JPH08507685A - ひとパピローマウイルス・カプシド蛋白およびウイルス様粒子の製造 - Google Patents
ひとパピローマウイルス・カプシド蛋白およびウイルス様粒子の製造Info
- Publication number
- JPH08507685A JPH08507685A JP6520236A JP52023694A JPH08507685A JP H08507685 A JPH08507685 A JP H08507685A JP 6520236 A JP6520236 A JP 6520236A JP 52023694 A JP52023694 A JP 52023694A JP H08507685 A JPH08507685 A JP H08507685A
- Authority
- JP
- Japan
- Prior art keywords
- hpv
- papillomavirus
- virus
- cells
- recombinant
- 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.)
- Withdrawn
Links
- 239000002245 particle Substances 0.000 title claims abstract description 75
- 108090000565 Capsid Proteins Proteins 0.000 title claims abstract description 34
- 102100023321 Ceruloplasmin Human genes 0.000 title claims abstract description 34
- 241000701806 Human papillomavirus Species 0.000 title claims description 78
- 238000004519 manufacturing process Methods 0.000 title claims description 16
- 238000000034 method Methods 0.000 claims abstract description 73
- 241001631646 Papillomaviridae Species 0.000 claims abstract description 57
- 208000015181 infectious disease Diseases 0.000 claims abstract description 49
- 230000014509 gene expression Effects 0.000 claims abstract description 40
- 241000701447 unidentified baculovirus Species 0.000 claims abstract description 36
- 108091026890 Coding region Proteins 0.000 claims abstract description 35
- 241000238631 Hexapoda Species 0.000 claims abstract description 27
- 230000000890 antigenic effect Effects 0.000 claims abstract description 21
- 239000012634 fragment Substances 0.000 claims abstract description 14
- 241000701828 Human papillomavirus type 11 Species 0.000 claims description 111
- 108090000623 proteins and genes Proteins 0.000 claims description 71
- 102000004169 proteins and genes Human genes 0.000 claims description 71
- 210000004027 cell Anatomy 0.000 claims description 57
- 241000700605 Viruses Species 0.000 claims description 48
- 241000282414 Homo sapiens Species 0.000 claims description 36
- 108020004414 DNA Proteins 0.000 claims description 15
- 239000013598 vector Substances 0.000 claims description 14
- 210000004392 genitalia Anatomy 0.000 claims description 13
- 241001465754 Metazoa Species 0.000 claims description 12
- 210000000234 capsid Anatomy 0.000 claims description 10
- 238000012546 transfer Methods 0.000 claims description 8
- 239000013604 expression vector Substances 0.000 claims description 7
- 239000002773 nucleotide Substances 0.000 claims description 6
- 125000003729 nucleotide group Chemical group 0.000 claims description 6
- 238000003259 recombinant expression Methods 0.000 claims description 5
- 108010076504 Protein Sorting Signals Proteins 0.000 claims description 4
- 230000035772 mutation Effects 0.000 claims description 4
- 241001203868 Autographa californica Species 0.000 claims description 3
- 238000010367 cloning Methods 0.000 claims description 3
- 210000003527 eukaryotic cell Anatomy 0.000 claims description 2
- 210000004962 mammalian cell Anatomy 0.000 claims description 2
- 210000001236 prokaryotic cell Anatomy 0.000 claims description 2
- 241000709701 Human poliovirus 1 Species 0.000 claims 4
- 230000037430 deletion Effects 0.000 claims 2
- 238000012217 deletion Methods 0.000 claims 2
- 238000001890 transfection Methods 0.000 claims 2
- 230000002463 transducing effect Effects 0.000 claims 1
- 230000002458 infectious effect Effects 0.000 abstract description 22
- 241000341655 Human papillomavirus type 16 Species 0.000 abstract description 19
- 241001428582 Human papillomavirus type 6 Species 0.000 abstract description 10
- 101710121996 Hexon protein p72 Proteins 0.000 abstract 1
- 101710125418 Major capsid protein Proteins 0.000 abstract 1
- 208000022361 Human papillomavirus infectious disease Diseases 0.000 description 61
- 241000283973 Oryctolagus cuniculus Species 0.000 description 49
- 210000002966 serum Anatomy 0.000 description 46
- 210000002845 virion Anatomy 0.000 description 35
- 238000002965 ELISA Methods 0.000 description 22
- 238000002360 preparation method Methods 0.000 description 21
- 238000001262 western blot Methods 0.000 description 20
- 239000000427 antigen Substances 0.000 description 18
- 102000036639 antigens Human genes 0.000 description 18
- 108091007433 antigens Proteins 0.000 description 18
- 239000000523 sample Substances 0.000 description 18
- 229960005486 vaccine Drugs 0.000 description 17
- 238000006386 neutralization reaction Methods 0.000 description 16
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 16
- 108700026244 Open Reading Frames Proteins 0.000 description 15
- 238000003556 assay Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 206010059313 Anogenital warts Diseases 0.000 description 13
- 238000010790 dilution Methods 0.000 description 13
- 239000012895 dilution Substances 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 12
- 238000001514 detection method Methods 0.000 description 12
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 12
- 238000003018 immunoassay Methods 0.000 description 12
- 108020004999 messenger RNA Proteins 0.000 description 12
- 239000008188 pellet Substances 0.000 description 12
- 239000002953 phosphate buffered saline Substances 0.000 description 12
- 201000010153 skin papilloma Diseases 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 101000980463 Treponema pallidum (strain Nichols) Chaperonin GroEL Proteins 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 11
- 230000001900 immune effect Effects 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 241000588724 Escherichia coli Species 0.000 description 10
- 208000009608 Papillomavirus Infections Diseases 0.000 description 10
- 238000010521 absorption reaction Methods 0.000 description 10
- 239000013592 cell lysate Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 241000282412 Homo Species 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 239000000499 gel Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 241000388186 Deltapapillomavirus 4 Species 0.000 description 8
- 208000000260 Warts Diseases 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 239000012228 culture supernatant Substances 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 238000004113 cell culture Methods 0.000 description 7
- 238000010276 construction Methods 0.000 description 7
- 230000003472 neutralizing effect Effects 0.000 description 7
- 230000003612 virological effect Effects 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000002671 adjuvant Substances 0.000 description 6
- 125000003275 alpha amino acid group Chemical class 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 210000003953 foreskin Anatomy 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 230000003053 immunization Effects 0.000 description 6
- 238000003119 immunoblot Methods 0.000 description 6
- 239000007943 implant Substances 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- 230000000877 morphologic effect Effects 0.000 description 6
- 229920002401 polyacrylamide Polymers 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 230000009257 reactivity Effects 0.000 description 6
- 208000035473 Communicable disease Diseases 0.000 description 5
- 241000701589 Human papillomavirus type 6b Species 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 5
- 229930006000 Sucrose Natural products 0.000 description 5
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 5
- 239000001110 calcium chloride Substances 0.000 description 5
- 229910001628 calcium chloride Inorganic materials 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 238000000635 electron micrograph Methods 0.000 description 5
- 229940042743 immune sera Drugs 0.000 description 5
- 230000036039 immunity Effects 0.000 description 5
- 238000002649 immunization Methods 0.000 description 5
- 230000002163 immunogen Effects 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 238000005215 recombination Methods 0.000 description 5
- 239000011550 stock solution Substances 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 238000004114 suspension culture Methods 0.000 description 5
- 108020004705 Codon Proteins 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000001493 electron microscopy Methods 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 229910001629 magnesium chloride Inorganic materials 0.000 description 4
- 230000003211 malignant effect Effects 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 208000003154 papilloma Diseases 0.000 description 4
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 4
- 230000006798 recombination Effects 0.000 description 4
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 230000006648 viral gene expression Effects 0.000 description 4
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 3
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 241000341657 Human papillomavirus type 18 Species 0.000 description 3
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 230000009260 cross reactivity Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000002173 dizziness Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001962 electrophoresis Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 230000008696 hypoxemic pulmonary vasoconstriction Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 3
- 108010052968 leupeptin Proteins 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 235000020030 perry Nutrition 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000007639 printing Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000005464 sample preparation method Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000012134 supernatant fraction Substances 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 230000014616 translation Effects 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- QFVHZQCOUORWEI-UHFFFAOYSA-N 4-[(4-anilino-5-sulfonaphthalen-1-yl)diazenyl]-5-hydroxynaphthalene-2,7-disulfonic acid Chemical compound C=12C(O)=CC(S(O)(=O)=O)=CC2=CC(S(O)(=O)=O)=CC=1N=NC(C1=CC=CC(=C11)S(O)(=O)=O)=CC=C1NC1=CC=CC=C1 QFVHZQCOUORWEI-UHFFFAOYSA-N 0.000 description 2
- 241000701814 Bovine papillomavirus type 2 Species 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 244000260524 Chrysanthemum balsamita Species 0.000 description 2
- 235000005633 Chrysanthemum balsamita Nutrition 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000701533 Escherichia virus T4 Species 0.000 description 2
- 241000785747 Mavirus Species 0.000 description 2
- 241001467552 Mycobacterium bovis BCG Species 0.000 description 2
- 239000000020 Nitrocellulose Substances 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 108020005202 Viral DNA Proteins 0.000 description 2
- -1 Zolecithin Chemical compound 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229940037642 autologous vaccine Drugs 0.000 description 2
- 229960000190 bacillus calmette–guérin vaccine Drugs 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 239000011539 homogenization buffer Substances 0.000 description 2
- 230000000521 hyperimmunizing effect Effects 0.000 description 2
- 210000004201 immune sera Anatomy 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000000464 low-speed centrifugation Methods 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- WTEVQBCEXWBHNA-YFHOEESVSA-N neral Chemical compound CC(C)=CCC\C(C)=C/C=O WTEVQBCEXWBHNA-YFHOEESVSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000011587 new zealand white rabbit Methods 0.000 description 2
- 229920001220 nitrocellulos Polymers 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 229960002566 papillomavirus vaccine Drugs 0.000 description 2
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000033458 reproduction Effects 0.000 description 2
- 108091008146 restriction endonucleases Proteins 0.000 description 2
- 239000012723 sample buffer Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- SNBCLPGEMZEWLU-QXFUBDJGSA-N 2-chloro-n-[[(2r,3s,5r)-3-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl]acetamide Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CNC(=O)CCl)[C@@H](O)C1 SNBCLPGEMZEWLU-QXFUBDJGSA-N 0.000 description 1
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 1
- QRXMUCSWCMTJGU-UHFFFAOYSA-N 5-bromo-4-chloro-3-indolyl phosphate Chemical compound C1=C(Br)C(Cl)=C2C(OP(O)(=O)O)=CNC2=C1 QRXMUCSWCMTJGU-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000201370 Autographa californica nucleopolyhedrovirus Species 0.000 description 1
- 101150071434 BAR1 gene Proteins 0.000 description 1
- 241000510930 Brachyspira pilosicoli Species 0.000 description 1
- 108091028690 C-myc mRNA Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 108020004638 Circular DNA Proteins 0.000 description 1
- WTEVQBCEXWBHNA-UHFFFAOYSA-N Citral Natural products CC(C)=CCCC(C)=CC=O WTEVQBCEXWBHNA-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000000907 Condylomata Acuminata Diseases 0.000 description 1
- 206010066944 Congenital condyloma Diseases 0.000 description 1
- 238000011537 Coomassie blue staining Methods 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 241001157141 Cutia Species 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 230000004568 DNA-binding 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
- 241000196324 Embryophyta Species 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 238000000729 Fisher's exact test Methods 0.000 description 1
- 241001669573 Galeorhinus galeus Species 0.000 description 1
- 102100035964 Gastrokine-2 Human genes 0.000 description 1
- 101710205776 Gastrokine-2 Proteins 0.000 description 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 101000869690 Homo sapiens Protein S100-A8 Proteins 0.000 description 1
- 101000742340 Human papillomavirus type 16 Minor capsid protein L2 Proteins 0.000 description 1
- 241000709704 Human poliovirus 2 Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 238000000585 Mann–Whitney U test Methods 0.000 description 1
- 241001024304 Mino Species 0.000 description 1
- 241000829388 Mus musculus polyomavirus 1 Species 0.000 description 1
- 241000282320 Panthera leo Species 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 241000232219 Platanista Species 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 229940096437 Protein S Drugs 0.000 description 1
- 102000029301 Protein S Human genes 0.000 description 1
- 108010066124 Protein S Proteins 0.000 description 1
- 102100032442 Protein S100-A8 Human genes 0.000 description 1
- 102000007568 Proto-Oncogene Proteins c-fos Human genes 0.000 description 1
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 1
- 241001156569 Ptychosperma lineare Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 241001504592 Trachurus trachurus Species 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- 230000010530 Virus Neutralization Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000001261 affinity purification Methods 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 210000000628 antibody-producing cell Anatomy 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 238000013320 baculovirus expression vector system Methods 0.000 description 1
- 102000005936 beta-Galactosidase Human genes 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 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
- 244000309466 calf Species 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 201000003565 cervix uteri carcinoma in situ Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- WTEVQBCEXWBHNA-JXMROGBWSA-N citral A Natural products CC(C)=CCC\C(C)=C\C=O WTEVQBCEXWBHNA-JXMROGBWSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000000432 density-gradient centrifugation Methods 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- 208000021145 human papilloma virus infection Diseases 0.000 description 1
- 230000004727 humoral immunity Effects 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000037230 mobility Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 229940031348 multivalent vaccine Drugs 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 239000011824 nuclear material Substances 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 238000001558 permutation test Methods 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 201000004303 plantar wart Diseases 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000447 polyanionic polymer Polymers 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000012521 purified sample Substances 0.000 description 1
- 208000001307 recurrent respiratory papillomatosis Diseases 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 238000009589 serological test Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 208000022159 squamous carcinoma in situ Diseases 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940031626 subunit vaccine Drugs 0.000 description 1
- 238000000856 sucrose gradient centrifugation Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 230000001131 transforming effect Effects 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
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 208000022625 uterine cervix carcinoma in situ Diseases 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 229960004854 viral vaccine Drugs 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000004260 weight control Methods 0.000 description 1
Classifications
-
- 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
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- 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
-
- 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
-
- 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
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- 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
- A61K2039/525—Virus
- A61K2039/5258—Virus-like particles
-
- 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
-
- 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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/14011—Baculoviridae
- C12N2710/14111—Nucleopolyhedrovirus, e.g. autographa californica nucleopolyhedrovirus
- C12N2710/14141—Use of virus, viral particle or viral elements as a vector
- C12N2710/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- 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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/20011—Papillomaviridae
- C12N2710/20022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- 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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/20011—Papillomaviridae
- C12N2710/20023—Virus like particles [VLP]
-
- 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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/20011—Papillomaviridae
- C12N2710/20034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Virology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biotechnology (AREA)
- Oncology (AREA)
- Biochemistry (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Microbiology (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Communicable Diseases (AREA)
- Mycology (AREA)
- General Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biophysics (AREA)
- Biomedical Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.細胞中でパピローマウイルスカプシド蛋白の発現を容易にする条件下、パ ピローマウイルスカプシド蛋白コード配列を含む組換え発現ベクターで細胞を形 質導入することを含む、細胞中でのパピローマウイルスのカプシド蛋白コード配 列発現方法。 2.上記組換え発現ベクターがバキュロウイルス発現系である、請求項1記載 の方法。 3.上記カプシド蛋白コード配列がL1蛋白コード配列、そのフラグメントま たは部分である、請求項1記載の方法。 4.上記パピローマウイルスが動物およびひとパピローマウイルスからなる群 から選ばれるものである、請求項1記載の方法。 5.上記パピローマウイルスが生殖器ひとパピローマウイルス型である、請求 項4記載の方法。 6.上記ひとパピローマウイルスが、HPV−6、HPV−11、HPV−1 6、HPV−18、HPV−33、HPV−35、HPV−5およびHPV−8 からなる群から選ばれるものである、請求項5記載の方法。 7.上記ひとパピローマウイルスが、HPV−11である、請求項6記載の方 法。 8.上記ひとパピローマウイルスが、HPV−6である、請求項6記載の方法 。 9.上記細胞が、原核細胞および真核細胞からなる群から選ばれるものである 、請求項1記載の方法。 10.上記細胞が哺乳動物細胞である、請求項1記載の方法。 11.上記細胞が昆虫細胞である、請求項1記載の方法。 12.上記形質導入段階が感染によるものである、請求項1記載の方法。 13.上記L1蛋白コード配列が、5個のヌクレオチドであるmRNA分解シ グナル配列AUUUAの突然変異または欠失したものを含むものである、請求項 3記載の方法。 14.昆虫細胞でのパピローマウイルスのカプシド蛋白コード配列発現方法で あって、 パピローマウイルスカプシド蛋白コード配列を、バキュロウイルス転移ベクタ ー中にクローニングすること; 上記バキュロウイルス転移ベクターおよびオートグラフィカ・カリホルニカ核 多面体(polyhedrosis)ウイルスゲノムDNAを昆虫細胞に同時形質導入するこ と、 組換えバキュロウイルスを回収すること、 細胞中で上記カプシド蛋白の発現を容易にする条件下、上記組換えバキュロウ イルスを昆虫細胞に感染させること、 を含むことを特徴とする方法。 15.上記カプシド蛋白コード配列がL1蛋白コード配列である、請求項14 記載の方法。 16.上記昆虫細胞がSf−9細胞である、請求項14記載の方法。 17.上記パピローマウイルスがひとパピローマウイルスである、請求項14 記載の方法。 18.上記ひとパピローマウイルスがHPV−6、HPV−11、HPV−1 6、HPV−18、HPV−33、HPV−35、HPV−5およびHPV−8 である、請求項17記載の方法。 19.上記ひとパピローマウイルスがHPV−11である、請求項18記載の 方法。 20.上記ひとパピローマウイルスがHPV−6である、請求項18記載の方 法。 21.請求項1または14記載の方法により製造された組換えパピローマウイ ルスカプシド蛋白。 22.請求項21記載の組換えカプシド蛋白から産生したパピローマウイルス ウイルス様−粒子、そのフラグメント、カプソメアまたは部分。 23.天然の感染パピローマウイルス粒子の抗原的特徴に類似する、パピロー マウイルスの組換えカプシド蛋白から産生したパピローマウイルスウイルス様− 粒子、そのフラグメント、カプソメアまたは部分。 24.上記カプシド蛋白が、L1蛋白コード配列、そのフラグメントまたは部 分によってコードされている、請求項23記載のウイルス−様粒子。 25.上記L1蛋白コード配列がバキュロウイルス発現系を用いて、細胞中で 発現されるものである、請求項24記載のウイルス様−粒子。 26.上記パピローマウイルスが、ひとおよび動物パピローマウイルスからな る群から選ばれるものである、請求項23記載のウイルス様−粒子。 27.上記ひとパピローマウイルスがHPV−6、HPV−11、HPV−1 6、HPV−18、HPV−33、HPV−35、HPV−5およびHPV−8 である、請求項26記載のウイルス様−粒子。 28.上記ひとパピローマウイルスがHPV−11である、請求項27記載の ウイルス様−粒子。 29.上記ひとパピローマウイルスがHPV−6である、請求項27記載のウ イルス様−粒子。 30.パピローマウイルス・ウイルス様−粒子、そのフラグメント、カプソメ アまたは部分の製造方法であって、 パピローマウイルスカプシド蛋白配列の発現を容易にする条件下、上記カプシ ド蛋白コード配列を含む組換え発現ベクターを細胞に感染させ、それによって上 記ウイルス様−粒子を製造することを特徴とする方法。 31.上記組換え発現ベクターがバキュロウイルス発現系である、請求項30 記載の方法。 32.上記パピローマウイルスがひとパピローマウイルスである、請求項30 記載の方法。 33.上記ひとパピローマウイルスがHPV−6、HPV−11、HPV−1 6、HPV−18、HPV−33、HPV−35、HPV−5およびHPV−8 である、請求項32記載の方法。 34.上記ひとパピローマウイルスがHPV−11である、請求項33記載の 方法。 35.上記ひとパピローマウイルスがHPV−6である、請求項33記載の方 法。 36.上記カプシド蛋白コード配列がL1蛋白コード配列である、請求項30 記載の方法。 37.上記細胞が昆虫細胞である、請求項30記載の方法。 38.上記L1蛋白コード配列が、5個のヌクレオチドであるmRNA分解シ グナル配列AUUUAの突然変異または欠失したものを含むものである、請求項 36記載の方法。 39.パピローマウイルス様−粒子、そのフラグメント、カプソメアまたは部 分の製造方法であって、 パピローマウイルスカプシド蛋白コード配列を、バキュロウイルス転移ベクタ ー中にクローニングすること; 上記バキュロウイルス転移ベクターおよびオートグラフィカ・カリホルニカ核 多面体(polyhedrosis)ウイルスゲノムDNAを昆虫細胞に同時形質導入するこ と、 組換えバキュロウイルスを回収すること、および 上記蛋白の発現を容易にする条件下、上記組換えバキュロウイルスを昆虫細胞 に感染させること、それによって上記ウイルス様−粒子を製造すること、 を含むことを特徴とする方法。 40.請求項30または39記載の方法により製造されたパピローマウイルス ・ウイルス様−粒子、そのフラグメント、カプソメアまたは部分。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/028,517 US8062642B1 (en) | 1993-03-09 | 1993-03-09 | Production of papillomavirus capsid protein and virus-like particles |
US20730994A | 1994-03-07 | 1994-03-07 | |
US08/028,517 | 1994-03-07 | ||
US08/207,309 | 1994-03-07 | ||
PCT/US1994/002443 WO1994020137A1 (en) | 1993-03-09 | 1994-03-08 | Production of human papillomavirus capsid protein and virus-like particles |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2006277056A Division JP4486075B2 (ja) | 1993-03-09 | 2006-10-11 | ひとパピローマウイルス・カプシド蛋白およびウイルス様粒子の製造 |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH08507685A true JPH08507685A (ja) | 1996-08-20 |
Family
ID=26703787
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP6520236A Withdrawn JPH08507685A (ja) | 1993-03-09 | 1994-03-08 | ひとパピローマウイルス・カプシド蛋白およびウイルス様粒子の製造 |
JP2006277056A Expired - Lifetime JP4486075B2 (ja) | 1993-03-09 | 2006-10-11 | ひとパピローマウイルス・カプシド蛋白およびウイルス様粒子の製造 |
JP2010023691A Expired - Lifetime JP5386392B2 (ja) | 1993-03-09 | 2010-02-05 | ひとパピローマウイルス・カプシド蛋白およびウイルス様粒子の製造 |
JP2010023690A Expired - Lifetime JP5306251B2 (ja) | 1993-03-09 | 2010-02-05 | ひとパピローマウイルス・カプシド蛋白およびウイルス様粒子の製造 |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2006277056A Expired - Lifetime JP4486075B2 (ja) | 1993-03-09 | 2006-10-11 | ひとパピローマウイルス・カプシド蛋白およびウイルス様粒子の製造 |
JP2010023691A Expired - Lifetime JP5386392B2 (ja) | 1993-03-09 | 2010-02-05 | ひとパピローマウイルス・カプシド蛋白およびウイルス様粒子の製造 |
JP2010023690A Expired - Lifetime JP5306251B2 (ja) | 1993-03-09 | 2010-02-05 | ひとパピローマウイルス・カプシド蛋白およびウイルス様粒子の製造 |
Country Status (14)
Country | Link |
---|---|
EP (3) | EP0688227B1 (ja) |
JP (4) | JPH08507685A (ja) |
AT (3) | ATE494005T1 (ja) |
AU (3) | AU688759C (ja) |
CA (1) | CA2157932C (ja) |
DE (9) | DE05075369T1 (ja) |
DK (2) | DK1618888T3 (ja) |
ES (3) | ES2242955T4 (ja) |
FR (1) | FR11C0022I2 (ja) |
HK (2) | HK1082196A1 (ja) |
LU (3) | LU91313I2 (ja) |
NL (3) | NL300265I2 (ja) |
PT (2) | PT1618888E (ja) |
WO (1) | WO1994020137A1 (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002516291A (ja) * | 1998-05-29 | 2002-06-04 | ユニバーシティー オブ ロチェスター | パピローマウイルス・ウイルス様粒子による経口免疫感作 |
JP2004510144A (ja) * | 2000-09-18 | 2004-04-02 | メディミューン,インコーポレイテッド | ワクチンの免疫原性を測定する試験管内検定 |
JP2010095530A (ja) * | 1997-10-06 | 2010-04-30 | Loyola Univ Of Chicago | パピローマウイルスカプソメアワクチン製剤および使用方法 |
Families Citing this family (70)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE234925T1 (de) | 1991-07-19 | 2003-04-15 | Univ Queensland | Impfstoffe gegen papillomavirus |
US5437951A (en) * | 1992-09-03 | 1995-08-01 | The United States Of America As Represented By The Department Of Health And Human Services | Self-assembling recombinant papillomavirus capsid proteins |
AUPM358894A0 (en) * | 1994-01-31 | 1994-02-24 | Csl Limited | Modified papilloma virus l2 protein and vlps formed therefrom |
DE4415743C2 (de) * | 1994-05-04 | 1996-10-10 | Deutsches Krebsforsch | Papillomviren, Mittel zu deren Nachweis sowie zur Therapie von durch sie verursachten Erkrankungen |
US5888516A (en) * | 1994-05-16 | 1999-03-30 | Merck & Co. Inc. | Recombinant papillomavirus vaccines |
AUPM566794A0 (en) * | 1994-05-17 | 1994-06-09 | University Of Queensland, The | Process and product |
CA2202090C (en) * | 1994-10-07 | 2012-04-17 | Lutz Gissmann | Papilloma virus-like particles, fusion proteins as well as processes for their production |
AU2003235191B2 (en) * | 1994-10-07 | 2006-09-21 | Loyola University Of Chicago | Papilloma virus-like particles, fusion proteins as well as processes for their production |
AR004464A1 (es) * | 1994-11-14 | 1998-12-16 | Merck Sharp & Dohme | Un metodo para producir una proteina de capside de papilomavirus |
CA2211995A1 (en) * | 1995-02-24 | 1996-08-29 | Cantab Pharmaceuticals Research Limited | Polypeptides useful as immunotherapeutic agents and methods of polypeptide preparation |
US5840306A (en) * | 1995-03-22 | 1998-11-24 | Merck & Co., Inc. | DNA encoding human papillomavirus type 18 |
IL117459A (en) * | 1995-03-22 | 2005-11-20 | Merck & Co Inc | Dna encoding human papillomavirus type 18 |
US5820870A (en) * | 1995-03-22 | 1998-10-13 | Merck & Co., Inc. | Recombinant human papillomavirus type 18 vaccine |
US5821087A (en) * | 1995-03-30 | 1998-10-13 | Merck & Co., Inc. | Production of recombinant human papillomavirus type II protein utilizing papillomavirus 6/11 hybrid DNA |
IL117591A0 (en) * | 1995-03-30 | 1996-07-23 | Merck & Co Inc | Synthetic DNA encoding human papillomavirus type 11 L1 protein |
CA2237224C (en) * | 1995-11-15 | 2006-06-27 | Steven Ludmerer | Synthetic hpv11 virus-like particles |
DE19543553B4 (de) * | 1995-11-22 | 2009-04-09 | Deutsches Primatenzentrum Gmbh | VP-Antigene des JC-Virus |
US6908615B1 (en) | 1996-03-18 | 2005-06-21 | Merck & Co., Inc. | DNA encoding human papilloma virus type 18 |
FR2749323B1 (fr) * | 1996-06-04 | 1998-07-10 | Pasteur Merieux Serums Vacc | Pseudo-particules virales utiles en tant que vecteur de delivrance d'acide nucleique |
DE69726886T2 (de) * | 1996-10-04 | 2004-10-14 | Merck & Co., Inc. (A New Jersey Corp.) | Synthetische hpv16 virus-ähnliche partikel |
DE69727830T2 (de) * | 1996-12-09 | 2004-10-07 | Merck & Co Inc | Synthetische hpv-16 virusähnliche partikel |
CA2229955C (en) | 1998-02-20 | 2003-12-09 | Medigene Gmbh | Papilloma virus capsomere vaccine formulations and methods of use |
US7182947B2 (en) | 1998-02-20 | 2007-02-27 | Medigene Ag | Papillomavirus truncated L1 protein and fusion protein constructs |
US7494658B2 (en) | 1998-02-20 | 2009-02-24 | Medigene Ag | Papilloma virus truncated L1 protein and fusion protein constructs |
US20020039584A1 (en) | 1998-02-20 | 2002-04-04 | Medigene Ag | Papilloma virus capsomere vaccine formulations and methods of use |
US6926897B1 (en) | 1998-03-24 | 2005-08-09 | Medigene Aktiengesellschaft | Medicament for the avoidance or treatment of papillomavirus-specific tumour |
US6692752B1 (en) | 1999-09-08 | 2004-02-17 | Smithkline Beecham Biologicals S.A. | Methods of treating human females susceptible to HSV infection |
DE19925199A1 (de) | 1999-06-01 | 2000-12-07 | Medigene Ag | Zytotoxische T-Zellepitope des Papillomavirus L1-Proteins und ihre Verwendung in Diagnostik und Therapie |
DE19925235A1 (de) | 1999-06-01 | 2000-12-07 | Medigene Ag | Zytotoxische T-Zellepitope des Papillomavirus L1-Proteins und ihre Verwendung in Diagnostik und Therapie |
GB0109297D0 (en) | 2001-04-12 | 2001-05-30 | Glaxosmithkline Biolog Sa | Vaccine |
AU2002367977B2 (en) | 2001-08-13 | 2008-06-19 | University Of Rochester | Transcutaneous immunization against papillomavirus with papillomavirus virus-like particles |
GB0206360D0 (en) | 2002-03-18 | 2002-05-01 | Glaxosmithkline Biolog Sa | Viral antigens |
DE602004031681D1 (de) | 2003-07-21 | 2011-04-14 | Transgene Sa | Multifunktionelle Cytokine |
EP1877087B1 (en) | 2005-04-15 | 2013-02-20 | GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Methods and compositions for producing an enhanced immune response to a human papillomavirus immunogen |
WO2006065166A1 (fr) * | 2005-07-26 | 2006-06-22 | Obschestvo S Ogranichennoi Otvetstvennostyu 'rusgen' | Composition de traitement et de prevention de l'infection de l'humain par le papillomavirus sur la base de la proteine l1 et des peptides de la proteine e7 |
TWI457133B (zh) | 2005-12-13 | 2014-10-21 | Glaxosmithkline Biolog Sa | 新穎組合物 |
US8778351B2 (en) | 2006-08-30 | 2014-07-15 | University Of Rochester | Combined human papillomavirus VLP/gene delivery system and use thereof as a vaccine for prophylaxis and immunotherapy of infectious diseases and tumors |
DK2068918T3 (da) | 2006-09-26 | 2012-07-30 | Infectious Disease Res Inst | Vaccinesammensætning omfattende syntetisk adjuvant |
US20090181078A1 (en) | 2006-09-26 | 2009-07-16 | Infectious Disease Research Institute | Vaccine composition containing synthetic adjuvant |
PL2137210T3 (pl) | 2007-03-02 | 2017-06-30 | Glaxosmithkline Biologicals Sa | Nowy sposób i kompozycje |
US9364529B2 (en) | 2007-04-29 | 2016-06-14 | Beijing Wantai Biological Pharmacy Enterprise Co., Ltd. | Truncated L1 protein of human papillomavirus type 18 |
EP2154147B1 (en) * | 2007-04-29 | 2015-10-07 | Beijing Wantai Biological Pharmacy Enterprise Co., Ltd. | A truncated l1 protein of human papillomavirus 16 |
BRPI0810959B1 (pt) | 2007-05-29 | 2021-06-29 | Xiamen Innovax Biotech Co., Ltd. | Proteína l1 do hpv11, polinucleotídeo, vetor, célula, composição, partícula do tipo vírus (vlp) hpv11, método para produzir uma proteína l1 do hpv, vacina para prevenção de condiloma acuminado ou de infecções por hpv e método para produzir uma vacina para prevenção de condiloma acuminado ou infecções por hpv |
WO2008145021A1 (en) * | 2007-05-29 | 2008-12-04 | Xiamen University | A truncated l1 protein of human papillomavirus 6 |
US20110091496A1 (en) * | 2008-01-19 | 2011-04-21 | Graham Barney S | Methods and compositions for the delivery of vaccines to disrupted epithelium |
EP2280728B1 (en) | 2008-05-26 | 2016-03-02 | Cadila Healthcare Limited | Combined measles-human papilloma vaccine |
GB0815872D0 (en) | 2008-09-01 | 2008-10-08 | Pasteur Institut | Novel method and compositions |
GB0820822D0 (en) | 2008-11-13 | 2008-12-24 | Inst Catala D Oncologia | Novel product and processes |
EP2414512A1 (en) * | 2009-04-03 | 2012-02-08 | Deutsches Krebsforschungszentrum | Enhanced production of papillomavirus-like particles with a modified baculovirus expression system |
RU2560182C2 (ru) | 2009-06-05 | 2015-08-20 | Инфекшес Дизиз Рисерч Инститьют | Синтетические глюкопиранозиллипидные адъюванты |
WO2011026111A1 (en) | 2009-08-31 | 2011-03-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Oral delivery of a vaccine to the large intestine to induce mucosal immunity |
EP2556377B1 (en) | 2010-04-08 | 2017-07-12 | University of Pittsburgh - Of the Commonwealth System of Higher Education | B-cell antigen presenting cell assay |
MX350795B (es) | 2011-04-08 | 2017-09-19 | Inmune Design Corp | Composiciones inmunogenicas y metodos para utilizar las composiciones para inducir respuestas inmunes humorales y celulares. |
TR201908003T4 (tr) | 2012-02-07 | 2019-06-21 | Infectious Disease Res Inst | TLR4 agonistleri içeren gelişmiş adjuvan formülasyonları ve bunların kullanım metotları. |
CN104203270A (zh) | 2012-03-18 | 2014-12-10 | 葛兰素史密丝克莱恩生物有限公司 | 针对人***状瘤病毒的接种方法 |
NZ701881A (en) | 2012-05-16 | 2016-10-28 | Immune Design Corp | Vaccines for hsv-2 |
JP6430949B2 (ja) | 2012-10-23 | 2018-11-28 | エモリー ユニバーシティ | Gm−csfとil−4のコンジュゲート、組成物、ならびにそれに関連する方法 |
SG11201508092YA (en) | 2013-04-18 | 2015-10-29 | Immune Design Corp | Gla monotherapy for use in cancer treatment |
US9463198B2 (en) | 2013-06-04 | 2016-10-11 | Infectious Disease Research Institute | Compositions and methods for reducing or preventing metastasis |
JP6741580B2 (ja) | 2013-12-31 | 2020-08-19 | インフェクシャス ディズィーズ リサーチ インスティチュート | 単一バイアルのワクチン製剤 |
CN108885212B (zh) | 2016-02-22 | 2022-05-31 | 勃林格殷格翰维特梅迪卡有限公司 | 固定生物分子的方法 |
CA3023672A1 (en) | 2016-05-16 | 2017-11-23 | Infectious Disease Research Institute | Pegylated liposomes and methods of use |
JP7195148B2 (ja) | 2016-05-16 | 2022-12-23 | アクセス ツー アドバンスト ヘルス インスティチュート | Tlrアゴニストを含有する製剤及び使用方法 |
IL298227B1 (en) | 2016-06-01 | 2024-05-01 | Access To Advanced Health Inst | Nanoalum particles containing a fixing factor |
CN111315362A (zh) | 2017-06-15 | 2020-06-19 | 传染病研究所 | 纳米结构脂质载剂和稳定乳剂以及其用途 |
KR20200066309A (ko) | 2017-09-08 | 2020-06-09 | 인펙셔스 디지즈 리서치 인스티튜트 (아이디알아이) | 사포닌을 포함하는 리포솜 제형 및 사용 방법 |
AU2020283768A1 (en) | 2019-05-25 | 2021-12-23 | Access To Advanced Health Institute | Composition and method for spray drying an adjuvant vaccine emulsion |
CA3174411A1 (en) | 2020-09-04 | 2022-03-10 | Ryan M. Kramer | Co-lyophilized rna and nanostructured lipid carrier |
CN117222428A (zh) | 2021-02-11 | 2023-12-12 | 葛兰素史克生物有限公司 | Hpv疫苗生产 |
WO2024052882A1 (en) | 2022-09-09 | 2024-03-14 | Access To Advanced Health Institute | Immunogenic vaccine composition incorporating a saponin |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4956288A (en) * | 1988-04-22 | 1990-09-11 | Biogen, Inc. | Method for producing cells containing stably integrated foreign DNA at a high copy number, the cells produced by this method, and the use of these cells to produce the polypeptides coded for by the foreign DNA |
NZ232913A (en) * | 1989-03-15 | 1992-08-26 | Gist Brocades Nv | Il-3 produced recombinantly and purified to homogeneity; vectors and pharmaceutical preparations |
ATE234925T1 (de) * | 1991-07-19 | 2003-04-15 | Univ Queensland | Impfstoffe gegen papillomavirus |
-
1994
- 1994-03-08 DE DE05075369T patent/DE05075369T1/de active Pending
- 1994-03-08 DE DE69434383T patent/DE69434383T2/de not_active Expired - Lifetime
- 1994-03-08 AT AT05075369T patent/ATE494005T1/de active
- 1994-03-08 WO PCT/US1994/002443 patent/WO1994020137A1/en active IP Right Grant
- 1994-03-08 ES ES94912186T patent/ES2242955T4/es not_active Expired - Lifetime
- 1994-03-08 ES ES05075369T patent/ES2263405T3/es not_active Expired - Lifetime
- 1994-03-08 PT PT05075369T patent/PT1618888E/pt unknown
- 1994-03-08 EP EP94912186A patent/EP0688227B1/en not_active Expired - Lifetime
- 1994-03-08 AT AT05075889T patent/ATE492289T1/de not_active IP Right Cessation
- 1994-03-08 EP EP05075369A patent/EP1618888B1/en not_active Expired - Lifetime
- 1994-03-08 DE DE1994634383 patent/DE122007000014I1/de active Pending
- 1994-03-08 ES ES05075889T patent/ES2263406T3/es not_active Expired - Lifetime
- 1994-03-08 EP EP05075889A patent/EP1588713B1/en not_active Expired - Lifetime
- 1994-03-08 DE DE201112100018 patent/DE122011100018I1/de active Pending
- 1994-03-08 JP JP6520236A patent/JPH08507685A/ja not_active Withdrawn
- 1994-03-08 PT PT94912186T patent/PT688227E/pt unknown
- 1994-03-08 CA CA2157932A patent/CA2157932C/en not_active Expired - Lifetime
- 1994-03-08 DE DE69435332T patent/DE69435332D1/de not_active Expired - Lifetime
- 1994-03-08 DE DE05075889T patent/DE05075889T1/de active Pending
- 1994-03-08 DE DE122007000089C patent/DE122007000089I1/de active Pending
- 1994-03-08 DE DE122007000090C patent/DE122007000090I1/de active Pending
- 1994-03-08 AU AU64436/94A patent/AU688759C/en not_active Expired
- 1994-03-08 DE DE69435331T patent/DE69435331D1/de not_active Expired - Lifetime
- 1994-03-08 DK DK05075369.8T patent/DK1618888T3/da active
- 1994-03-08 AT AT94912186T patent/ATE296111T1/de active
- 1994-03-08 DK DK94912186T patent/DK0688227T3/da active
-
2006
- 2006-03-14 HK HK06103227.3A patent/HK1082196A1/xx not_active IP Right Cessation
- 2006-03-28 HK HK06103842.8A patent/HK1082206A1/xx not_active IP Right Cessation
- 2006-10-11 JP JP2006277056A patent/JP4486075B2/ja not_active Expired - Lifetime
-
2007
- 2007-02-21 LU LU91313C patent/LU91313I2/fr unknown
- 2007-02-21 NL NL300265C patent/NL300265I2/nl unknown
- 2007-03-07 AU AU2007201006A patent/AU2007201006B2/en not_active Expired
- 2007-03-07 AU AU2007201005A patent/AU2007201005B2/en not_active Expired
- 2007-12-14 LU LU91391C patent/LU91391I2/fr unknown
- 2007-12-14 NL NL300309C patent/NL300309I2/nl unknown
- 2007-12-14 NL NL300310C patent/NL300310I1/nl unknown
- 2007-12-14 LU LU91392C patent/LU91392I2/fr unknown
-
2010
- 2010-02-05 JP JP2010023691A patent/JP5386392B2/ja not_active Expired - Lifetime
- 2010-02-05 JP JP2010023690A patent/JP5306251B2/ja not_active Expired - Lifetime
-
2011
- 2011-07-04 FR FR11C0022C patent/FR11C0022I2/fr active Active
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010095530A (ja) * | 1997-10-06 | 2010-04-30 | Loyola Univ Of Chicago | パピローマウイルスカプソメアワクチン製剤および使用方法 |
JP2002516291A (ja) * | 1998-05-29 | 2002-06-04 | ユニバーシティー オブ ロチェスター | パピローマウイルス・ウイルス様粒子による経口免疫感作 |
JP2004510144A (ja) * | 2000-09-18 | 2004-04-02 | メディミューン,インコーポレイテッド | ワクチンの免疫原性を測定する試験管内検定 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5386392B2 (ja) | ひとパピローマウイルス・カプシド蛋白およびウイルス様粒子の製造 | |
JP4046949B2 (ja) | 自己組立て組換えパピローマウイルスキャプシッド蛋白質 | |
US7169585B2 (en) | Papillomavirus vaccine | |
US6153201A (en) | Oral immunization with papillomavirus virus-like particles | |
US8062642B1 (en) | Production of papillomavirus capsid protein and virus-like particles | |
AU683220C (en) | Self-assembling recombinant papillomavirus capsid proteins | |
Rose | Production and characterization of human papillomavirus (HPV) virus-like particles (VLPs): novel diagnostic reagents and vaccine candidates for genital HPV disease |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20050322 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20050620 |
|
RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20050620 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20050620 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20050922 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20051017 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20060613 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20060911 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20061025 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20061025 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20061214 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20070215 |
|
A761 | Written withdrawal of application |
Free format text: JAPANESE INTERMEDIATE CODE: A761 Effective date: 20081107 |