JP4233458B2 - アラニンデヒドロゲナーゼ、セリンデヒドラターゼおよび/またはグルタミンシンテターゼを発現する結核ワクチンとしてのリコンビナントbcg株 - Google Patents
アラニンデヒドロゲナーゼ、セリンデヒドラターゼおよび/またはグルタミンシンテターゼを発現する結核ワクチンとしてのリコンビナントbcg株 Download PDFInfo
- Publication number
- JP4233458B2 JP4233458B2 JP2003586182A JP2003586182A JP4233458B2 JP 4233458 B2 JP4233458 B2 JP 4233458B2 JP 2003586182 A JP2003586182 A JP 2003586182A JP 2003586182 A JP2003586182 A JP 2003586182A JP 4233458 B2 JP4233458 B2 JP 4233458B2
- Authority
- JP
- Japan
- Prior art keywords
- bcg
- seq
- mycobacterium bovis
- alanine
- strain
- 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.)
- Expired - Fee Related
Links
- 102000005396 glutamine synthetase Human genes 0.000 title claims description 47
- 108020002326 glutamine synthetase Proteins 0.000 title claims description 47
- 108010031025 Alanine Dehydrogenase Proteins 0.000 title claims description 43
- 102100023162 L-serine dehydratase/L-threonine deaminase Human genes 0.000 title description 4
- 108020000318 saccharopine dehydrogenase Proteins 0.000 title description 4
- 229960002109 tuberculosis vaccine Drugs 0.000 title description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 84
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 70
- 229960005486 vaccine Drugs 0.000 claims description 53
- 150000007523 nucleic acids Chemical class 0.000 claims description 49
- 229960001153 serine Drugs 0.000 claims description 47
- 108020004707 nucleic acids Proteins 0.000 claims description 46
- 102000039446 nucleic acids Human genes 0.000 claims description 46
- 241001467552 Mycobacterium bovis BCG Species 0.000 claims description 42
- 230000000694 effects Effects 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 32
- 241000186359 Mycobacterium Species 0.000 claims description 30
- 230000002163 immunogen Effects 0.000 claims description 26
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 25
- 102100035717 Serine racemase Human genes 0.000 claims description 25
- 108010006152 Serine racemase Proteins 0.000 claims description 25
- 108090000623 proteins and genes Proteins 0.000 claims description 25
- 235000004279 alanine Nutrition 0.000 claims description 24
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 22
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 21
- 229920001184 polypeptide Polymers 0.000 claims description 18
- 235000018102 proteins Nutrition 0.000 claims description 18
- 102000004169 proteins and genes Human genes 0.000 claims description 18
- 241000124008 Mammalia Species 0.000 claims description 17
- 241000187479 Mycobacterium tuberculosis Species 0.000 claims description 15
- 239000002671 adjuvant Substances 0.000 claims description 10
- 230000009036 growth inhibition Effects 0.000 claims description 10
- 241000186366 Mycobacterium bovis Species 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 5
- 230000001747 exhibiting effect Effects 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 238000012360 testing method Methods 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 3
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 244000052769 pathogen Species 0.000 claims description 2
- 230000017066 negative regulation of growth Effects 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 80
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 70
- 229960003767 alanine Drugs 0.000 description 70
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 68
- 239000002609 medium Substances 0.000 description 41
- 229910052757 nitrogen Inorganic materials 0.000 description 40
- 201000008827 tuberculosis Diseases 0.000 description 39
- 235000001014 amino acid Nutrition 0.000 description 32
- 150000001413 amino acids Chemical class 0.000 description 32
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 30
- 229940024606 amino acid Drugs 0.000 description 28
- 230000005764 inhibitory process Effects 0.000 description 27
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 20
- 101150049512 ald gene Proteins 0.000 description 18
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- 230000014509 gene expression Effects 0.000 description 16
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 15
- 239000012634 fragment Substances 0.000 description 14
- 230000036039 immunity Effects 0.000 description 13
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 12
- 229960001230 asparagine Drugs 0.000 description 12
- 229960000190 bacillus calmette–guérin vaccine Drugs 0.000 description 12
- 101150100082 sdaA gene Proteins 0.000 description 10
- 108020004414 DNA Proteins 0.000 description 9
- 229930195712 glutamate Natural products 0.000 description 9
- 229940049906 glutamate Drugs 0.000 description 9
- 239000002773 nucleotide Substances 0.000 description 9
- 125000003729 nucleotide group Chemical group 0.000 description 9
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 9
- 229920000053 polysorbate 80 Polymers 0.000 description 9
- 230000001681 protective effect Effects 0.000 description 9
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 8
- 230000004048 modification Effects 0.000 description 8
- 238000012986 modification Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000010367 cloning Methods 0.000 description 7
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000013612 plasmid Substances 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 238000002255 vaccination Methods 0.000 description 7
- 241000894006 Bacteria Species 0.000 description 6
- 230000005526 G1 to G0 transition Effects 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 6
- 229930195714 L-glutamate Natural products 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 229930182816 L-glutamine Natural products 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 230000001580 bacterial effect Effects 0.000 description 5
- 239000008121 dextrose Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000028993 immune response Effects 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 239000013028 medium composition Substances 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000187480 Mycobacterium smegmatis Species 0.000 description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 238000012217 deletion Methods 0.000 description 4
- 230000037430 deletion Effects 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000002018 overexpression Effects 0.000 description 4
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 4
- 230000009469 supplementation Effects 0.000 description 4
- 102000009027 Albumins Human genes 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 241000064099 Massilioclostridium coli Species 0.000 description 3
- 241000186367 Mycobacterium avium Species 0.000 description 3
- 101150095197 PALD1 gene Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- NWMHDZMRVUOQGL-CZEIJOLGSA-N almurtide Chemical compound OC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)CO[C@@H]([C@H](O)[C@H](O)CO)[C@@H](NC(C)=O)C=O NWMHDZMRVUOQGL-CZEIJOLGSA-N 0.000 description 3
- FRHBOQMZUOWXQL-UHFFFAOYSA-L ammonium ferric citrate Chemical compound [NH4+].[Fe+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FRHBOQMZUOWXQL-UHFFFAOYSA-L 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 239000007640 basal medium Substances 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 238000009396 hybridization Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 239000004313 iron ammonium citrate Substances 0.000 description 3
- 235000000011 iron ammonium citrate Nutrition 0.000 description 3
- 230000004726 long-term protective immunity Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 208000027531 mycobacterial infectious disease Diseases 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 239000006152 selective media Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 230000001052 transient effect Effects 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- ZLUSTGDGOTYUPV-DKWTVANSSA-N (2s)-2-aminopropanoic acid;propane-1,2,3-triol Chemical compound C[C@H](N)C(O)=O.OCC(O)CO ZLUSTGDGOTYUPV-DKWTVANSSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 102000016938 Catalase Human genes 0.000 description 2
- 108010053835 Catalase Proteins 0.000 description 2
- 125000000030 D-alanine group Chemical group [H]N([H])[C@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 2
- 108010041986 DNA Vaccines Proteins 0.000 description 2
- 229940021995 DNA vaccine Drugs 0.000 description 2
- 101100364969 Dictyostelium discoideum scai gene Proteins 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 108020000311 Glutamate Synthase Proteins 0.000 description 2
- 206010018691 Granuloma Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 241000588915 Klebsiella aerogenes Species 0.000 description 2
- 235000019766 L-Lysine Nutrition 0.000 description 2
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 2
- 125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
- 229930064664 L-arginine Natural products 0.000 description 2
- 235000014852 L-arginine Nutrition 0.000 description 2
- 239000004395 L-leucine Substances 0.000 description 2
- 235000019454 L-leucine Nutrition 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 229930195722 L-methionine Natural products 0.000 description 2
- 125000002842 L-seryl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])O[H] 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 101100364971 Mus musculus Scai gene Proteins 0.000 description 2
- 206010062207 Mycobacterial infection Diseases 0.000 description 2
- 108700015872 N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine Proteins 0.000 description 2
- 108090000913 Nitrate Reductases Proteins 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- -1 cationic amino acids Chemical class 0.000 description 2
- 210000002421 cell wall Anatomy 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 150000004665 fatty acids Chemical group 0.000 description 2
- 230000037433 frameshift Effects 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 229930027917 kanamycin Natural products 0.000 description 2
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 2
- 229960000318 kanamycin Drugs 0.000 description 2
- 229930182823 kanamycin A Natural products 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 229960003136 leucine Drugs 0.000 description 2
- 230000007787 long-term memory Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 229940091250 magnesium supplement Drugs 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 229960004452 methionine Drugs 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 230000002688 persistence Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- 229940076788 pyruvate Drugs 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 208000014794 superficial urinary bladder carcinoma Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 2
- 229910000368 zinc sulfate Inorganic materials 0.000 description 2
- 229960001763 zinc sulfate Drugs 0.000 description 2
- YHQZWWDVLJPRIF-JLHRHDQISA-N (4R)-4-[[(2S,3R)-2-[acetyl-[(3R,4R,5S,6R)-3-amino-4-[(1R)-1-carboxyethoxy]-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]amino]-3-hydroxybutanoyl]amino]-5-amino-5-oxopentanoic acid Chemical compound C(C)(=O)N([C@@H]([C@H](O)C)C(=O)N[C@H](CCC(=O)O)C(N)=O)C1[C@H](N)[C@@H](O[C@@H](C(=O)O)C)[C@H](O)[C@H](O1)CO YHQZWWDVLJPRIF-JLHRHDQISA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 108010029697 CD40 Ligand Proteins 0.000 description 1
- 102100032937 CD40 ligand Human genes 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108010036824 Citrate (pro-3S)-lyase Proteins 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 238000000018 DNA microarray Methods 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 108050001049 Extracellular proteins Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108020003285 Isocitrate lyase Proteins 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- 229930182844 L-isoleucine Natural products 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000186362 Mycobacterium leprae Species 0.000 description 1
- 241000187492 Mycobacterium marinum Species 0.000 description 1
- 108700020354 N-acetylmuramyl-threonyl-isoglutamine Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010008038 Synthetic Vaccines Proteins 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000006023 anti-tumor response Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 108010079058 casein hydrolysate Proteins 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000013599 cloning vector Substances 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000004163 cytometry Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940111685 dibasic potassium phosphate Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 229960004642 ferric ammonium citrate Drugs 0.000 description 1
- 231100000221 frame shift mutation induction Toxicity 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960002743 glutamine Drugs 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 1
- 238000011554 guinea pig model Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 229940124644 immune regulator Drugs 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229940050906 magnesium chloride hexahydrate Drugs 0.000 description 1
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 238000010197 meta-analysis Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 108700007621 mifamurtide Proteins 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 229940035032 monophosphoryl lipid a Drugs 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 201000009671 multidrug-resistant tuberculosis Diseases 0.000 description 1
- 229940031348 multivalent vaccine Drugs 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 229940124551 recombinant vaccine Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000013605 shuttle vector Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 229940031626 subunit vaccine Drugs 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- XETCRXVKJHBPMK-MJSODCSWSA-N trehalose 6,6'-dimycolate Chemical compound C([C@@H]1[C@H]([C@H](O)[C@@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](COC(=O)C(CCCCCCCCCCC3C(C3)CCCCCCCCCCCCCCCCCC)C(O)CCCCCCCCCCCCCCCCCCCCCCCCC)O2)O)O1)O)OC(=O)C(C(O)CCCCCCCCCCCCCCCCCCCCCCCCC)CCCCCCCCCCC1CC1CCCCCCCCCCCCCCCCCC XETCRXVKJHBPMK-MJSODCSWSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/04—Mycobacterium, e.g. Mycobacterium tuberculosis
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0004—Oxidoreductases (1.)
- C12N9/0012—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7)
- C12N9/0014—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7) acting on the CH-NH2 group of donors (1.4)
- C12N9/0016—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7) acting on the CH-NH2 group of donors (1.4) with NAD or NADP as acceptor (1.4.1)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C12N15/74—Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/88—Lyases (4.)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/93—Ligases (6)
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Physics & Mathematics (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Oncology (AREA)
- Biophysics (AREA)
- Food Science & Technology (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Cell Biology (AREA)
- Plant Pathology (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
Description
本発明は、BCG株が有する増殖の窒素源として天然に存在するアミノ酸を使用する能力に対する限定を乗り越えるワクチンを提供する。さらにまた、L−アラニン、D−アラニンまたはL−セリンは、アンモニウムが存在しているときでさえBCG株の増殖を阻害する。機能的アラニンデヒドロゲナーゼ(配列番号1;配列番号2)のBCG株での発現はアラニンによるBCGの増殖阻害を軽減する。同様に、機能的L−セリンデヒドラターゼ(配列番号5;配列番号6)のBCG株での発現はL−セリンによるBCGの増殖阻害を軽減する。そのような阻害のメカニズムはグルタミンシンテターゼの阻害から生じる。グルタミンシンテターゼ(配列番号7から配列番号14)のBCGでの過剰発現はアラニンおよびL−セリンによるBCGの増殖阻害を軽減する。機能的アラニンデヒドロゲナーゼ(配列番号1;配列番号2)、L−セリンデヒドラターゼ(配列番号5;配列番号6)および/またはグルタミンシンテターゼ(配列番号7から配列番号14)を発現(または過剰発現)するリコンビナントBCG株はホストの体内でより長期間生存し続けて結果として長期の防御免疫を誘導する。そのような持続的リコンビナントBCG株は、結核および他のマイコバクテリア感染の予防のためのより有効なワクチンを提供する。
BCGワクチン株は増殖のための窒素源としてアミノ酸を利用する能力が限られている。さらにまた、天然に存在するアミノ酸L−アラニンおよびL−セリンはBCG株の増殖を阻害することを我々は発見した。BCGでの機能的L−アラニンデヒドロゲナーゼ(配列番号1;配列番号2)の発現はアラニンによる増殖阻害を軽減する。BCGでの機能的L−セリンデヒドラターゼ(配列番号5;配列番号6)の発現はL−セリンによる増殖阻害を軽減する。同様に、グルタミンシンテターゼ(配列番号7から配列番号14)の過剰発現は、アラニンおよびセリンによる増殖阻害を軽減させる。これらの新規な発見は重要である。なぜならば、機能的なアラニンデヒドロゲナーゼ(配列番号1;配列番号2)、L−セリンデヒドラターゼ(配列番号5;配列番号6)および/またはグルタミンシンテターゼ(配列番号7から配列番号14)を発現(または過剰発現)するリコンビナントBCG株はヒトホストの体内でより良好に生存し、長期の記憶免疫を誘導し、結核予防のためのより有効なワクチンを提供し、特に成人の肺結核を防ぐからである。
改変
本明細書に開示した核酸分子のDNA配列に多くの改変を加えることができる。そのような改変は当業者には明白であろう。本発明は、細菌または哺乳類細胞で発現を指令可能な、本明細書に開示した配列(またはそのフラグメント)のヌクレオチド改変を含む。改変にはヌクレオチドの置換、挿入もしくは欠失、またはヌクレオチドの相対的位置もしくは順序の変更が含まれる。
本発明の核酸分子はまた、本発明の核酸分子に対して少なくとも約60%の同一性、少なくとも70%の同一性、少なくとも80%の同一性、少なくとも90%の同一性、少なくとも95%の同一性、少なくとも96%の同一性、少なくとも97%の同一性、少なくとも98%の同一性、またはもっとも好ましくは少なくとも99%または99.5%の同一性を有し、細菌または哺乳類細胞で核酸分子発現可能な核酸分子(またはそのフラグメント)を含む。同一性とは、最高の順序適合が得られるようにアラインメントを実施した2つのヌクレオチド配列の類似性を指す。同一性は当業界で公知の方法にしたがって計算される。例えば、あるヌクレオチド配列(“配列A”と呼ぶ)が配列番号1の一部分と90%同一性を有する場合、配列Aは配列番号1の照合された部分の各100ヌクレオチドにつき10個までの点変異(例えば他のヌクレオチドをもつ置換)を含みうることを除けば配列Aは配列番号1の照合された部分と同一である。
本発明は、本明細書に記載された核酸とストリンジェントな条件下でハイブリダイズするために十分な同一性を有する配列をもつDNAを含む(ハイブリダイゼーション技術は当業界では周知である)。本発明はまた配列番号1から配列番号14の配列またはその相補性配列の1つまたは2つ以上とハイブリダイズする核酸分子を含む。そのような核酸分子は、好ましくは高度にストリンジェントな条件下でハイブリダイズする(以下を参照されたい:Sambrook et al. Molecular Cloning: A Laboratory Manual, Most Recent Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY)。高度にストリンジェントな洗浄は好ましくは低塩濃度(好ましくは約0.2%のSSC)および約50−65℃の温度を有する。
当業者には生リコンビナントワクチンの製造は公知である。典型的にはそのようなワクチンは注射可能な溶液または懸濁液として製造される。注射前に液体となる溶液または懸濁液に適した固体形態に製造してもよい。前記調製物はまた乳化されてもよく、またはタンパク質をリポソームに被包化してもよい。生の免疫原性成分は、医薬的に許容され活性成分と適合する賦形剤としばしば混合される。適切な賦形剤は、例えば、水、食塩水、デキストロース、グリセロール、エタノールなど、またはその組み合わせなどである。さらにまた、所望の場合には、本ワクチンは微量の補助物質、例えば湿潤剤、乳化剤、pH緩衝剤および/またはワクチンの有効性を高めるアジュバントを含むことができる。有効でありうるアジュバントの例には以下が含まれるがこれらに限定されるものではない:水酸化アルミニウム、N−アセチル−ムラミル−L−スレオニル−D−イソグルタミン(thr−MDP)、N−アセチル−ノル−ムラミル−L−アラニル−D−イソグルタミン(CGP11637、nor−MDPと称される)、N−アセチルムラミル−L−アラニル−D−イソグルタミニル−L−アラニン−2−(1'−2'−ジパルミトイル−sn−グリセロ−3−ヒドロキシホスホリルオキシ)−エチルアミン(CGP19835A、MTE−PEと称される)およびRIBI(細菌から抽出された3つの成分(モノホスホリル脂質A、トレハロースジミコレートおよび細胞壁骨格(MPL+TDM+CWS))を2%スクォレン/トゥイーン80(登録商標)乳液中に含む)。
簡便には、前記ワクチンは非経口的に、例えば注射(皮下または筋肉内)によって投与される。他の投与態様に適したさらに別の製剤には座薬および、いくつかの事例では経口製剤が含まれる。座薬のためには、伝統的な結合剤および担体には例えばポリアルキレングリコールまたはトリグリセリドが含まれるであろう。そのような座薬は、0.5%から10%、好ましくは1%から2%の範囲の活性成分を含む混合物から成形されるであろう。経口製剤には通常用いられる賦形剤、例えば医薬グレードのマンニトール、ラクトース、澱粉、ステアリン酸マグネシウム、サッカリンナトリウム、セルロース炭酸マグネシウムなどが含まれる。これらの製剤は、溶液、懸濁液、錠剤、ピル、カプセル、徐放性製剤または散剤の形態をもち、10%から95%、好ましくは25%から70%の活性成分を含む。
本発明の医薬組成物は、Mycobacterium tuberculosisまたはMycobacterium bovisによる攻撃に対して哺乳類を治療または予防するために用いられる。本発明の医薬組成物はまた、変性疾患、障害または異常な身体状態(例えば癌)をもつ患者の治療に用いられる。
Mycobacterium bovis−BCGの増殖を阻害する本発明の培地組成物は唯一の窒素源としてアラニンまたはセリンを含む。アラニンが唯一の窒素源であるときアラニンは0.03mM以上の量で存在し、セリンが唯一の窒素源であるときセリンは0.03mM以上の量で存在する。
免疫診断に適し、適切な標識試薬を含むキットは、本発明の生リコンビナントMycobacterium bovisBCG株を含む適切な材料を適切な容器に残りの試薬およびアッセイの実施に必要な材料並びに適切なアッセイ使用説明書セットとともに包装することによって構築される。いかなる免疫学的検査様式も意図され(例えばELISA、ウェスタンブロット、サンドイッチアッセイなど)、それらは当業者に周知である。
細菌株および培養条件:12のMycobacterium bovisBCG株:BCG−Japan、BCG−Russia、BCG−Moreau、BCG−Sweden、BCG−Birkhaug、BCG−Frappier、BCG−Pasteur、BCG−Glaxo、BCG−Phipps、BCG−Tice、BCG−Denmark、およびBCG−Pragueを本実験に用い、それらはマーセル=ベーア博士(Dr. Macel Behr, McGill University)から入手した。前記の株の特性については以前に詳細に記載された(Behr et al. 1999)。ミドルブルック7H9培地(Midlebrook 7H9, Difco)は1リットル当たり以下を含む:硫酸アンモニウム、0.5g;L−グルタメート、0.5g;クエン酸ナトリウム、0.1g;ピリドキシン、1mg;ビオチン、0.5mg;リン酸二ナトリウム、2.5g;リン酸一カリウム、1g;クエン酸第二鉄アンモニウム、40mg;硫酸マグネシウム、50mg;塩化カルシウム、0.5mg;硫酸亜鉛、1mg;硫酸銅、1mg;およびグリセロール2mL(前記の他に5gのアルブミン(ウシ、V分画)、デキストロース2gおよび0.05%トゥイーン80を滅菌後に添加)。Sauton培地は1リットル当たり以下を含む:L−アスパラギン、4g;硫酸一カリウム、0.5g;硫酸マグネシウム、0.5g;クエン酸第二鉄アンモニウム、50mg;クエン酸、2g;硫酸亜鉛、1mg;およびグリセロール、60mL(0.05%トゥイーン80を滅菌後に添加)。グリセロール−アラニン−塩類(GAS)培地は1リットル当たり以下を含む:塩化アンモニウム、2g;L−アラニン、1g;バクトカシトーン(Bacto Casitone, Difco)、0.3g;二塩基性リン酸カリウム、4g;クエン酸、2g;クエン酸第二鉄アンモニウム、50mg;塩化マグネシウム6水和物、1.2g;硫酸カリウム、0.6g;10Mの水酸化ナトリウム、1.8mL;および10mLのグリセロール。トゥイーン80を滅菌後に0.05%添加した。BCG培養は37℃で定常的に振盪しながら3−4週間増殖させた。
Andersen, A. B. F. , P. F. Andersen, and L. Ljungqvist. 1992. 「Structure and function of a 40,000−molecular−weight protein antigen of Mycobacterium tuberculosis.」 Infect.Immun.60:2317−23.
Andersen, P.2001. 「TB vaccines: progressand problems.」 Trends Immunol. 22: 160−8.
Baldwin, S. L. F., C.F.D’Souza,A.D.F.Rob
erts,B.P.F.Kelly,A.A.F.Frank,M.A.F.Lui,J.B.F.Ulmer,K.F.Huygen,D.M.F.McMurray,and I. M.Orme.1998.「Evaluation of new vaccines in the mouse and guinea pig model of tuberculosis.」 Infect.Immun.66: 2951−9.
Behr,M.A.F.,M.A.F.Wilson,W.P.F.Gill,H.F.Salamon,G.K.F.Schoolnik,S.F.Rane,and P.M.Small. 1999.「Comparative genomics of BCG vaccines by whole−genome DNA microarray.」 Science 284: 1520−3.
Brandt,L.,C.J.Feino,O.A.Weinreich,B.Chilima,P.Hirsch,R.Appelberg,and P.Andersen. 2002.「Failure of the Mycobacterium bovis BCG Vaccine: Some Species of Environmental Mycobacteria Block Multiplication of BCG and Induction of Protective Immunity to Tuberculosis.」 Infect.Immun.70:672−678.
Barclay,R.and P.R.Wheeler.1989.「Metabolism of mycobacterium in tissues,」 p. 37− 106. In C.Ratledge,J.Stanford,and J.M.Grange(ed.),「Clinical aspects of mycobacterial disease.」 Academic Press, London, United Kindom.
Brosch,R.F.,S.V.F.Gordon,C.F.Buchrieser, A. S.F.Pym,T.F.Garnier,and S.T.Cole.2000.「Comparative genomics uncovers large tandem chromosomal duplications in Mycobacterium bovisBCG Pasteur.」 Yeast 17: 111−23.
Colditz,G.A.F.,T.F.F.Brewer,C.S.F.Berkey, M.E.F.Wilson,E.F.Burdick,H.V.F.Fineberg,and F.Mosteller.1994. 「Efficacy of BCG vaccine in the prevention of tuberculosis. Meta−analysis of the published literature.」 JAMA 271: 698−702.
de Boer,E.C.,Bevers,R.F.,Kurth,K.H.,and Schamhart,D.H.1996.「Double fluorescent flow cytometric assessment of bacterial internalization and binding byepithelialcells.」 Cytometry. 25:381−387.
Dunn,P.L.F.and R.J.North.1995. 「Virulence ranking of some Mycobacterium tuberculosis and Mycobacterium bovis strains according to their ability to multiply in the lungs, induce lung pathology, and cause mortality in mice.」 Infect. Immun. 63: 3428−37.
Fine,P.E.1995.「Variation in protection by BCG: implications of and for heterologous immunity.」 Lancet 346: 1339−45.
Fine,P.E.1989.「The BCG story: lessons from the past and implications for the future.」 Rev.Infect.Dis.11:S353−9.
Fine,P.E.F.and E.Vynnycky.1998.「The effect of heterologous immunity upon the apparent efficacy of (e.g.BCG) vaccines. Vaccine 16: 1923−8.
Fritz,C.F., S.F.Maass,A.F.Kreft,and F.C.Bange. 2002. 「Dependence of Mycobacterium bovis BCG on anaerobic nitrate reductase for persistence is tissue specific.」 Infect. Immun. 70:286−91.
Harth, G.F., P.C.F.Zamecnik, J.Y.F.Tang, D. F.Tabatadze, and M.A.Horwitz. 2000. 「Treatment of Mycobacterium tuberculosis with antisense oligonucleotides to glutamine synthetase mRNA inhibits glutamine synthetase activity, formation of the poly−L−glutamate/glutamine cell wall structure, and bacterial replication.」 Proc.Natl.
Acad. Sci. USA 97:418−23.
Harth, G.F., D.L.F.Clemens, and M.A.Horwitz. 1994. 「Glutamine synthetase of Mycobacterium tuberculosis : extracellular release and characterization of its enzymatic activity.」 Proc.Natl.Acad.Sci.USA 91: 9342−6.
Hogan, L.H.F., W.F.Markofski, A.F.Bock, B. F.Barger, J.D.F.Morrissey, and M.Sandor. 2001. 「Mycobacterium bovis BCG−induced granuloma formation depends on gamma interferon and CD40 ligand but does not require CD28.」 Infect.Immun. 69:2596− 603.
Hutter,B. F. and M. Singh. 1999. 「Properties of the 40 kDa antigen of Mycobacterium tuberculosis, a functional L−alanine dehydrogenase.」 Biochem.J. 343:669−72.
Hutter,B. F. and T. Dick. 1998. 「Increased alanine dehydrogenase activity during dormancy in Mycobacterium smegmatis.」 FEMSMicrobiol. Lett. 167:7−11.
Janes, B.K.F. and R.A.Bender. 1998. 「Alanine catabolism in Klebsiella aerogenes : molecular characterization of the dadAB operon and its regulation by the nitrogen assimilation control protein.」 J. Bacteriol 180:563−70.
Lagranderie, M.R. F., A.M.F.Balazuc, E.F.Deriaud, C.D.F.Leclerc, and M.Gheorghiu. 1996. 「Comparison of immune responses of mice immunized with five different Mycobacterium bovis BCG vaccine strains.」 Infect. Immun. 64:1−9.
Lamm, D.L.2000. 「Efficacy and safety of bacille Calmette−Guerin immunotherapy in superficial bladder cancer.」 Clin.Infect. Dis. 31 (Suppl 3):S86−90.
Lockyer, C.R., and Gillatt,D.A. 2001. 「BCG immunotherapy for superficial bladder cancer.」 J.R.Soc.Med.94:119−23.
McKinney, J.D.F., z.B.Honer,E.J.F.Munoz−Elias, A.F.Miczak, B.F.Chen, W.T.F.Chan, D. F.Swenson, J.C.F.Sacchettini, W.R.J.Jacobs, and D.G.Russell. 2000. 「Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase.」 Nature 406:735−8.
Moisan,J.F., W.F.Wojciechowski, C.F.Guilbault, C.F.Lachance, S.Di Marco, E.F.Skamene, G.F.Matlashewski, and D.Radzioch. 2001. 「Clearance of infection with
Mycobacterium bovis BCG in mice is enhanced by treatment with S28463(R−848), and its efficiency depends on expression of wild−type Nramp 1 (resistance allele).」−Antimicrob. Agents Chemother. 45:3059−64.
Oettinger,T.F., M.F.Jorgensen, A.F.Ladefoged,K.F.Haslov, and P.Andersen. 1999. 「Development of the Mycobacterium bovis BCG vaccine: review of the historical and biochemical evidence for a genealogical tree.」 Tuber. Lung Dis. 79:243−50.
Orme,I.M. 2001. 「The search for new vaccines against tuberculosis.」 J.Leukoc.Biol.
70:1−10.
Prescott,S., Jackson,A.M., Hawkyard,S.J.,Alexandroff,A.B., and James,K. 2000. 「Mechanisms of action of intravesical bacilleCalmette−Guerin : local immune mechanisms.」 Clin. Infect. Dis. 31(Suppl 3):S91−3.
Reitzer,L.J. 1996.「 Ammonium assimilation and the biosynthesis of glutamine, glutamate, aspartate, asparagine, L−alanine, and D−alanine」, p.380−390. In Neidhardt, F.C. (ed.),Escherichia coli and Salrnonella, ASM Press, Washington, D. C.
Sterne,J.A., L.C.Rodrigues, and I.N.Guedes. 1998. 「Does the efficacy of BCG decline with time since vaccination?」 International Journal of Tuberculosis & Lung Disease 2:200−207.
Young,D.B. 2000. 「Current tuberculosis vaccine development.」 Clin.Infect.Dis. 30: S254−6.
Yu,S.F., E.F.Fiss, and W.R.J.Jacobs. 1998. 「Analysis of the exochelin locus in Mycobacterium smegmatis : biosynthesis genes have homology with genes of the pept
ide synthetase family.」 J.Bacteriol. 180:4676−85.
Claims (20)
- アラニンデヒドロゲナーゼ活性またはL−セリンデヒドラターゼ活性を示す少なくとも1つのタンパク質またはポリペプチドを発現し、アラニンおよび/またはL−セリンによる増殖の阻害を軽減することができる生リコンビナントMycobacterium bovis−BCG株。
- 前記少なくとも1つのタンパク質またはポリペプチドが、アラニンデヒドロゲナーゼ(配列番号1から配列番号2)およびL−セリンデヒドラターゼ(配列番号5から配列番号6)から成る群から選択される請求項1の生リコンビナントMycobacterium bovis−BCG株。
- 前記少なくとも1つのタンパク質またはポリペプチドが、配列番号1および配列番号5から成る群から選択される少なくとも1つの核酸分子と少なくとも90%の配列同一性を有する配列を含む核酸によりコードされる請求項1または2の生リコンビナントMycobacterium bovis−BCG株。
- グルタミンシンテターゼ活性を示す少なくとも1つのタンパク質またはポリペプチドを過剰発現し、アラニンおよび/またはL−セリンによる増殖の阻害を軽減することができる生リコンビナントMycobacterium bovis−BCG株。
- 前記少なくとも1つのタンパク質またはポリペプチドが、グルタミンシンテターゼ(配列番号7から配列番号14)から成る群から選択される請求項4の生リコンビナントMycobacterium bovis−BCG株。
- 前記少なくとも1つのタンパク質またはポリペプチドが、配列番号7、配列番号9、配列番号11および配列番号13から成る群から選択される少なくとも1つの核酸分子と少なくとも90%の配列同一性を有する配列を含む核酸によりコードされる請求項4または5の生リコンビナントMycobacterium bovis−BCG株。
- 前記Mycobacterium bovis−BCG株が、Mycobacterium bovis−BCG−Russia、Mycobacterium bovis−BCG−Moreau、Mycobacterium bovis−BCG−Japan、Mycobacterium bovis−BCG−Sweden、Mycobacterium bovis−BCG−Birkhaug、Mycobacterium bovis−BCG−Prague、Mycobacterium bovis−BCG−Glaxo、Mycobacterium bovis−BCG−Denmark、Mycobacterium bovis−BCG−Tice、Mycobacterium bovis−BCG−Frappier、Mycobacterium bovis−BCG−Connaught、Mycobacterium bovis−BCG−Phipps、およびMycobacterium bovis−BCG−Pasteurから成る群から選択される請求項1、2、3、4、5または6の生リコンビナントMycobacterium bovis−BCG株。
- 請求項1、2、3、4、5、6または7の生リコンビナントMycobacterium bovis−BCG株を含む医薬組成物。
- 請求項1、2、3、4、5、6または7の生リコンビナントMycobacterium bovis−BCG株を含む、マイコバクテリアによる攻撃に対し哺乳類を治療または予防するワクチンまたは免疫原性組成物。
- 前記マイコバクテリアがMycobacterium tuberculosisである請求項9のワクチンまたは免疫原性組成物。
- 医薬的に許容できる担体をさらに含む請求項9または10のワクチンまたは免疫原性組成物。
- さらにアジュバントを含む請求項9、10または11のワクチンまたは免疫原性組成物。
- 1つ以上の他の病源体に由来する免疫原性物質をさらに含む請求項9、10、11または12のワクチンまたは免疫原性組成物。
- 請求項1、2、3、4、5、6または7の生リコンビナントMycobacterium bovis−BCG株をヒトを除く哺乳類に投与することを含む、Mycobacterium tuberculosisまたはMycobacterium bovisによる攻撃に対し前記哺乳類を治療または予防する方法。
- 前記哺乳類が牛である請求項14の方法。
- 前記ワクチンまたは免疫原性組成物がアジュバントの存在下で投与される請求項14の方法。
- 請求項1、2、3、4、5、6または7の生リコンビナントMycobacterium bovis−BCG株をヒトを除く哺乳類に投与することを含む、癌に対して前記哺乳類を治療または予防する方法。
- 前記ワクチンまたは免疫原性組成物がアジュバントの存在下で投与される請求項17の方法。
- 前記癌が膀胱癌である請求項17または18の方法。
- 請求項1、2、3、4、5、6または7の生リコンビナントMycobacterium bovis−BCG株を含む検査キット。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US37245002P | 2002-04-16 | 2002-04-16 | |
PCT/CA2003/000566 WO2003089462A2 (en) | 2002-04-16 | 2003-04-16 | Tuberculosis vaccines including recombinant bcg strains expressing alanine dehydrogenase, serine dehydratase and/or glutamine synthetase |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2006508633A JP2006508633A (ja) | 2006-03-16 |
JP4233458B2 true JP4233458B2 (ja) | 2009-03-04 |
Family
ID=29250855
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2003586182A Expired - Fee Related JP4233458B2 (ja) | 2002-04-16 | 2003-04-16 | アラニンデヒドロゲナーゼ、セリンデヒドラターゼおよび/またはグルタミンシンテターゼを発現する結核ワクチンとしてのリコンビナントbcg株 |
Country Status (9)
Country | Link |
---|---|
US (1) | US7611720B2 (ja) |
JP (1) | JP4233458B2 (ja) |
CN (1) | CN100572540C (ja) |
AU (1) | AU2003218838A1 (ja) |
CA (1) | CA2481108C (ja) |
GB (1) | GB2403477B (ja) |
RU (1) | RU2339692C2 (ja) |
WO (1) | WO2003089462A2 (ja) |
ZA (1) | ZA200408344B (ja) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006000045A1 (en) * | 2004-06-25 | 2006-01-05 | Proteome Systems Intellectual Property Pty Ltd | Novel methods of diagnosis and treatment of m. tuberculosis infection and reagents therefor i |
EP1806401B1 (en) * | 2004-10-13 | 2013-07-31 | Mitsui Chemicals, Inc. | Dna encoding novel enzyme having d-serine synthase activity, method of producing the enzyme and method of producing d-serine by using the same |
RU2473365C1 (ru) * | 2008-10-20 | 2013-01-27 | Юниверсити Оф Цюрих | Вакцина mycobacterium tuberculosis |
CA2824417C (en) * | 2011-01-11 | 2019-02-26 | Cadila Pharmaceuticals Limited | Mycobacterium w for use in treating cancer |
US20140127251A1 (en) | 2011-04-11 | 2014-05-08 | Alarum Development Ltd. | Vaccines for prevention and treatment of tuberculosis |
CN114748615A (zh) * | 2022-04-29 | 2022-07-15 | 成都安永鼎业生物技术有限公司 | 一种治疗用重组卡介苗的冻干制剂及其制备方法和用途 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU6097998A (en) * | 1997-01-29 | 1998-08-18 | Flohe, Leopold | L-alanine dehydrogenase of mycobacterium marinum |
US6291190B1 (en) * | 1998-08-25 | 2001-09-18 | The Board Of Trustees Of The Leland Stanford Junior University | Molecular differences between species of the M. tuberculosis complex |
US6471967B1 (en) * | 2000-04-17 | 2002-10-29 | The Regents Of The University Of California | Recombinant intracellular pathogen vaccines and methods for use |
-
2003
- 2003-04-16 WO PCT/CA2003/000566 patent/WO2003089462A2/en active Application Filing
- 2003-04-16 AU AU2003218838A patent/AU2003218838A1/en not_active Abandoned
- 2003-04-16 JP JP2003586182A patent/JP4233458B2/ja not_active Expired - Fee Related
- 2003-04-16 CA CA2481108A patent/CA2481108C/en not_active Expired - Fee Related
- 2003-04-16 GB GB0425165A patent/GB2403477B/en not_active Expired - Lifetime
- 2003-04-16 RU RU2004133751/13A patent/RU2339692C2/ru not_active IP Right Cessation
- 2003-04-16 CN CNB038022761A patent/CN100572540C/zh not_active Expired - Lifetime
- 2003-04-16 US US10/511,718 patent/US7611720B2/en not_active Expired - Fee Related
-
2004
- 2004-10-14 ZA ZA2004/08344A patent/ZA200408344B/en unknown
Also Published As
Publication number | Publication date |
---|---|
AU2003218838A8 (en) | 2003-11-03 |
AU2003218838A1 (en) | 2003-11-03 |
US20070264286A1 (en) | 2007-11-15 |
US7611720B2 (en) | 2009-11-03 |
RU2004133751A (ru) | 2005-08-10 |
GB2403477A (en) | 2005-01-05 |
CA2481108C (en) | 2013-05-28 |
CN1703513A (zh) | 2005-11-30 |
WO2003089462A3 (en) | 2004-05-21 |
GB2403477B (en) | 2006-08-23 |
ZA200408344B (en) | 2005-11-30 |
WO2003089462A2 (en) | 2003-10-30 |
RU2339692C2 (ru) | 2008-11-27 |
GB0425165D0 (en) | 2004-12-15 |
CA2481108A1 (en) | 2003-10-30 |
CN100572540C (zh) | 2009-12-23 |
JP2006508633A (ja) | 2006-03-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Tullius et al. | Glutamine synthetase GlnA1 is essential for growth of Mycobacterium tuberculosis in human THP-1 macrophages and guinea pigs | |
King et al. | Aerotolerance and peroxide resistance in peroxidase and PerR mutants of Streptococcus pyogenes | |
Jubier-Maurin et al. | Identification of the nik gene cluster of Brucella suis: regulation and contribution to urease activity | |
Chacon et al. | Mycobacterium smegmatis D-alanine racemase mutants are not dependent on D-alanine for growth | |
Kaniga et al. | Molecular and functional characterization of Salmonella enterica serovar typhimurium poxA gene: effect on attenuation of virulence and protection | |
Chen et al. | Mycobacterium bovis BCG vaccines exhibit defects in alanine and serine catabolism | |
WO2003004520A2 (en) | Mycobacterial antigens expressed during latency | |
AU2002314358A1 (en) | Mycobacterial antigens expressed during latency | |
JP7035063B2 (ja) | phoP-phoRを過剰発現する組換えBCG | |
Ribardo et al. | Analysis of the LIV system of Campylobacter jejuni reveals alternative roles for LivJ and LivK in commensalism beyond branched-chain amino acid transport | |
Viswanathan et al. | The cytochrome c maturation locus of Legionella pneumophila promotes iron assimilation and intracellular infection and contains a strain-specific insertion sequence element | |
KR20190084097A (ko) | 세균의 폴레이트 수송의 약화에 의한 세균 병독성의 약독화 | |
West et al. | Role of phosphoglucomutase of Bordetella bronchiseptica in lipopolysaccharide biosynthesis and virulence | |
JP4233458B2 (ja) | アラニンデヒドロゲナーゼ、セリンデヒドラターゼおよび/またはグルタミンシンテターゼを発現する結核ワクチンとしてのリコンビナントbcg株 | |
US20040001866A1 (en) | Attenuated mycobacterium tuberculosis vaccines | |
Fuchs et al. | Characterization of a Bordetella pertussis diaminopimelate (DAP) biosynthesis locus identifies dapC, a novel gene coding for an N-succinyl-L, L-DAP aminotransferase | |
JP2011116659A (ja) | 組換え皮膚壊死トキソイドを含有する豚萎縮性鼻炎用薬剤 | |
Nies et al. | Transition metal homeostasis | |
JP5994127B2 (ja) | 新規な組換えbcgワクチン | |
JP2015518719A (ja) | 結核菌群菌を弱毒化して結核ワクチンを製造する方法 | |
WO2005111205A1 (en) | Tuberculosis vaccine | |
Ulsen et al. | Genes of non‐typeable Haemophilus influenzae expressed during interaction with human epithelial cell lines | |
LIU et al. | Patent 2481108 Summary | |
US6929799B2 (en) | D-alanine racemase mutants of mycobacteria and uses therefore | |
WO2002102409A1 (en) | Inactivated mycobacterial ompatb and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20071030 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20080130 |
|
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: 20081202 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20081209 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20111219 Year of fee payment: 3 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20121219 Year of fee payment: 4 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20131219 Year of fee payment: 5 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |