CN100346829C - 包含免疫刺激性寡核苷酸和母育酚的佐剂组合物 - Google Patents
包含免疫刺激性寡核苷酸和母育酚的佐剂组合物 Download PDFInfo
- Publication number
- CN100346829C CN100346829C CNB018206603A CN01820660A CN100346829C CN 100346829 C CN100346829 C CN 100346829C CN B018206603 A CNB018206603 A CN B018206603A CN 01820660 A CN01820660 A CN 01820660A CN 100346829 C CN100346829 C CN 100346829C
- Authority
- CN
- China
- Prior art keywords
- tocol
- antigen
- vaccine
- adjuvant
- adjunvant composition
- 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
- 239000002671 adjuvant Substances 0.000 title claims abstract description 69
- DFUSDJMZWQVQSF-XLGIIRLISA-N (2r)-2-methyl-2-[(4r,8r)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-ol Chemical compound OC1=CC=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 DFUSDJMZWQVQSF-XLGIIRLISA-N 0.000 title claims abstract description 60
- 108091034117 Oligonucleotide Proteins 0.000 title claims abstract description 40
- 230000003308 immunostimulating effect Effects 0.000 title claims abstract description 34
- 239000000427 antigen Substances 0.000 claims abstract description 85
- 108091007433 antigens Proteins 0.000 claims abstract description 85
- 102000036639 antigens Human genes 0.000 claims abstract description 85
- 229960005486 vaccine Drugs 0.000 claims abstract description 76
- 239000000203 mixture Substances 0.000 claims abstract description 62
- 239000000839 emulsion Substances 0.000 claims description 43
- 238000002360 preparation method Methods 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 20
- 239000002158 endotoxin Substances 0.000 claims description 18
- 229920006008 lipopolysaccharide Polymers 0.000 claims description 17
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 16
- 239000001397 quillaja saponaria molina bark Substances 0.000 claims description 16
- 229930182490 saponin Natural products 0.000 claims description 16
- 150000007949 saponins Chemical class 0.000 claims description 16
- 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 claims description 13
- 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 claims description 13
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 claims description 13
- 229940031439 squalene Drugs 0.000 claims description 13
- 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 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229940087168 alpha tocopherol Drugs 0.000 claims description 10
- 229960000984 tocofersolan Drugs 0.000 claims description 10
- 239000002076 α-tocopherol Substances 0.000 claims description 10
- 235000004835 α-tocopherol Nutrition 0.000 claims description 10
- 229960001438 immunostimulant agent Drugs 0.000 claims description 7
- 239000003022 immunostimulating agent Substances 0.000 claims description 7
- 239000002773 nucleotide Substances 0.000 claims description 7
- 125000003729 nucleotide group Chemical group 0.000 claims description 7
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- 150000001721 carbon Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 2
- 108091033319 polynucleotide Proteins 0.000 claims 1
- 239000002157 polynucleotide Substances 0.000 claims 1
- 102000040430 polynucleotide Human genes 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 41
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 11
- 201000010099 disease Diseases 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- CTMZLDSMFCVUNX-VMIOUTBZSA-N cytidylyl-(3'->5')-guanosine Chemical class O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=C(C(N=C(N)N3)=O)N=C2)O)[C@@H](CO)O1 CTMZLDSMFCVUNX-VMIOUTBZSA-N 0.000 description 52
- 239000003921 oil Substances 0.000 description 33
- 235000019198 oils Nutrition 0.000 description 33
- 206010028980 Neoplasm Diseases 0.000 description 23
- 108090000765 processed proteins & peptides Proteins 0.000 description 19
- 241001597008 Nomeidae Species 0.000 description 18
- 239000003795 chemical substances by application Substances 0.000 description 16
- 210000003491 skin Anatomy 0.000 description 16
- 235000017709 saponins Nutrition 0.000 description 14
- 238000011282 treatment Methods 0.000 description 14
- 108090000623 proteins and genes Proteins 0.000 description 13
- 230000004927 fusion Effects 0.000 description 12
- 235000018102 proteins Nutrition 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- -1 thiophosphate di-phosphate ester Chemical class 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 241000701806 Human papillomavirus Species 0.000 description 9
- 241000700605 Viruses Species 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- 230000000890 antigenic effect Effects 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
- 239000002502 liposome Substances 0.000 description 9
- 230000004060 metabolic process Effects 0.000 description 9
- 239000002953 phosphate buffered saline Substances 0.000 description 9
- 108700006640 OspA Proteins 0.000 description 8
- 238000011160 research Methods 0.000 description 8
- 230000004044 response Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 201000008827 tuberculosis Diseases 0.000 description 8
- 102100037840 Dehydrogenase/reductase SDR family member 2, mitochondrial Human genes 0.000 description 7
- 102100034872 Kallikrein-4 Human genes 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- 101710188053 Protein D Proteins 0.000 description 7
- 101710132893 Resolvase Proteins 0.000 description 7
- 238000013459 approach Methods 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 108010024383 kallikrein 4 Proteins 0.000 description 7
- 150000002632 lipids Chemical class 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 238000002255 vaccination Methods 0.000 description 7
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000700721 Hepatitis B virus Species 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 239000012634 fragment Substances 0.000 description 6
- 208000002672 hepatitis B Diseases 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 6
- 229920000053 polysorbate 80 Polymers 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 208000017667 Chronic Disease Diseases 0.000 description 5
- 208000035473 Communicable disease Diseases 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
- 241000341655 Human papillomavirus type 16 Species 0.000 description 5
- 206010020751 Hypersensitivity Diseases 0.000 description 5
- 241000223960 Plasmodium falciparum Species 0.000 description 5
- UZQJVUCHXGYFLQ-AYDHOLPZSA-N [(2s,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-4-[(2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-6-(hy Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O)O[C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CC[C@H]2[C@@]1(C=O)C)C)(C)CC(O)[C@]1(CCC(CC14)(C)C)C(=O)O[C@H]1[C@@H]([C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O[C@H]4[C@@H]([C@@H](O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O)[C@H](O)[C@@H](CO)O4)O)[C@H](O)[C@@H](CO)O3)O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UZQJVUCHXGYFLQ-AYDHOLPZSA-N 0.000 description 5
- 208000026935 allergic disease Diseases 0.000 description 5
- 230000007815 allergy Effects 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 238000007918 intramuscular administration Methods 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 239000003053 toxin Substances 0.000 description 5
- 231100000765 toxin Toxicity 0.000 description 5
- 241000712461 unidentified influenza virus Species 0.000 description 5
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 4
- 208000030507 AIDS Diseases 0.000 description 4
- 241000589969 Borreliella burgdorferi Species 0.000 description 4
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 4
- 241000606161 Chlamydia Species 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 4
- 241000606790 Haemophilus Species 0.000 description 4
- 244000286779 Hansenula anomala Species 0.000 description 4
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 4
- 108700023315 OspC Proteins 0.000 description 4
- 241000224016 Plasmodium Species 0.000 description 4
- 101100431670 Rattus norvegicus Ybx3 gene Proteins 0.000 description 4
- 241000607142 Salmonella Species 0.000 description 4
- 241000219287 Saponaria Species 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004945 emulsification Methods 0.000 description 4
- 210000002615 epidermis Anatomy 0.000 description 4
- 230000002949 hemolytic effect Effects 0.000 description 4
- 108010037896 heparin-binding hemagglutinin Proteins 0.000 description 4
- 108010057760 hepatic sialoglycoprotein receptor Proteins 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 229940035032 monophosphoryl lipid a Drugs 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000001593 sorbitan monooleate Substances 0.000 description 4
- 235000011069 sorbitan monooleate Nutrition 0.000 description 4
- 229940035049 sorbitan monooleate Drugs 0.000 description 4
- 241000223836 Babesia Species 0.000 description 3
- 241000193830 Bacillus <bacterium> Species 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 241000589876 Campylobacter Species 0.000 description 3
- 241000222122 Candida albicans Species 0.000 description 3
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 3
- 241000194032 Enterococcus faecalis Species 0.000 description 3
- 241000224467 Giardia intestinalis Species 0.000 description 3
- 102000000440 Melanoma-associated antigen Human genes 0.000 description 3
- 108050008953 Melanoma-associated antigen Proteins 0.000 description 3
- 241000588655 Moraxella catarrhalis Species 0.000 description 3
- 101100346932 Mus musculus Muc1 gene Proteins 0.000 description 3
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 3
- 102100038358 Prostate-specific antigen Human genes 0.000 description 3
- 102000012479 Serine Proteases Human genes 0.000 description 3
- 108010022999 Serine Proteases Proteins 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 241000223996 Toxoplasma Species 0.000 description 3
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 3
- 241000607734 Yersinia <bacteria> Species 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 201000008680 babesiosis Diseases 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 208000000292 ehrlichiosis Diseases 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 102000037865 fusion proteins Human genes 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000012737 microarray-based gene expression Methods 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 238000012243 multiplex automated genomic engineering Methods 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 210000002307 prostate Anatomy 0.000 description 3
- 230000002685 pulmonary effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 description 3
- 239000008158 vegetable oil Substances 0.000 description 3
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 2
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 2
- 108010082126 Alanine transaminase Proteins 0.000 description 2
- 206010059313 Anogenital warts Diseases 0.000 description 2
- 241000193738 Bacillus anthracis Species 0.000 description 2
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 description 2
- 108030001720 Bontoxilysin Proteins 0.000 description 2
- 241000588807 Bordetella Species 0.000 description 2
- 241000588779 Bordetella bronchiseptica Species 0.000 description 2
- 241000588780 Bordetella parapertussis Species 0.000 description 2
- 241000588832 Bordetella pertussis Species 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 241000589875 Campylobacter jejuni Species 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 241001647372 Chlamydia pneumoniae Species 0.000 description 2
- 241001647378 Chlamydia psittaci Species 0.000 description 2
- 241000193163 Clostridioides difficile Species 0.000 description 2
- 241000193403 Clostridium Species 0.000 description 2
- 241000193449 Clostridium tetani Species 0.000 description 2
- 208000000907 Condylomata Acuminata Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 241000186227 Corynebacterium diphtheriae Species 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- 241000224431 Entamoeba Species 0.000 description 2
- 241000224432 Entamoeba histolytica Species 0.000 description 2
- 241000305071 Enterobacterales Species 0.000 description 2
- 241000194033 Enterococcus Species 0.000 description 2
- 241000588722 Escherichia Species 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 241000606768 Haemophilus influenzae Species 0.000 description 2
- 241000590002 Helicobacter pylori Species 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- 241000589248 Legionella Species 0.000 description 2
- 208000007764 Legionnaires' Disease Diseases 0.000 description 2
- 241000222722 Leishmania <genus> Species 0.000 description 2
- 241000589929 Leptospira interrogans Species 0.000 description 2
- 241000186781 Listeria Species 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 208000008771 Lymphadenopathy Diseases 0.000 description 2
- 101710105759 Major outer membrane porin Proteins 0.000 description 2
- 101710164702 Major outer membrane protein Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000186367 Mycobacterium avium Species 0.000 description 2
- 241000187482 Mycobacterium avium subsp. paratuberculosis Species 0.000 description 2
- 241000186366 Mycobacterium bovis Species 0.000 description 2
- 241000187480 Mycobacterium smegmatis Species 0.000 description 2
- 241000588650 Neisseria meningitidis Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 208000030852 Parasitic disease Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102100035181 Plastin-1 Human genes 0.000 description 2
- 241000233872 Pneumocystis carinii Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 101710132594 Protein E6 Proteins 0.000 description 2
- 241000589516 Pseudomonas Species 0.000 description 2
- 241000606701 Rickettsia Species 0.000 description 2
- 241000606695 Rickettsia rickettsii Species 0.000 description 2
- 241001354013 Salmonella enterica subsp. enterica serovar Enteritidis Species 0.000 description 2
- 241000531795 Salmonella enterica subsp. enterica serovar Paratyphi A Species 0.000 description 2
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 2
- 241000242680 Schistosoma mansoni Species 0.000 description 2
- 241000607764 Shigella dysenteriae Species 0.000 description 2
- 241000607760 Shigella sonnei Species 0.000 description 2
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 2
- 241000191940 Staphylococcus Species 0.000 description 2
- 241000191963 Staphylococcus epidermidis Species 0.000 description 2
- 241000193985 Streptococcus agalactiae Species 0.000 description 2
- 241000194019 Streptococcus mutans Species 0.000 description 2
- 241000193996 Streptococcus pyogenes Species 0.000 description 2
- 108010002687 Survivin Proteins 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 241000589886 Treponema Species 0.000 description 2
- 241000589892 Treponema denticola Species 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 241000607598 Vibrio Species 0.000 description 2
- 241000607626 Vibrio cholerae Species 0.000 description 2
- 241000607447 Yersinia enterocolitica Species 0.000 description 2
- 241000607479 Yersinia pestis Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 239000013566 allergen Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 229960001212 bacterial vaccine Drugs 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229940053031 botulinum toxin Drugs 0.000 description 2
- 239000006189 buccal tablet Substances 0.000 description 2
- 229940046011 buccal tablet Drugs 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 239000000039 congener Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000000551 dentifrice Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229940032049 enterococcus faecalis Drugs 0.000 description 2
- 238000013401 experimental design Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229940085435 giardia lamblia Drugs 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 229940037467 helicobacter pylori Drugs 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 208000037798 influenza B Diseases 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 239000007937 lozenge Substances 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
- 229940124735 malaria vaccine Drugs 0.000 description 2
- 230000035800 maturation Effects 0.000 description 2
- 229940100688 oral solution Drugs 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 229940023488 pill Drugs 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 108010049148 plastin Proteins 0.000 description 2
- 229920002627 poly(phosphazenes) Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 150000004804 polysaccharides Chemical class 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 210000004988 splenocyte Anatomy 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 229940021747 therapeutic vaccine Drugs 0.000 description 2
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 2
- 230000037317 transdermal delivery Effects 0.000 description 2
- GVJHHUAWPYXKBD-QLVXXPONSA-N (S,R,R)-alpha-tocopherol Chemical compound [H][C@@](C)(CCCC(C)C)CCC[C@@]([H])(C)CCC[C@@]1(C)CCC2=C(O1)C(C)=C(C)C(O)=C2C GVJHHUAWPYXKBD-QLVXXPONSA-N 0.000 description 1
- LAOOXBLMIJHMFO-UHFFFAOYSA-N 1-[2-(diethylamino)ethylamino]-4-methylthioxanthen-9-one;hydron;chloride Chemical compound Cl.S1C2=CC=CC=C2C(=O)C2=C1C(C)=CC=C2NCCN(CC)CC LAOOXBLMIJHMFO-UHFFFAOYSA-N 0.000 description 1
- XWBADQOPXPRKBX-FMIVXFBMSA-N 1-n,1-n-diethyl-4-n-[6-methoxy-2-[(e)-2-(4-nitrophenyl)ethenyl]quinolin-4-yl]pentane-1,4-diamine Chemical compound N=1C2=CC=C(OC)C=C2C(NC(C)CCCN(CC)CC)=CC=1\C=C\C1=CC=C([N+]([O-])=O)C=C1 XWBADQOPXPRKBX-FMIVXFBMSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- SEBPXHSZHLFWRL-UHFFFAOYSA-N 3,4-dihydro-2,2,5,7,8-pentamethyl-2h-1-benzopyran-6-ol Chemical compound O1C(C)(C)CCC2=C1C(C)=C(C)C(O)=C2C SEBPXHSZHLFWRL-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 241000238876 Acari Species 0.000 description 1
- 101000768957 Acholeplasma phage L2 Uncharacterized 37.2 kDa protein Proteins 0.000 description 1
- 101000823746 Acidianus ambivalens Uncharacterized 17.7 kDa protein in bps2 3'region Proteins 0.000 description 1
- 101000916369 Acidianus ambivalens Uncharacterized protein in sor 5'region Proteins 0.000 description 1
- 101000769342 Acinetobacter guillouiae Uncharacterized protein in rpoN-murA intergenic region Proteins 0.000 description 1
- 101000823696 Actinobacillus pleuropneumoniae Uncharacterized glycosyltransferase in aroQ 3'region Proteins 0.000 description 1
- 101000786513 Agrobacterium tumefaciens (strain 15955) Uncharacterized protein outside the virF region Proteins 0.000 description 1
- 101000618005 Alkalihalobacillus pseudofirmus (strain ATCC BAA-2126 / JCM 17055 / OF4) Uncharacterized protein BpOF4_00885 Proteins 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
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010001935 American trypanosomiasis Diseases 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 102100020724 Ankyrin repeat, SAM and basic leucine zipper domain-containing protein 1 Human genes 0.000 description 1
- 101100162403 Arabidopsis thaliana ALEU gene Proteins 0.000 description 1
- 240000005528 Arctium lappa Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 101000967489 Azorhizobium caulinodans (strain ATCC 43989 / DSM 5975 / JCM 20966 / LMG 6465 / NBRC 14845 / NCIMB 13405 / ORS 571) Uncharacterized protein AZC_3924 Proteins 0.000 description 1
- 102100035526 B melanoma antigen 1 Human genes 0.000 description 1
- 241000193755 Bacillus cereus Species 0.000 description 1
- 101000823761 Bacillus licheniformis Uncharacterized 9.4 kDa protein in flaL 3'region Proteins 0.000 description 1
- 101000819719 Bacillus methanolicus Uncharacterized N-acetyltransferase in lysA 3'region Proteins 0.000 description 1
- 101000789586 Bacillus subtilis (strain 168) UPF0702 transmembrane protein YkjA Proteins 0.000 description 1
- 101000792624 Bacillus subtilis (strain 168) Uncharacterized protein YbxH Proteins 0.000 description 1
- 101000790792 Bacillus subtilis (strain 168) Uncharacterized protein YckC Proteins 0.000 description 1
- 101000819705 Bacillus subtilis (strain 168) Uncharacterized protein YlxR Proteins 0.000 description 1
- 101000948218 Bacillus subtilis (strain 168) Uncharacterized protein YtxJ Proteins 0.000 description 1
- 101000718627 Bacillus thuringiensis subsp. kurstaki Putative RNA polymerase sigma-G factor Proteins 0.000 description 1
- 241001536481 Banzi virus Species 0.000 description 1
- 101710125089 Bindin Proteins 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 101000641200 Bombyx mori densovirus Putative non-structural protein Proteins 0.000 description 1
- 241000589968 Borrelia Species 0.000 description 1
- 241000589978 Borrelia hermsii Species 0.000 description 1
- 241000495356 Borrelia microti Species 0.000 description 1
- 241001148604 Borreliella afzelii Species 0.000 description 1
- 241000142472 Borreliella andersonii Species 0.000 description 1
- 241001148605 Borreliella garinii Species 0.000 description 1
- 241000589893 Brachyspira hyodysenteriae Species 0.000 description 1
- 101100328096 Caenorhabditis elegans clec-88 gene Proteins 0.000 description 1
- 241000589877 Campylobacter coli Species 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102100035882 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 241000606153 Chlamydia trachomatis Species 0.000 description 1
- 241000498849 Chlamydiales Species 0.000 description 1
- 108010049048 Cholera Toxin Proteins 0.000 description 1
- 102000009016 Cholera Toxin Human genes 0.000 description 1
- 101710164918 Choline-binding protein Proteins 0.000 description 1
- 241000251730 Chondrichthyes Species 0.000 description 1
- 101000947633 Claviceps purpurea Uncharacterized 13.8 kDa protein Proteins 0.000 description 1
- 241000193155 Clostridium botulinum Species 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 241000186216 Corynebacterium Species 0.000 description 1
- 108091029430 CpG site Proteins 0.000 description 1
- 241000221204 Cryptococcus neoformans Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 1
- 101100481408 Danio rerio tie2 gene Proteins 0.000 description 1
- 102100031262 Deleted in malignant brain tumors 1 protein Human genes 0.000 description 1
- 241000725619 Dengue virus Species 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 241000605314 Ehrlichia Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241001133638 Entamoeba equi Species 0.000 description 1
- 101000948901 Enterobacteria phage T4 Uncharacterized 16.0 kDa protein in segB-ipI intergenic region Proteins 0.000 description 1
- 241000194031 Enterococcus faecium Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101000805958 Equine herpesvirus 4 (strain 1942) Virion protein US10 homolog Proteins 0.000 description 1
- 101000790442 Escherichia coli Insertion element IS2 uncharacterized 11.1 kDa protein Proteins 0.000 description 1
- 101000788354 Escherichia phage P2 Uncharacterized 8.2 kDa protein in gpA 5'region Proteins 0.000 description 1
- 241000201295 Euphrasia Species 0.000 description 1
- 101710154643 Filamentous hemagglutinin Proteins 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- 101000770304 Frankia alni UPF0460 protein in nifX-nifW intergenic region Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 101000797344 Geobacillus stearothermophilus Putative tRNA (cytidine(34)-2'-O)-methyltransferase Proteins 0.000 description 1
- 101000748410 Geobacillus stearothermophilus Uncharacterized protein in fumA 3'region Proteins 0.000 description 1
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 1
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 1
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- 241001316290 Gypsophila Species 0.000 description 1
- 101000772675 Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) UPF0438 protein HI_0847 Proteins 0.000 description 1
- 101000631019 Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) Uncharacterized protein HI_0350 Proteins 0.000 description 1
- 101100406392 Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) omp26 gene Proteins 0.000 description 1
- 101000768938 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 8.9 kDa protein in int-C1 intergenic region Proteins 0.000 description 1
- 235000014683 Hansenula anomala Nutrition 0.000 description 1
- 241000589989 Helicobacter Species 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 241000724675 Hepatitis E virus Species 0.000 description 1
- 241000709721 Hepatovirus A Species 0.000 description 1
- 101000785414 Homo sapiens Ankyrin repeat, SAM and basic leucine zipper domain-containing protein 1 Proteins 0.000 description 1
- 101000874316 Homo sapiens B melanoma antigen 1 Proteins 0.000 description 1
- 101000844721 Homo sapiens Deleted in malignant brain tumors 1 protein Proteins 0.000 description 1
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 1
- 101001005720 Homo sapiens Melanoma-associated antigen 4 Proteins 0.000 description 1
- 101000628547 Homo sapiens Metalloreductase STEAP1 Proteins 0.000 description 1
- 101000874141 Homo sapiens Probable ATP-dependent RNA helicase DDX43 Proteins 0.000 description 1
- 101001136592 Homo sapiens Prostate stem cell antigen Proteins 0.000 description 1
- 101001130441 Homo sapiens Ras-related protein Rap-2a Proteins 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 101100540311 Human papillomavirus type 16 E6 gene Proteins 0.000 description 1
- 101000767631 Human papillomavirus type 16 Protein E7 Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 241000710842 Japanese encephalitis virus Species 0.000 description 1
- 101000782488 Junonia coenia densovirus (isolate pBRJ/1990) Putative non-structural protein NS2 Proteins 0.000 description 1
- 101000811523 Klebsiella pneumoniae Uncharacterized 55.8 kDa protein in cps region Proteins 0.000 description 1
- 101000818409 Lactococcus lactis subsp. lactis Uncharacterized HTH-type transcriptional regulator in lacX 3'region Proteins 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
- 102100032241 Lactotransferrin Human genes 0.000 description 1
- 241000589242 Legionella pneumophila Species 0.000 description 1
- 101000878851 Leptolyngbya boryana Putative Fe(2+) transport protein A Proteins 0.000 description 1
- 241000589902 Leptospira Species 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 241000186779 Listeria monocytogenes Species 0.000 description 1
- 208000016604 Lyme disease Diseases 0.000 description 1
- 241000712079 Measles morbillivirus Species 0.000 description 1
- 102100025077 Melanoma-associated antigen 4 Human genes 0.000 description 1
- 102100026712 Metalloreductase STEAP1 Human genes 0.000 description 1
- 101000758828 Methanosarcina barkeri (strain Fusaro / DSM 804) Uncharacterized protein Mbar_A1602 Proteins 0.000 description 1
- 101001122401 Middle East respiratory syndrome-related coronavirus (isolate United Kingdom/H123990006/2012) Non-structural protein ORF3 Proteins 0.000 description 1
- 241001092142 Molina Species 0.000 description 1
- 241000588621 Moraxella Species 0.000 description 1
- 241000711386 Mumps virus Species 0.000 description 1
- 101100369076 Mus musculus Tdgf1 gene Proteins 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 241000186362 Mycobacterium leprae Species 0.000 description 1
- 101001055788 Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155) Pentapeptide repeat protein MfpA Proteins 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- HCUVEUVIUAJXRB-UHFFFAOYSA-N OC1=C(C=C(CNC(CCCC=2SC=CC=2)=O)C=C1)OC Chemical compound OC1=C(C=C(CNC(CCCC=2SC=CC=2)=O)C=C1)OC HCUVEUVIUAJXRB-UHFFFAOYSA-N 0.000 description 1
- FOVFMAQZMMHBOI-UHFFFAOYSA-N OP(O)(S)=S.OP(O)(S)=S Chemical group OP(O)(S)=S.OP(O)(S)=S FOVFMAQZMMHBOI-UHFFFAOYSA-N 0.000 description 1
- 101000740670 Orgyia pseudotsugata multicapsid polyhedrosis virus Protein C42 Proteins 0.000 description 1
- 101710116435 Outer membrane protein Proteins 0.000 description 1
- 229910018828 PO3H2 Inorganic materials 0.000 description 1
- 102000036673 PRAME Human genes 0.000 description 1
- 108060006580 PRAME Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 108010081690 Pertussis Toxin Proteins 0.000 description 1
- 101000769182 Photorhabdus luminescens Uncharacterized protein in pnp 3'region Proteins 0.000 description 1
- 101710099976 Photosystem I P700 chlorophyll a apoprotein A1 Proteins 0.000 description 1
- 101000983333 Plasmodium falciparum (isolate NF54) 25 kDa ookinete surface antigen Proteins 0.000 description 1
- 206010035500 Plasmodium falciparum infection Diseases 0.000 description 1
- 241000233870 Pneumocystis Species 0.000 description 1
- 101710183389 Pneumolysin Proteins 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 206010036631 Presenile dementia Diseases 0.000 description 1
- 102100035724 Probable ATP-dependent RNA helicase DDX43 Human genes 0.000 description 1
- 102100036735 Prostate stem cell antigen Human genes 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 101710132595 Protein E7 Proteins 0.000 description 1
- 101000961392 Pseudescherichia vulneris Uncharacterized 29.9 kDa protein in crtE 3'region Proteins 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 101000731030 Pseudomonas oleovorans Poly(3-hydroxyalkanoate) polymerase 2 Proteins 0.000 description 1
- 101001065485 Pseudomonas putida Probable fatty acid methyltransferase Proteins 0.000 description 1
- 241001454523 Quillaja saponaria Species 0.000 description 1
- 235000009001 Quillaja saponaria Nutrition 0.000 description 1
- 102100022851 Rab5 GDP/GTP exchange factor Human genes 0.000 description 1
- 102100031420 Ras-related protein Rap-2a Human genes 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 101710203837 Replication-associated protein Proteins 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- 101000711023 Rhizobium leguminosarum bv. trifolii Uncharacterized protein in tfuA 3'region Proteins 0.000 description 1
- 101000948156 Rhodococcus erythropolis Uncharacterized 47.3 kDa protein in thcA 5'region Proteins 0.000 description 1
- 101000917565 Rhodococcus fascians Uncharacterized 33.6 kDa protein in fasciation locus Proteins 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- 101000790284 Saimiriine herpesvirus 2 (strain 488) Uncharacterized 9.5 kDa protein in DHFR 3'region Proteins 0.000 description 1
- 241001138501 Salmonella enterica Species 0.000 description 1
- 241000607149 Salmonella sp. Species 0.000 description 1
- 241000217239 Schizotrypanum Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 108010079723 Shiga Toxin Proteins 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 241000607762 Shigella flexneri Species 0.000 description 1
- 101710084578 Short neurotoxin 1 Proteins 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 101000936719 Streptococcus gordonii Accessory Sec system protein Asp3 Proteins 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 108010011834 Streptolysins Proteins 0.000 description 1
- 101000788499 Streptomyces coelicolor Uncharacterized oxidoreductase in mprA 5'region Proteins 0.000 description 1
- 101001102841 Streptomyces griseus Purine nucleoside phosphorylase ORF3 Proteins 0.000 description 1
- 101000708557 Streptomyces lincolnensis Uncharacterized 17.2 kDa protein in melC2-rnhH intergenic region Proteins 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 101710172711 Structural protein Proteins 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
- 229930006000 Sucrose Natural products 0.000 description 1
- 101710137302 Surface antigen S Proteins 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 108010055044 Tetanus Toxin Proteins 0.000 description 1
- 101000649826 Thermotoga neapolitana Putative anti-sigma factor antagonist TM1081 homolog Proteins 0.000 description 1
- 102000057032 Tissue Kallikreins Human genes 0.000 description 1
- 108700022175 Tissue Kallikreins Proteins 0.000 description 1
- 101710182223 Toxin B Proteins 0.000 description 1
- 101710182532 Toxin a Proteins 0.000 description 1
- 241000223997 Toxoplasma gondii Species 0.000 description 1
- 101710134694 Transcriptional regulator ICP22 homolog Proteins 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 241000589884 Treponema pallidum Species 0.000 description 1
- 241000224526 Trichomonas Species 0.000 description 1
- 241000224527 Trichomonas vaginalis Species 0.000 description 1
- 241000223104 Trypanosoma Species 0.000 description 1
- 241000223109 Trypanosoma cruzi Species 0.000 description 1
- 206010064390 Tumour invasion Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 101000827562 Vibrio alginolyticus Uncharacterized protein in proC 3'region Proteins 0.000 description 1
- 101000778915 Vibrio parahaemolyticus serotype O3:K6 (strain RIMD 2210633) Uncharacterized membrane protein VP2115 Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 206010047799 Vulvovaginitis trichomonal Diseases 0.000 description 1
- 241000710772 Yellow fever virus Species 0.000 description 1
- 241000607477 Yersinia pseudotuberculosis Species 0.000 description 1
- 241000606834 [Haemophilus] ducreyi Species 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- HESIBZMZTMHXQS-UHFFFAOYSA-M alumanyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[AlH2] HESIBZMZTMHXQS-UHFFFAOYSA-M 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- 101150078331 ama-1 gene Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000003716 antitrichomonal agent Substances 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 229940065181 bacillus anthracis Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 101150093710 clec-87 gene Proteins 0.000 description 1
- 231100001102 clostridial toxin Toxicity 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000009133 cooperative interaction Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 101150014604 cpg-3 gene Proteins 0.000 description 1
- 101150024925 cpg-7 gene Proteins 0.000 description 1
- 101150087279 cpg-8 gene Proteins 0.000 description 1
- 101150030550 cpg-9 gene Proteins 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- FBHSPRKOSMHSIF-GRMWVWQJSA-N deflazacort Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)=N[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O FBHSPRKOSMHSIF-GRMWVWQJSA-N 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- NAGJZTKCGNOGPW-UHFFFAOYSA-K dioxido-sulfanylidene-sulfido-$l^{5}-phosphane Chemical compound [O-]P([O-])([S-])=S NAGJZTKCGNOGPW-UHFFFAOYSA-K 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229940007078 entamoeba histolytica Drugs 0.000 description 1
- 230000000369 enteropathogenic effect Effects 0.000 description 1
- 230000000688 enterotoxigenic effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- ZINJLDJMHCUBIP-UHFFFAOYSA-N ethametsulfuron-methyl Chemical compound CCOC1=NC(NC)=NC(NC(=O)NS(=O)(=O)C=2C(=CC=CC=2)C(=O)OC)=N1 ZINJLDJMHCUBIP-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000021472 generally recognized as safe Nutrition 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 1
- 210000000224 granular leucocyte Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 244000052637 human pathogen Species 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000002130 immunocastration Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 108700032552 influenza virus INS1 Proteins 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000003866 lung sarcoma Diseases 0.000 description 1
- 101710130522 mRNA export factor Proteins 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000004531 microgranule Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- RNTRDTWDTOZSEV-UHFFFAOYSA-N norphytene Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)=C RNTRDTWDTOZSEV-UHFFFAOYSA-N 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 239000000668 oral spray Substances 0.000 description 1
- 229940041678 oral spray Drugs 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 108010021711 pertactin Proteins 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 201000000317 pneumocystosis Diseases 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 229950000845 politef Drugs 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 108700042226 ras Genes Proteins 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 229940075118 rickettsia rickettsii Drugs 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000001843 schistosomicidal effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 229940007046 shigella dysenteriae Drugs 0.000 description 1
- 229940115939 shigella sonnei Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000002344 surface layer Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940118376 tetanus toxin Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 230000001810 trypsinlike Effects 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 239000012646 vaccine adjuvant Substances 0.000 description 1
- 229940124931 vaccine adjuvant Drugs 0.000 description 1
- 230000002477 vacuolizing effect Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000010497 wheat germ oil Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
- 229940098232 yersinia enterocolitica Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Communicable Diseases (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
本发明涉及供疫苗用的新型佐剂组合物。特别是,本发明的佐剂组合物包含免疫刺激性寡核苷酸和母育酚的组合。本发明也提供一种包含本发明佐剂组合物和至少一种抗原的疫苗。还提供多种生产本发明佐剂组合物和疫苗的方法及其作为药物的应用。另外,本发明提供通过胃肠外或粘膜给予本发明的疫苗来治疗易感或患有疾病的个体的方法。
Description
本发明涉及供疫苗用的新型佐剂组合物。具体地说,本发明的佐剂组合物包含免疫刺激性寡核苷酸和母育酚组合。本发明也提供包含本发明佐剂组合物和至少一种抗原的疫苗。还提供生产本发明佐剂组合物和疫苗的方法以及它们作为药物的应用。另外,本发明提供通过胃肠外或粘膜给予本发明的疫苗治疗易感或患有疾病的个体的方法。
已知含有未甲基化CpG二核苷酸(“CpG”)的免疫刺激性寡核苷酸当通过系统和粘膜两种途径给予时是佐剂(WO96/02555,EP468520,Davis等,J.Immunol,1998,160(2):870-876:McCluskie和Davis,J.Immunol,1998,161(9):4463-6)。CpG是DNA中存在的胞嘧啶-鸟苷二核苷酸基序的缩写。从历史的角度来讲,观察到BCG的DNA部分能够发挥抗肿瘤效应。在进一步的研究中,表明衍生于BCG基因序列的合成寡核苷酸能够诱发免疫刺激效应(在体外以及在体内)。这些研究的作者推断,包括一个中心CG基序的某些回文序列带有这种活性。所述CG基序在免疫刺激中的中心作用后来在出版物Krieg,Nature374,第546页1995中得以阐明。详细的分析已经表明,CG基序必须处于某种序列环境中,并且这样的序列在细菌DNA中是常见的,但在脊椎动物DNA中是罕见的。所述免疫刺激性序列通常是:嘌呤、嘌呤、C、G、嘧啶、嘧啶;其中二核苷酸CG基序未被甲基化,但已知其它未甲基化CpG序列有免疫刺激性,并且可以用于本发明。
在所述六核苷酸的某些组合中,存在回文序列。或者作为一种基序的重复或者作为不同基序的组合的这些基序中的几种,可以存在于同一寡核苷酸中。含有这些免疫刺激性序列中一种或多种的寡核苷酸的存在,可以激活各种免疫亚群,包括自然杀伤细胞(所述细胞产生干扰素γ并且具有溶细胞活性)和巨噬细胞(Wooldrige等Vol89(no.8),1977)。虽然现在已经表明,不具有这种共有序列的其它含未甲基化CpG的序列是免疫调节性的。
CpG当配制到疫苗中时,一般在自由溶液中与游离抗原一起给予(WO 96/02555;McCluskie和Davis,参见上文),或者与抗原共价缀合(PCT公布号WO 98/16247),或者与诸如氢氧化铝的载体一起配制((肝炎表面抗原)Davis等,参见上文;Brazolot-Millan等,Proc.Natl.Acad.Sci.,USA,1998,95(26),15553-8)。其它含CpG制剂包括在WO 99/61056和WO 00/09159中描述的那些制剂。
包含CpG的母育酚(维生素E)和乳化佐剂在EP 0 382 271 B1和US5667784中有描述。
多年来已经了解油乳化佐剂,包括对弗氏完全和不完全矿物油乳化佐剂的研究。从那时起已经进行了许多研究,以设计这些有效、但有反应原性的佐剂制剂的稳定且很好耐受的替代物。在WO 95/17210中描述了包含母育酚的油乳液。
本发明基于这样一个惊人的发现:免疫刺激性寡核苷酸和母育酚的组合构成了极其有效的佐剂制剂。这些佐剂制剂的成分在诱发抗原特异性抗体方面更好地协同相互作用,有效地诱发通常与Th1型免疫系统相关的免疫应答。因此,所述佐剂组合不仅适合于疾病的免疫预防,而且出乎意料地适合于诸如持续性病毒、细菌或寄生虫感染的疾病以及诸如癌症的慢性疾病的免疫治疗。
所述免疫刺激性序列通常是:嘌呤、嘌呤、C、G、嘧啶、嘧啶;其中二核苷酸CG基序未被甲基化。供本发明佐剂或疫苗使用的优选寡核苷酸最好包含两个或两个以上被至少3个、更优选至少6个或6个以上核苷酸隔开的二核苷酸CpG基序。本发明的寡核苷酸通常是脱氧核苷酸。在一个优选实施方案中,所述寡核苷酸中的核苷酸间键合是二硫代磷酸酯(phosphorodithioate)键,或者更优选是硫代磷酸酯键,虽然磷酸二酯键和其它核苷酸间键合在本发明的范围内,包括具有混合核苷酸间键合的寡核苷酸。产生硫代磷酸酯寡核苷酸或二硫代磷酸酯的方法在US5,666,153、US5,278,302和WO95/26204中有描述。优选寡核苷酸的实例具有以下序列。所述序列优选含有硫代磷酸酯修饰的核苷酸间键合。
OLIGO 1(SEQ ID NO:1):TCC ATG ACG TTC CTG ACG TT(CpG 1826)
OLIGO 2(SEQ ID NO:2):TCT CCC AGC GTG CGC CAT(CpG 1758)
OLIGO 3(SEQ ID NO:3):ACC GAT GAC GTC GCC GGT GAC GGC ACC ACG
OLIGO 4(SEQ ID NO:4):TCG TCG TTT TGT CGT TTT GTC GTT(CpG 2006)
OLIGO 5(SEQ ID NO:5);TCC ATG ACG TTC CTG ATG CT(CpG 1668)
可供选择的CpG寡核苷酸可以包含其中具有不重要的缺失或添加的上述优选序列。本发明中使用的CpG寡核苷酸可以用本领域已知的任何方法合成(例如EP 468520)。利用自动合成仪,可以方便地合成这类寡核苷酸。
本发明中使用的寡核苷酸通常是脱氧核苷酸。在一个优选实施方案中,所述寡核苷酸中的核苷酸间键合是二硫代磷酸酯键,或者更优选是硫代磷酸酯键,虽然磷酸二酯在本发明的范围内。考虑了包含不同核苷酸间键合的寡核苷酸,例如混合的硫代磷酸酯磷酸二酯。可以使用稳定所述寡核苷酸的其它核苷酸间键合。
可以有利地用于本发明佐剂组合中的母育酚在EP 0 382 271 B1中有描述。其中公开的母育酚用以下通式描述:
其中R可以是H或者一个或多个选自以下的相同或不同的取代基:烷基、烷氧基、酰氧基、羟基、硫酸酯基和磷酸酯基;R1和R3相互独立地为H或烷基;R2为H或烷基,并且在每个单位中可以不同;虚线表示在一个单位中额外的碳-碳键存在或者不存在;且n=1-10的数值;R、R1、R2和R3中的烷基可以具体选自具有1-4个碳原子的直链或支链碳链,例如甲基、乙基、丁基或异丁基。
在EP 0 382 271 B1中描述的进一步限定的优选亚组通过引用结合到本文中。一种特别优选的母育酚是D,L,α-生育酚(CAS No.10191-41-0;化学名称:(2RS,4’RS,8’RS)-2,5,7,8-四甲基-2-(4’,8’,12’-三甲基-十三烷基)-6-苯并二氢吡喃醇(chromanol)),它以ROCHETM市售。
母育酚优选为油乳液形式,更优选为水包油(油/水)型乳液。母育酚可以如EP 0 382 271 B1中所述方法配制,其中母育酚可以是母育酚小滴的分散体,任选包含乳化剂,小滴的直径优选小于1微米。另一方面,母育酚可以与其它油联合使用,以构成油乳液的油相。以下描述可以与母育酚联用的油乳液的实例。
已经提出水包油型乳液佐剂本身可用作佐剂组合物(EP 0 399843B),水包油型乳液和其它活性剂的组合也已经描述为供疫苗用的佐剂(WO 95/17210;WO 98/56414;WO 99/12565;WO 99/11241)。其它的油乳化佐剂已有描述,例如油包水型乳液(US5,422,109;EP 0 480 982B2)和水包油包水(W/O/W)型乳液(US 5,424,067;EP 0 480 981 B)。所有这些都形成优选油乳液体系以掺入母育酚,并且最终与CpG混合,构成本发明的佐剂。
可供与母育酚联合的油的选择,可以是天然或合成的,并且可以是无机的或是有机的。无机和有机油的实例对于本领域技术人员而言将是显而易见的。
所述乳液体系的油相优选包含可代谢油。术语可代谢油的含义是本领域众所周知的。可代谢可以定义为“能够通过代谢作用被转化”(Dorland’s Illustrated Medical Dictionary,W.B.Sanders Company,25thedition(1974))。所述油可以是任何植物油、鱼油、动物油或合成油,对于受体而言是无毒的,并且能够通过代谢作用被转化。坚果(例如花生油)、种子和谷粒是常见的植物油来源。合成油也是本发明的部分,可以包括市售的油例如NEOBEETM以及其它油。角鲨烯(2,6,10,15,19,23-六甲基-2,6,10,14,18,22-二十四烷六烯)是一种在鲨鱼鱼肝油中大量存在的不饱和油,而在橄榄油、麦胚油、米糠油和酵母中以较低量存在,并且是供本发明使用的特别优选的油。鉴于角鲨烯是胆固醇生物合成的中间体(Merck index,10th Edition,entry no.8619)的这一事实,角鲨烯是一种可代谢油。
可供与CpG联合构成本发明佐剂的特别优选的油乳液是包含母育酚和乳化剂的水包油型乳液,特别是角鲨烯/水型乳液。
优选乳液体系的实例在WO 95/17210和WO 99/11241中有描述,所述文献公开了基于角鲨烯、α-生育酚和TWEEN 80、任选与免疫刺激剂QS21和/或3D-MPL一起配制的乳化佐剂。
在稳定的水包油型乳液中存在的油珠大小优选低于1微米,可以大致在在30-600nm范围内,优选直径大致在30-500nm左右,最优选直径大致为150-500nm,特别是通过光子相关光谱学测定直径约为150nm。在这一方面,按数目计80%的油珠应该在所述优选范围内,更优选按数目计超过90%、最优选超过95%的油珠在所限定的大小范围内。在本发明油乳液中存在的所述成分的量通常为2-10%范围内的油,例如角鲨烯;并且当存在时,为2-10%α生育酚;和0.3-3%表面活性剂,例如聚氧乙烯脱水山梨醇一油酸酯。油(优选角鲨烯):母育酚(优选α-生育酚)之比优选等于或小于1,因为这一比率提供了更为稳定的乳液。也可以存在大约1%水平的乳化剂,例如Tween80或Span85。在某些情况下,可能有利的是本发明的疫苗还含有稳定剂。
产生水包油型乳液的方法是本领域技术人员众所周知的。通常,所述方法包括将含母育酚的油相与表面活性剂例如PBS/TWEEN80TM溶液混合,然后用均化器均化,包括使所述混合物两次通过注射器针头的方法适合于将小体积液体均化,这对于本领域技术人员而言是显而易见的。同样,本领域技术人员改进在微流化床中的乳化法(M110S微流控机(microfluidics machine),最多50道(pass),在6巴最大输入压(输出压约850巴)下2分钟),来产生更小或更大体积的乳液。这种改进可以通过常规实验来完成,包括测量所得的乳液,直至获得具有所需直径油珠的制剂。
在本发明的一个替代实施方案中,所述母育酚和CpG组合可以另外包括其它免疫刺激剂,例如LPS或其衍生物或者皂苷。其它免疫刺激剂的实例在以下文献中有描述:“Vaccine Design-The Subunit andAdjuvant Approach”1995,Pharmaceutical Biotechnology,Volume 6,Powell,M.F.和Newman,M.J.编著,Plenum Press,New York和London,ISBN0-306-44867-X。
因此,本发明的CpG/母育酚佐剂组合可以有利地包括至少一种肠细菌脂多糖衍生佐剂。长期以来已知肠细菌脂多糖(LPS)是免疫系统的一种有效的刺激物,虽然其在佐剂中的应用由于其毒性效应而一直被缩减。Ribi等(1986,Immunology and Immunopharmacology of bacterialendotoxins,Plenum Publ.Corp.,NY,第407-419页)已经描述了通过从还原末端葡糖胺除去核心糖基团和除去磷酸酯而产生的LPS的一种无毒衍生物-单磷酰脂质A(MPL),MPL具有以下结构:
一种进一步解毒形式的MPL通过从二糖主链的3位除去酰基链而产生,称为3-O-去酰化单磷酰脂质A(3D-MPL)。它可以用GB2122204B中所述的方法来纯化和制备,该文献也公开了二磷脂脂质A及其3-O-去酰化变体的制备。一种优选形式的3D-MPL为直径小于0.2μm的小粒径的乳液形式,其生产方法公开于WO94/21292中。在WO 9843670A2中描述了包含单磷酰脂质A和表面活性剂的水性制剂。
待配制到本发明的佐剂组合中的细菌脂多糖衍生佐剂可以从细菌来源纯化和加工,或者它们可以是合成的。例如,在Ribi等1986(参见上文)中描述了纯化单磷酰脂质A,而在GB 2220211和US 4912094中描述了来源于沙门氏菌(Salmonella sp.)的3-O-去酰化单磷酰或二磷脂脂质A。其它纯化的和合成的脂多糖已有描述(WO 98/01139;US6,005,099和EP 0 729 473 B1;Hilgers等,1986.Int.Arch.Allergy.Immunol.,79(4):392-6;Hilgers等,1987,Immunology,60(1):141-6;和EP 0 549 074 B1)。特别优选的细菌脂多糖佐剂是US 6,005,099和EP 0729 473 B1中描述的3D-MPL和β(1-6)葡糖胺二糖。
因此,可以用于本发明的LPS衍生物是在结构上与LPS或MPL或3D-MPL相似的那些免疫刺激剂。在本发明的另一方面,所述LPS衍生物可以是酰化单糖,它是MPL上述结构的亚部分。
一种优选的二糖佐剂是具有以下结构式的纯化或合成脂质A:
其中R2可以是H或PO3H2;R3可以是具有下式的酰基链或β-羟基肉豆蔻酰基或3-酰氧基酰基残基:
并且其中X和Y具有从0至约20的数值。
所述佐剂组合物也可以进一步包括皂苷。在EP 0 761 231B中描述了3D-MPL和来源于皂树Quillaja Saponaria molina树皮的皂苷佐剂的组合。WO 95/17210公开了一种基于与免疫刺激剂QS21一起配制、任选与3D-MPL一起配制的角鲨烯、α-生育酚和聚氧乙烯脱水山梨醇一油酸酯(TWEEN80)的佐剂乳液体系。CpG和WO 95/17210中所上述佐剂系统的组合,构成了本发明的一个优选方面。WO 96/33739和WO98/15287描述了包含皂苷和颗粒性载体结构、任选包含3D-MPL和/或水包油型乳液的佐剂制剂;所述制剂当与母育酚和CpG联合时,构成了本发明的优选佐剂。
已知皂苷为供系统给药用的疫苗中的佐剂。在本领域中已经广泛地研究了各种皂苷的佐剂和溶血活性(Lacaille-Dubois和Wagner,参见上文)。例如,在US5,057,540和“Saponins as vaccine adjuvants”,Kensil,C.R.,Crit Rev Ther Drug Carrier Syst,1996,12(1-2):1-55;和EP 0 362279 B1中描述了Quil A(来源于南美皂树Quillaja Saponaria Molina的树皮)及其级分。
包含Quil A级分的称为免疫刺激复合物(Immune StimulatingComplexes)(ISCOMS)的颗粒性结构具有溶血性,已经用于疫苗的生产(Morein,B.,EP 0 109 942 B1)。据报道这些结构具有佐剂活性(EP 0 109942 B1;WO 96/11711)。
溶血性皂苷QS21和QS17(Quil A的HPLC纯化级分)已被描述为有效的系统性佐剂,其生产方法公开于美国专利第5,057,540号和EP 0362 279 B1中。在这些参考文献中也描述了作为系统疫苗用有效佐剂的QS7(Quil-A的一种非溶血性级分)的应用。QS21的应用在Kensil等(1991.J.Immunologyvol 146,431-437)中有进一步的描述。QS21和聚山梨醇酯或环糊精的组合也是已知的(WO99/10008)。包含Quil A级分诸如QS21和QS7的颗粒性佐剂系统描述于WO 96/33739和WO96/11711中。已经用于系统疫苗接种研究的其它皂苷包括来源于其它植物种例如丝石竹属(Gypsophila)和肥皂草属(Saponaria)的那些皂苷(Bomford等,Vaccine,10(9):572-577,1992)。
本发明的佐剂组合可以任选地还包含另外一种载体,使得CpG可以与颗粒性载体实体结合,以增强所述组合的佐剂性(adjuvanticity)。因此,本发明佐剂组合中使用的CpG可以处于自由溶液中,或者可以与颗粒性载体例如无机盐(例如但不限于铝盐或钙盐)、脂质体、ISCOM、聚合物(例如但不限于聚乳酸、聚羟基乙酸、聚磷腈(polyphosphazine)、聚氨基酸、藻酸盐、脱乙酰壳多糖)或微粒络合。所述载体优选为阳离子型的。所述CpG也可以以这样一种方式配制,使得它与母育酚或含母育酚的油乳液结合。这可以通过以使乳液成为阳离子型的方式配制所述乳液而达到。或者,可以将CpG与同乳液油相相关的脂质缀合(WO 00/15256)。
本发明的疫苗还包含一种抗原,所述抗原可以与CpG-载体复合物例如CpG/母育酚/油珠或者CpG/金属盐复合物结合或不结合。所述抗原可以是游离悬浮液,或者与一种单独的载体结合。在本发明的一个优选方面,所述抗原与CpG/载体复合物结合。
按照本发明的一种优选佐剂组合由一种或多种在两个相邻CG基序之间含有至少3个、优选至少6个核苷酸的CpG寡核苷酸、以及母育酚例如D,Lα-生育酚组成。这种组合优选还包含一种LPS的佐剂活性衍生物和一种选自金属盐或水包油型乳液的颗粒性载体。最优选所述佐剂组合包含CpG 2006(SEQ ID NO:4)或CpG 1758(SEQ ID NO:2)或CpG 1826(SEQ ID NO:1)和角鲨烯/D,Lα-生育酚乳液;这种优选佐剂还任选包含3-O-去酰化单磷酰或二磷酰脂质A和/或QS21或这两者。一种优选的佐剂系统包含QS21、3D-MPL和母育酚的组合以及CpG。
本发明的佐剂组合可以用作系统佐剂,或者用作粘膜佐剂。给患者接种疫苗已经通过多种给药途径进行,其中最常用的给药途径是将疫苗给予个体的深部肌肉中(肌内注射)。其它熟知的疫苗接种途径包括皮下、鼻内、经口、直肠和腹膜内和皮内给药。虽然本发明的疫苗可以通过任一种途径给予,但将所述疫苗给予皮肤中构成了本发明的一个优选实施方案。
人类皮肤构成覆盖表皮的外部“角性”外皮,称为角质层。在这一表皮之下,是称为真皮的皮层,真皮又覆盖皮下组织。研究人员已经指出,将疫苗注射到皮肤中、特别是注射到真皮中,刺激免疫应答,这也可能与许多其它优点相关。用本文所述疫苗的皮内疫苗接种构成了本发明的一个优选特征。
皮内注射的常规技术-“芒图法(mantoux procedure)”包括下述步骤:清洁皮肤,然后用一只手绷紧皮肤,将小号针头(26-31号)的斜面朝上,以10-15°的角度插入针头。一旦针头的斜面插入,则压低针头的针筒并且进一步插入针头,同时提供轻压,在皮肤下将针头挑起。然后非常缓慢地注射液体,从而在皮肤表面形成水泡或肿块,然后缓慢抽出针头。
最近,描述了具体设计用以将液体药剂给予皮肤内或穿过皮肤给予的装置,例如在WO 99/34850和EP 1092444中描述的装置,以及例如在以下文献中描述的喷射注射装置:WO 01/13977;US5,480,381、US5,599,302、US5,334,144、US5,993,412、US5,649,912、US5,569,189、US5,704,911、US5,383,851、US5,893,397、US5,466,220、US5,339,163、US5,312,335、US5,503,627、US5,064,413、US5,520,639、US4,596,556、US4,790,824、US4,941,880、US4,940,460、WO 97/37705和WO 97/13537。皮内给予疫苗制剂的替代方法可以包括常规注射器和针头、或者设计用于射击给予(ballistic delivery)固体疫苗(WO 99/27961)或透皮贴剂(WO 97/48440;WO 98/28037)的装置;或者施用于皮肤表面(透皮递药WO 98/20734;WO 98/28037)。
当将本发明的疫苗给予皮肤、或更具体地讲给予真皮内时,所述疫苗为小体积液体,特别是约0.05-0.2ml体积的液体。
当用于本文时,术语“真皮内给药”是指将疫苗给予皮肤内的真皮区。然而,疫苗不一定仅仅给予真皮内。真皮在人类皮肤中是皮肤内位于距表面约1.0mm-2.0mm的层,但在个体之间以及在机体的不同部位有一定量的变化。一般而言,可以预料在皮肤表面下行进1.5mm则达到真皮。真皮位于表面的角质层和表皮与下面的皮下层之间。根据给药模式,疫苗可能最终仅位于或者主要位于真皮内,或者它可能最终分布于表皮和真皮内。
在各种各样治疗方案(包括例如口服、胃肠外、静脉内、真皮内、经皮、鼻内和肌内给药和制剂)中用于使用本文所述的特定组合物的合适给药和治疗方案的开发是本领域众所周知的,为了一般的说明目的,其中某些方案在下文中作简单的论述。
在某些应用中,本文公开的药用组合物可以通过口服给药给予动物。因此,这些组合物可以用惰性稀释剂或可吸收的食用载体来配制,或者它们可以包封在硬壳或软壳明胶胶囊中,或者它们可以压制为片剂,或者它们可以直接掺入食物中。
所述活性化合物可以甚至掺有赋形剂,并且以可摄取的片剂、口含片、锭剂、胶囊剂、酏剂、混悬液、糖浆剂、糯米纸囊剂等的形式使用(参见例如Mathiowitz等Nature 1997Mar27;386(6623):410-4;Hwang等,Crit Rev Ther Drug Carrier Syst 1998;15(3):243-84;美国专利5,641,515;美国专利5,580,579和美国专利5,792,451)。片剂、锭剂、丸剂、胶囊剂等也可以含有多种额外成分中的任一种,例如粘合剂,诸如西黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂,诸如磷酸二钙;崩解剂,例如玉米淀粉、马铃薯淀粉、藻酸等;润滑剂,诸如硬脂酸镁;和甜味剂(诸如可以加入蔗糖、乳糖或糖精)或者矫味剂诸如薄荷油、冬绿树油或者樱桃调味料。当剂量单位形式为胶囊时,除含有上述类型的材料外,它还可以含有液体载体。各种其它材料可以作为包衣存在,或者存在各种其它材料以便在其它情况下改进所述剂量单位的物理形式。例如,可以给片剂、丸剂或胶囊剂包上虫胶、糖或者这两者。当然,在制备任何剂量单位形式中使用的任何材料都应该是药物级纯的,并且在所用的量下基本上是无毒的。另外,所述活性化合物可以掺入到缓释制剂和配方中。通常,这些制剂将含有至少约0.1%或0.1%以上的所述有效成分,虽然所述有效成分的百分率自然可以变化,可以适宜地在总制剂的重量或体积的约1%或2%和约60%或70%或70%以上之间。自然,每种治疗上有用的组合物中的活性化合物的量可以以这样一种方式制备,使得在任何给定单位剂量的所述化合物中获得合适的剂量。制备这种药用制剂的领域的技术人员将考虑多种因素,诸如溶解性、生物利用度、生物半寿期、给药途径、制品的贮藏期以及其它药理学考虑因素,因此,可能需要各种各样的剂量和治疗方案。
另一方面,对于口服给药而言,本发明的组合物可以掺有一种或多种漱口剂、牙粉、口含片、口腔喷雾剂或舌下口服给药制剂形式的赋形剂。或者,可以将所述有效成分掺入到口服溶液剂中,例如含有硼酸钠、甘油和碳酸氢钾的口服溶液剂,或者分散于牙粉中,或者以治疗有效量加入到组合物中,所述组合物可以包括水、粘合剂、摩擦剂、矫味剂、发泡剂和湿润剂。或者,所述组合物可以被制作为可以置于舌下或者溶于口腔的片剂或溶液剂形式。
在某些情况下,胃肠外、静脉内、肌内或甚至腹膜内给予本文公开的药用组合物将是理想的。这类途径对于技术人员而言是众所周知的,其中某些途径例如在美国专利5,543,158;美国专利5,641,515和美国专利5,399,363中有进一步的描述。在某些实施方案中,作为游离碱或者药理学上可接受的盐的活性化合物的溶液,可以在水中适当地与表面活性剂例如羟丙基纤维素混合来制备。可以在甘油、液态聚乙二醇和其混合物中以及在油中制备分散体。在常规贮藏和使用条件下,这些制剂一般将含有防腐剂,以防止微生物生长。
适用于注射应用的说明性药物形式包括无菌水溶液或者分散体、以及供临时制备无菌注射液或分散体用的无菌散剂(例如参见美国专利5,466,468)。在所有情况下,所述形式必须是无菌的,并且必须是流体,从而存在易注射性。它必须在生产和贮藏条件下稳定,并且必须防止微生物例如细菌和真菌的污染作用。载体可以是溶剂或分散介质,含有例如水、乙醇、多元醇(例如甘油、丙二醇和液态聚乙二醇等)、其合适的混合物和/或植物油。可以借助包衣例如卵磷脂、在分散体的情况下通过维持所需的粒径和/或借助表面活性剂,可以维持适当的流动性。用各种抗细菌剂和抗真菌剂,例如对羟基苯甲酸酯类、三氯叔丁醇、苯酚、山梨酸、硫柳汞等,可以有助于防止微生物的作用。在许多情况下,最好包括等渗剂,例如糖或氯化钠。通过在组合物中使用延迟吸收的药剂,例如一硬脂酸铝和明胶,可以达到注射用组合物的延长吸收。
在一个实施方案中,对于水溶液的胃肠外给药而言,所述溶液在必要时应该适当地缓冲,并且首先用足够的盐水或葡萄糖使液体稀释剂等渗。这些特定的水溶液尤其适用于静脉内、肌内、皮下和腹膜内给药。在这一方面,根据本说明书,可以使用的无菌水性介质对于本领域技术人员而言是已知的。例如,可以将一个剂量溶于1ml等渗氯化钠溶液中,或者加入至1000ml皮下输液中,或者在建议的输注部位注射(参见例如“Remington’s Pharmaceutical Sciences”15th Edition,第1035-1038和1570-1580页)。根据待治疗受治疗者的病症,必定发生某些剂量的变化。此外,对于人类给药而言,制剂当然最好符合FDAOffice of Biologics标准所要求的无菌性、热原性和一般安全性和纯度的标准。所述载体还可以包括任一种和所有的溶剂、分散介质、溶媒、包衣、稀释剂、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂、缓冲剂、载体溶液、混悬剂、胶体等。这类介质和药剂在药用活性物质方面的应用是本领域众所周知的。除了由于任何常规的介质或药剂与所述有效成分不配伍,则考虑了其在治疗组合物中的应用。补充的有效成分也可以掺入到所述组合物中。短语“药学上可接受的”是指当给予人类时不产生过敏反应或类似的不想要的反应的分子实体和组合物。
在某些实施方案中,所述药用组合物可以通过鼻内喷雾剂、吸入和/或其它气雾剂递药载体来给予。例如在美国专利5,756,353和美国专利5,804,212中,已经描述了用于通过鼻腔气雾喷雾剂将基因、核酸和肽组合物直接传递至肺部的方法。同样,用鼻内微粒树脂(Takenaga等,J Controlled Release 1998 Mar 2;52(1-2):81-7)和溶血磷脂酰基-甘油化合物(美国专利5,725,871)递药也是制药领域众所周知的。同样,说明性的在聚四氟乙烯形式的支持基质中经粘膜给药在美国专利5,780,045中有描述。
所述疫苗制剂的系统给药方法可以包括常规的注射器和针头、或者设计用于射击给予固体疫苗的装置(WO 99/27961)、或者无针加压液体喷射装置(US 4,596,556;US 5,993,412)、或者透皮贴剂(WO 97/48440;WO 98/28037)。本发明也可以用来增强用于皮肤的抗原的免疫原性(透皮递药WO 98/20734;WO 98/28037)。因此,本发明提供一种预先填充本发明的疫苗或佐剂组合物的供系统给药用的递药装置。
因此,本发明提供一种预先填充本发明的疫苗或佐剂组合物的供系统给药用的递药装置。因此,提供一种在个体内诱发免疫应答的方法,所述方法包括将本发明的疫苗给予所述个体,其中所述疫苗通过胃肠外途径或系统途径给予。
本发明的疫苗制剂最好含有能够诱发针对人类病原体的免疫应答的抗原或抗原组合物,所述抗原或抗原组合物来源于HIV-1(例如tat、nef、gp120或gp160);人疱疹病毒,诸如gD或其衍生物或者立即早期蛋白诸如得自HSV1或HSV2的ICP27;巨细胞病毒((尤其是人巨细胞病毒)(诸如gB或其衍生物);轮状病毒(包括减毒活病毒);EB病毒(诸如gp350或其衍生物);水痘-带状疱疹病毒(诸如gpI、II和IE63);或者来源于肝炎病毒,例如乙型肝炎病毒(例如乙型肝炎病毒表面抗原或其衍生物)、甲型肝炎病毒、丙型肝炎病毒和戊型肝炎病毒;或者来源于其它病毒病原体,例如副粘病毒:呼吸道合胞病毒(诸如F和G蛋白或其衍生物)、副流感病毒、麻疹病毒、腮腺炎病毒、人乳头瘤病毒(例如HPV6、11、16、18,..)、黄病毒(例如黄热病毒、登革热病毒、蜱传脑炎病毒、日本脑炎病毒)或者流感病毒(完整的活病毒或者灭活病毒、在鸡蛋或MDCK细胞中生长的裂解流感病毒(split influenzavirus)、或者完整的流感病毒体(如R.Gluck,Vaccine,1992,10,915-920所述)或者其纯化或重组蛋白,诸如HA、NP、NA或M蛋白、或其组合);或者来源于细菌病原体,诸如奈瑟氏球菌(Neisseria spp.)包括淋病奈瑟氏球菌(N.gonorrhea)和明脑膜炎奈瑟氏球菌(N.meningitidis)(例如夹膜多糖及其缀合物、运铁蛋白结合蛋白、乳铁蛋白结合蛋白、PilC、粘附素);化脓链球菌(S.pyogenes)(例如M蛋白或其片段、C5A蛋白酶、脂磷壁酸质)、无乳链球菌(S.agalactiae)、变异链球菌(S.mutans);杜氏嗜血菌(H.ducreyi);莫拉氏菌(Moraxella spp.),包括粘膜炎莫拉氏菌(M.catarrhalis),也称为粘膜炎布兰汉氏球菌(Branhamella catarrhalis)(例如高分子量和低分子量粘附素和侵袭素);博德特氏菌(Bordetella spp.),包括百日咳博德特氏菌(B.pertussis)(例如pertactin、百日咳毒素或其衍生物、丝状血凝素、腺苷酸环化酶、菌毛)、副百日咳博德特氏菌(B.parapertussis)和支气管炎博德特氏菌(B.bronchiseptica);分枝杆菌(Mycobacterium spp.)包括结核分枝杆菌(M.tuberculosis)(例如ESAT6、抗原85A、-B或-C)、牛分枝杆菌(M.bovis)、麻风分枝杆菌(M.lerae)、鸟分枝杆菌(M.avium)、副结核分枝杆菌(M.paratuberculosis)、耻垢分枝杆菌(M.smegmatis);军团菌(Legionellaspp.),包括嗜肺军团菌(L.pneumophila);埃希氏菌(Escherichia spp.),包括肠毒性大肠杆菌(E.coli)(例如定居因子、热不稳定性毒素或其衍生物、热稳定性毒素或其衍生物)、肠出血性大肠杆菌、肠致病性大肠杆菌(例如志贺菌毒素样毒素或其衍生物);弧菌(Vibrio spp.),包括霍乱弧菌(V.cholera)(例如霍乱毒素或其衍生物);志贺氏菌(Shigellaspp.),包括索氏志贺氏菌(S.sonnei)、痢疾志贺氏菌(S.dysenteriae)、弗氏志贺氏菌(S.flexnerii);耶尔森氏菌(Yersinia spp.),包括小肠结肠炎耶尔森氏菌(Y.enterocolitica)(例如Yop蛋白)、鼠疫耶尔森氏菌(Y.pestis)、假结核耶尔森氏菌(Y.pseudotuberculosis);弯曲杆菌(Campylobacter spp.),包括空肠弯曲杆菌(C.jejuni)(例如毒素、粘附素和侵袭素)和大肠弯曲杆菌(C.coli);沙门氏菌(Salmonella spp.),包括伤寒沙门氏菌(S.typhi)、副伤寒沙门氏菌(S.paratyphi)、猪霍乱沙门氏菌(S.choleraesuis)、肠炎沙门氏菌(S.enteritidis);李斯特氏菌(Listeriaspp.),包括单核细胞增生李斯特氏菌(L.monocytogenes);螺杆菌(Helicobacter spp.),包括幽门螺杆菌(H.pylori)(例如脲酶、过氧化氢酶、空泡毒素(vacuolating toxin));假单胞菌(Pseudomonas spp.),包括铜绿假单胞菌(P.aeruginosa);葡萄球菌(Staphylococcus spp.),包括金黄色葡萄球菌(S.aureus)、表皮葡萄球菌(S.epidermidis);肠球菌(Enterococcus spp.),包括粪肠球菌(E.faecalis)、屎肠球菌(E.faecium);梭菌(Clostridium spp.),包括破伤风梭菌(C.tetani)(例如破伤风毒素及其衍生物)、肉毒梭菌(C.bolutinum)(例如肉毒杆菌毒素及其衍生物)、艰难梭菌(C.difficile)(例如梭菌毒素A或B及其衍生物);芽孢杆菌(Bacillus spp.),包括炭疽芽孢杆菌(B.anthracis)(例如肉毒杆菌毒素及其衍生物);棒杆菌(Corynebacterium spp.),包括白喉棒杆菌(C.diphtheriae)(例如白喉毒素及其衍生物);疏螺旋体(Borrelia spp.),包括布氏疏螺旋体(B.burgdorferi)(例如OspA、OspC、DbpA、DbpB)、嘎氏疏螺旋体(B.garinii)(例如OspA、OspC、DbpA、DbpB)、阿氏疏螺旋体(B.afzelii)(例如OspA、OspC、DbpA、DbpB)、B.andersonii(例如OspA、OspC、DbpA、DbpB)、赫氏蜱疏螺旋体(B.hermsii);埃里希氏体(Ehrlichia spp.),包括马埃里希氏体(E.equi)以及人粒细胞性埃利希病的病原体;立克次氏体(Rickettsia spp.),包括立氏立克次氏体(R.rickettsii);衣原体(Chlamydia spp.),包括砂眼衣原体(C.trachomatis)(例如MOMP、肝素结合蛋白)、肺炎衣原体(C.pneumoniae)(例如MOMP、肝素结合蛋白)、鹦鹉热衣原体(C.psittaci);钩端螺旋体(Leptospiraspp.),包括问号钩端螺旋体(L.interrogans);密螺旋体(Treponemaspp.),包括苍白密螺旋体(T.pallidum)(例如稀有外膜蛋白)、齿垢密螺旋体(T.denticola)、猪痢疾密螺旋体(T.hyodysenteriae);或者来源于寄生虫,例如疟原虫(Plasmodium spp.),包括恶性疟原虫(P.falciparum);弓形虫(Toxoplasma spp.),包括鼠弓形虫(T.gondii)(例如SAG2、SAG3、Tg34);内阿米巴(Entamoeba spp.),包括溶组织内阿米巴(E.histolytica);巴贝虫(Babesia spp.),包括田鼠巴贝虫(B.microti);锥虫(Trypanosoma spp.),包括克氏锥虫(T.cruzi);贾第鞭毛虫(Giardiaspp.),包括兰氏贾第鞭毛虫(G.lamblia);利什曼原虫(Leshmania spp.),包括大型利什曼原虫(L.major);肺囊虫(Pneumocystis spp.),包括卡氏肺囊虫(P.carinii);毛滴虫(Trichomonas spp.),包括阴道毛滴虫(T.vaginalis);血吸虫(Schisostoma spp.),包括曼氏血吸虫(S.mansoni);或者来源于酵母,例如念珠菌(Candida spp.),包括白色念珠菌(C.albicans);隐球菌(Cryptococcus spp.),包括新型隐球菌(C.neoformans)。
结核分枝杆菌的其它优选具体抗原例如为Tb Ra12、Tb H9、TbRa35、Tb38-1、Erd 14、DPV、MTI、MSL、mTTC2和hTCCI(WO99/51748)。结核分枝杆菌的蛋白也包括其融合蛋白和其变异体,其中至少两种、优选三种结核分枝杆菌多肽融合为一种较大的蛋白。优选融合体包括Ra12-TbH9-Ra35、Erd14-DPV-MTI、DPV-MITI-MSL、Erd14-DPV-MITI-MSL-mTCC2、Erd14-DPV-MTI-MSL、DPV-MTI-MSL-mTCC2、TbH9-DPV-MTI(WO99/51748)。
衣原体的最优选抗原包括例如高分子量蛋白(HWMP)(WO99/17741)、ORF3(EP 366 412)和推定的膜蛋白(Pmps)。所述疫苗制剂的其它衣原体抗原可以选自WO 99/28475中所述的组。
优选的细菌疫苗包含来源于以下的抗原:链球菌,包括肺炎链球菌(例如夹膜多糖及其缀合物、PsaA、PspA、链球菌溶血素、胆碱结合蛋白)和蛋白质抗原肺炎球菌溶血素(Biochem Biophys Acta,1989,67,1007;Rubins等,Microbial Pathogenesis,25,337-342)及其突变型解毒衍生物(WO 90/06951;WO 99/03884)。其它优选的细菌疫苗包括来源于以下的抗原:嗜血菌(Haemophilu spp.),包括乙型流感嗜血菌(H.influenzae type B)(例如PRP及其缀合物、不可分型的流感嗜血菌例如OMP26、高分子量粘附素、P5、P6、蛋白D和脂蛋白D、以及丝束蛋白和丝束蛋白衍生肽(US 5,843,464)或者其多拷贝变异体或融合蛋白。
乙型肝炎病毒表面抗原的衍生物是本领域众所周知的,尤其包括在欧洲专利申请EP-A-414374、EP-A-030 4578和EP 198-474中叙述的那些PreS1、PreS2S抗原。在一个优选方面,本发明的疫苗制剂包含HIV-1抗原gp120,尤其是当在CHO细胞中表达时。在再一实施方案中,本发明的疫苗制剂包含上文限定的gD2t。
在本发明的一个优选实施方案中,含有要求保护的佐剂的疫苗包含来源于被认为引起生殖器疣的人乳头瘤病毒(HPV)(HPV6或HPV11和其它HPV毒株)和引起宫颈癌的HPV病毒(HPV16、HPV18和其它HPV毒株)的抗原。
生殖器疣预防性或治疗性疫苗的特别优选的形式包含L1颗粒或壳粒、以及包含一种或多种选自HPV6和HPV11蛋白E6、E7、L1和L2的抗原的融合蛋白。
融合蛋白的最优选形式为:WO 96/26277中公开的L2E7和GB9717953.5(PCT/EP98/05285)中公开的蛋白D(1/3)-E7。
一种优选的HPV宫颈感染或宫颈癌预防性或治疗性疫苗组合物可以包含HPV16或18抗原。例如,L1或L2抗原单体、或者L1或L2抗原在一起作为病毒样颗粒(VLP)存在,或者单独的L1蛋白在VPL或壳粒结构中单独存在。这样的抗原、病毒样颗粒和壳粒本身是已知的。参见例如WO94/00152、WO94/20137、WO94/05792和WO93/02184。
可以单独包括或者作为融合蛋白包括其它早期蛋白,例如E7、E2或者尤其是E5;这种早期蛋白的特别优选的实施方案包括包含L1E7融合蛋白的VLP(WO96/11272)。
特别优选的HPV16抗原包含与蛋白D载体融合的早期蛋白E6或E7,形成蛋白D一得自HPV16的E6或E7融合体或者其组合;或者E6或E7与L2的组合(WO96/26277)。
另一方面,HPV16或18早期蛋白E6和E7可以以单个分子存在,优选为蛋白D-E6/E7融合体。这种疫苗可以任选地含有得自HPV18的E6和E7蛋白中的任一种或这两种,优选为蛋白D-E6或者蛋白D-E7融合蛋白、或者蛋白DE6/E7融合蛋白的形式。
本发明的疫苗还可以包含来自其它HPV毒株、最好来自毒株HPV31或33的抗原。
本发明的疫苗还包含来源于引起疟疾的寄生虫的抗原。例如来自恶性疟原虫的优选抗原包括RTS,S和TRAP。RTS是一种杂种蛋白,包含通过乙型肝炎病毒表面抗原的preS2部分的4个氨基酸与乙型肝炎病毒表面(S)抗原连接的恶性疟原虫环子孢子(CS)蛋白的基本全部的C末端部分。其完整结构公开于以WO 93/10152公布的、要求英国专利申请第9124390.7号优先权的国际专利申请号PCT/EP92/02591中。当在酵母中表达时,RTS作为脂蛋白颗粒产生,而当其与HBV的S抗原共同表达时,它产生一种称为RTS,S的混合颗粒。TRAP抗原描述于以WO 90/01496公布的国际专利申请PCT/GB89/00895中。本发明的一个优选实施方案是疟疾疫苗,其中所述抗原制剂包含RTS,S和TRAP抗原的组合。可能作为候选者而成为多级疟疾疫苗成分的其它疟原虫抗原是恶性疟原虫MSP1、AMA1、MSP3、EBA、GLURP、RAP1、RAP2、钳合蛋白、PfEMP1、Pf332、LSAI、LSA3、STARP、SALSA、PfEXP1、Pfs25、Pfs28、PFS27/25、Pfs16、Pfs48/45、Pfs230以及疟原虫中的其它类似物。
所述制剂也可以含有抗肿瘤抗原,可用于癌症的免疫治疗性治疗。例如,所述佐剂制剂可应用于肿瘤排斥抗原,例如前列腺癌、乳癌、结肠直肠癌、肺癌、胰腺癌、肾癌或黑素瘤的抗原。示例性抗原包括MAGE1、3和MAGE4、或者其它MAGE抗原例如在WO99/40188中公开的其它MAGE抗原、PRAME、BAGE、Lage(也称为NY Eos 1)SAGE和HAGE(WO99/53061)或GAGE(Robbins和Kawakami,1996,Current Opinions in Immunology 8,第628-636页;Van den Eynde等,International Journal of Clinical & Laboratory Research(1997年提交);Correale等(1997),Journal of the National Cancer Institute 89,第293页)。实际上这些抗原在各种各样的肿瘤类型例如黑素瘤、肺癌、肉瘤和膀胱癌中表达。
供本发明使用的MAGE抗原可以作为具有一种表达增强子或免疫学融合配偶体所融合蛋白表达。特别是,可以将Mage蛋白与得自乙型流感嗜血菌的蛋白D或其脂质化(lipidated)衍生物融合。特别是,所述融合配偶体可以包含蛋白D的前1/3。这类构建体公开于WO 99/40188中。
其它肿瘤特异性抗原适合于与本发明的佐剂一起使用,所述肿瘤特异性抗原包括但不限于肿瘤特异性神经节苷脂诸如GM2以及GM3或其与载体蛋白的缀合物;或者所述抗原可以是自身肽类激素,例如全长促性腺素释放激素(GnRH,WO 95/20600),这是一种10个氨基酸长的短肽,可用于治疗许多癌症,或者可用于免疫去势(immunocastration)。
在一个优选实施方案中,使用例如诸如以下的前列腺抗原:前列腺特异性抗原(PSA)、PAP、PSCA(PNAS 95(4)1735-1740 1998)、PSMA或者称为Prostase的抗原。
Prostase是一种前列腺特异性丝氨酸蛋白酶(胰蛋白酶样),有254个氨基酸,具有一个保守的丝氨酸蛋白酶催化三联体H-D-S和一个表明有潜在的分泌功能的氨基末端前原肽序列(P.Nelson,Lu Gan,C.Ferguson,P.Moss,R.Gelinas,L.Hood和K.Wand,“Molecular cloningand characterisation of prostase,an androgen-regulated serine protease withprostate restricted expression,载于Proc.Natl.Acad.Sci.USA(1999)96,3114-3119)。已经描述了一个推定的糖基化位点。预测的结构非常类似其它已知的丝氨酸蛋白酶,表明成熟多肽折叠成一个单一的结构域。所述成熟蛋白长224个氨基酸,具有一个表明是经天然加工的A2表位。
Prostase的核苷酸序列和导出的多肽序列以及同源物公开于Ferguson等(Proc.Natl.Acad.Sci.USA 1999,96,3114-3119)和国际专利申请WO 98/12302(也是相应的授权专利US 5,955,306)、WO98/20117(也是相应的授权专利US 5,840,871和US 5,786,148)(前列腺特异性激肽释放酶)和WO 00/04149(P703P)。
本发明提供包含基于prostase蛋白及其片段和同源物(“衍生物”)的prostase蛋白融合体的制剂。这类衍生物适用于治疗性疫苗制剂中,适用于治疗前列腺肿瘤。通常,所述片段将含有至少20个、优选50个、更优选100个连续氨基酸,如在上述引用的专利和专利申请中公开的。
再一种优选的前列腺抗原被称为P501S,Wo98/37814中的SEQ IDno113。在上述引用的专利申请中公开了包含至少20个、优选50个、更优选100个连续氨基酸的其免疫原性片段和部分。参见例如PS108(WO 98/50567)。
其它前列腺特异性抗原可从Wo98/37418和WO/004149中得知。另一种抗原是STEAP PNAS 96 14523 14528 7-12 1999。
可用于本发明内容的其它肿瘤相关抗原包括:Plu-1(J Biol.Chem274(22)15633-15645,1999)、HASH-1、HasH-2、Cripto(Salomon等Bioessays 199,2161-70,美国专利5654140)、Criptin(美国专利5 981215)。另外,特别适合于癌症治疗中的疫苗的抗原也包括酪氨酸酶和生存素(survivin)。
粘蛋白衍生肽诸如Muc1参见例如US 5744,144、US 5827,666、WO 8805054、US 4,963,484。尤其考虑了Muc 1衍生肽,该肽包含Muc 1肽的至少一个重复单位,优选包含至少两个这类重复单位,并且该肽为SM3抗体所识别(US 6 054 438)。其它粘蛋白衍生肽包括得自Muc 5的肽。
本发明也可与乳癌抗原例如her 2/Neu、mammaglobin(美国专利5668267)或者WO/0052165、WO99/33869、WO99/19479、WO98/45328中公开的那些抗原联合使用。Her 2 neu抗原特别公开于美国专利5,801,005中。优选Her 2 neu包含完整的胞外结构域(包含大约氨基酸1-645)或其片段和胞内结构域的至少一个免疫原性部分或完整的胞内结构域(大约C末端的580个氨基酸)。特别是,所述胞内部分应该包含磷酸化结构域或其片段。这类构建体公开于WO00/44899中。一种特别优选的构建体称为ECD PD,第二种称为ECD PD,参见Wo/00/44899。本文所用的her 2 neu可以来源于大鼠、小鼠或人类。
所述制剂可以包含与肿瘤支持机制(例如血管生成、肿瘤侵袭)相关的抗原,例如tie2、VEGF。
可以预见,本发明的组合物将可用来配制含有来源于疏螺旋体的抗原的疫苗。例如,抗原可以包括核酸、病原体源抗原或抗原制剂、重组生产的蛋白或肽、以及嵌合融合蛋白。特别是,所述抗原为OspA。所述OspA可以是借助于宿主细胞(大肠杆菌)脂质化形式的完整成熟蛋白(称为(Lipo-OspA))或其非脂质化衍生物。这类非脂质化衍生物包括非脂质化NS1-OspA融合蛋白,它具有流感病毒非结构蛋白(NS1)的前81个N末端氨基酸和完整的OspA蛋白,而另一种衍生物MDP-OspA是携带3个额外的N末端氨基酸的OspA的非脂质化形式。
本发明的疫苗可以用于预防或治疗变态反应。这类疫苗应该包含变应原特异性抗原(例如Der p1)和变应原非特异性抗原(例如来源于人IgE的肽,包括但不限于stanworth十肽(EP 0 477 231 B1))。
本发明的疫苗也可以用来预防或治疗除变态反应、癌症或传染病以外的慢性疾病。这样的慢性疾病是诸如动脉粥样硬化和早老性痴呆的疾病。
本发明的疫苗尤其适合于诸如慢性病症和癌症的疾病的免疫治疗性治疗,也适合于持续性感染的治疗。因此,本发明的疫苗特别适合于传染病例如肺结核(TB)、AIDS和乙型肝炎(HepB)病毒感染的免疫治疗。
因此提供:可供传染病例如TB、AIDS和HepB的免疫治疗用的本发明疫苗和佐剂;以及这类佐剂和疫苗在传染病例如TB、AIDS和HepB的免疫治疗药物的生产中的应用。在TB方面,提供一种治疗患有TB感染的个体的方法,所述方法包括将本发明的疫苗给予所述个体,从而减少该个体的细菌载荷。细菌载荷的减少包括肺部痰中存在的TB量的减少,导致TB疾病的缓解或治愈。
此外,在AIDS方面,提供一种治疗易感或患有ADIS的个体的方法。所述方法包括将本发明的疫苗给予所述个体,从而减少由后续HIV感染所致的CD4+T细胞下降的量,或者使已经感染HIV的个体中CD4+T细胞的下降减慢或使其停止。
另外,在持续性乙型肝炎病毒感染方面,提供一种治疗易感或患有HepB的个体的方法。因此提供一种包括下述步骤的方法:将本发明的疫苗给予所述个体,从而减少血清中的HepB载荷水平(根据DNA清除来测定)以及减少肝损伤量(根据丙氨酸转移酶(ALT)的血清水平的降低或稳定化来检测)。
每剂疫苗中的蛋白量被选择为在典型的接种者体内诱发免疫保护性应答而无显著的毒副作用的量。这样一种量将视使用哪种特定免疫原和将其如何呈递而变化。一般而言,预期每剂将包含1-1000μg蛋白,优选1-500μg,优选1-100μg,最优选1-50μg。特定疫苗的最适量可以通过包括观察接种疫苗的受治疗者的合适免疫应答的标准研究来确定。
本发明的佐剂或疫苗中CpG或免疫刺激性寡核苷酸的量一般为小量,但根据疫苗制剂,其范围可以为1-1000μg/剂,优选1-500μg/剂,更优选1-100μg/剂。
如果有的话,用于本发明佐剂中的LPS衍生物的量可以在1-1000μg/剂范围内,优选1-500μg/剂,更优选1-250μg/剂,最优选1-100μg/剂。因此,CpG∶LPS衍生物(w/w)之比将1∶1000-1000∶1范围内,通常在1∶100-100∶1范围内,优选在1∶10-1∶1或1∶1-10∶1范围内,最优选为1∶1、4∶1或10∶1。
本发明的制剂可以既可以用于预防目的,也可用于治疗目的。因此,提供皂苷和CpG分子的组合在用于病毒性、细菌性、寄生虫性感染、变态反应、癌症和其它非慢性疾病的预防和治疗用的疫苗的生产中的应用。因此,本发明提供一种治疗易感或患有传染病或癌症或者变态反应或自身免疫病的哺乳动物的方法。在本发明的再一方面,提供一种如本文所述的用作药物的疫苗或佐剂组合,所述疫苗或佐剂组合包含皂苷和CpG。疫苗的制备在New Trends and Developments inVaccines,Voller等编著,University Park Press.Baltimore,Maryland,U.S.A.1978中有全面的描述。
可以预见,本发明的组合物将可用来配制含有来源于各种各样来源的抗原的疫苗。例如,抗原可以包括人类、细菌或病毒的核酸、病原体源抗原或抗原制剂、肿瘤衍生抗原或抗原制剂、宿主源抗原包括来源于IgE的肽诸如IgE的组胺释放十肽(也称为Stanworth十肽)、重组生产的蛋白或肽、以及嵌合融合蛋白。
本发明也提供一种通过含有利于Th1型免疫应答的免疫刺激性寡核苷酸的疫苗产生的改变针对抗原的免疫应答质量的方法,所述方法包括用免疫刺激性寡核苷酸和含母育酚的水包油型乳液来配制所述疫苗。具体地说,所述改变免疫应答质量的方法导致通过在小鼠模型中测定产生Th1型免疫应答,其中由所述疫苗诱发的抗原特异性IgG同种型的特征在于,根据通过同种型特异性ELISA测定的中点效价(midpoint titre)来测定,IgG1构成总抗原特异性IgG的50%以下。优选根据通过同种型特异性ELISA测定的中点效价来测定,IgG1构成总抗原特异性IgG的40%以下。
也提供一种生产疫苗组合物的方法,所述方法包括配制包含母育酚的水包油型乳液,将所述母育酚乳液与免疫刺激性寡核苷酸混合形成佐剂,并且将所述佐剂和抗原或抗原组合物配制在一起。
也提供一种治疗易感或患有疾病的个体的方法,所述方法包括给予所述个体一种包含免疫刺激性寡核苷酸和母育酚的组合的疫苗组合物。也提供了本文所述的疫苗在医药中的应用。
还提供了一种生产疫苗或佐剂的方法,所述方法包括取LPS的衍生物、取CpG分子,然后将它们与抗原在药学上可接受的赋形剂中、在无皂苷的情况下混合。供本发明组合用的合适的药学上可接受的赋形剂的实例包括水、磷酸缓冲盐溶液、等渗缓冲液。
优选本发明的佐剂由母育酚和可代谢油乳液以及免疫刺激性寡核苷酸组成,或者基本上由它们组成。更优选所述佐剂组合物基本上由母育酚和可代谢油乳液、免疫刺激性寡核苷酸和皂苷组成。在上述两种实施方案中,所述母育酚优选为α-生育酚,所述可代谢油优选为角鲨烯,而免疫刺激性寡核苷酸优选为CpG 2006(SEQ ID NO.4);本发明清楚地设想了在这些实施方案内的所有变化和组合。最优选所述佐剂组合物由α-生育酚和角鲨烯乳液、CpG 2006(SEQ ID NO.4)和QS21组成,或者基本上由它们组成。
本发明的最优选疫苗含有Her2Neu抗原,优选为与磷酸化结构域连接的Her2Neu的胞外结构域的融合体(ECD-PD)(如WO 00/44899中所述方法生产的))。因此,本发明提供一种治疗患有癌症的个体的方法,所述方法包括给予所述个体一种包含免疫刺激性寡核苷酸、母育酚和ECD-PD的组合的疫苗组合物。在这种治疗方法中,也考虑了在上文中已经描述的免疫刺激性寡核苷酸和母育酚的所有优选特征。
通过以下实施例例证本发明,但本发明不限于以下实施例。
实施例1 用ECD-PD抗原免疫小鼠
这一实验设计用所述抗原研究各种各样的佐剂制剂,所述抗原是与磷酸化结构域连接的Her2Neu胞外结构域的融合体(ECD-PD),该融合体在CHO细胞中依照WO 00/44899的方法生产。
组别 | 抗原(25μg) | 佐剂 |
1 | ECD-PD | 无(磷酸缓冲盐溶液(PBS)) |
2 | ECD-PD | 在膜中具有QS21和3D-MPL的脂质体 |
3 | ECD-PD | 具有QS21和3D-MPL的含母育酚水包油型乳液 |
4 | ECD-PD | CpG |
5 | ECD-PD | 在膜中具有QS21和3D-MPL的脂质体+CpG |
6 | ECD-PD | 具有QS21和3D-MPL的含母育酚水包油型乳液+CpG |
7 | ECD-PD | 3D-MPL+CpG |
8 | ECD-PD | QS21+CpG |
9 | ECD-PD | 含母育酚水包油型乳液+CpG |
10 | ECD-PD | 在膜中具有QS21的脂质体+CpG |
11 | ECD-PD | 在膜中具有3D-MPL的脂质体+CpG |
在上述组别中使用的含母育酚水包油型乳液使用D,L,α-生育酚(CAS No.10191-41-0;化学名称:(2RS,4’RS,8’RS)-2,5,7,8-四甲基-2-(4’,8’,12’-三甲基-十三烷基)-6-二氢苯并呋喃醇));它以ROCHETM市售。如果存在母育酚,则所述母育酚存在于水包油型乳液中,所述乳液包含与2.5%(体积)角鲨烯组合的2.5%(体积)母育酚。将这两种油混合,加入聚氧乙烯脱水山梨醇一油酸酯(Tween 80TM),然后进行微流化(M110S microfluidics machine,最多50道,在6巴最大输入压(输出压约为850巴)下达2分钟,如WO 95/17210中所述)。因此,第3组、第6组和第9组基于添加含水QS21、3D-MPL或CpG的上述母育酚乳液。
如果在任一种以上疫苗组中存在QS21和3D-MPL,则它们以5μg/剂存在;以50μg剂量加入CpG(OLIGO 4(SEQ ID NO:4):TCG TCGTTT TGT CGT TTT GTC GTT)。
第2组、第5组、第10组使用的佐剂依照EP 0 822 831 B1(所述文献的内容通过引用结合到本文中)中所述技术来制备。第11组在脂质体膜中包含3D-MPL。简而言之,将3D-MPL、二油酰磷脂酰胆碱和胆固醇混合在一起,然后微流化为单室脂质体(如EP 0 822 831 B1中所述,但去除QS21)。
第4组、第7组和第8组中使用的佐剂为水性悬浮液或水溶液。
疫苗接种方法
给各组B6F1小鼠以14天的间隔肌内接种疫苗4次(以50μl的体积)。给予第4剂疫苗后14天,用2×106表达Her2Neu的TC1肿瘤细胞皮下攻击小鼠。
肿瘤细胞系TC1:
得自C57BL.6小鼠的原代肺上皮细胞用HPV16 E6和E7无限增殖化,然后用活化ras癌基因转化,产生表达E6和E7的致瘤性细胞系(Lin KY Cancer Res 1996 Jan 1,56(1):21-61)。用小鼠抗HPV 16 E7Mab(Triton Corp.Alameda,CA)通过固定和透化的TC1细胞的FACS分析,证实E7的表达。通过用编码Her2Neu的逆转录病毒载体转导这些TC1细胞,产生Her2Neu-TC1肿瘤细胞系。在使用blastocydin的选择期后,分离出抗性克隆,并通过FACS,根据Her2Neu的表达筛选所述克隆。选择出具有最高Her2Neu表达的克隆,鉴定2×106细胞的攻击剂量具有与野生型TC1细胞相似的生长动力学,并且导致在100%的对照动物中产生肿瘤。
1周两次测量各个肿瘤的大小,并且以组平均值来表示。
结果
图1显示了第1、2、4、5和6组的肿瘤生长结果。图2显示了第1、5、6、7和11组的肿瘤生长结果。图3显示了第1、5、6、8、9和10组的肿瘤生长结果。包含母育酚和CpG的制剂诱发了肿瘤的完全消退。
图4和图5显示了在与5μg/ml免疫原(ECD-PD)或胞外结构域(ECD)或胞内结构域(ICD)或Her2Neu一起孵育后体外脾细胞的淋巴组织增生。
图6和图7显示了依据通过ELISA测量的总Ig(图6)或者依据这些应答中IgG同种型分布(图7)的抗免疫原(ECD-PD)的体液免疫应答。
实施例2 用P703P抗原免疫小鼠
该实验设计用来用作为抗原Prostase(Ferguson,等(Proc.NatlAcad.Sci.USA 1999,96,3114-3119))和流感病毒NS1的N末端1-81片段的融合体(P703P-NS1)的抗原,研究各种各样的佐剂制剂。
组别 | 抗原(25μg) | 佐剂 |
1 | P703P-NS1 | 无(磷酸缓冲盐溶液(PBS)) |
2 | P703P-NS1 | CpG |
3 | P703P-NS1 | 在膜中具有QS21的脂质体+CpG |
4 | P703P-NS1 | 在膜中具有QS21和3D-MPL的脂质体+CpG |
5 | P703P-NS1 | 具有QS21和3D-MPL的含母育酚水包油型乳液+CpG |
6 | P703P-NS1 | 含母育酚水包油型乳液+CpG |
在上述组别中使用的含母育酚水包油型乳液使用D,L,α-生育酚(CAS No.10191-41-0;化学名称:(2RS,4’RS,8’RS)-2,5,7,8-四甲基-2-(4’,8’,12’-三甲基-十三烷基)-6-二氢苯并呋喃醇));它以ROCHETM市售。如果存在母育酚,则所述母育酚存在于水包油型乳液中,所述乳液包含与2.5%(体积)角鲨烯组合的2.5%(体积)母育酚。将这两种油混合,加入聚氧乙烯脱水山梨醇一油酸酯(Tween 80TM),然后进行微流化(M110S microfluidics machine,最多50道,在6巴最大输入压(输出压约为850巴)下达2分钟,如WO 95/17210中所述)。因此,第5组和第6组基于添加含水QS21、3D-MPL和/或CpG的上述母育酚乳液。
如果在任一种以上疫苗组中存在QS21和3D-MPL,则它们以5μg/剂存在;以50μg剂量加入CpG(OLIGO 4(SEQ ID NO:4):TCG TCGTTT TGT CGT TTT GTC GTT)。
第3组和第4组使用的佐剂依照EP 0 822 831 B1(所述文献的内容通过引用结合到本文中)中所述技术来制备。
疫苗接种方法
给各组B6F1小鼠以14天的间隔肌内接种疫苗4次(以50μl的体积)。
结果
图8和图9显示了第2次疫苗接种后和第4次疫苗接种后14天、在与3μg/ml免疫原(NS1-P703P)或者毕赤酵母表达的P703P或者非特异性NS1-OspA融合蛋白一起体外孵育后的脾细胞体外淋巴组织增生。
图10和图11显示了依据通过中点效价ELISA测量的总Ig(图10)或者依据这些应答中IgG同种型分布(图11)的抗免疫原(NS1-P703P)的体液免疫应答。
Claims (14)
2.权利要求1的佐剂组合物,其中具有1-4个碳原子的直链或支链碳链是甲基、乙基、丁基或异丁基。
3.权利要求2的佐剂组合物,其中母育酚是D、L、α-生育酚。
4.权利要求1的佐剂组合物,其中所述水包油型乳液还包含角鲨烯。
5.权利要求1或2的佐剂组合物,其中所述免疫刺激性寡核苷酸选自:TCC ATG ACG TTC CTG ACG TT;TCT CCC AGC GTGCGC CAT;ACC GAT GAC GTC GCC GGT GAC GGC ACC ACG;TCG TCG TTT TGT CGT TTT GTC GTT;TCC ATG ACG TTC CTGATG CT。
6.权利要求1或2的佐剂组合物,其中所述免疫刺激性寡核苷酸含有两个或更多由3个或更多核苷酸分开的未甲基化CG重复。
7.权利要求6的佐剂组合物,其中所述免疫刺激性寡核苷酸含有两个或更多由6个核苷酸分开的未甲基化CG重复。
8.权利要求1的佐剂组合物,其中所述佐剂还包含一种额外的免疫刺激剂。
9.权利要求8的佐剂组合物,其中所述额外的免疫刺激剂选自脂多糖或皂苷。
10.权利要求9的佐剂组合物,其中脂多糖是3D-MPL。
11.权利要求9的佐剂组合物,其中皂苷是QS21。
12.一种疫苗组合物,所述组合物包含权利要求1-11中任一项要求保护的佐剂组合物以及抗原。
13.权利要求12的疫苗组合物,其中所述抗原是ECD-PD。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0025577.8A GB0025577D0 (en) | 2000-10-18 | 2000-10-18 | Vaccine |
GB0025577.8 | 2000-10-18 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1481254A CN1481254A (zh) | 2004-03-10 |
CN100346829C true CN100346829C (zh) | 2007-11-07 |
Family
ID=9901557
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB018206603A Expired - Fee Related CN100346829C (zh) | 2000-10-18 | 2001-10-16 | 包含免疫刺激性寡核苷酸和母育酚的佐剂组合物 |
Country Status (21)
Country | Link |
---|---|
US (1) | US20040047869A1 (zh) |
EP (1) | EP1326639B1 (zh) |
JP (1) | JP2004511529A (zh) |
KR (1) | KR20030044016A (zh) |
CN (1) | CN100346829C (zh) |
AT (1) | ATE383872T1 (zh) |
AU (2) | AU2168902A (zh) |
BR (1) | BR0114785A (zh) |
CA (1) | CA2425310A1 (zh) |
CZ (1) | CZ20031094A3 (zh) |
DE (1) | DE60132474T2 (zh) |
ES (1) | ES2299530T3 (zh) |
GB (1) | GB0025577D0 (zh) |
HU (1) | HUP0303720A3 (zh) |
IL (1) | IL155283A0 (zh) |
MX (1) | MXPA03003406A (zh) |
NO (1) | NO20031646L (zh) |
NZ (1) | NZ525321A (zh) |
PL (1) | PL365322A1 (zh) |
WO (1) | WO2002032454A1 (zh) |
ZA (1) | ZA200302887B (zh) |
Families Citing this family (55)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030026782A1 (en) * | 1995-02-07 | 2003-02-06 | Arthur M. Krieg | Immunomodulatory oligonucleotides |
US6207646B1 (en) * | 1994-07-15 | 2001-03-27 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
EP0855184A1 (en) * | 1997-01-23 | 1998-07-29 | Grayson B. Dr. Lipford | Pharmaceutical composition comprising a polynucleotide and an antigen especially for vaccination |
US6406705B1 (en) * | 1997-03-10 | 2002-06-18 | University Of Iowa Research Foundation | Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant |
US20030022854A1 (en) | 1998-06-25 | 2003-01-30 | Dow Steven W. | Vaccines using nucleic acid-lipid complexes |
US6693086B1 (en) * | 1998-06-25 | 2004-02-17 | National Jewish Medical And Research Center | Systemic immune activation method using nucleic acid-lipid complexes |
AU783344B2 (en) | 1999-02-17 | 2005-10-20 | Csl Limited | Immunogenic complexes and methods relating thereto |
KR100917101B1 (ko) * | 2000-08-04 | 2009-09-15 | 도요 보세키 가부시키가이샤 | 플렉시블 금속적층체 및 그 제조방법 |
MXPA03011611A (es) * | 2001-06-29 | 2004-07-01 | Becton Dickinson Co | Administracion intradermica de vacunas y agentes terapeuticos genicos a traves de microcanula. |
DK1446162T3 (da) * | 2001-08-17 | 2008-12-08 | Coley Pharm Gmbh | Kombinationsmotiv-immunstimulatoriske oligonukleotider med forbedret aktivitet |
GB0123580D0 (en) * | 2001-10-01 | 2001-11-21 | Glaxosmithkline Biolog Sa | Vaccine |
CA2388049A1 (en) | 2002-05-30 | 2003-11-30 | Immunotech S.A. | Immunostimulatory oligonucleotides and uses thereof |
US7605138B2 (en) * | 2002-07-03 | 2009-10-20 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US7569553B2 (en) * | 2002-07-03 | 2009-08-04 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US7807803B2 (en) * | 2002-07-03 | 2010-10-05 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US20040053880A1 (en) * | 2002-07-03 | 2004-03-18 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US7576066B2 (en) * | 2002-07-03 | 2009-08-18 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
JP2005532405A (ja) * | 2002-07-10 | 2005-10-27 | アクゾ・ノベル・エヌ・ベー | 融合タンパク質とサポニンアジュバントとを含む免疫原性組成物 |
US7998492B2 (en) * | 2002-10-29 | 2011-08-16 | Coley Pharmaceutical Group, Inc. | Methods and products related to treatment and prevention of hepatitis C virus infection |
WO2004087203A2 (en) * | 2003-04-02 | 2004-10-14 | Coley Pharmaceutical Group, Ltd. | Immunostimulatory nucleic acid oil-in-water formulations for topical application |
US20050013812A1 (en) * | 2003-07-14 | 2005-01-20 | Dow Steven W. | Vaccines using pattern recognition receptor-ligand:lipid complexes |
CA2536139A1 (en) * | 2003-09-25 | 2005-04-07 | Coley Pharmaceutical Group, Inc. | Nucleic acid-lipophilic conjugates |
TWI235440B (en) * | 2004-03-31 | 2005-07-01 | Advanced Semiconductor Eng | Method for making leadless semiconductor package |
US20080032384A1 (en) * | 2004-04-22 | 2008-02-07 | Takehiko Nomura | Pharmaceutical Preparation Containing Bacterial Cell Wall Skeleton |
JP2008506789A (ja) * | 2004-07-18 | 2008-03-06 | シーエスエル、リミテッド | インターフェロン−ガンマ応答強化を誘発するための免疫刺激複合体及びオリゴヌクレオチド処方物 |
TW200722101A (en) | 2005-03-23 | 2007-06-16 | Glaxosmithkline Biolog Sa | Novel composition |
KR100740237B1 (ko) * | 2005-05-10 | 2007-07-18 | 아이진 주식회사 | 올리고뉴클레오타이드 및 비독성 다당체를 포함하는면역보조제 |
CA2614320A1 (en) * | 2005-07-07 | 2007-01-18 | Coley Pharmaceutical Group, Inc. | Anti-ctla-4 antibody and cpg-motif-containing synthetic oligodeoxynucleotide combination therapy for cancer treatment |
US11707520B2 (en) | 2005-11-03 | 2023-07-25 | Seqirus UK Limited | Adjuvanted vaccines with non-virion antigens prepared from influenza viruses grown in cell culture |
CA2628397C (en) * | 2005-11-04 | 2013-08-20 | Novartis Vaccines And Diagnostics S.R.L. | Changing th1/th2 balance in split influenza vaccines with adjuvants |
PL2368572T3 (pl) | 2005-11-04 | 2020-11-16 | Seqirus UK Limited | Szczepionki z adjuwantem z niewirionowymi antygenami otrzymane z wirusów grypy hodowanych w hodowli komórkowej |
TWI457133B (zh) * | 2005-12-13 | 2014-10-21 | Glaxosmithkline Biolog Sa | 新穎組合物 |
MX2009000660A (es) | 2006-07-17 | 2009-04-08 | Glaxosmithkline Biolog Sa | Vacuna de influenza. |
AU2007280690C1 (en) | 2006-07-31 | 2012-08-23 | Curevac Gmbh | Nucleic acid of formula (I): GIXmGn, or (II): CIXmCn, in particular as an immune-stimulating agent/adjuvant |
DE102006035618A1 (de) * | 2006-07-31 | 2008-02-07 | Curevac Gmbh | Nukleinsäure der Formel (I): GlXmGn, insbesondere als immunstimulierendes Adjuvanz |
BRPI0716959A2 (pt) * | 2006-09-26 | 2013-10-29 | Infectious Disease Res Inst | Composição de vacina contendo adjuvante sintético |
PT2078080E (pt) | 2006-09-27 | 2015-09-18 | Coley Pharm Gmbh | Análogos dos oligonucleotídeos cpg que contêm análogos t hidrofóbicos com atividade imunoestimulante potenciada |
WO2008043774A1 (en) * | 2006-10-12 | 2008-04-17 | Glaxosmithkline Biologicals S.A. | Vaccine comprising an oil in water emulsion adjuvant |
TW200908994A (en) | 2007-04-20 | 2009-03-01 | Glaxosmithkline Biolog Sa | Vaccine |
WO2009030254A1 (en) | 2007-09-04 | 2009-03-12 | Curevac Gmbh | Complexes of rna and cationic peptides for transfection and for immunostimulation |
KR101483715B1 (ko) | 2008-01-31 | 2015-01-19 | 큐어백 게엠바하 | 면역증강제/애주번트인 화학식(NuGlXmGnNv)a를 포함하는 핵산 및 이의 유도체 |
ES2569907T3 (es) | 2008-06-27 | 2016-05-13 | Zoetis Services Llc | Composiciones adyuvantes novedosas |
JP5667566B2 (ja) * | 2008-08-06 | 2015-02-12 | ノバルティス アーゲー | 免疫原性組成物における使用のための微粒子 |
WO2010037408A1 (en) | 2008-09-30 | 2010-04-08 | Curevac Gmbh | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
CN102307590A (zh) | 2009-02-10 | 2012-01-04 | 诺华有限公司 | 具有减少量的角鲨烯的流感疫苗 |
US20110053829A1 (en) | 2009-09-03 | 2011-03-03 | Curevac Gmbh | Disulfide-linked polyethyleneglycol/peptide conjugates for the transfection of nucleic acids |
EP2955230A1 (en) | 2010-07-30 | 2015-12-16 | CureVac AG | Complexation of nucleic acids with disulfide-crosslinked cationic components for transfection and immunostimulation |
WO2013113326A1 (en) | 2012-01-31 | 2013-08-08 | Curevac Gmbh | Pharmaceutical composition comprising a polymeric carrier cargo complex and at least one protein or peptide antigen |
NZ701881A (en) | 2012-05-16 | 2016-10-28 | Immune Design Corp | Vaccines for hsv-2 |
MX370573B (es) | 2013-04-18 | 2019-12-17 | Immune Design Corp | Monoterapia con glucopiranosil lipido a para usarse en el tratamiento del cancer. |
US9463198B2 (en) | 2013-06-04 | 2016-10-11 | Infectious Disease Research Institute | Compositions and methods for reducing or preventing metastasis |
AU2014310934B2 (en) | 2013-08-21 | 2019-09-12 | CureVac SE | Respiratory syncytial virus (RSV) vaccine |
CN109675029A (zh) | 2013-09-19 | 2019-04-26 | 硕腾服务有限责任公司 | 油基佐剂 |
WO2015149944A2 (en) | 2014-04-01 | 2015-10-08 | Curevac Gmbh | Polymeric carrier cargo complex for use as an immunostimulating agent or as an adjuvant |
HUE063288T2 (hu) | 2015-01-16 | 2024-01-28 | Zoetis Services Llc | Száj és körömfájás betegség vakcina |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1138298A (zh) * | 1993-12-23 | 1996-12-18 | 史密斯克莱·比奇曼生物公司 | 疫苗 |
CN1056085C (zh) * | 1989-02-04 | 2000-09-06 | 阿克佐公司 | 母育酚在疫苗中用作佐剂 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6589940B1 (en) * | 1997-06-06 | 2003-07-08 | Dynavax Technologies Corporation | Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof |
DK1187629T3 (da) * | 1999-04-19 | 2005-01-17 | Glaxosmithkline Biolog Sa | Adjuvanssammensætning omfattende saponin og et immunostimulerende oligonucleotid |
-
2000
- 2000-10-18 GB GBGB0025577.8A patent/GB0025577D0/en not_active Ceased
-
2001
- 2001-10-16 MX MXPA03003406A patent/MXPA03003406A/es unknown
- 2001-10-16 WO PCT/EP2001/011985 patent/WO2002032454A1/en active IP Right Grant
- 2001-10-16 CZ CZ20031094A patent/CZ20031094A3/cs unknown
- 2001-10-16 PL PL01365322A patent/PL365322A1/xx unknown
- 2001-10-16 DE DE60132474T patent/DE60132474T2/de not_active Expired - Lifetime
- 2001-10-16 NZ NZ525321A patent/NZ525321A/en unknown
- 2001-10-16 HU HU0303720A patent/HUP0303720A3/hu unknown
- 2001-10-16 US US10/399,356 patent/US20040047869A1/en not_active Abandoned
- 2001-10-16 IL IL15528301A patent/IL155283A0/xx unknown
- 2001-10-16 JP JP2002535691A patent/JP2004511529A/ja active Pending
- 2001-10-16 BR BR0114785-4A patent/BR0114785A/pt not_active Withdrawn
- 2001-10-16 EP EP01987673A patent/EP1326639B1/en not_active Expired - Lifetime
- 2001-10-16 AU AU2168902A patent/AU2168902A/xx active Pending
- 2001-10-16 AU AU2002221689A patent/AU2002221689B2/en not_active Ceased
- 2001-10-16 CN CNB018206603A patent/CN100346829C/zh not_active Expired - Fee Related
- 2001-10-16 CA CA002425310A patent/CA2425310A1/en not_active Abandoned
- 2001-10-16 AT AT01987673T patent/ATE383872T1/de not_active IP Right Cessation
- 2001-10-16 ES ES01987673T patent/ES2299530T3/es not_active Expired - Lifetime
- 2001-10-16 KR KR10-2003-7005466A patent/KR20030044016A/ko not_active Application Discontinuation
-
2003
- 2003-04-10 NO NO20031646A patent/NO20031646L/no not_active Application Discontinuation
- 2003-04-11 ZA ZA200302887A patent/ZA200302887B/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1056085C (zh) * | 1989-02-04 | 2000-09-06 | 阿克佐公司 | 母育酚在疫苗中用作佐剂 |
CN1138298A (zh) * | 1993-12-23 | 1996-12-18 | 史密斯克莱·比奇曼生物公司 | 疫苗 |
Also Published As
Publication number | Publication date |
---|---|
PL365322A1 (en) | 2004-12-27 |
DE60132474T2 (de) | 2009-01-15 |
EP1326639A1 (en) | 2003-07-16 |
IL155283A0 (en) | 2003-11-23 |
EP1326639B1 (en) | 2008-01-16 |
ES2299530T3 (es) | 2008-06-01 |
AU2168902A (en) | 2002-04-29 |
NZ525321A (en) | 2004-06-25 |
ZA200302887B (en) | 2004-07-12 |
BR0114785A (pt) | 2003-12-23 |
KR20030044016A (ko) | 2003-06-02 |
JP2004511529A (ja) | 2004-04-15 |
NO20031646D0 (no) | 2003-04-10 |
CZ20031094A3 (cs) | 2003-09-17 |
MXPA03003406A (es) | 2005-01-25 |
WO2002032454A1 (en) | 2002-04-25 |
NO20031646L (no) | 2003-06-14 |
US20040047869A1 (en) | 2004-03-11 |
AU2002221689B2 (en) | 2004-04-01 |
HUP0303720A3 (en) | 2004-11-29 |
CN1481254A (zh) | 2004-03-10 |
GB0025577D0 (en) | 2000-12-06 |
ATE383872T1 (de) | 2008-02-15 |
HUP0303720A2 (hu) | 2004-03-29 |
CA2425310A1 (en) | 2002-04-25 |
DE60132474D1 (de) | 2008-03-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100346829C (zh) | 包含免疫刺激性寡核苷酸和母育酚的佐剂组合物 | |
CN1227030C (zh) | 包含皂甙和免疫刺激寡核苷酸的佐剂组合物 | |
AU2002221689A1 (en) | Adjuvant composition comprising an immunostimulatory oligonucleotide and a tocol | |
KR20200066309A (ko) | 사포닌을 포함하는 리포솜 제형 및 사용 방법 | |
CN1893974A (zh) | 免疫原性组合物 | |
CN1889977A (zh) | 含白介素18和皂苷佐剂系统的疫苗组合物 | |
JP2005507898A (ja) | ワクチン | |
JP5307859B2 (ja) | ワクチン |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |