JP6645982B2 - 免疫応答を誘導するための新規の方法 - Google Patents
免疫応答を誘導するための新規の方法 Download PDFInfo
- Publication number
- JP6645982B2 JP6645982B2 JP2016559965A JP2016559965A JP6645982B2 JP 6645982 B2 JP6645982 B2 JP 6645982B2 JP 2016559965 A JP2016559965 A JP 2016559965A JP 2016559965 A JP2016559965 A JP 2016559965A JP 6645982 B2 JP6645982 B2 JP 6645982B2
- Authority
- JP
- Japan
- Prior art keywords
- composition
- adjuvant
- less
- antigen
- months
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title claims description 104
- 230000028993 immune response Effects 0.000 title claims description 26
- 230000001939 inductive effect Effects 0.000 title claims description 23
- 239000000203 mixture Substances 0.000 claims description 270
- 239000002671 adjuvant Substances 0.000 claims description 198
- 239000000427 antigen Substances 0.000 claims description 118
- 102000036639 antigens Human genes 0.000 claims description 118
- 108091007433 antigens Proteins 0.000 claims description 118
- 230000002163 immunogen Effects 0.000 claims description 98
- 101000980463 Treponema pallidum (strain Nichols) Chaperonin GroEL Proteins 0.000 claims description 39
- 239000002502 liposome Substances 0.000 claims description 31
- 238000009472 formulation Methods 0.000 claims description 26
- 201000004792 malaria Diseases 0.000 claims description 24
- 239000012634 fragment Substances 0.000 claims description 17
- 230000003053 immunization Effects 0.000 claims description 17
- 238000002649 immunization Methods 0.000 claims description 17
- -1 50 μg Chemical compound 0.000 claims description 13
- 239000002245 particle Substances 0.000 claims description 12
- 241000223810 Plasmodium vivax Species 0.000 claims description 9
- 244000045947 parasite Species 0.000 claims description 9
- 241000223960 Plasmodium falciparum Species 0.000 claims description 6
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 claims 1
- 101710117490 Circumsporozoite protein Proteins 0.000 claims 1
- 102000004169 proteins and genes Human genes 0.000 description 44
- 108090000623 proteins and genes Proteins 0.000 description 44
- 239000000556 agonist Substances 0.000 description 39
- 229930182490 saponin Natural products 0.000 description 39
- 150000007949 saponins Chemical class 0.000 description 39
- 235000017709 saponins Nutrition 0.000 description 39
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 33
- 102000002689 Toll-like receptor Human genes 0.000 description 29
- 108020000411 Toll-like receptor Proteins 0.000 description 29
- 230000003111 delayed effect Effects 0.000 description 25
- 229960005486 vaccine Drugs 0.000 description 23
- 241000699670 Mus sp. Species 0.000 description 22
- 150000001413 amino acids Chemical group 0.000 description 21
- 230000005867 T cell response Effects 0.000 description 20
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 14
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 14
- 208000015181 infectious disease Diseases 0.000 description 14
- 210000001744 T-lymphocyte Anatomy 0.000 description 13
- 108090000765 processed proteins & peptides Proteins 0.000 description 12
- 101150106931 IFNG gene Proteins 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 239000007764 o/w emulsion Substances 0.000 description 11
- 229920001184 polypeptide Polymers 0.000 description 11
- 102000004196 processed proteins & peptides Human genes 0.000 description 11
- 230000004044 response Effects 0.000 description 10
- 210000003046 sporozoite Anatomy 0.000 description 10
- 108700012920 TNF Proteins 0.000 description 9
- 229930182558 Sterol Natural products 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 150000003432 sterols Chemical class 0.000 description 8
- 235000003702 sterols Nutrition 0.000 description 8
- 102000004127 Cytokines Human genes 0.000 description 7
- 108090000695 Cytokines Proteins 0.000 description 7
- 238000002965 ELISA Methods 0.000 description 7
- 208000009182 Parasitemia Diseases 0.000 description 7
- 208000030852 Parasitic disease Diseases 0.000 description 7
- 150000002632 lipids Chemical class 0.000 description 7
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 238000002255 vaccination Methods 0.000 description 7
- 101710137302 Surface antigen S Proteins 0.000 description 6
- 210000004207 dermis Anatomy 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 229940035032 monophosphoryl lipid a Drugs 0.000 description 6
- 150000003904 phospholipids Chemical class 0.000 description 6
- 210000003491 skin Anatomy 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 241000700721 Hepatitis B virus Species 0.000 description 5
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 5
- 102000000588 Interleukin-2 Human genes 0.000 description 5
- UZQJVUCHXGYFLQ-AYDHOLPZSA-N [(2s,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-4-[(2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-6-(hy Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O)O[C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CC[C@H]2[C@@]1(C=O)C)C)(C)CC(O)[C@]1(CCC(CC14)(C)C)C(=O)O[C@H]1[C@@H]([C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O[C@H]4[C@@H]([C@@H](O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O)[C@H](O)[C@@H](CO)O4)O)[C@H](O)[C@@H](CO)O3)O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UZQJVUCHXGYFLQ-AYDHOLPZSA-N 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004899 c-terminal region Anatomy 0.000 description 5
- 238000012217 deletion Methods 0.000 description 5
- 230000037430 deletion Effects 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 210000000265 leukocyte Anatomy 0.000 description 5
- 230000003204 osmotic effect Effects 0.000 description 5
- 230000000405 serological effect Effects 0.000 description 5
- 238000011269 treatment regimen Methods 0.000 description 5
- 201000008827 tuberculosis Diseases 0.000 description 5
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 description 4
- 108010076504 Protein Sorting Signals Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 210000002615 epidermis Anatomy 0.000 description 4
- 230000001900 immune effect Effects 0.000 description 4
- 230000036039 immunity Effects 0.000 description 4
- 239000007951 isotonicity adjuster Substances 0.000 description 4
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 4
- 230000003252 repetitive effect Effects 0.000 description 4
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 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
- 238000006467 substitution reaction Methods 0.000 description 4
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 4
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 3
- 108010068327 4-hydroxyphenylpyruvate dioxygenase Proteins 0.000 description 3
- 238000000729 Fisher's exact test Methods 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- 101710152205 Sporozoite antigen Proteins 0.000 description 3
- 210000000447 Th1 cell Anatomy 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 229960000074 biopharmaceutical Drugs 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 102000037865 fusion proteins Human genes 0.000 description 3
- 208000002672 hepatitis B Diseases 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 229940124735 malaria vaccine Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 230000001850 reproductive effect Effects 0.000 description 3
- 239000012646 vaccine adjuvant Substances 0.000 description 3
- 229940124931 vaccine adjuvant Drugs 0.000 description 3
- 239000011534 wash buffer Substances 0.000 description 3
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 2
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 description 2
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 description 2
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 2
- IJFVSSZAOYLHEE-SSEXGKCCSA-N 1,2-dilauroyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCC IJFVSSZAOYLHEE-SSEXGKCCSA-N 0.000 description 2
- YFWHNAWEOZTIPI-DIPNUNPCSA-N 1,2-dioctadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCCCC YFWHNAWEOZTIPI-DIPNUNPCSA-N 0.000 description 2
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 2
- 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 2
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 241000725619 Dengue virus Species 0.000 description 2
- 101710088335 Diacylglycerol acyltransferase/mycolyltransferase Ag85A Proteins 0.000 description 2
- 101710088334 Diacylglycerol acyltransferase/mycolyltransferase Ag85B Proteins 0.000 description 2
- 241000255925 Diptera Species 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 101000831567 Homo sapiens Toll-like receptor 2 Proteins 0.000 description 2
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 102000004895 Lipoproteins Human genes 0.000 description 2
- 108090001030 Lipoproteins Proteins 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
- 101000983333 Plasmodium falciparum (isolate NF54) 25 kDa ookinete surface antigen Proteins 0.000 description 2
- 241001505483 Plasmodium falciparum 3D7 Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 235000009001 Quillaja saponaria Nutrition 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
- 102100024333 Toll-like receptor 2 Human genes 0.000 description 2
- 102100039390 Toll-like receptor 7 Human genes 0.000 description 2
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- YGPZYYDTPXVBRA-RTDBHSBRSA-N [(2r,3s,4r,5r,6s)-2-[[(2r,3r,4r,5s,6r)-3-[[(3r)-3-dodecanoyloxytetradecanoyl]amino]-6-(hydroxymethyl)-5-phosphonooxy-4-[(3r)-3-tetradecanoyloxytetradecanoyl]oxyoxan-2-yl]oxymethyl]-3,6-dihydroxy-5-[[(3r)-3-hydroxytetradecanoyl]amino]oxan-4-yl] (3r)-3-hydr Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](O)O1 YGPZYYDTPXVBRA-RTDBHSBRSA-N 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000003196 chaotropic effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000007933 dermal patch Substances 0.000 description 2
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 description 2
- 239000003797 essential amino acid Substances 0.000 description 2
- 235000020776 essential amino acid Nutrition 0.000 description 2
- 229960002743 glutamine Drugs 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 229960001438 immunostimulant agent Drugs 0.000 description 2
- 239000003022 immunostimulating agent Substances 0.000 description 2
- 230000003308 immunostimulating effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229940042880 natural phospholipid Drugs 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229940054269 sodium pyruvate Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- NEZDNQCXEZDCBI-WJOKGBTCSA-N (2-aminoethoxy)[(2r)-2,3-bis(tetradecanoyloxy)propoxy]phosphinic acid Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCC NEZDNQCXEZDCBI-WJOKGBTCSA-N 0.000 description 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 1
- SLKDGVPOSSLUAI-PGUFJCEWSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCCCC SLKDGVPOSSLUAI-PGUFJCEWSA-N 0.000 description 1
- BIABMEZBCHDPBV-BEBVUIBBSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-BEBVUIBBSA-N 0.000 description 1
- MWRBNPKJOOWZPW-NYVOMTAGSA-N 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-NYVOMTAGSA-N 0.000 description 1
- OZSITQMWYBNPMW-GDLZYMKVSA-N 1,2-ditetradecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCC OZSITQMWYBNPMW-GDLZYMKVSA-N 0.000 description 1
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- PAZGBAOHGQRCBP-HGWHEPCSSA-N 1-hexadecanoyl-2-[(9Z)-octadec-9-enoyl]-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC PAZGBAOHGQRCBP-HGWHEPCSSA-N 0.000 description 1
- PAZGBAOHGQRCBP-DDDNOICHSA-N 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC PAZGBAOHGQRCBP-DDDNOICHSA-N 0.000 description 1
- KQPKMEYBZUPZGK-UHFFFAOYSA-N 4-[(4-azido-2-nitroanilino)methyl]-5-(hydroxymethyl)-2-methylpyridin-3-ol Chemical group CC1=NC=C(CO)C(CNC=2C(=CC(=CC=2)N=[N+]=[N-])[N+]([O-])=O)=C1O KQPKMEYBZUPZGK-UHFFFAOYSA-N 0.000 description 1
- 101710166488 6 kDa early secretory antigenic target Proteins 0.000 description 1
- 210000002925 A-like Anatomy 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 101100065968 Cereibacter sphaeroides fbp1 gene Proteins 0.000 description 1
- 101100012235 Cereibacter sphaeroides fbp2 gene Proteins 0.000 description 1
- 102100031673 Corneodesmosin Human genes 0.000 description 1
- 101710139375 Corneodesmosin Proteins 0.000 description 1
- 208000001490 Dengue Diseases 0.000 description 1
- 206010012310 Dengue fever Diseases 0.000 description 1
- 101710204837 Envelope small membrane protein Proteins 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- 101000993654 Escherichia coli (strain K12) Pantothenate kinase Proteins 0.000 description 1
- 101100055028 Escherichia coli (strain K12) afuB gene Proteins 0.000 description 1
- 208000002476 Falciparum Malaria Diseases 0.000 description 1
- 108010000916 Fimbriae Proteins Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101000669460 Homo sapiens Toll-like receptor 5 Proteins 0.000 description 1
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- ULNXMMYXQKGNPG-LPEHRKFASA-N Met-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCSC)N ULNXMMYXQKGNPG-LPEHRKFASA-N 0.000 description 1
- 241001092142 Molina Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 101100377720 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) fbpA gene Proteins 0.000 description 1
- 101100377732 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) fbpB gene Proteins 0.000 description 1
- 101100054729 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) hspX gene Proteins 0.000 description 1
- 101100291914 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) mpt64 gene Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- SUHOOTKUPISOBE-UHFFFAOYSA-N O-phosphoethanolamine Chemical compound NCCOP(O)(O)=O SUHOOTKUPISOBE-UHFFFAOYSA-N 0.000 description 1
- BZQFBWGGLXLEPQ-UHFFFAOYSA-N O-phosphoryl-L-serine Natural products OC(=O)C(N)COP(O)(O)=O BZQFBWGGLXLEPQ-UHFFFAOYSA-N 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 101000726057 Plasmodium falciparum Circumsporozoite protein Proteins 0.000 description 1
- 206010035500 Plasmodium falciparum infection Diseases 0.000 description 1
- 201000011336 Plasmodium falciparum malaria Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- YDTUEBLEAVANFH-RCWTZXSCSA-N Pro-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 YDTUEBLEAVANFH-RCWTZXSCSA-N 0.000 description 1
- 241001454523 Quillaja saponaria Species 0.000 description 1
- 101001000212 Rattus norvegicus Decorin Proteins 0.000 description 1
- 101710088839 Replication initiation protein Proteins 0.000 description 1
- 241000235343 Saccharomycetales Species 0.000 description 1
- 241000694414 Sapindus saponaria Species 0.000 description 1
- 229940124614 TLR 8 agonist Drugs 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 108010060804 Toll-Like Receptor 4 Proteins 0.000 description 1
- 102000008233 Toll-Like Receptor 4 Human genes 0.000 description 1
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 description 1
- 102100039357 Toll-like receptor 5 Human genes 0.000 description 1
- 102100033110 Toll-like receptor 8 Human genes 0.000 description 1
- 102100033117 Toll-like receptor 9 Human genes 0.000 description 1
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 description 1
- 101900123149 Varicella-zoster virus Envelope glycoprotein E Proteins 0.000 description 1
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 1
- MECHNRXZTMCUDQ-UHFFFAOYSA-N Vitamin D2 Natural products C1CCC2(C)C(C(C)C=CC(C)C(C)C)CCC2C1=CC=C1CC(O)CCC1=C MECHNRXZTMCUDQ-UHFFFAOYSA-N 0.000 description 1
- ZZWQHNRGJQENEP-KXQOOQHDSA-N [(2r)-2,3-bis[(2-tetradecylsulfanylacetyl)oxy]propyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCSCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CSCCCCCCCCCCCCCC ZZWQHNRGJQENEP-KXQOOQHDSA-N 0.000 description 1
- FVJZSBGHRPJMMA-DHPKCYQYSA-N [(2r)-3-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-2-octadecanoyloxypropyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-DHPKCYQYSA-N 0.000 description 1
- BPHQZTVXXXJVHI-IADGFXSZSA-N [(2r)-3-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-2-tetradecanoyloxypropyl] tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-IADGFXSZSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000240 adjuvant effect Effects 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 102000007362 alpha-Crystallins Human genes 0.000 description 1
- 108010007908 alpha-Crystallins Proteins 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000005875 antibody response Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 229940076810 beta sitosterol Drugs 0.000 description 1
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- 201000011510 cancer Diseases 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 208000025729 dengue disease Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229950006137 dexfosfoserine Drugs 0.000 description 1
- BIABMEZBCHDPBV-UHFFFAOYSA-N dipalmitoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-UHFFFAOYSA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- FVJZSBGHRPJMMA-UHFFFAOYSA-N distearoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229960002061 ergocalciferol Drugs 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
- 101150016690 esxA gene Proteins 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 101150028082 fbpA gene Proteins 0.000 description 1
- 101150082784 fbpB gene Proteins 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N glycerol 1-phosphate Chemical compound OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 150000002327 glycerophospholipids Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 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
- 101150007644 hspX gene Proteins 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000002356 laser light scattering Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 101150014428 mpt64 gene Proteins 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 244000000040 protozoan parasite Species 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 description 1
- 229940032091 stigmasterol Drugs 0.000 description 1
- 235000016831 stigmasterol Nutrition 0.000 description 1
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
- 235000001892 vitamin D2 Nutrition 0.000 description 1
- 239000011653 vitamin D2 Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Images
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
- A61K39/002—Protozoa antigens
- A61K39/015—Hemosporidia antigens, e.g. Plasmodium antigens
-
- 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
- A61K39/02—Bacterial antigens
- A61K39/04—Mycobacterium, e.g. Mycobacterium tuberculosis
-
- 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
- A61K39/12—Viral antigens
- A61K39/29—Hepatitis virus
- A61K39/292—Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
-
- 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
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- 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
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
-
- 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
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55572—Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55577—Saponins; Quil A; QS21; ISCOMS
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55588—Adjuvants of undefined constitution
-
- 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
- A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
-
- 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
- A61K2039/70—Multivalent vaccine
-
- 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
- C12N2730/00—Reverse transcribing DNA viruses
- C12N2730/00011—Details
- C12N2730/10011—Hepadnaviridae
- C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
- C12N2730/10134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pulmonology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB1405921.6A GB201405921D0 (en) | 2014-04-02 | 2014-04-02 | Novel methods for inducing an immune response |
| GB1405921.6 | 2014-04-02 | ||
| PCT/EP2015/057424 WO2015150568A1 (en) | 2014-04-02 | 2015-04-02 | Novel methods for inducing an immune response |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2017511324A JP2017511324A (ja) | 2017-04-20 |
| JP2017511324A5 JP2017511324A5 (enExample) | 2018-05-17 |
| JP6645982B2 true JP6645982B2 (ja) | 2020-02-14 |
Family
ID=50737873
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016560336A Expired - Fee Related JP6655549B2 (ja) | 2014-04-02 | 2015-04-02 | 免疫応答を誘導するための新規方法 |
| JP2016559965A Active JP6645982B2 (ja) | 2014-04-02 | 2015-04-02 | 免疫応答を誘導するための新規の方法 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016560336A Expired - Fee Related JP6655549B2 (ja) | 2014-04-02 | 2015-04-02 | 免疫応答を誘導するための新規方法 |
Country Status (18)
| Country | Link |
|---|---|
| US (3) | US10688168B2 (enExample) |
| EP (2) | EP3125930B1 (enExample) |
| JP (2) | JP6655549B2 (enExample) |
| KR (2) | KR20160132115A (enExample) |
| CN (2) | CN106456739A (enExample) |
| AR (1) | AR099960A1 (enExample) |
| AU (1) | AU2015239025B2 (enExample) |
| BE (1) | BE1022355B1 (enExample) |
| BR (2) | BR112016022787A2 (enExample) |
| CA (2) | CA2943007C (enExample) |
| EA (1) | EA037405B1 (enExample) |
| ES (2) | ES2961840T3 (enExample) |
| GB (1) | GB201405921D0 (enExample) |
| IL (1) | IL247493B (enExample) |
| MX (3) | MX2016012932A (enExample) |
| SG (1) | SG11201607086QA (enExample) |
| WO (2) | WO2015150567A1 (enExample) |
| ZA (1) | ZA201605955B (enExample) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201405921D0 (en) * | 2014-04-02 | 2014-05-14 | Glaxosmithkline Biolog Sa | Novel methods for inducing an immune response |
| GB201621686D0 (en) | 2016-12-20 | 2017-02-01 | Glaxosmithkline Biologicals Sa | Novel methods for inducing an immune response |
| FR3066920A1 (fr) | 2017-05-30 | 2018-12-07 | Glaxosmithkline Biologicals S.A. | Nouveaux procedes de fabrication d'un adjuvant |
| WO2019106192A1 (en) | 2017-12-01 | 2019-06-06 | Glaxosmithkline Biologicals Sa | Saponin purification |
| CA3142300C (en) | 2019-06-05 | 2025-02-04 | Glaxosmithkline Biologicals Sa | SAPONIN PURIFICATION |
| CN113125756B (zh) * | 2020-07-15 | 2022-10-25 | 南京岚煜生物科技有限公司 | 抗体标准品赋值和抗原中和当量确定的方法 |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US152200A (en) * | 1874-06-16 | Improvement in garters | ||
| US1002607A (en) * | 1905-08-28 | 1911-09-05 | John Willard Taylor | Paper pulley. |
| UA56132C2 (uk) * | 1995-04-25 | 2003-05-15 | Смітклайн Бічем Байолоджікалс С.А. | Композиція вакцини (варіанти), спосіб стабілізації qs21 відносно гідролізу (варіанти), спосіб приготування композиції вакцини |
| EP1569515A4 (en) | 2002-10-23 | 2006-04-26 | Glaxosmithkline Biolog Sa | MALARIA vaccine method |
| EA016648B1 (ru) | 2004-10-14 | 2012-06-29 | Круселл Холланд Б.В. | Применение дефектного по репликации рекомбинантного аденовируса, содержащего гетерологичную нуклеиновую кислоту, кодирующую антиген cs возбудителя малярии, и белкового антигена, содержащего белок cs или его фрагмент, для лечения или профилактики малярии |
| PL2457926T3 (pl) * | 2005-04-29 | 2015-03-31 | Glaxosmithkline Biologicals Sa | Nowy sposób profilaktyki lub leczenia zakażenia m. tuberculosis |
| TWI457133B (zh) | 2005-12-13 | 2014-10-21 | Glaxosmithkline Biolog Sa | 新穎組合物 |
| EP2368568A1 (en) * | 2006-11-01 | 2011-09-28 | Immport Therapeutics, INC. | Compositions and methods for immunodominant antigens |
| HUE031411T2 (en) * | 2007-03-02 | 2017-07-28 | Glaxosmithkline Biologicals Sa | New Methods and Preparations |
| PE20090146A1 (es) * | 2007-04-20 | 2009-03-23 | Glaxosmithkline Biolog Sa | Composicion inmunogenica contra el virus influenza |
| WO2010010179A1 (en) * | 2008-07-25 | 2010-01-28 | Glaxosmithkline Biologicals S.A. | The tuberculosis rv2386c protein, compositions and uses thereof |
| UA107330C2 (uk) * | 2008-07-25 | 2014-12-25 | Глаксосмітклайн Байолоджікалз С.А. | Туберкульозний білок rv3616c та його застосування |
| EP2315597B1 (en) * | 2008-07-25 | 2017-08-23 | GlaxoSmithKline Biologicals S.A. | Novel compositions and methods |
| PL2528621T3 (pl) * | 2010-01-27 | 2017-07-31 | Glaxosmithkline Biologicals S.A. | Zmodyfikowane antygeny gruźlicy |
| HUE028452T2 (en) * | 2010-12-14 | 2016-12-28 | Glaxosmithkline Biologicals Sa | Mycobacterium antigenic preparations |
| US20170056345A1 (en) * | 2014-02-18 | 2017-03-02 | Stc.Unm | Booster drug therapy for mycobacterium infections |
| GB201405921D0 (en) * | 2014-04-02 | 2014-05-14 | Glaxosmithkline Biolog Sa | Novel methods for inducing an immune response |
| JP2017513860A (ja) * | 2014-04-24 | 2017-06-01 | スタテンス セールム インスティトゥート | 新規結核菌（ｍ．ｔｕｂｅｒｃｕｌｏｓｉｓ）ワクチン |
| GB201513176D0 (en) * | 2015-07-27 | 2015-09-09 | Glaxosmithkline Biolog Sa | Novel methods for inducing an immune response |
-
2014
- 2014-04-02 GB GBGB1405921.6A patent/GB201405921D0/en not_active Ceased
-
2015
- 2015-04-02 BR BR112016022787-5A patent/BR112016022787A2/pt not_active Application Discontinuation
- 2015-04-02 WO PCT/EP2015/057423 patent/WO2015150567A1/en not_active Ceased
- 2015-04-02 CA CA2943007A patent/CA2943007C/en active Active
- 2015-04-02 ES ES15713532T patent/ES2961840T3/es active Active
- 2015-04-02 JP JP2016560336A patent/JP6655549B2/ja not_active Expired - Fee Related
- 2015-04-02 JP JP2016559965A patent/JP6645982B2/ja active Active
- 2015-04-02 IL IL247493A patent/IL247493B/en unknown
- 2015-04-02 ES ES15713531T patent/ES2853773T3/es active Active
- 2015-04-02 US US15/300,852 patent/US10688168B2/en active Active
- 2015-04-02 SG SG11201607086QA patent/SG11201607086QA/en unknown
- 2015-04-02 US US15/300,338 patent/US10624961B2/en active Active
- 2015-04-02 CN CN201580030331.2A patent/CN106456739A/zh active Pending
- 2015-04-02 CN CN201580016665.4A patent/CN106456738B/zh active Active
- 2015-04-02 MX MX2016012932A patent/MX2016012932A/es unknown
- 2015-04-02 AU AU2015239025A patent/AU2015239025B2/en active Active
- 2015-04-02 EP EP15713531.0A patent/EP3125930B1/en active Active
- 2015-04-02 CA CA2943711A patent/CA2943711A1/en not_active Abandoned
- 2015-04-02 EA EA201691638A patent/EA037405B1/ru not_active IP Right Cessation
- 2015-04-02 KR KR1020167029523A patent/KR20160132115A/ko not_active Ceased
- 2015-04-02 MX MX2016012982A patent/MX2016012982A/es unknown
- 2015-04-02 BR BR112016022463A patent/BR112016022463A2/pt not_active Application Discontinuation
- 2015-04-02 WO PCT/EP2015/057424 patent/WO2015150568A1/en not_active Ceased
- 2015-04-02 BE BE2015/5209A patent/BE1022355B1/fr not_active IP Right Cessation
- 2015-04-02 EP EP15713532.8A patent/EP3125929B8/en active Active
- 2015-04-02 KR KR1020237017095A patent/KR102762440B1/ko active Active
- 2015-04-06 AR ARP150101025A patent/AR099960A1/es unknown
-
2016
- 2016-08-26 ZA ZA2016/05955A patent/ZA201605955B/en unknown
- 2016-09-30 MX MX2022013912A patent/MX2022013912A/es unknown
-
2020
- 2020-03-11 US US16/815,635 patent/US11951161B2/en active Active
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11951161B2 (en) | Methods for inducing an immune response | |
| US11679153B2 (en) | Methods for inducing an immune response | |
| JP2008544969A (ja) | 抗マラリアワクチン | |
| KR20100068390A (ko) | 백신 | |
| KR101362097B1 (ko) | 플라스모디움 항원을 포함하는 백신 | |
| US11583578B2 (en) | Plasmodium falciparum recombinanr xiexumapoeozoite protein compositions and method for vaccine delivery | |
| BE1022373B1 (fr) | Nouveaux vaccins antipaludeens | |
| WO2016046113A1 (en) | Novel methods for inducing an immune response |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180328 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180328 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190108 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190404 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20190709 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20191107 |
|
| A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20191118 |
|
| 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: 20191218 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200109 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6645982 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |