (en) | 1985-05-02 | 1987-06-30 | Cetus Corporation | Human tumor necrosis factor |
US4810648A (en) | 1986-01-08 | 1989-03-07 | Rhone Poulenc Agrochimie | Haloarylnitrile degrading gene, its use, and cells containing the gene |
US4897445A (en) | 1986-06-27 | 1990-01-30 | The Administrators Of The Tulane Educational Fund | Method for synthesizing a peptide containing a non-peptide bond |
CA2163032C (en) | 1993-06-03 | 2001-02-06 | John Landon | Antibody fragments in therapy |
AUPM322393A0 (en) | 1993-12-24 | 1994-01-27 | Austin Research Institute, The | Mucin carbohydrate compounds and their use in immunotherapy |
ATE244300T1 (de) | 1996-01-17 | 2003-07-15 | Imp College Innovations Ltd | Immunotherapie mit verwendung von zytotoxischen t lymphozyten (ctl) |
US5849589A (en) | 1996-03-11 | 1998-12-15 | Duke University | Culturing monocytes with IL-4, TNF-α and GM-CSF TO induce differentiation to dendric cells |
US6406705B1 (en) | 1997-03-10 | 2002-06-18 | University Of Iowa Research Foundation | Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant |
WO2001016174A2 (en) * | 1999-08-30 | 2001-03-08 | Rolf Kiessling | Induction of cytotoxic t lymphocyte response by hla class ia restricted epitopes of mycobacterial heat shock protein 65 |
ES2447115T3 (es) * | 1999-10-11 | 2014-03-11 | Institut Pasteur | Vectores para la preparación de composiciones inmunoterapéuticas |
KR20020097200A (ko) * | 2000-03-21 | 2002-12-31 | 엘리트라 파마슈티컬즈, 인코포레이티드 | 원핵세포에서의 필수유전자의 동정 |
US20040191260A1 (en) | 2003-03-26 | 2004-09-30 | Technion Research & Development Foundation Ltd. | Compositions capable of specifically binding particular human antigen presenting molecule/pathogen-derived antigen complexes and uses thereof |
WO2001072768A2 (en) | 2000-03-27 | 2001-10-04 | Technion Research And Development Foundation Ltd. | Single chain class i major histo-compatibility complexes, constructs encoding same and methods of generating same |
US7834146B2 (en) * | 2000-05-08 | 2010-11-16 | Monsanto Technology Llc | Recombinant polypeptides associated with plants |
EP1289564B1 (en) | 2000-06-05 | 2018-07-18 | Altor BioScience Corporation | T cell receptor fusions and conjugates and methods of use thereof |
US6992176B2 (en) | 2002-02-13 | 2006-01-31 | Technion Research & Development Foundation Ltd. | Antibody having a T-cell receptor-like specificity, yet higher affinity, and the use of same in the detection and treatment of cancer, viral infection and autoimmune disease |
EP1485075A4 (en) | 2002-02-20 | 2006-04-26 | Dyax Corp | MHC-PEPTIDE COMPLEX BINDING LIGANDS |
US7569664B2 (en) | 2002-10-09 | 2009-08-04 | Immunocore Limited | Single chain recombinant T cell receptors |
CA2505558C (en) | 2002-11-09 | 2013-07-02 | Avidex Limited | T cell receptor display |
GB0304068D0 (en) | 2003-02-22 | 2003-03-26 | Avidex Ltd | Substances |
KR100692416B1 (ko) * | 2003-05-26 | 2007-03-09 | 학교법인 배재학당 | Faf1 단편 및 그를 함유하는 종양 전이 억제제 |
EP2368906A1 (en) | 2004-04-29 | 2011-09-28 | SK Corp. | Fas associated factor 1 |
US7314630B2 (en) * | 2005-01-07 | 2008-01-01 | Yao-Xiong Hu | Compounds and methods of early diagnosis of cervical cancer and genital condyloma with HPV, CHSP60 tumor suppressor H-Ras, K-Ras and PTEN derived peptides modified |
ATE461214T1 (de) | 2005-09-05 | 2010-04-15 | Immatics Biotechnologies Gmbh | Tumor-assoziierte peptide, welche an unterschiedliche menschliche leukozytenantigene der klasse ii binden |
HUE026142T2 (en) * | 2007-07-27 | 2016-05-30 | Immatics Biotechnologies Gmbh | New immunogenic epitope for immunotherapy |
PT2113253E (pt) | 2008-04-30 | 2010-06-15 | Immatics Biotechnologies Gmbh | Formulações novas de peptídeos associados a tumores que se ligam a moléculas de classe i ou ii do antígeno leucocitário humano (hla) para vacinas |
GB201004551D0 (en) * | 2010-03-19 | 2010-05-05 | Immatics Biotechnologies Gmbh | NOvel immunotherapy against several tumors including gastrointestinal and gastric cancer |
GB201006360D0 (en) | 2010-04-16 | 2010-06-02 | Immatics Biotechnologies Gmbh | Method for differentially quantifying naturally processed HLA-restricted peptides for cancer, autoimmune and infectious diseases immunotherapy development |
KR101224466B1 (ko) * | 2010-05-20 | 2013-01-22 | 가톨릭대학교 산학협력단 | 토포아이소머라아제 2 알파 유래의 종양항원 단백질, 유전자, 또는 펩타이드 |
BR112013010213A2 (pt) | 2010-10-26 | 2019-09-24 | Technion Research & Development Foundation Ltd | anticorpos que unem ligantes solúveis de receptores de célula t |
WO2013057586A1 (en) | 2011-10-19 | 2013-04-25 | Oslo Universitetssykehus Hf | Compositions and methods for producing soluble t - cell receptors |
GB201411037D0 (en) * | 2014-06-20 | 2014-08-06 | Immatics Biotechnologies Gmbh | Novel immunotherapy against several tumors of the blood, in particular chronic lymphoid leukemai (CLL) |
-
2014
- 2014-05-09 GB GBGB1408255.6A patent/GB201408255D0/en not_active Ceased
-
2015
- 2015-05-08 MA MA049280A patent/MA49280A/fr unknown
- 2015-05-08 MA MA049287A patent/MA49287A/fr unknown
- 2015-05-08 EA EA201692103A patent/EA035456B1/ru not_active IP Right Cessation
- 2015-05-08 EP EP15732544.0A patent/EP3140319B1/en active Active
- 2015-05-08 HU HUE15732544A patent/HUE045177T2/hu unknown
- 2015-05-08 PT PT157325440T patent/PT3140319T/pt unknown
- 2015-05-08 EP EP19185183.1A patent/EP3604327A1/en not_active Withdrawn
- 2015-05-08 EP EP18193811.9A patent/EP3449937A1/en not_active Withdrawn
- 2015-05-08 ME MEP-2019-258A patent/ME03565B/me unknown
- 2015-05-08 MX MX2016014711A patent/MX2016014711A/es unknown
- 2015-05-08 US US14/707,230 patent/US10064924B2/en active Active
- 2015-05-08 DK DK15732544.0T patent/DK3140319T3/da active
- 2015-05-08 WO PCT/EP2015/060168 patent/WO2015169945A2/en active Application Filing
- 2015-05-08 RS RS20191183A patent/RS59471B1/sr unknown
- 2015-05-08 SI SI201530901T patent/SI3140319T1/sl unknown
- 2015-05-08 SG SG11201608332SA patent/SG11201608332SA/en unknown
- 2015-05-08 BR BR112016025035A patent/BR112016025035A2/pt not_active Application Discontinuation
- 2015-05-08 MA MA39907A patent/MA39907B1/fr unknown
- 2015-05-08 ES ES15732544T patent/ES2747734T3/es active Active
- 2015-05-08 JP JP2016567242A patent/JP6659582B2/ja not_active Expired - Fee Related
- 2015-05-08 LT LTEP15732544.0T patent/LT3140319T/lt unknown
- 2015-05-08 AU AU2015257652A patent/AU2015257652B2/en not_active Ceased
- 2015-05-08 PL PL15732544T patent/PL3140319T3/pl unknown
- 2015-05-08 CA CA2946349A patent/CA2946349A1/en not_active Abandoned
- 2015-05-08 KR KR1020167034386A patent/KR20170003976A/ko unknown
- 2015-05-08 EA EA202090751A patent/EA202090751A3/ru unknown
- 2015-05-08 CR CR20160531A patent/CR20160531A/es unknown
- 2015-05-08 CN CN201580022755.4A patent/CN106459167A/zh active Pending
- 2015-05-11 TW TW107127195A patent/TW201920246A/zh unknown
- 2015-05-11 TW TW104114918A patent/TWI668230B/zh not_active IP Right Cessation
-
2018
- 2018-07-11 US US16/032,231 patent/US10286052B2/en active Active
-
2020
- 2020-01-04 AU AU2020200066A patent/AU2020200066A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003530083A (ja) * | 1999-12-10 | 2003-10-14 | エピミューン インコーポレイテッド | ペプチドおよび核酸組成物を使用する、HER2/neuに対する細胞性免疫応答の誘導 |
JP2005514029A (ja) * | 2001-11-07 | 2005-05-19 | マンカインド コーポレイション | 抗原提示細胞におけるエピトープ同調 |
Non-Patent Citations (2)
Title |
---|
BUCHSBAUM ET AL., IMMUNOGENETICS, vol. 55, JPN6019006072, 2003, pages 172 - 176, ISSN: 0003981664 * |
STICKEL S JULIANE: "HLA CLASS I LIGANDOME ANALYSIS IN ACUTE MYELOID LEUKEMIA-NOVEL-T-CELL EPITOPES FOR 以下備考", BLOOD, vol. V122 N21, JPN5017004757, 15 November 2013 (2013-11-15), ISSN: 0003981663 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019102710A1 (ja) * | 2017-11-21 | 2019-05-31 | 尚史 三輪 | ヒト癌細胞転移阻害薬およびヒト癌細胞判定薬 |
JPWO2019102710A1 (ja) * | 2017-11-21 | 2021-01-28 | 尚史 三輪 | ヒト癌細胞転移阻害薬およびヒト癌細胞判定薬 |
JP7045042B2 (ja) | 2017-11-21 | 2022-03-31 | 尚史 三輪 | ヒト癌細胞転移阻害薬およびヒト癌細胞判定薬 |
US11696938B2 (en) | 2017-11-21 | 2023-07-11 | Naofumi Miwa | Human cancer cell metastasis inhibitory agent and human cancer cell determination agent |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6659582B2 (ja) | 急性骨髄性白血病(aml)などの血液のいくつかの腫瘍に対する新規免疫療法 | |
JP6560261B2 (ja) | 数種の血液腫瘍、特に慢性リンパ性白血病(cll)に対する新規免疫療法 | |
JP6884752B2 (ja) | 前立腺がんおよびその他のがんに対する免疫療法において使用するための新規ペプチドおよびペプチドの組み合わせ | |
US10875892B2 (en) | Immunotherapy against several tumors of the blood, in particular chronic lymphoid leukemia (CLL) | |
JP2019502360A (ja) | Cllおよびその他のがんに対する免疫療法において使用するための新規ペプチドおよびペプチドの組み合わせ | |
CN109748953B (zh) | 用于治疗多种肿瘤(例如包括nsclc在内的肺癌)的新型免疫疗法 | |
JP2022502358A (ja) | がんに対するa*01拘束性ペプチドおよびペプチド組み合わせによる免疫療法 | |
US10525115B2 (en) | Immunotherapy against several tumors of the blood, such as acute myeloid leukemia (AML) | |
JP2020014460A (ja) | 数種の血液腫瘍、特に慢性リンパ性白血病(cll)に対する新規免疫療法 | |
JP2021035361A (ja) | Nhlおよびその他のがんに対する免疫療法において使用するための新規ペプチドおよびペプチドの組み合わせ |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180115 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180115 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190226 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190524 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190723 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190826 |
|
A524 | Written submission of copy of amendment under article 19 pct |
Free format text: JAPANESE INTERMEDIATE CODE: A524 Effective date: 20190826 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20200122 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200206 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6659582 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |