JP2019521679A - 強力でバランスのとれた双方向性プロモーター - Google Patents
強力でバランスのとれた双方向性プロモーター Download PDFInfo
- Publication number
- JP2019521679A JP2019521679A JP2018566443A JP2018566443A JP2019521679A JP 2019521679 A JP2019521679 A JP 2019521679A JP 2018566443 A JP2018566443 A JP 2018566443A JP 2018566443 A JP2018566443 A JP 2018566443A JP 2019521679 A JP2019521679 A JP 2019521679A
- Authority
- JP
- Japan
- Prior art keywords
- promoter
- hcmv
- adenovirus
- recombinant
- bidirectional
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000013598 vector Substances 0.000 claims abstract description 184
- 230000002457 bidirectional effect Effects 0.000 claims abstract description 183
- 108700019146 Transgenes Proteins 0.000 claims abstract description 157
- 241000700605 Viruses Species 0.000 claims abstract description 72
- 238000000034 method Methods 0.000 claims abstract description 72
- 230000002441 reversible effect Effects 0.000 claims abstract description 15
- 241000701161 unidentified adenovirus Species 0.000 claims description 157
- 239000000427 antigen Substances 0.000 claims description 81
- 108091007433 antigens Proteins 0.000 claims description 76
- 102000036639 antigens Human genes 0.000 claims description 76
- 239000003623 enhancer Substances 0.000 claims description 55
- 150000007523 nucleic acids Chemical class 0.000 claims description 33
- 238000004519 manufacturing process Methods 0.000 claims description 26
- 102000039446 nucleic acids Human genes 0.000 claims description 25
- 108020004707 nucleic acids Proteins 0.000 claims description 25
- 238000012217 deletion Methods 0.000 claims description 24
- 230000037430 deletion Effects 0.000 claims description 24
- 230000028993 immune response Effects 0.000 claims description 24
- 241000598171 Human adenovirus sp. Species 0.000 claims description 16
- 239000013600 plasmid vector Substances 0.000 claims description 9
- 241000701024 Human betaherpesvirus 5 Species 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 108020004511 Recombinant DNA Proteins 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 102000053602 DNA Human genes 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000001939 inductive effect Effects 0.000 claims description 4
- 241000218605 Macacine betaherpesvirus 3 Species 0.000 claims description 3
- 230000014509 gene expression Effects 0.000 description 181
- 210000004027 cell Anatomy 0.000 description 117
- 108090000623 proteins and genes Proteins 0.000 description 76
- 229960005486 vaccine Drugs 0.000 description 33
- 102000004169 proteins and genes Human genes 0.000 description 32
- 241000701029 Murid betaherpesvirus 1 Species 0.000 description 30
- 241000701022 Cytomegalovirus Species 0.000 description 25
- 241000282414 Homo sapiens Species 0.000 description 25
- 238000013461 design Methods 0.000 description 24
- 239000000203 mixture Substances 0.000 description 24
- 239000013612 plasmid Substances 0.000 description 24
- 230000002068 genetic effect Effects 0.000 description 21
- 238000013518 transcription Methods 0.000 description 20
- 230000035897 transcription Effects 0.000 description 20
- 108060001084 Luciferase Proteins 0.000 description 18
- 238000000746 purification Methods 0.000 description 18
- 230000001105 regulatory effect Effects 0.000 description 18
- 239000013603 viral vector Substances 0.000 description 18
- 108091092195 Intron Proteins 0.000 description 17
- 239000005089 Luciferase Substances 0.000 description 17
- 239000002773 nucleotide Substances 0.000 description 17
- 125000003729 nucleotide group Chemical group 0.000 description 17
- 108020004414 DNA Proteins 0.000 description 15
- 238000002474 experimental method Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 238000001415 gene therapy Methods 0.000 description 13
- 239000002671 adjuvant Substances 0.000 description 12
- 230000006870 function Effects 0.000 description 12
- 230000003612 virological effect Effects 0.000 description 12
- 241000282560 Macaca mulatta Species 0.000 description 11
- 230000008901 benefit Effects 0.000 description 11
- 239000012634 fragment Substances 0.000 description 11
- 108090000765 processed proteins & peptides Proteins 0.000 description 11
- 230000000890 antigenic effect Effects 0.000 description 10
- 230000002950 deficient Effects 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 238000011144 upstream manufacturing Methods 0.000 description 10
- 238000002255 vaccination Methods 0.000 description 10
- 230000002163 immunogen Effects 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- 102000004196 processed proteins & peptides Human genes 0.000 description 9
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 8
- 241000725643 Respiratory syncytial virus Species 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- 238000010369 molecular cloning Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 241001217856 Chimpanzee adenovirus Species 0.000 description 7
- 241001135569 Human adenovirus 5 Species 0.000 description 7
- 108700026244 Open Reading Frames Proteins 0.000 description 7
- 238000010222 PCR analysis Methods 0.000 description 7
- 108700008625 Reporter Genes Proteins 0.000 description 7
- 108091023040 Transcription factor Proteins 0.000 description 7
- 238000010276 construction Methods 0.000 description 7
- 230000010076 replication Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 238000012546 transfer Methods 0.000 description 7
- 108091026890 Coding region Proteins 0.000 description 6
- 241000725303 Human immunodeficiency virus Species 0.000 description 6
- 101710163270 Nuclease Proteins 0.000 description 6
- 108091028043 Nucleic acid sequence Proteins 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 210000001744 T-lymphocyte Anatomy 0.000 description 6
- 102000040945 Transcription factor Human genes 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000000120 cytopathologic effect Effects 0.000 description 6
- 239000003599 detergent Substances 0.000 description 6
- 229920001184 polypeptide Polymers 0.000 description 6
- 239000013641 positive control Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 101150061166 tetR gene Proteins 0.000 description 6
- 241000990167 unclassified Simian adenoviruses Species 0.000 description 6
- 241001115402 Ebolavirus Species 0.000 description 5
- 108700039887 Essential Genes Proteins 0.000 description 5
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 229940021704 adenovirus vaccine Drugs 0.000 description 5
- 239000000556 agonist Substances 0.000 description 5
- 210000003719 b-lymphocyte Anatomy 0.000 description 5
- 108010006025 bovine growth hormone Proteins 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 230000000295 complement effect Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000006801 homologous recombination Effects 0.000 description 5
- 238000002744 homologous recombination Methods 0.000 description 5
- 230000005847 immunogenicity Effects 0.000 description 5
- 238000004020 luminiscence type Methods 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 238000010361 transduction Methods 0.000 description 5
- 230000026683 transduction Effects 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- CXURGFRDGROIKG-UHFFFAOYSA-N 3,3-bis(chloromethyl)oxetane Chemical compound ClCC1(CCl)COC1 CXURGFRDGROIKG-UHFFFAOYSA-N 0.000 description 4
- 101000834253 Gallus gallus Actin, cytoplasmic 1 Proteins 0.000 description 4
- 101710154606 Hemagglutinin Proteins 0.000 description 4
- 101001098455 Human herpesvirus 8 type P (isolate GK18) OX-2 membrane glycoprotein homolog Proteins 0.000 description 4
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 4
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 4
- 101710173835 Penton protein Proteins 0.000 description 4
- 101710176177 Protein A56 Proteins 0.000 description 4
- 239000004098 Tetracycline Substances 0.000 description 4
- 108700009124 Transcription Initiation Site Proteins 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 239000013604 expression vector Substances 0.000 description 4
- 239000000835 fiber Substances 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 210000004962 mammalian cell Anatomy 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 101150024821 tetO gene Proteins 0.000 description 4
- 229960002180 tetracycline Drugs 0.000 description 4
- 229930101283 tetracycline Natural products 0.000 description 4
- 235000019364 tetracycline Nutrition 0.000 description 4
- 150000003522 tetracyclines Chemical class 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 238000003146 transient transfection Methods 0.000 description 4
- 238000000108 ultra-filtration Methods 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 241000701242 Adenoviridae Species 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 102100037084 C4b-binding protein alpha chain Human genes 0.000 description 3
- 101710159767 C4b-binding protein alpha chain Proteins 0.000 description 3
- 108090000565 Capsid Proteins Proteins 0.000 description 3
- 102100023321 Ceruloplasmin Human genes 0.000 description 3
- 241000557626 Corvus corax Species 0.000 description 3
- -1 CymR Proteins 0.000 description 3
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 3
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102100021519 Hemoglobin subunit beta Human genes 0.000 description 3
- 108091005904 Hemoglobin subunit beta Proteins 0.000 description 3
- 101710094396 Hexon protein Proteins 0.000 description 3
- 101000831496 Homo sapiens Toll-like receptor 3 Proteins 0.000 description 3
- 108700002232 Immediate-Early Genes Proteins 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 241000282577 Pan troglodytes Species 0.000 description 3
- 241000288906 Primates Species 0.000 description 3
- 238000012300 Sequence Analysis Methods 0.000 description 3
- 108010034546 Serratia marcescens nuclease Proteins 0.000 description 3
- 102000002689 Toll-like receptor Human genes 0.000 description 3
- 108020000411 Toll-like receptor Proteins 0.000 description 3
- 102100024324 Toll-like receptor 3 Human genes 0.000 description 3
- 108020005202 Viral DNA Proteins 0.000 description 3
- 108700010877 adenoviridae proteins Proteins 0.000 description 3
- 239000013592 cell lysate Substances 0.000 description 3
- 230000006037 cell lysis Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000011210 chromatographic step Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000012459 cleaning agent Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000000185 hemagglutinin Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 201000004792 malaria Diseases 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 230000008488 polyadenylation Effects 0.000 description 3
- 230000001902 propagating effect Effects 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 230000014616 translation Effects 0.000 description 3
- 241001529453 unidentified herpesvirus Species 0.000 description 3
- 208000010370 Adenoviridae Infections Diseases 0.000 description 2
- 206010060931 Adenovirus infection Diseases 0.000 description 2
- 101100004644 Arabidopsis thaliana BAT1 gene Proteins 0.000 description 2
- 101100519158 Arabidopsis thaliana PCR2 gene Proteins 0.000 description 2
- 102000014914 Carrier Proteins Human genes 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- 230000006820 DNA synthesis Effects 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 241000710188 Encephalomyocarditis virus Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 2
- 241000282575 Gorilla Species 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 241001115401 Marburgvirus Species 0.000 description 2
- 241001136036 Murid betaherpesvirus 2 Species 0.000 description 2
- 102100026379 Neurofibromin Human genes 0.000 description 2
- 241000223960 Plasmodium falciparum Species 0.000 description 2
- 108020005067 RNA Splice Sites Proteins 0.000 description 2
- 101900083372 Rabies virus Glycoprotein Proteins 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 102000004446 Serum Response Factor Human genes 0.000 description 2
- 108010042291 Serum Response Factor Proteins 0.000 description 2
- 241000700584 Simplexvirus Species 0.000 description 2
- 108091081024 Start codon Proteins 0.000 description 2
- 108700026226 TATA Box Proteins 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- 241000710886 West Nile virus Species 0.000 description 2
- 108091006088 activator proteins Proteins 0.000 description 2
- 208000011589 adenoviridae infectious disease Diseases 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
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 108091008324 binding proteins Proteins 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000011026 diafiltration Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012537 formulation buffer Substances 0.000 description 2
- 238000012395 formulation development Methods 0.000 description 2
- 238000001476 gene delivery Methods 0.000 description 2
- 210000002443 helper t lymphocyte Anatomy 0.000 description 2
- 230000003308 immunostimulating effect Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 230000002934 lysing effect Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000006384 oligomerization reaction Methods 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 2
- 230000006798 recombination Effects 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229930182490 saponin Natural products 0.000 description 2
- 150000007949 saponins Chemical class 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000005026 transcription initiation Effects 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 230000010415 tropism Effects 0.000 description 2
- 201000008827 tuberculosis Diseases 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- ZYPDJSJJXZWZJJ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-piperidin-4-yloxypyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)OC1CCNCC1 ZYPDJSJJXZWZJJ-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 108010068327 4-hydroxyphenylpyruvate dioxygenase Proteins 0.000 description 1
- 230000005730 ADP ribosylation Effects 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 231100000699 Bacterial toxin Toxicity 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000701106 Bovine adenovirus 3 Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 102000001902 CC Chemokines Human genes 0.000 description 1
- 108010040471 CC Chemokines Proteins 0.000 description 1
- 241000701157 Canine mastadenovirus A Species 0.000 description 1
- 102000009016 Cholera Toxin Human genes 0.000 description 1
- 108010049048 Cholera Toxin Proteins 0.000 description 1
- 108091033380 Coding strand Proteins 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 102100025278 Coxsackievirus and adenovirus receptor Human genes 0.000 description 1
- 101710176411 Coxsackievirus and adenovirus receptor Proteins 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
- 241000725619 Dengue virus Species 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 101710088335 Diacylglycerol acyltransferase/mycolyltransferase Ag85A Proteins 0.000 description 1
- 101710088334 Diacylglycerol acyltransferase/mycolyltransferase Ag85B Proteins 0.000 description 1
- 101150029662 E1 gene Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 101710146739 Enterotoxin Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 101710145505 Fiber protein Proteins 0.000 description 1
- 241000711950 Filoviridae Species 0.000 description 1
- 108090000331 Firefly luciferases Proteins 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- 208000007212 Foot-and-Mouth Disease Diseases 0.000 description 1
- 241000710198 Foot-and-mouth disease virus Species 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 108091092584 GDNA Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 108010006207 Galactose repressor proteins Proteins 0.000 description 1
- 241000447437 Gerreidae Species 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 1
- 229940033330 HIV vaccine Drugs 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000718007 Homo sapiens Aldo-keto reductase family 1 member A1 Proteins 0.000 description 1
- 101000836540 Homo sapiens Aldo-keto reductase family 1 member B1 Proteins 0.000 description 1
- 101000733802 Homo sapiens Apolipoprotein A-I Proteins 0.000 description 1
- 101000961414 Homo sapiens Membrane cofactor protein Proteins 0.000 description 1
- 241000205701 Human adenovirus 26 Species 0.000 description 1
- 241000701124 Human adenovirus 35 Species 0.000 description 1
- 241001626332 Human adenovirus 49 Species 0.000 description 1
- 241000701806 Human papillomavirus Species 0.000 description 1
- 241000714192 Human spumaretrovirus Species 0.000 description 1
- 101710128560 Initiator protein NS1 Proteins 0.000 description 1
- 101150008942 J gene Proteins 0.000 description 1
- 241000710842 Japanese encephalitis virus Species 0.000 description 1
- 108010054278 Lac Repressors Proteins 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- 241000710118 Maize chlorotic mottle virus Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000701244 Mastadenovirus Species 0.000 description 1
- 241000712079 Measles morbillivirus Species 0.000 description 1
- 102000000490 Mediator Complex Human genes 0.000 description 1
- 108010080991 Mediator Complex Proteins 0.000 description 1
- 102100039373 Membrane cofactor protein Human genes 0.000 description 1
- 108010057081 Merozoite Surface Protein 1 Proteins 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 101710144127 Non-structural protein 1 Proteins 0.000 description 1
- 108091007494 Nucleic acid- binding domains Proteins 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 102000010292 Peptide Elongation Factor 1 Human genes 0.000 description 1
- 108010077524 Peptide Elongation Factor 1 Proteins 0.000 description 1
- 102000011755 Phosphoglycerate Kinase Human genes 0.000 description 1
- 241000223830 Plasmodium yoelii Species 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 241001068263 Replication competent viruses Species 0.000 description 1
- 108010034634 Repressor Proteins Proteins 0.000 description 1
- 102000009661 Repressor Proteins Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241001217859 Simian adenovirus 1 Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 108010008038 Synthetic Vaccines Proteins 0.000 description 1
- 101001099217 Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8) Triosephosphate isomerase Proteins 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 108050004197 Trp repressor Proteins 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 241000219977 Vigna Species 0.000 description 1
- 241001115400 Zaire ebolavirus Species 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- NTGGOTYRTOXKMQ-UHFFFAOYSA-K aluminum;potassium;phosphate Chemical compound [Al+3].[K+].[O-]P([O-])([O-])=O NTGGOTYRTOXKMQ-UHFFFAOYSA-K 0.000 description 1
- 210000001776 amniocyte Anatomy 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000000688 bacterial toxin Substances 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 238000010364 biochemical engineering Methods 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 210000000852 deltoid muscle Anatomy 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 108010067396 dornase alfa Proteins 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 239000000147 enterotoxin Substances 0.000 description 1
- 231100000655 enterotoxin Toxicity 0.000 description 1
- 238000003114 enzyme-linked immunosorbent spot assay Methods 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 238000011331 genomic analysis Methods 0.000 description 1
- 239000005090 green fluorescent protein Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000009851 immunogenic response Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 229940033324 influenza A vaccine Drugs 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 229940124735 malaria vaccine Drugs 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000007479 molecular analysis Methods 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 229940035032 monophosphoryl lipid a Drugs 0.000 description 1
- 229940031348 multivalent vaccine Drugs 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 230000000174 oncolytic effect Effects 0.000 description 1
- 229940126578 oral vaccine Drugs 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 108010083127 phage repressor proteins Proteins 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 1
- 239000002644 phorbol ester Substances 0.000 description 1
- 101150088856 pix gene Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002331 protein detection Methods 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 229940107568 pulmozyme Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 229940124551 recombinant vaccine Drugs 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 238000007480 sanger sequencing Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009044 synergistic interaction Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 230000029812 viral genome replication Effects 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/53—DNA (RNA) vaccination
-
- 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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/10011—Adenoviridae
- C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
- C12N2710/10321—Viruses as such, e.g. new isolates, mutants or their genomic sequences
-
- 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
- C12N2710/10011—Adenoviridae
- C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
- C12N2710/10341—Use of virus, viral particle or viral elements as a vector
- C12N2710/10343—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
- C12N2710/16011—Herpesviridae
- C12N2710/16111—Cytomegalovirus, e.g. human herpesvirus 5
- C12N2710/16122—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
- C12N2710/16011—Herpesviridae
- C12N2710/16111—Cytomegalovirus, e.g. human herpesvirus 5
- C12N2710/16141—Use of virus, viral particle or viral elements as a vector
- C12N2710/16143—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
- C12N2830/00—Vector systems having a special element relevant for transcription
- C12N2830/15—Vector systems having a special element relevant for transcription chimeric enhancer/promoter combination
-
- 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
- C12N2830/00—Vector systems having a special element relevant for transcription
- C12N2830/20—Vector systems having a special element relevant for transcription transcription of more than one cistron
- C12N2830/205—Vector systems having a special element relevant for transcription transcription of more than one cistron bidirectional
Landscapes
- Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- General Health & Medical Sciences (AREA)
- Plant Pathology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- Microbiology (AREA)
- Biophysics (AREA)
- Immunology (AREA)
- Virology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
細胞培養:
PER.C6(登録商標)細胞(Fallaux et al.,1998)を、10mMのMgCl2を添加した10%ウシ胎児血清(FBS)含有ダルベッコ変法イーグル培地(DMEM)中で維持した。
異なる双方向性プロモーター構築物をpAdApt35プラスミド(Vogels et al.2007)またはpshuttle26プラスミドにクローニングした。Pshuttle26は、以前に記載されたpAdapt26プラスミド(Abbink et al.,2007)に基づいて構築した。Ad26ベクターゲノムの右側部分を含む2−Kb断片を合成し、CMVプロモーターのSpeI部位が最初に単一bp置換の導入によって破壊されたpAdApt26.Lucにサブクローニングした。結果として、pshuttle26は、Ad26コスミドとの相同組換えにより、またはAd26完全長ゲノムプラスミドとの相同組換えにより、アデノウイルスベクターを構築するために使用され得る。
全てのアデノウイルスをPER.C6細胞中で相同組換えにより生成し、以前に記載されているようにして生成した(rAd35では(Havenga et al.,2006);rAd26では(Abbink et al.,2007))。簡単に記載すると、PER.C6細胞を、製造業者(Life Technologies)によって提供された使用説明書に従ってリポフェクタミンを使用して、プラスミドをコードするrAdベクターでトランスフェクトした。rAd35ベクターをレスキューするために、pAdApt35プラスミドおよびpWE/Ad35.pIX−rITR.dE3.5orf6コスミドを使用し、一方、rAd26ベクターのためにpShuttle26プラスミドおよびpWE.Ad26.dE3.5orf6コスミドを使用した。十分な細胞変性効果(CPE)に達した1日後に細胞を収集し、凍結解凍させ、3,000rpmで5分間遠心分離し、−20℃で貯蔵した。次いで、ウイルスを、マルチウェル24組織培養プレートの単一ウェルで培養したPER.C6細胞内でプラーク精製し、増幅させた。T25組織培養フラスコを使用して培養されたPER.C6細胞において、さらに増幅させた。
発現の強度および発現バランスを評価するために、高感度緑色蛍光タンパク質(eGFPタンパク質アクセッション番号AAB02572.1)およびホタルルシフェラーゼ(ルシフェラーゼタンパク質アクセッション番号ACH53166)をコードするレポーター遺伝子を用いてウイルスベクターを作製した。相対eGFP平均蛍光強度(MFI)およびルシフェラーゼ相対発光量(RLU)を、HEK293細胞(pAdAptベクターまたはpshuttleベクターによる一過性トランスフェクション)またはA549細胞(ウイルス感染)との各プロモーターおよびレポーター遺伝子の組み合わせについて記録した。ルシフェラーゼ活性は、Luminoskan(商標)Ascentマイクロプレート照度計において、0.1%DTT(1M)の存在下、細胞溶解物中で測定した。eGFP蛍光は、フローサイトメーター(FACS)において、トリプシン処理、遠心分離、およびPBS/1%FBS(非ウイルス物質)またはCellFix(ウイルス物質)における細胞ペレットの再懸濁により測定した。
PER.C6細胞内にいくつかの継代を含む生産工程における遺伝的安定性を確実にするために、ワクチンベクターの遺伝的安定性試験を実施した。組換えワクチンベクターの作製、プラーク精製、およびT25形態への増殖を上述のように行った。簡単に記載すると、組換えウイルスをE1相補細胞株PER.C6においてプラスミドトランスフェクションによって作製し、プラーク精製した。マルチウェル24(MW24)からT25フラスコへの規模拡大のために5つのプラークを選択した。続いて、新しいPER.C6細胞をウイルス継代数13までT25形態で感染させた。感染の2日後に完全細胞変性効果を与える所定の感染性容積(rAd35では50、rAd26では900のウイルス粒子/細胞比の範囲内にあることが遡及的に判定された)を使用してウイルスを増殖させた。ウイルスDNAをp13材料から単離し、PCR分析により、完全導入遺伝子発現カセットの存在を試験した。ワクチンベクターをPER.C6細胞内で継代数13まで増殖させた。感染の2日後に完全なCPEを与える方法で増殖を行った。rAd35ウイルスは、完全CPEの2日後に回収し、一方、rAd26ウイルスは、完全CPEの1日後に回収した。ウイルスDNAを継代2、継代5、継代10、および継代13で単離し、導入遺伝子発現カセットの両側に位置するプライマーを使用したPCR分析により、欠失が存在しないことを試験した。欠失変異体の欠如は、以下のパラメータによって定義した:PCR産物のバンドサイズは、陽性対照(ウイルスレスキューのために使用されたプラスミドのPCR産物)に一致し、予測されたPCR産物を下回るバンドはなく(追加的なバンドが非特異的なPCR産物であることが示されない限り、それらは、陽性対照にも存在するため)、承認されたアッセイ:PCR H2O対照においてバンドがない。遺伝的安定性をさらに確認するために、発現カセットおよびいくつかのプラーク隣接領域のPCR産物の配列を決定した。
強力な双方向マウスCMV(mCMV)プロモーターを、以前の研究(国際公開第2016/166088号パンフレット)の、アデノウイルスベクターのE1領域における双方向性発現カセットからの2つの抗原の発現に有用なプロモーターとして同定した。mCMV双方向性プロモーターを有するベクターは、抗原を発現し、遺伝的に安定であり、コードされた抗原の両方に対する免疫応答を誘導したが、抗原発現および誘導された免疫応答は、以下に説明するようにバランスがとれていなかった。双方向性プロモーターの右側に置かれた抗原の発現は、双方向性プロモーターの左側に置かれた抗原よりも高く、双方向性プロモーターの右側に置かれた抗原に対してより高い免疫応答を生じた。mCMVの発現レベルの双方向の差は、約10倍であった。しかし、1つの抗原のみを発現する2つのベクターの混合物を置換するために、特定の用途では、両方の抗原の同等レベルの抗原発現を誘導するバランスのとれた双方向性プロモーターが望ましい。さらに、双方向性プロモーターのサイズが比較的小さい場合に有益であろう。
1.rCMV−hEF1α I(図1A、配列番号1)
2.rCMV−hEF1α II(図1B、配列番号2)
3.rhCMV−CAG1(図1C、配列番号3)
4.hCMV−rhCMV(図1D、配列番号4)
5.rCMV−CAG(図1E、配列番号5)
6.rhCMV−CAG2(図1F、配列番号6)
7.rCMV bidir 1(図1G、配列番号10)
8.rCMV bidir 2(図1H、配列番号8)
9.rCMV bidir 1.1(図1I、配列番号7)
10.hCMV−CAG4(図1J、配列番号11)
1.mCMV bidir.
2.hCMV−CAG
3.mCMV−CAG
第1のスクリーニング実験において、異なる双方向性プロモーターコンストラクトからの発現を、レポーター遺伝子ルシフェラーゼおよびeGFPを使用して、HEK293における一過性トランスフェクションにより、定量的強度読み出しについて評価した。pAdapt35プラスミドの一過性トランスフェクションでは、双方向性プロモーターは、双方向性プロモーターの左側にルシフェラーゼ導入遺伝子を、右側にeGFP導入遺伝子を有した。
アデノウイルスベクターのE1領域からの発現の強度およびバランスをさらに評価するために、本発明者らは、E1領域にhCMV−rhCMV双方向性発現カセットを有するAd26ベクターおよびAd35ベクターを生成した。4つの異なるベクトル、すなわちAd26.eGFP.hCMV−rhCMV.Luc、Ad26.Luc.hCMV−rhCMV.eGFP、Ad35.eGFP.hCMV−rhCMV.LucおよびAd35.Luc.hCMV−rhCMV.eGFPを作成し、非相補性A549細胞の形質導入時のレポーター遺伝子発現の強度およびバランスを評価した。形質導入は、100VP/細胞および1000VP/細胞で行った。両方のVP/細胞比での結果は、類似していたため、1000VP/細胞での形質導入の結果のみを図4に示す。100VP/細胞および1000VP/細胞での発現の10倍の差異を推定するために、一方向性hCMVプロモーターの制御下でレポーター遺伝子を発現する陽性対照ベクターAd.LucおよびAd.eGFPの形質導入を示す。パネル4Aは、hCMV−rhCMVが、1000VP/細胞でのAd26.LucおよびAd26.eGFP対照ベクターよりわずかに低い発現レベルにおいて、Ad26 E1双方向性発現カセットからの両方のレポーター遺伝子の強力な発現を誘導することを示す。Ad26.Luc.hCMV−rhCMV.eGFPをAd26.Luc.mCMV bidir.eGFPとさらに直接比較すると、Ad26.Luc.hCMV−rhCMV.eGFPは、mCMV bidirと比べてeGFP導入遺伝子の発現の低下を示すが、全体的によりバランスのとれた導入遺伝子の発現も示している。パネル4Bは、Ad35ベクターにおけるhCMV−rhCMV双方向性発現カセットからの導入遺伝子の発現を示す。興味深いことに、Ad35ベクターにおける発現プロフィールは、Ad26ベクターにおける発現プロフィールとわずかに異なっていた。したがって、強力な双方向性プロモーターは、異なる血清型に由来するrAdVにおいて使用され得るが、異なるプロモーターは、1つのrAdVにおける使用が他のものよりも最適であり得、さらに、プロモーターおよび発現カセットの複雑な設計が最適なウイルスベクターのために必要とされることを例示する。
導入遺伝子の発現に加えて、AdVを産生している間の遺伝的安定性は、2つの抗原を発現する有用なAdVにとって重要なパラメータである。したがって、先行出願の国際公開第2016/166088号パンフレットに記載のように遺伝的安定性を試験した。簡潔に記載すると、ベクターAd26.Luc.hCMV−rhCMV.eGFPおよびAd26.eGFP.hCMV−rhCMV.LucをPER.C6細胞におけるプラスミドトランスフェクションによって生成し、ウイルス集団をプラークピッキングによって単離した。1ベクター当たり10個のプラークをウイルス継代数(vpn)3まで増殖させた。その後、5つのプラークを選択し、vpn13まで継代を延長した。遺伝的安定性をE1発現カセット領域(図5)ならびにE3およびE4領域(E3およびE4PCRのデータは示さず)の同一性PCRによって評価した。小さい欠失または点変異の欠如をvpn13のE1 PCR産物の標準的なサンガーシーケンシングによって確認した。Ad26.Luc.hCMV−rhCMV.eGFPおよびAd26.eGFP.hCMV−rhCMV.Lucの両方の5つのプラークのうちの5つがvpn13まで遺伝的に安定なままであった。
上記のように、新しい双方向性プロモーターコンストラクトのパネルをスクリーニングすることにより、いずれの双方向性プロモーターコンストラクトが所望のプロモーター特性を与えるかを予測することは不可能であることがわかった。実際、非常に類似しているように思われる双方向性プロモーターコンストラクトでさえ、必ずしも同じ結果を与えない。例えば、左側にヒトCMVプロモーター(hCMV)および右側に短いアカゲザルCMVプロモーター(rhCMV)を有する双方向性hCMV−rhCMVプロモーターは、特にrAd26およびrAd35ベクターのE1領域からの2つの異なる導入遺伝子のバランスのとれた発現を示した。驚くべきことに、双方向性hCMV−rhCMVプロモーターは、導入遺伝子発現の強度およびバランスを兼ね備え、かつまた長さが1kB未満と非常に小さい。双方向性hCMV−rhCMVプロモーターを有するrAdは、PER.C6細胞においてP13に連続継代した後でさえも遺伝的に安定であることがわかった。したがって、本発明の双方向性hCMV−rhCMVプロモーターは、遺伝子治療およびワクチンに使用することができる組換えウイルスベクターでの使用、特にバランスのとれた強力な発現が重要である場合、および/または小サイズの双方向性hCMV−rhCMVプロモーターが有用である場合の使用に驚くほど好ましい特性を備えたプロモーターである。
米国特許文献:
US5057540A(10/15/1991).“Saponin adjuvant”.Kensil,Charlotte A.;Marciani,Dante J.
US5122458A(6/16/1992).“Use of a bGH gDNA polyadenylation signal in expression of non−bGH polypeptides in higher eukaryotic cells”.Post,Leonard E.;Palermo,Daniel P.;Thomsen,Darrell R.;Rottman,Fritz M.;Goodwin,Edward C.;Woychik,Richard P.
US5559099A(9/24/1996).“Penton base protein and methods of using same”.Wickham,Thomas J.;Kovesdi,Imre;Brough,Douglas E.;McVey,Duncan L.;Brader,Joseph T.
US5837511A(11/17/1998).“Non−group C adenoviral vectors”.Falck Pedersen,Erik S.;Crystal,Ronald G.;Mastrangeli,Andrea;Abrahamson,Karil
US5837520A(11/17/1998).“Method of purification of viral vectors”.Shabram,Paul W.;Huyghe,Bernard G.;Liu,Xiaodong;Shepard,H.Michael
US5846782A(12/8/1998).“Targeting adenovirus with use of constrained peptide motifs”.Wickham,Thomas J.;Roelvink,Petrus W.;Kovesdi,Imre
US5851806A(12/22/1998).“Complementary adenoviral systems and cell lines”.Kovesdi,Imre;Brough,Douglas E.;McVey,Duncan L.;Bruder,Joseph T.;Lizonova,Alena
US5891690A(4/6/1999).“Adenovirus E1−complementing cell lines”.Massie,Bernard
US5965541A(10/12/1999).“Vectors and methods for gene transfer to cells”.Wickham,Thomas J.;Kovesdi,Imre;Brough,Douglas E.
US5981225A(11/9/1999).“Gene transfer vector,recombinant adenovirus particles containing the same,method for producing the same and method of use of the same”.Kochanek,Stefan;Schiedner,Gudrun
US5994106A(11/30/1999).“Stocks of recombinant,replication−deficient adenovirus free of replication−competent adenovirus”.Kovesdi,Imre;Brough,Douglas E.;McVey,Duncan L.;Bruder,Joseph T.;Lizonova,Alena
US5994128A(11/30/1999).“Packaging systems for human recombinant adenovirus to be used in gene therapy”.Fallaux,Frits Jacobus;Hoeben,Robert Cornelis;Van der Eb,Alex Jan;Bout,Abraham;Valerio,Domenico
US6020191A(2/1/2000).“Adenoviral vectors capable of facilitating increased persistence of transgene expression”.Scaria,Abraham;Gregory,Richard J.;Wadsworth,Samuel C.
US6040174A(3/21/2000).“Defective adenoviruses and corresponding complementation lines”.Imler,Jean Luc;Mehtali,Majid;Pavirani,Andrea
US6083716A(7/4/2000).“Chimpanzee adenovirus vectors”.Wilson,James M.;Farina,Steven F.;Fisher,Krishna J.
US6113913A(9/5/2000).“Recombinant adenovirus”.Brough,Douglas E.;Kovesdi,Imre
US6225289B1(5/1/2001).“Methods and compositions for preserving adenoviral vectors”.Kovesdi,Imre;Ransom,Stephen C.
US6261823B1(7/17/2001).“Methods for purifying viruses”.Tang,John Chu Tay;Vellekamp,Gary;Bondoc,Jr.,Laureano L.
US6485958B2(11/26/2002).“Method for producing recombinant adenovirus”.Blanche,Francis;Guillaume,Jean Marc
US7326555B2(2/5/2008).“Methods of adenovirus purification”.Konz,Jr.,John O.;Lee,Ann L.;To,Chi Shung Brian;Goerke,Aaron R
US8932607B2(1/13/2015).“Batches of recombinant adenovirus with altered terminal ends”.Custers,Jerome H.H.V.;Vellinga,Jort
欧州特許文献:
EP1230354B1(1/7/2004).“PERMANENT AMNIOCYTE CELL LINE,THE PRODUCTION THEREOF AND ITS USE FOR PRODUCING GENE TRANSFER VECTORS”.KOCHANEK,Stefan;SCHIEDNER,Gudrun
EP1601776B1(7/2/2008).“EXPRESSION VECTORS COMPRISING THE MCMV IE2 PROMOTER”.CHATELLARD,Philippe;IMHOF,Markus
EP853660B1(1/22/2003).“METHOD FOR PRESERVING INFECTIOUS RECOMBINANT VIRUSES,AQUEOUS VIRAL SUSPENSION AND USE AS MEDICINE”.SENE,Claude
国際特許出願公報:
WO2003049763A1(6/19/2003).“COMPOSITION FOR THE PRESERVATION OF VIRUSES”.SETIAWAN,Kerrie;CAMERON,Fiona,Helen
WO2003061708A1(7/31/2003).“STABILIZED FORMULATIONS OF ADENOVIRUS”.PUNGOR,Erno
WO2003078592A2(9/25/2003).“METHOD FOR THE PURIFICATION,PRODUCTION AND FORMULATION OF ONCOLYTIC ADENOVIRUSES”.MEMARZADEH,Bahram;PENNATHUR−DAS,Rukmini;WYPYCH,Joseph;YU,De Chao
WO2003104467A1(12/18/2003).“MEANS AND METHODS FOR THE PRODUCTION OF ADENOVIRUS VECTORS”.VOGELS,Ronald;BOUT,Abraham
WO2004001032A2(12/31/2003).“STABLE ADENOVIRAL VECTORS AND METHODS FOR PROPAGATION THEREOF”.VOGELS,Ronald;HAVENGA,Menzo,Jans,Emco;ZUIJDGEEST,David,Adrianus,Theodorus
WO2004004762A1(1/15/2004).“ISCOM PREPARATION AND USE THEREOF”.MOREIN,Bror;LOeVGREN BENGTSSON,Karin
WO2004020971A2(3/11/2004).“CHROMATOGRAPHIC METHODS FOR ADENOVIRUS PURIFICATION”.SENESAC,Joseph
WO2004037294A2(5/6/2004).“NEW SETTINGS FOR RECOMBINANT ADENOVIRAL−BASED VACCINES”.HAVENGA,Menzo,Jans,Emco;HOLTERMAN,Lennart;KOSTENSE,Stefan;PAU,Maria,Grazia;SPRANGERS,Mieke,Caroline;VOGELS,Ronald
WO2004055187A1(7/1/2004).“RECOMBINANT VIRAL−BASED MALARIA VACCINES”.PAU,Maria Grazia;HOLTERMAN,Lennart;KASPERS,Jorn;STEGMANN,Antonius,Johannes,Hendrikus
WO2005002620A1(1/13/2005).“QUIL A FRACTION WITH LOW TOXICITY AND USE THEREOF”.MOREIN,Bror;LOeVGREN BENGTSSON,Karin;EKSTROeM,Jill;RANLUND,Katarina
WO2005071093A2(8/4/2005).“CHIMPANZEE ADENOVIRUS VACCINE CARRIERS”.CIRILLO,Agostino;COLLOCA,Stefano;ERCOLE,Bruno,Bruni;MEOLA,Annalisa;NICOSIA,Alfredo;SPORENO,Elisabetta
WO2005080556A2(9/1/2005).“VIRUS PURIFICATION METHODS”.WEGGEMAN,Miranda;VAN CORVEN,Emile Joannes Josephus Maria
WO2006053871A2(5/26/2006).“MULTIVALENT VACCINES COMPRISING RECOMBINANT VIRAL VECTORS”.HAVENGA,Menzo,Jans,Emco;VOGELS,Ronald;SADOFF,Jerald;HONE,David;SKEIKY,Yasir Abdul Wahid;RADOSEVIC,Katarina
WO2006108707A1(10/19/2006).“VIRUS PURIFICATION USING ULTRAFILTRATION”.WEGGEMAN,Miranda
WO2006120034A1(11/16/2006).“VACCINE COMPOSITION”.ERTL,Peter,Franz;TITE,John,Philip;VAN WELY,Catherine Ann
WO2007073513A2(6/28/2007).“METHOD FOR PROPAGATING ADENOVIRAL VECTORS ENCODING INHIBITORY GENE PRODUCTS”.GALL,Jason,G.,D.;BROUGH,Douglas,E.;RICHTER,King,C.
WO2007100908A2(9/7/2007).“CHIMERIC ADENOVIRAL VECTORS”.TUCKER,Sean,N.
WO2007104792A2(9/20/2007).“RECOMBINANT ADENOVIRUSES BASED ON SEROTYPE 26 AND 48,AND USE THEREOF”.BAROUCH,Dan H.;HAVENGA,Menzo Jans Emko
WO2007110409A1(10/4/2007).“COMPOSITIONS COMPRISING A RECOMBINANT ADENOVIRUS AND AN ADJUVANT”.HAVENGA,Menzo Jans Emko;RADOSEVIC,Katarina
WO2009026183A1(2/26/2009).“USE OF CHIMERIC HIV/SIV GAG PROTEINS TO OPTIMIZE VACCINE−INDUCED T CELL RESPONSES AGAINST HIV GAG”.NABEL,Gary,J.;YANG,Zhi−Yong;SHI,Wei;BAROUCH,Dan,H.
WO2009117134A2(9/24/2009).“AEROSOLIZED GENETIC VACCINES AND METHODS OF USE”.ROEDERER,Mario;RAO,Srinivas;NABEL,Gary,J.;ANDREWS,Charla,Anne
WO2010085984A1(8/5/2010).“SIMIAN ADENOVIRUS NUCLEIC ACID− AND AMINO ACID−SEQUENCES,VECTORS CONTAINING SAME,AND USES THEREOF”.COLLOCA,Stefano;NICOSIA,Alfredo;CORTESE,Riccardo;AMMENDOLA,Virginia;AMBROSIO,Maria
WO2010086189A2(8/5/2010).“SIMIAN ADENOVIRUS NUCLEIC ACID− AND AMINO ACID−SEQUENCES,VECTORS CONTAINING SAME,AND USES THEREOF”.COLLOCA,Stefano;NICOSIA,Alfredo;CORTESE,Riccardo;AMMENDOLA,Virginia;AMBROSIO,Maria
WO2010096561A1(8/26/2010).“SYNTHETIC HIV/SIV GAG PROTEINS AND USES THEREOF”.NABEL,Gary J.;YANG,Zhi−yong;SHI,Wei;BAROUCH,Dan H.
WO2011045378A1(4/21/2011).“METHOD FOR THE PURIFICATION OF ADENOVIRUS PARTICLES”.DE VOCHT,Marcel,Leo;VEENSTRA,Marloes
WO2011045381A1(4/21/2011).“PROCESS FOR ADENOVIRUS PURIFICATION FROM HIGH CELL DENSITY CULTURES”.DE VOCHT,Marcel,Leo;VEENSTRA,Marloes
WO2013139911A1(9/26/2013).“VACCINE AGAINST RSV”.RADOSEVIC,Katarina;CUSTERS,Jerome H.H.V.;VELLINGA,Jort;WIDJOJOATMODJO,Myra N.
WO2013139916A1(9/26/2013).“VACCINE AGAINST RSV”.RADOSEVIC,Katarina;CUSTERS,Jerome H.H.V.;VELLINGA,Jort;WIDJOJOATMODJO,Myra,N.
他の参考文献:
書籍
Ausubel et al.,Current Protocols in Molecular Biology,Wiley Interscience Publishers,NY(1995)
Ausubel F.M.,et al.(editors).Current Protocols in Molecular Biology;the series Methods in Enzymology,Academic Press,Inc.(1987)
Freshney,R.I.,Culture of animal cells:A manual of basic technique,fourth edition,Wiley−Liss Inc.,ISBN 0−471−34889−9(2000)
Frokjaer S.and Hovgaard L.(editors),Pharmaceutical Formulation Development of Peptides and Proteins,Taylor&Francis(2000)
Gennaro,A.R.(editor),Remington’s Pharmaceutical Sciences,18th edition,.,Mack Publishing Company(1990)
Horowitz,M.S.,Adenoviruses,Chapter 68,in Virology,(B.N.Fields et al.(editors),3rd Ed.,Raven Press,Ltd.,New York(1996)
Kibbe A.(editor),Handbook of Pharmaceutical Excipients,3rd edition,Pharmaceutical Press(2000)
Kruse and Paterson(editors),Tissue Culture,Academic Press.(1973)
MacPherson M.J.,Hams B.D.,Taylor G.R.(editors),PCR2:A Practical Approach(1995)
Sambrook et al.,Molecular Cloning,a Laboratory Manual,2nd Ed.,Cold Spring Harbor Press,Cold Spring Harbor,N.Y.(1989)
Sambrook,Fritsch and Maniatis,Molecular Cloning:A Laboratory Manual,2nd Ed.,(1989)
Shenk,Thomas,Adenoviridae and their Replication,Chapter 67,in Virology,B.N.Fields et al.(editors).,3rd Ed.,Raven Press,Ltd.,New York(1996)
Watson et al.,Recombinant DNA,2nd ed.,Scientific American Books.(1992)
学術誌
Abbink,P.,Lemckert,A.A.,Ewald,B.A.,Lynch,D.M.,Denholtz,M.,Smits,S.,...Barouch,D.H.(2007).Comparative seroprevalence and immunogenicity of six rare serotype recombinant adenovirus vaccine vectors from subgroups B and D.J Virol,81(9),4654−4663.doi:10.1128/JVI.02696−06
Abbink,P.,Maxfield,L.F.,Ng’ang’a,D.,Borducchi,E.N.,Iampietro,M.J.,Bricault,C.A.,...Barouch,D.H.(2015).Construction and evaluation of novel rhesus monkey adenovirus vaccine vectors.J Virol,89(3),1512−1522.doi:10.1128/JVI.02950−14
Abrahamsen,K.,Kong,H.L.,Mastrangeli,A.,Brough,D.,Lizonova,A.,Crystal,R.G.,&Falck−Pedersen,E.(1997).Construction of an adenovirus type 7a E1A−vector.J Virol,71(11),8946−8951.
Addison,C.L.,Hitt,M.,Kunsken,D.,&Graham,F.L.(1997).Comparison of the human versus murine cytomegalovirus immediate early gene promoters for transgene expression by adenoviral vectors.J Gen Virol,78(Pt 7),1653−1661.doi:10.1099/0022−1317−78−7−1653
Amendola,M.,Venneri,M.A.,Biffi,A.,Vigna,E.,&Naldini,L.(2005).Coordinate dual−gene transgenesis by lentiviral vectors carrying synthetic bidirectional promoters.Nat Biotechnol,23(1),108−116.
Andrianaki,A.,Siapati,E.K.,Hirata,R.K.,Russell,D.W.,&Vassilopoulos,G.(2010).Dual transgene expression by foamy virus vectors carrying an endogenous bidirectional promoter.Gene Ther,17(3),380−388.doi:10.1038/gt.2009.147
Bangari,D.S.,&Mittal,S.K.(2006).Development of nonhuman adenoviruses as vaccine vectors.Vaccine,24(7),849−862.doi:10.1016/j.vaccine.2005.08.101
Barry,P.A.,Alcendor,D.J.,Power,M.D.,Kerr,H.,&Luciw,P.A.(1996).Nucleotide sequence and molecular analysis of the rhesus cytomegalovirus immediate−early gene and the UL121−117 open reading frames.Virology,215(1),61−72.doi:10.1006/viro.1996.0007
Barski,O.A.,Siller−Lopez,F.,Bohren,K.M.,Gabbay,K.H.,&Aguilar−Cordova,E.(2004).Human aldehyde reductase promoter allows simultaneous expression of two genes in opposite directions.Biotechniques,36(3),382−384,386,388.
Belousova,N.,Harris,R.,Zinn,K.,Rhodes−Selser,M.A.,Kotov,A.,Kotova,O.,...Alvarez,R.D.(2006).Circumventing recombination events encountered with production of a clinical−grade adenoviral vector with a double−expression cassette.Mol Pharmacol,70(5),1488−1493.
Brough,D.E.,Lizonova,A.,Hsu,C.,Kulesa,V.A.,&Kovesdi,I.(1996).A gene transfer vector−cell line system for complete functional complementation of adenovirus early regions E1 and E4.J Virol,70(9),6497−6501.
Chan,Y.J.,Chiou,C.J.,Huang,Q.,&Hayward,G.S.(1996).Synergistic interactions between overlapping binding sites for the serum response factor and ELK−1 proteins mediate both basal enhancement and phorbol ester responsiveness of primate cytomegalovirus major immediate−early promoters in monocyte and T−lymphocyte cell types.J Virol,70(12),8590−8605.
Chang,Y.N.,Jeang,K.T.,Chiou,C.J.,Chan,Y.J.,Pizzorno,M.,&Hayward,G.S.(1993).Identification of a large bent DNA domain and binding sites for serum response factor adjacent to the NFI repeat cluster and enhancer region in the major IE94 promoter from simian cytomegalovirus.J Virol,67(1),516−529.
Chatellard,P.,Pankiewicz,R.,Meier,E.,Durrer,L.,Sauvage,C.,&Imhof,M.O.(2007).The IE2 promoter/enhancer region from mouse CMV provides high levels of therapeutic protein expression in mammalian cells.Biotechnol Bioeng,96(1),106−117.doi:10.1002/bit.21172
Cohen,C.J.,Xiang,Z.Q.,Gao,G.P.,Ertl,H.C.,Wilson,J.M.,&Bergelson,J.M.(2002).Chimpanzee adenovirus CV−68 adapted as a gene delivery vector interacts with the coxsackievirus and adenovirus receptor.J Gen Virol,83(Pt 1),151−155.
Collins,P.J.,Kobayashi,Y.,Nguyen,L.,Trinklein,N.D.,&Myers,R.M.(2007).The ets−related transcription factor GABP directs bidirectional transcription.PLoS Genet,3(11),e208.doi:10.1371/journal.pgen.0030208
Fallaux,F.J.,Bout,A.,van der Velde,I.,van den Wollenberg,D.J.,Hehir,K.M.,Keegan,J.,...Hoeben,R.C.(1998).New helper cells and matched early region 1−deleted adenovirus vectors prevent generation of replication−competent adenoviruses.Hum Gene Ther,9(13),1909−1917.
Farina,S.F.,Gao,G.P.,Xiang,Z.Q.,Rux,J.J.,Burnett,R.M.,Alvira,M.R.,...Wilson,J.M.(2001).Replication−defective vector based on a chimpanzee adenovirus.J Virol,75(23),11603−11613.doi:10.1128/JVI.75.23.11603−11613.2001
Gao,G.P.,Engdahl,R.K.,&Wilson,J.M.(2000).A cell line for high−yield production of E1−deleted adenovirus vectors without the emergence of replication−competent virus.Hum Gene Ther,11(1),213−219.doi:10.1089/10430340050016283
Geisbert,T.W.,Bailey,M.,Hensley,L.,Asiedu,C.,Geisbert,J.,Stanley,D.,...Sullivan,N.J.(2011).Recombinant adenovirus serotype 26(Ad26)and Ad35 vaccine vectors bypass immunity to Ad5 and protect nonhuman primates against ebolavirus challenge.J Virol,85(9),4222−4233.doi:10.1128/JVI.02407−10
Goerke,A.R.,To,B.C.,Lee,A.L.,Sagar,S.L.,&Konz,J.O.(2005).Development of a novel adenovirus purification process utilizing selective precipitation of cellular DNA.Biotechnol Bioeng,91(1),12−21.doi:10.1002/bit.20406
Hansen,S.G.,Strelow,L.I.,Franchi,D.C.,Anders,D.G.,&Wong,S.W.(2003).Complete sequence and genomic analysis of rhesus cytomegalovirus.J Virol,77(12),6620−6636.
Harro,C.D.,Robertson,M.N.,Lally,M.A.,O’Neill,L.D.,Edupuganti,S.,Goepfert,P.A.,...Mehrotra,D.V.(2009).Safety and immunogenicity of adenovirus−vectored near−consensus HIV type 1 clade B gag vaccines in healthy adults.AIDS Res Hum Retroviruses,25(1),103−114.
Harro,C.,Sun,X.,Stek,J.E.,Leavitt,R.Y.,Mehrotra,D.V.,Wang,F.,...Merck,V.Study Group.(2009).Safety and immunogenicity of the Merck adenovirus serotype 5(MRKAd5)and MRKAd6 human immunodeficiency virus type 1 trigene vaccines alone and in combination in healthy adults.Clin Vaccine Immunol,16(9),1285−1292.doi:10.1128/CVI.00144−09
Havenga,M.,Vogels,R.,Zuijdgeest,D.,Radosevic,K.,Mueller,S.,Sieuwerts,M.,...Goudsmit,J.(2006).Novel replication−incompetent adenoviral B−group vectors:high vector stability and yield in PER.C6 cells.J Gen Virol,87(Pt 8),2135−2143.
Heilbronn,R.,&Weger,S.(2010).Viral vectors for gene transfer:current status of gene therapeutics.Handb Exp Pharmacol(197),143−170.doi:10.1007/978−3−642−00477−3_5
Hoganson,D.K.,Ma,J.C.,Asato,L.,Ong,M.,Printz,M.A.,Huyghe,B.G.,...D’Andrea,M.J.(2002).Development of a Stable Adenoviral Vector Formulation.BioProcessing J.,1(1),43−48.
Holman,D.H.,Wang,D.,Raviprakash,K.,Raja,N.U.,Luo,M.,Zhang,J.,...Dong,J.Y.(2007).Two complex,adenovirus−based vaccines that together induce immune responses to all four dengue virus serotypes.Clin Vaccine Immunol,14(2),182−189.
Holterman,L.,Vogels,R.,van der Vlugt,R.,Sieuwerts,M.,Grimbergen,J.,Kaspers,J.,...Havenga,M.(2004).Novel replication−incompetent vector derived from adenovirus type 11(Ad11)for vaccination and gene therapy:low seroprevalence and non−cross−reactivity with Ad5.J Virol,78(23),13207−13215.doi:10.1128/JVI.78.23.13207−13215.2004
Hu,X.,Meng,W.,Dong,Z.,Pan,W.,Sun,C.,&Chen,L.(2011).Comparative immunogenicity of recombinant adenovirus−vectored vaccines expressing different forms of hemagglutinin(HA)proteins from the H5 serotype of influenza A viruses in mice.Virus Res,155(1),156−162.doi:10.1016/j.virusres.2010.09.014
Kim,D.W.,Uetsuki,T.,Kaziro,Y.,Yamaguchi,N.,&Sugano,S.(1990).Use of the human elongation factor 1 alpha promoter as a versatile and efficient expression system.Gene,91(2),217−223.
Kobinger,G.P.,Feldmann,H.,Zhi,Y.,Schumer,G.,Gao,G.,Feldmann,F.,...Wilson,J.M.(2006).Chimpanzee adenovirus vaccine protects against Zaire Ebola virus.Virology,346(2),394−401.doi:10.1016/j.virol.2005.10.042
Lasaro,M.O.,&Ertl,H.C.(2009).New insights on adenovirus as vaccine vectors.Mol Ther,17(8),1333−1339.doi:10.1038/mt.2009.130
Lemckert,A.A.,Grimbergen,J.,Smits,S.,Hartkoorn,E.,Holterman,L.,Berkhout,B.,...Havenga,M.J.(2006).Generation of a novel replication−incompetent adenoviral vector derived from human adenovirus type 49:manufacture on PER.C6 cells,tropism and immunogenicity.J Gen Virol,87(Pt 10),2891−2899.doi:10.1099/vir.0.82079−0
Mullick,A.,Xu,Y.,Warren,R.,Koutroumanis,M.,Guilbault,C.,Broussau,S.,...Massie,B.(2006).The cumate gene−switch:a system for regulated expression in mammalian cells.BMC Biotechnol,6,43.doi:10.1186/1472−6750−6−43
Na,M.,&Fan,X.(2010).Design of Ad5F35 vectors for coordinated dual gene expression in candidate human hematopoietic stem cells.Exp Hematol,38(6),446−452.doi:10.1016/j.exphem.2010.03.007
Nan,X.,Peng,B.,Hahn,T.W.,Richardson,E.,Lizonova,A.,Kovesdi,I.,&Robert−Guroff,M.(2003).Development of an Ad7 cosmid system and generation of an Ad7deltaE1deltaE3HIV(MN)env/rev recombinant virus.Gene Ther,10(4),326−336.doi:10.1038/sj.gt.3301903
Ogun,S.A.,Dumon−Seignovert,L.,Marchand,J.B.,Holder,A.A.,&Hill,F.(2008).The oligomerization domain of C4−binding protein(C4bp)acts as an adjuvant,and the fusion protein comprised of the 19−kilodalton merozoite surface protein 1 fused with the murine C4bp domain protects mice against malaria.Infect Immun,76(8),3817−3823.doi:10.1128/IAI.01369−07
Ophorst,O.J.,Radosevic,K.,Havenga,M.J.,Pau,M.G.,Holterman,L.,Berkhout,B.,...Tsuji,M.(2006).Immunogenicity and protection of a recombinant human adenovirus serotype 35−based malaria vaccine against Plasmodium yoelii in mice.Infect Immun,74(1),313−320.
Pham,L.,Nakamura,T.,Gabriela Rosales,A.,Carlson,S.K.,Bailey,K.R.,Peng,K.W.,&Russell,S.J.(2009).Concordant activity of transgene expression cassettes inserted into E1,E3 and E4 cloning sites in the adenovirus genome.J Gene Med,11(3),197−206.
Post,D.E.,&Van Meir,E.G.(2001).Generation of bidirectional hypoxia/HIF−responsive expression vectors to target gene expression to hypoxic cells.Gene Ther,8(23),1801−1807.doi:10.1038/sj.gt.3301605
Powell,S.K.,Rivera−Soto,R.,&Gray,S.J.(2015).Viral expression cassette elements to enhance transgene target specificity and expression in gene therapy.Discov Med,19(102),49−57.
Richardson,J.S.,Yao,M.K.,Tran,K.N.,Croyle,M.A.,Strong,J.E.,Feldmann,H.,&Kobinger,G.P.(2009).Enhanced protection against Ebola virus mediated by an improved adenovirus−based vaccine.PLoS One,4(4),e5308.doi:10.1371/journal.pone.0005308
Robbins,P.D.,&Ghivizzani,S.C.(1998).Viral vectors for gene therapy.Pharmacol Ther,80(1),35−47.
Sandford,G.R.,&Burns,W.H.(1996).Rat cytomegalovirus has a unique immediate early gene enhancer.Virology,222(2),310−317.doi:10.1006/viro.1996.0428
Schepp−Berglind,J.,Luo,M.,Wang,D.,Wicker,J.A.,Raja,N.U.,Hoel,B.D.,...Dong,J.Y.(2007).Complex adenovirus−mediated expression of West Nile virus C,PreM,E,and NS1 proteins induces both humoral and cellular immune responses.Clin Vaccine Immunol,14(9),1117−1126.
Sullivan,N.J.,Geisbert,T.W.,Geisbert,J.B.,Shedlock,D.J.,Xu,L.,Lamoreaux,L.,...Nabel,G.J.(2006).Immune protection of nonhuman primates against Ebola virus with single low−dose adenovirus vectors encoding modified GPs.PLoS Med,3(6),e177.doi:10.1371/journal.pmed.0030177
Sullivan,N.J.,Geisbert,T.W.,Geisbert,J.B.,Xu,L.,Yang,Z.Y.,Roederer,M.,...Nabel,G.J.(2003).Accelerated vaccination for Ebola virus haemorrhagic fever in non−human primates.Nature,424(6949),681−684.doi:10.1038/nature01876
Tatsis,N.,Blejer,A.,Lasaro,M.O.,Hensley,S.E.,Cun,A.,Tesema,L.,...Ertl,H.C.(2007).A CD46−binding chimpanzee adenovirus vector as a vaccine carrier.Mol Ther,15(3),608−617.doi:10.1038/sj.mt.6300078
Vemula,S.V.,&Mittal,S.K.(2010).Production of adenovirus vectors and their use as a delivery system for influenza vaccines.Expert Opin Biol Ther,10(10),1469−1487.doi:10.1517/14712598.2010.519332
Vogels,R.,Zuijdgeest,D.,van Meerendonk,M.,Companjen,A.,Gillissen,G.,Sijtsma,J.,...Havenga,M.J.(2007).High−level expression from two independent expression cassettes in replication−incompetent adenovirus type 35 vector.J Gen Virol,88(Pt 11),2915−2924.
Vogels,R.,Zuijdgeest,D.,van Rijnsoever,R.,Hartkoorn,E.,Damen,I.,de Bethune,M.P.,...Havenga,M.(2003).Replication−deficient human adenovirus type 35 vectors for gene transfer and vaccination:efficient human cell infection and bypass of preexisting adenovirus immunity.J Virol,77(15),8263−8271.
Voigt,S.,Sandford,G.R.,Hayward,G.S.,&Burns,W.H.(2005).The English strain of rat cytomegalovirus(CMV)contains a novel captured CD200(vOX2)gene and a spliced CC chemokine upstream from the major immediate−early region:further evidence for a separate evolutionary lineage from that of rat CMV Maastricht.J Gen Virol,86(Pt 2),263−274.doi:10.1099/vir.0.80539−0
Walther,W.,&Stein,U.(2000).Viral vectors for gene transfer:a review of their use in the treatment of human diseases.Drugs,60(2),249−271.
Zhou,D.,Cun,A.,Li,Y.,Xiang,Z.,&Ertl,H.C.(2006).A chimpanzee−origin adenovirus vector expressing the rabies virus glycoprotein as an oral vaccine against inhalation infection with rabies virus.Mol Ther,14(5),662−672.doi:10.1016/j.ymthe.2006.03.027
Zhou,D.,Wu,T.L.,Lasaro,M.O.,Latimer,B.P.,Parzych,E.M.,Bian,A.,...Ertl,H.C.(2010).A universal influenza A vaccine based on adenovirus expressing matrix−2 ectodomain and nucleoprotein protects mice from lethal challenge.Mol Ther,18(12),2182−2189.doi:10.1038/mt.2010.202
Claims (17)
- 1つの方向において第1の導入遺伝子に、かつ逆方向において第2の導入遺伝子に作動可能に連結された双方向性プロモーター(hCMV−rhCMVプロモーター)を含む組換え核酸分子であって、前記hCMV−rhCMVプロモーターは、
(i)エンハンサーと、その両側に配置されている、
(ii)前記エンハンサーの一方の側のヒトサイトメガロウイルス主要最初期プロモーター(hCMVプロモーター)と、
(iii)前記エンハンサーの他方の側のアカゲザルサイトメガロウイルス主要最初期プロモーター(rhCMVプロモーター)と
を含み、
(iv)前記第1の導入遺伝子は、前記hCMVプロモーターの下流に位置し、および
(v)前記第2の導入遺伝子は、前記rhCMVプロモーターの下流に位置する、組換え核酸分子。 - 前記エンハンサーは、ヒトサイトメガロウイルス主要最初期エンハンサー(hCMVエンハンサー)である、請求項1に記載の組換え核酸分子。
- 前記第1および第2の導入遺伝子は、異なり、およびそれらの少なくとも1つは、抗原をコードする、請求項1または2に記載の組換え核酸分子。
- 請求項1〜3のいずれか一項に記載の組換え核酸分子を含む組換えベクターまたは組換えウイルス。
- プラスミドベクターである、請求項4に記載の組換えベクター。
- アデノウイルスである、請求項4に記載の組換えウイルス。
- 前記アデノウイルスは、E1領域に欠失を有する、請求項6に記載の組換えアデノウイルス。
- ヒトアデノウイルス血清型35またはヒトアデノウイルス血清型26である、請求項6または7に記載の組換えアデノウイルス。
- 遺伝的に安定な組換えアデノウイルスであって、前記アデノウイルスが標的細胞に感染すると、それぞれが強力に発現される第1および第2の導入遺伝子を含む遺伝的に安定な組換えアデノウイルスを製造する方法であって、
a)1つの方向において第1の導入遺伝子に、かつ逆方向において第2の導入遺伝子に作動可能に連結された請求項1に記載の双方向性hCMV−rhCMVプロモーターを含むコンストラクトを調製する工程と、
b)前記コンストラクトを前記組換えアデノウイルスのゲノムに組み込む工程と
を含む方法。 - 前記エンハンサーは、hCMVエンハンサーである、請求項9に記載の方法。
- 前記組換えアデノウイルスは、そのゲノムのE1領域に欠失を有する、請求項9または10に記載の方法。
- 前記第1および第2の導入遺伝子は、異なり、およびそれらの少なくとも1つは、抗原をコードする、請求項9〜11のいずれか一項に記載の方法。
- 前記組換えアデノウイルスは、ヒトアデノウイルス血清型35またはヒトアデノウイルス血清型26である、請求項9〜12のいずれか一項に記載の方法。
- 細胞内で少なくとも2つの導入遺伝子を発現させる方法であって、請求項4〜8のいずれか一項に記載の組換えベクターまたは組換えウイルスを細胞に提供する工程を含む方法。
- 少なくとも2つの抗原に対する免疫応答を誘導する方法であって、請求項4〜8のいずれか一項に記載の組換えベクターまたは組換えウイルスを対象に投与する工程を含む方法。
- 請求項6〜8のいずれか一項に記載の組換えアデノウイルスのゲノムを含む組換えDNA分子。
- 請求項4〜8のいずれか一項に記載の組換えベクターまたは組換えウイルスと、薬学的に許容される担体または賦形剤とを含む医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP16175189.6 | 2016-06-20 | ||
EP16175189 | 2016-06-20 | ||
PCT/EP2017/064952 WO2017220499A1 (en) | 2016-06-20 | 2017-06-19 | Potent and balanced bidirectional promoter |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019521679A true JP2019521679A (ja) | 2019-08-08 |
JP6683847B2 JP6683847B2 (ja) | 2020-04-22 |
Family
ID=56363700
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018566443A Active JP6683847B2 (ja) | 2016-06-20 | 2017-06-19 | 強力でバランスのとれた双方向性プロモーター |
Country Status (14)
Country | Link |
---|---|
US (2) | US11001858B2 (ja) |
EP (1) | EP3472327B1 (ja) |
JP (1) | JP6683847B2 (ja) |
KR (1) | KR102307065B1 (ja) |
CN (1) | CN109312362B (ja) |
AU (1) | AU2017283118B2 (ja) |
BR (1) | BR112018075969A2 (ja) |
CA (1) | CA3027807A1 (ja) |
ES (1) | ES2821876T3 (ja) |
IL (1) | IL263622A (ja) |
MX (1) | MX2018015540A (ja) |
RU (1) | RU2745500C2 (ja) |
WO (1) | WO2017220499A1 (ja) |
ZA (1) | ZA201808581B (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2023501879A (ja) * | 2020-04-23 | 2023-01-20 | フェデラル ステート バジェタリー インスティテューション“ナショナル リサーチ センター フォー エピデミオロジー アンド マイクロバイオロジー ネームド アフター ザ オナラリー アカデミシャン エヌ.エフ.ガマレヤ”オブ ザ ミニストリー オブ ヘルス オブ ザ ロシアン フェデレーション | 重症急性呼吸器症候群ウイルスsars-cov-2に対する特異的免疫を誘導するための免疫生物学的製剤 |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW202043256A (zh) | 2019-01-10 | 2020-12-01 | 美商健生生物科技公司 | 前列腺新抗原及其用途 |
WO2021099906A1 (en) | 2019-11-18 | 2021-05-27 | Janssen Biotech, Inc. | Vaccines based on mutant calr and jak2 and their uses |
TW202144389A (zh) | 2020-02-14 | 2021-12-01 | 美商健生生物科技公司 | 在多發性骨髓瘤中表現之新抗原及其用途 |
TW202144388A (zh) | 2020-02-14 | 2021-12-01 | 美商健生生物科技公司 | 在卵巢癌中表現之新抗原及其用途 |
US20210315986A1 (en) | 2020-04-13 | 2021-10-14 | Janssen Biotech, Inc. | Psma and steap1 vaccines and their uses |
WO2022140759A2 (en) | 2020-12-23 | 2022-06-30 | Janssen Biotech, Inc. | Neoantigen peptide mimics |
CN113416746A (zh) * | 2021-03-25 | 2021-09-21 | 上海晶诺生物科技有限公司 | 一种aTc诱导表达结核分枝杆菌基因的整合型质粒 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002503461A (ja) * | 1998-02-11 | 2002-02-05 | マキシジェン, インコーポレイテッド | 遺伝子ワクチンベクター工学 |
JP2011015685A (ja) * | 2001-03-09 | 2011-01-27 | Gene Stream Pty Ltd | 新規な発現ベクター |
WO2011025717A2 (en) * | 2009-08-31 | 2011-03-03 | The Brigham And Women's Hospital, Inc. | Promoter system for regulatable gene expression in mammalian cells |
WO2015175639A1 (en) * | 2014-05-13 | 2015-11-19 | The Trustees Of The University Of Pennsylvania | Compositions comprising aav expressing dual antibody constructs and uses thereof |
Family Cites Families (72)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0173552B1 (en) | 1984-08-24 | 1991-10-09 | The Upjohn Company | Recombinant dna compounds and the expression of polypeptides such as tpa |
US5057540A (en) | 1987-05-29 | 1991-10-15 | Cambridge Biotech Corporation | Saponin adjuvant |
NZ230747A (en) | 1988-09-30 | 1992-05-26 | Bror Morein | Immunomodulating matrix comprising a complex of at least one lipid and at least one saponin; certain glycosylated triterpenoid saponins derived from quillaja saponaria molina |
JPH0832638B2 (ja) | 1989-05-25 | 1996-03-29 | カイロン コーポレイション | サブミクロン油滴乳剤を含んで成るアジュバント製剤 |
FR2705686B1 (fr) | 1993-05-28 | 1995-08-18 | Transgene Sa | Nouveaux adénovirus défectifs et lignées de complémentation correspondantes. |
EP0784690B1 (en) | 1994-06-10 | 2006-08-16 | Genvec, Inc. | Complementary adenoviral vector systems and cell lines |
US5851806A (en) | 1994-06-10 | 1998-12-22 | Genvec, Inc. | Complementary adenoviral systems and cell lines |
US5846782A (en) | 1995-11-28 | 1998-12-08 | Genvec, Inc. | Targeting adenovirus with use of constrained peptide motifs |
US5559099A (en) | 1994-09-08 | 1996-09-24 | Genvec, Inc. | Penton base protein and methods of using same |
US5965541A (en) | 1995-11-28 | 1999-10-12 | Genvec, Inc. | Vectors and methods for gene transfer to cells |
AUPM873294A0 (en) | 1994-10-12 | 1994-11-03 | Csl Limited | Saponin preparations and use thereof in iscoms |
US5837520A (en) | 1995-03-07 | 1998-11-17 | Canji, Inc. | Method of purification of viral vectors |
SI0833934T2 (sl) | 1995-06-15 | 2013-04-30 | Crucell Holland B.V. | Pakirni sistemi za humani rekombinantni adenovirus za uporabo v genski terapiji |
US5837511A (en) | 1995-10-02 | 1998-11-17 | Cornell Research Foundation, Inc. | Non-group C adenoviral vectors |
CA2177085C (en) | 1996-04-26 | 2007-08-14 | National Research Council Of Canada | Adenovirus e1-complementing cell lines |
CZ438398A3 (cs) | 1996-07-01 | 1999-03-17 | Rhone-Poulenc Rorer S. A. | Způsob přípravy rekombinantních adenovirů |
FR2751343B1 (fr) | 1996-07-16 | 1998-12-18 | Transgene Sa | Procede de conservation de virus recombinants infectieux, suspension aqueuse virale et utilisation comme medicament |
WO1998010087A1 (en) | 1996-09-06 | 1998-03-12 | Trustees Of The University Of Pennsylvania | Chimpanzee adenovirus vectors |
US7732129B1 (en) | 1998-12-01 | 2010-06-08 | Crucell Holland B.V. | Method for the production and purification of adenoviral vectors |
AU732703B2 (en) | 1996-11-20 | 2001-04-26 | Crucell Holland B.V. | An improved method for the production and purification of adenoviral vectors |
US6261823B1 (en) | 1996-12-13 | 2001-07-17 | Schering Corporation | Methods for purifying viruses |
EP0973866A4 (en) | 1997-03-04 | 2000-04-19 | Baxter Int | ADENOVIRUS E1-COMPLEMENTING CELL LINES |
US6020191A (en) | 1997-04-14 | 2000-02-01 | Genzyme Corporation | Adenoviral vectors capable of facilitating increased persistence of transgene expression |
US6210683B1 (en) | 1997-09-05 | 2001-04-03 | Merck & Co., Inc. | Stabilizers containing recombinant human serum albumin for live virus vaccines |
DE69942708D1 (de) | 1998-02-17 | 2010-10-07 | Schering Corp | Virus enthaltende Zusammensetzungen und Methoden zur Konzentration von Viruspräparaten |
US5981225A (en) | 1998-04-16 | 1999-11-09 | Baylor College Of Medicine | Gene transfer vector, recombinant adenovirus particles containing the same, method for producing the same and method of use of the same |
US6670188B1 (en) | 1998-04-24 | 2003-12-30 | Crucell Holland B.V. | Packaging systems for human recombinant adenovirus to be used in gene therapy |
US6113913A (en) | 1998-06-26 | 2000-09-05 | Genvec, Inc. | Recombinant adenovirus |
DK1133316T3 (da) | 1998-11-16 | 2009-05-25 | Introgen Therapeutics Inc | Adenovirus-formulering til genterapi |
US6225289B1 (en) | 1998-12-10 | 2001-05-01 | Genvec, Inc. | Methods and compositions for preserving adenoviral vectors |
DE60043126D1 (de) | 1999-05-17 | 2009-11-19 | Crucell Holland Bv | Von Adenovirus abgeleitete Gentransfervehikel, die zumindest ein Element des Adenovirus Typ 35 enthalten |
US6492169B1 (en) | 1999-05-18 | 2002-12-10 | Crucell Holland, B.V. | Complementing cell lines |
US6913922B1 (en) | 1999-05-18 | 2005-07-05 | Crucell Holland B.V. | Serotype of adenovirus and uses thereof |
EP1200622A4 (en) | 1999-07-06 | 2004-12-22 | Merck & Co Inc | HIV VACCINE COMPRISING A GAG GENE VEHICLE ADENOVIRUS |
DE19955558C2 (de) | 1999-11-18 | 2003-03-20 | Stefan Kochanek | Permanente Amniozyten-Zelllinie, ihre Herstellung und Verwendung zur Herstellung von Gentransfervektoren |
EP2420247A1 (en) | 2000-03-07 | 2012-02-22 | Merck Sharp & Dohme Corp. | Adenovirus formulations |
EP1320621A4 (en) | 2000-09-15 | 2005-11-23 | Merck & Co Inc | ADVANCED FIRST-GENE ADENOVIRAL VACCINES EXPRESSING CODON OPTIMIZATION OF THE GAG, POL AND NEF PROTEINS OF HIV-1 AND CHANGES THEREOF |
WO2003049764A1 (en) | 2001-12-12 | 2003-06-19 | Fh Faulding & Co Limited | Composition for viral preservation |
PL371261A1 (en) | 2002-01-18 | 2005-06-13 | Schering Aktiengesellschaft | Stabilized formulations of adenovirus |
US20030180936A1 (en) | 2002-03-15 | 2003-09-25 | Memarzadeh Bahram Eric | Method for the purification, production and formulation of oncolytic adenoviruses |
US7285265B2 (en) | 2002-04-25 | 2007-10-23 | Crucell Holland B.V. | Stable adenoviral vectors and methods for propagation thereof |
PL215165B1 (pl) | 2002-04-25 | 2013-10-31 | Crucell Holland Bv | Rekombinowany wektor adenowirusowy oraz sposób wytwarzania rekombinowanego wektora adenowirusowego |
EP1506287B1 (en) | 2002-05-14 | 2007-04-25 | Merck & Co., Inc. | Methods of adenovirus purification |
SE0202110D0 (sv) | 2002-07-05 | 2002-07-05 | Isconova Ab | Iscom preparation and use thereof |
CA2496918A1 (en) | 2002-08-28 | 2004-03-11 | Introgen Therapeutics Inc. | Chromatographic methods for adenovirus purification |
EP1553983A2 (en) | 2002-10-23 | 2005-07-20 | Crucell Holland B.V. | New settings for recombinant adenoviral-based vaccines |
AU2003298361B2 (en) | 2002-12-17 | 2009-05-14 | Crucell Holland B.V. | Recombinant viral-based malaria vaccines |
CN100429315C (zh) | 2003-03-11 | 2008-10-29 | 雪兰诺实验室有限公司 | 含有mcmv ie2启动子的表达载体 |
SE0301998D0 (sv) | 2003-07-07 | 2003-07-07 | Isconova Ab | Quil A fraction with low toxicity and use thereof |
ATE449105T1 (de) | 2004-01-23 | 2009-12-15 | Angeletti P Ist Richerche Bio | Impfstoffträger für schimpansen-adenovirus |
EP1718738A2 (en) | 2004-02-23 | 2006-11-08 | Crucell Holland B.V. | Virus purification methods |
SG159554A1 (en) | 2004-11-16 | 2010-03-30 | Crucell Holland Bv | Multivalent vaccines comprising recombinant viral vectors |
CA2602944C (en) | 2005-04-11 | 2015-08-11 | Crucell Holland B.V. | Virus purification using ultrafiltration |
CN103088060A (zh) | 2005-05-12 | 2013-05-08 | 葛兰素集团有限公司 | 疫苗组合物 |
WO2007073513A2 (en) | 2005-11-10 | 2007-06-28 | Genvec, Inc. | Method for propagating adenoviral vectors encoding inhibitory gene products |
AU2007220988B2 (en) | 2006-02-28 | 2010-06-03 | Vaxart, Inc | Chimeric adenoviral vectors |
US20100143302A1 (en) | 2006-03-16 | 2010-06-10 | Crucell Holland B.V. | Recombinant Adenoviruses Based on Serotype 26 and 48, and Use Thereof |
US20090110695A1 (en) | 2006-03-27 | 2009-04-30 | Menzo Jans Emko Havenga | Compositions Comprising a Recombinant Adenovirus and an Adjuvant |
WO2009026183A1 (en) | 2007-08-17 | 2009-02-26 | The Government Of The U.S.A., As Represented By The Secretary, Department Of Health & Human Services | Use of chimeric hiv/siv gag proteins to optimize vaccine-induced t cell responses against hiv gag |
WO2009117134A2 (en) | 2008-03-21 | 2009-09-24 | National Institutes Of Health | Aerosolized genetic vaccines and methods of use |
AU2010209938A1 (en) | 2009-02-02 | 2011-08-25 | Glaxosmithkline Biologicals Sa | Simian adenovirus nucleic acid- and amino acid-sequences, vectors containing same, and uses thereof |
WO2010085984A1 (en) | 2009-02-02 | 2010-08-05 | Okairos Ag | Simian adenovirus nucleic acid- and amino acid-sequences, vectors containing same, and uses thereof |
WO2010096561A1 (en) | 2009-02-18 | 2010-08-26 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Synthetic hiv/siv gag proteins and uses thereof |
KR101800245B1 (ko) | 2009-05-21 | 2017-11-22 | 노파르티스 아게 | 비-내인성 pol i 프로모터를 사용하는 역 유전학 |
CA2776461C (en) | 2009-10-15 | 2020-08-25 | Crucell Holland B.V. | Method for the purification of adenovirus particles. |
JP5465331B2 (ja) | 2009-10-15 | 2014-04-09 | クルセル ホランド ベー ヴェー | 高細胞密度の培養物からのアデノウイルスの精製方法 |
US8932607B2 (en) | 2012-03-12 | 2015-01-13 | Crucell Holland B.V. | Batches of recombinant adenovirus with altered terminal ends |
KR102050616B1 (ko) | 2012-03-22 | 2019-12-03 | 얀센 백신스 앤드 프리벤션 비.브이. | Rsv에 대한 백신 |
CN104540951B (zh) | 2012-06-07 | 2017-07-04 | 美国陶氏益农公司 | 使用芸苔属双向组成型启动子表达转基因的构建体和方法 |
ES2540753T3 (es) * | 2012-09-24 | 2015-07-13 | Lonza Biologics Plc. | Vectores de expresión que comprenden secuencias quiméricas de promotor y amplificador de citomegalovirus |
CN105051198A (zh) | 2012-11-16 | 2015-11-11 | 貝丝以色列女执事医疗中心 | 重组腺病毒及其用途 |
EP3283634B1 (en) | 2015-04-14 | 2019-05-22 | Janssen Vaccines & Prevention B.V. | Recombinant adenovirus expressing two transgenes with a bidirectional promoter |
-
2017
- 2017-06-19 MX MX2018015540A patent/MX2018015540A/es unknown
- 2017-06-19 CA CA3027807A patent/CA3027807A1/en active Pending
- 2017-06-19 JP JP2018566443A patent/JP6683847B2/ja active Active
- 2017-06-19 US US16/310,701 patent/US11001858B2/en active Active
- 2017-06-19 EP EP17732079.3A patent/EP3472327B1/en active Active
- 2017-06-19 KR KR1020197001188A patent/KR102307065B1/ko active IP Right Grant
- 2017-06-19 BR BR112018075969-4A patent/BR112018075969A2/pt active Search and Examination
- 2017-06-19 ES ES17732079T patent/ES2821876T3/es active Active
- 2017-06-19 WO PCT/EP2017/064952 patent/WO2017220499A1/en unknown
- 2017-06-19 CN CN201780037963.0A patent/CN109312362B/zh active Active
- 2017-06-19 AU AU2017283118A patent/AU2017283118B2/en active Active
- 2017-06-19 RU RU2019101191A patent/RU2745500C2/ru active
-
2018
- 2018-12-10 IL IL263622A patent/IL263622A/en unknown
- 2018-12-19 ZA ZA2018/08581A patent/ZA201808581B/en unknown
-
2021
- 2021-03-17 US US17/204,312 patent/US11781155B2/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002503461A (ja) * | 1998-02-11 | 2002-02-05 | マキシジェン, インコーポレイテッド | 遺伝子ワクチンベクター工学 |
JP2011015685A (ja) * | 2001-03-09 | 2011-01-27 | Gene Stream Pty Ltd | 新規な発現ベクター |
WO2011025717A2 (en) * | 2009-08-31 | 2011-03-03 | The Brigham And Women's Hospital, Inc. | Promoter system for regulatable gene expression in mammalian cells |
WO2015175639A1 (en) * | 2014-05-13 | 2015-11-19 | The Trustees Of The University Of Pennsylvania | Compositions comprising aav expressing dual antibody constructs and uses thereof |
Non-Patent Citations (3)
Title |
---|
GENE THERAPY, vol. 10, JPN6019019155, 2003, pages 1941 - 1949, ISSN: 0004181808 * |
JOURNAL OF GENERAL VIROLOGY, vol. 95, JPN6019019157, 2014, pages 1574 - 1584, ISSN: 0004181809 * |
JOURNAL OF VIROLOGY, vol. 76, no. 18, JPN6019019158, 2002, pages 9493 - 9504, ISSN: 0004181810 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2023501879A (ja) * | 2020-04-23 | 2023-01-20 | フェデラル ステート バジェタリー インスティテューション“ナショナル リサーチ センター フォー エピデミオロジー アンド マイクロバイオロジー ネームド アフター ザ オナラリー アカデミシャン エヌ.エフ.ガマレヤ”オブ ザ ミニストリー オブ ヘルス オブ ザ ロシアン フェデレーション | 重症急性呼吸器症候群ウイルスsars-cov-2に対する特異的免疫を誘導するための免疫生物学的製剤 |
Also Published As
Publication number | Publication date |
---|---|
CN109312362B (zh) | 2022-06-28 |
ES2821876T3 (es) | 2021-04-28 |
MX2018015540A (es) | 2019-04-11 |
US11781155B2 (en) | 2023-10-10 |
US20210198694A1 (en) | 2021-07-01 |
JP6683847B2 (ja) | 2020-04-22 |
BR112018075969A2 (pt) | 2019-04-02 |
ZA201808581B (en) | 2021-07-28 |
RU2019101191A (ru) | 2020-07-21 |
EP3472327A1 (en) | 2019-04-24 |
IL263622A (en) | 2019-01-31 |
RU2745500C2 (ru) | 2021-03-25 |
US20190225987A1 (en) | 2019-07-25 |
RU2019101191A3 (ja) | 2020-10-28 |
KR20190019147A (ko) | 2019-02-26 |
CA3027807A1 (en) | 2017-12-28 |
AU2017283118A1 (en) | 2018-12-13 |
KR102307065B1 (ko) | 2021-09-30 |
AU2017283118B2 (en) | 2019-02-07 |
CN109312362A (zh) | 2019-02-05 |
US11001858B2 (en) | 2021-05-11 |
EP3472327B1 (en) | 2020-08-19 |
WO2017220499A1 (en) | 2017-12-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11781155B2 (en) | Potent and balanced bidirectional promoter | |
US20210261984A1 (en) | Potent and short promoter for expression of heterologous genes | |
EP3283634B1 (en) | Recombinant adenovirus expressing two transgenes with a bidirectional promoter | |
US20230279425A1 (en) | Potent and balanced bidirectional promoter | |
ES2733593T3 (es) | Adenovirus recombinante que expresa dos transgenes con un promotor bidireccional | |
EA045609B1 (ru) | Высокоактивный и короткий промотор, предназначенный для экспрессии гетерологичных генов |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20181218 |
|
A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20181218 |
|
A975 | Report on accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A971005 Effective date: 20190423 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190528 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20191015 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20191029 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20191224 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200214 |
|
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: 20200324 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200326 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6683847 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 |