TWI549688B - 合成的葡萄吡喃糖基脂質佐劑 - Google Patents
合成的葡萄吡喃糖基脂質佐劑 Download PDFInfo
- Publication number
- TWI549688B TWI549688B TW104113418A TW104113418A TWI549688B TW I549688 B TWI549688 B TW I549688B TW 104113418 A TW104113418 A TW 104113418A TW 104113418 A TW104113418 A TW 104113418A TW I549688 B TWI549688 B TW I549688B
- Authority
- TW
- Taiwan
- Prior art keywords
- antigen
- gla
- etoac
- mmol
- compound
- Prior art date
Links
- -1 glucopyranosyl lipid Chemical class 0.000 title claims description 29
- 239000002671 adjuvant Substances 0.000 title description 70
- 239000000203 mixture Substances 0.000 claims description 189
- 239000000427 antigen Substances 0.000 claims description 150
- 102000036639 antigens Human genes 0.000 claims description 149
- 108091007433 antigens Proteins 0.000 claims description 149
- 206010028980 Neoplasm Diseases 0.000 claims description 33
- 208000015181 infectious disease Diseases 0.000 claims description 29
- 201000011510 cancer Diseases 0.000 claims description 25
- 208000023275 Autoimmune disease Diseases 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000000524 functional group Chemical group 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 9
- 206010020751 Hypersensitivity Diseases 0.000 claims description 7
- 230000007815 allergy Effects 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 238000003259 recombinant expression Methods 0.000 claims description 7
- 208000026935 allergic disease Diseases 0.000 claims description 6
- 208000036284 Rhinitis seasonal Diseases 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 204
- 150000001875 compounds Chemical class 0.000 description 111
- 235000019439 ethyl acetate Nutrition 0.000 description 97
- 229960005486 vaccine Drugs 0.000 description 79
- 238000000034 method Methods 0.000 description 62
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
- 230000028993 immune response Effects 0.000 description 49
- 239000000243 solution Substances 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- 210000004027 cell Anatomy 0.000 description 44
- 239000003921 oil Substances 0.000 description 40
- 238000005481 NMR spectroscopy Methods 0.000 description 39
- 235000019198 oils Nutrition 0.000 description 38
- 108090000623 proteins and genes Proteins 0.000 description 38
- 102000004169 proteins and genes Human genes 0.000 description 35
- 235000018102 proteins Nutrition 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000000839 emulsion Substances 0.000 description 33
- 108090000765 processed proteins & peptides Proteins 0.000 description 29
- 150000002148 esters Chemical class 0.000 description 26
- 102000002689 Toll-like receptor Human genes 0.000 description 25
- 108020000411 Toll-like receptor Proteins 0.000 description 25
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 25
- 102000004196 processed proteins & peptides Human genes 0.000 description 22
- 201000008827 tuberculosis Diseases 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 21
- 239000008194 pharmaceutical composition Substances 0.000 description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 20
- 230000000694 effects Effects 0.000 description 20
- 238000009472 formulation Methods 0.000 description 20
- 201000004792 malaria Diseases 0.000 description 20
- 230000004044 response Effects 0.000 description 20
- 239000000556 agonist Substances 0.000 description 19
- 201000010099 disease Diseases 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 19
- 102000004127 Cytokines Human genes 0.000 description 18
- 108090000695 Cytokines Proteins 0.000 description 18
- 241000701806 Human papillomavirus Species 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 230000003308 immunostimulating effect Effects 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 18
- 210000001744 T-lymphocyte Anatomy 0.000 description 17
- 210000000987 immune system Anatomy 0.000 description 17
- 230000003053 immunization Effects 0.000 description 17
- 238000002649 immunization Methods 0.000 description 17
- 229920001184 polypeptide Polymers 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- 229930182490 saponin Natural products 0.000 description 16
- 235000017709 saponins Nutrition 0.000 description 16
- 150000007949 saponins Chemical class 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 108010074328 Interferon-gamma Proteins 0.000 description 14
- CTMZLDSMFCVUNX-VMIOUTBZSA-N cytidylyl-(3'->5')-guanosine Chemical group 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 14
- 244000052769 pathogen Species 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 210000001519 tissue Anatomy 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 13
- 108091034117 Oligonucleotide Proteins 0.000 description 13
- 206010057190 Respiratory tract infections Diseases 0.000 description 13
- 230000000890 antigenic effect Effects 0.000 description 13
- 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 13
- 238000011282 treatment Methods 0.000 description 13
- 241000725303 Human immunodeficiency virus Species 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 241000700605 Viruses Species 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 12
- 230000001717 pathogenic effect Effects 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000002255 vaccination Methods 0.000 description 12
- 241000223960 Plasmodium falciparum Species 0.000 description 11
- 239000000568 immunological adjuvant Substances 0.000 description 11
- 230000006698 induction Effects 0.000 description 11
- 150000007523 nucleic acids Chemical group 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- 229940046168 CpG oligodeoxynucleotide Drugs 0.000 description 10
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 102000037865 fusion proteins Human genes 0.000 description 10
- 108020001507 fusion proteins Proteins 0.000 description 10
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 9
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 239000002158 endotoxin Substances 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 244000045947 parasite Species 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 9
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 9
- 208000030507 AIDS Diseases 0.000 description 8
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 8
- 108700006640 OspA Proteins 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 8
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 150000002632 lipids Chemical class 0.000 description 8
- 229920006008 lipopolysaccharide Polymers 0.000 description 8
- UOZZAMWODZQSOA-CQSZACIVSA-N methyl (3r)-3-hydroxytetradecanoate Chemical compound CCCCCCCCCCC[C@@H](O)CC(=O)OC UOZZAMWODZQSOA-CQSZACIVSA-N 0.000 description 8
- 239000003607 modifier Substances 0.000 description 8
- 108020004707 nucleic acids Proteins 0.000 description 8
- 102000039446 nucleic acids Human genes 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 229940031439 squalene Drugs 0.000 description 8
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- SQQXRXKYTKFFSM-UHFFFAOYSA-N chembl1992147 Chemical compound OC1=C(OC)C(OC)=CC=C1C1=C(C)C(C(O)=O)=NC(C=2N=C3C4=NC(C)(C)N=C4C(OC)=C(O)C3=CC=2)=C1N SQQXRXKYTKFFSM-UHFFFAOYSA-N 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 7
- 229940124669 imidazoquinoline Drugs 0.000 description 7
- 230000036039 immunity Effects 0.000 description 7
- 230000001571 immunoadjuvant effect Effects 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 235000000346 sugar Nutrition 0.000 description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- 241000589968 Borrelia Species 0.000 description 6
- 108010012236 Chemokines Proteins 0.000 description 6
- 102000019034 Chemokines Human genes 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- 238000002965 ELISA Methods 0.000 description 6
- 102100037850 Interferon gamma Human genes 0.000 description 6
- 241000222722 Leishmania <genus> Species 0.000 description 6
- 208000016604 Lyme disease Diseases 0.000 description 6
- 241000223810 Plasmodium vivax Species 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 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 6
- 239000003599 detergent Substances 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 239000002955 immunomodulating agent Substances 0.000 description 6
- 229940121354 immunomodulator Drugs 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 230000002458 infectious effect Effects 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 210000002540 macrophage Anatomy 0.000 description 6
- 231100000252 nontoxic Toxicity 0.000 description 6
- 230000003000 nontoxic effect Effects 0.000 description 6
- 239000007764 o/w emulsion Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 230000003389 potentiating effect Effects 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 230000004936 stimulating effect Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000003053 toxin Substances 0.000 description 6
- 231100000765 toxin Toxicity 0.000 description 6
- 108700012359 toxins Proteins 0.000 description 6
- 241000193830 Bacillus <bacterium> Species 0.000 description 5
- 241000222122 Candida albicans Species 0.000 description 5
- 241000606161 Chlamydia Species 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 101000831567 Homo sapiens Toll-like receptor 2 Proteins 0.000 description 5
- 102000008070 Interferon-gamma Human genes 0.000 description 5
- 102000013462 Interleukin-12 Human genes 0.000 description 5
- 108010065805 Interleukin-12 Proteins 0.000 description 5
- 208000004554 Leishmaniasis Diseases 0.000 description 5
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 5
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 5
- 241000607768 Shigella Species 0.000 description 5
- 102100024333 Toll-like receptor 2 Human genes 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- 229940037003 alum Drugs 0.000 description 5
- 101150078331 ama-1 gene Proteins 0.000 description 5
- UPAZUDUZKTYFBG-HNPUZVNISA-N azane [(2S,3R,4R,5S,6R)-2,5-dihydroxy-6-[[(2R,3R,4R,5S,6R)-6-(hydroxymethyl)-5-phosphonooxy-3-[[(3R)-3-tetradecanoyloxytetradecanoyl]amino]-4-[(3R)-3-tetradecanoyloxytetradecanoyl]oxyoxan-2-yl]oxymethyl]-3-[[(3R)-3-hydroxytetradecanoyl]amino]oxan-4-yl] (3R)-3-hydroxytetradecanoate Chemical compound [NH4+].CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)N[C@H]1[C@H](OC[C@H]2O[C@H](O)[C@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H]2O)O[C@H](CO)[C@@H](OP(O)([O-])=O)[C@@H]1OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC UPAZUDUZKTYFBG-HNPUZVNISA-N 0.000 description 5
- 230000001580 bacterial effect Effects 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 239000002274 desiccant Substances 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 210000005260 human cell Anatomy 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 239000002480 mineral oil Substances 0.000 description 5
- 229940042472 mineral oil Drugs 0.000 description 5
- 235000010446 mineral oil Nutrition 0.000 description 5
- 239000002773 nucleotide Substances 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000013598 vector Substances 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- NDCDVTWILZGAIG-HXUWFJFHSA-N (3r)-3-phenylmethoxytetradecanoic acid Chemical compound CCCCCCCCCCC[C@H](CC(O)=O)OCC1=CC=CC=C1 NDCDVTWILZGAIG-HXUWFJFHSA-N 0.000 description 4
- ATRNZOYKSNPPBF-CYBMUJFWSA-N (R)-3-hydroxytetradecanoic acid Chemical compound CCCCCCCCCCC[C@@H](O)CC(O)=O ATRNZOYKSNPPBF-CYBMUJFWSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 102100037840 Dehydrogenase/reductase SDR family member 2, mitochondrial Human genes 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 108010002350 Interleukin-2 Proteins 0.000 description 4
- 102000000588 Interleukin-2 Human genes 0.000 description 4
- 102000008072 Lymphokines Human genes 0.000 description 4
- 108010074338 Lymphokines Proteins 0.000 description 4
- 241001467552 Mycobacterium bovis BCG Species 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 102000003945 NF-kappa B Human genes 0.000 description 4
- 108010057466 NF-kappa B Proteins 0.000 description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 description 4
- 108700023315 OspC Proteins 0.000 description 4
- 241000224016 Plasmodium Species 0.000 description 4
- 101710188053 Protein D Proteins 0.000 description 4
- 101100431670 Rattus norvegicus Ybx3 gene Proteins 0.000 description 4
- 101710132893 Resolvase Proteins 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 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 4
- 229930006000 Sucrose Natural products 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000005867 T cell response Effects 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 4
- 206010047505 Visceral leishmaniasis Diseases 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 229940087168 alpha tocopherol Drugs 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 230000005875 antibody response Effects 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000001363 autoimmune Effects 0.000 description 4
- 229960000190 bacillus calmette–guérin vaccine Drugs 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 238000003745 diagnosis Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 229940011399 escin Drugs 0.000 description 4
- 229930186222 escin Natural products 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 150000004676 glycans Chemical class 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 229960003130 interferon gamma Drugs 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- XSLAPWFITBDFTF-JOCHJYFZSA-N methyl (3r)-3-[(4-methoxyphenyl)methoxy]tetradecanoate Chemical compound CCCCCCCCCCC[C@H](CC(=O)OC)OCC1=CC=C(OC)C=C1 XSLAPWFITBDFTF-JOCHJYFZSA-N 0.000 description 4
- DSQRYVDYSWWRDB-OAQYLSRUSA-N methyl (3r)-3-phenylmethoxytetradecanoate Chemical compound CCCCCCCCCCC[C@H](CC(=O)OC)OCC1=CC=CC=C1 DSQRYVDYSWWRDB-OAQYLSRUSA-N 0.000 description 4
- ZAZKJZBWRNNLDS-UHFFFAOYSA-N methyl tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OC ZAZKJZBWRNNLDS-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 229920001282 polysaccharide Polymers 0.000 description 4
- 239000005017 polysaccharide Substances 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- 150000003573 thiols Chemical group 0.000 description 4
- 229960000984 tocofersolan Drugs 0.000 description 4
- 241000712461 unidentified influenza virus Species 0.000 description 4
- 239000002076 α-tocopherol Substances 0.000 description 4
- 235000004835 α-tocopherol Nutrition 0.000 description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 3
- OBECRJHRCDNGOR-OAQYLSRUSA-N (3r)-3-[(4-methoxyphenyl)methoxy]tetradecanoic acid Chemical compound CCCCCCCCCCC[C@H](CC(O)=O)OCC1=CC=C(OC)C=C1 OBECRJHRCDNGOR-OAQYLSRUSA-N 0.000 description 3
- ROYVLWKXIKKQQP-HSZRJFAPSA-N (3r)-3-decoxytetradecanoic acid Chemical compound CCCCCCCCCCC[C@H](CC(O)=O)OCCCCCCCCCC ROYVLWKXIKKQQP-HSZRJFAPSA-N 0.000 description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 241000588807 Bordetella Species 0.000 description 3
- 241000588832 Bordetella pertussis Species 0.000 description 3
- 241000589876 Campylobacter Species 0.000 description 3
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 3
- 206010007134 Candida infections Diseases 0.000 description 3
- 241000193403 Clostridium Species 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 230000006820 DNA synthesis Effects 0.000 description 3
- 241000224432 Entamoeba histolytica Species 0.000 description 3
- 241000194033 Enterococcus Species 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 241000224466 Giardia Species 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 208000031886 HIV Infections Diseases 0.000 description 3
- 208000037357 HIV infectious disease Diseases 0.000 description 3
- 241000606768 Haemophilus influenzae Species 0.000 description 3
- 241000238631 Hexapoda Species 0.000 description 3
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 3
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 3
- 241000257303 Hymenoptera Species 0.000 description 3
- 102000004895 Lipoproteins Human genes 0.000 description 3
- 108090001030 Lipoproteins Proteins 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 108010057081 Merozoite Surface Protein 1 Proteins 0.000 description 3
- 206010062207 Mycobacterial infection Diseases 0.000 description 3
- 241000186366 Mycobacterium bovis Species 0.000 description 3
- 241000186362 Mycobacterium leprae Species 0.000 description 3
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 3
- 241000588653 Neisseria Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 241000233870 Pneumocystis Species 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000242678 Schistosoma Species 0.000 description 3
- 241000242677 Schistosoma japonicum Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 3
- 235000009754 Vitis X bourquina Nutrition 0.000 description 3
- 235000012333 Vitis X labruscana Nutrition 0.000 description 3
- 240000006365 Vitis vinifera Species 0.000 description 3
- 235000014787 Vitis vinifera Nutrition 0.000 description 3
- 241000607734 Yersinia <bacteria> Species 0.000 description 3
- 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 3
- YXNHAAYVQLFBMW-YRTCJPGSSA-K [Ru](Cl)(Cl)Cl.COC1=CC=C(CO[C@H](CC)CCCCCCCCCCC)C=C1 Chemical compound [Ru](Cl)(Cl)Cl.COC1=CC=C(CO[C@H](CC)CCCCCCCCCCC)C=C1 YXNHAAYVQLFBMW-YRTCJPGSSA-K 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 230000005784 autoimmunity Effects 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 210000000601 blood cell Anatomy 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 201000003984 candidiasis Diseases 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- NAGJZTKCGNOGPW-UHFFFAOYSA-K dioxido-sulfanylidene-sulfido-$l^{5}-phosphane Chemical compound [O-]P([O-])([S-])=S NAGJZTKCGNOGPW-UHFFFAOYSA-K 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
- 239000000975 dye Substances 0.000 description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 229960002442 glucosamine Drugs 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000002949 hemolytic effect Effects 0.000 description 3
- 108010037896 heparin-binding hemagglutinin Proteins 0.000 description 3
- 208000002672 hepatitis B Diseases 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 230000016784 immunoglobulin production Effects 0.000 description 3
- 230000015788 innate immune response Effects 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 238000012737 microarray-based gene expression Methods 0.000 description 3
- 239000004005 microsphere Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- 238000012243 multiplex automated genomic engineering Methods 0.000 description 3
- 208000027531 mycobacterial infectious disease Diseases 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 229920000136 polysorbate Polymers 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 241000701161 unidentified adenovirus Species 0.000 description 3
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 2
- 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 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- GMRQFYUYWCNGIN-UHFFFAOYSA-N 1,25-Dihydroxy-vitamin D3' Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CC(O)C1=C GMRQFYUYWCNGIN-UHFFFAOYSA-N 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- 241001147657 Ancylostoma Species 0.000 description 2
- 206010059313 Anogenital warts Diseases 0.000 description 2
- 241001124076 Aphididae Species 0.000 description 2
- 241000193738 Bacillus anthracis Species 0.000 description 2
- 208000023328 Basedow disease Diseases 0.000 description 2
- 108030001720 Bontoxilysin Proteins 0.000 description 2
- 241000588780 Bordetella parapertussis Species 0.000 description 2
- 241000589978 Borrelia hermsii Species 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- 241000589877 Campylobacter coli Species 0.000 description 2
- 241000222173 Candida parapsilosis Species 0.000 description 2
- 241001647372 Chlamydia pneumoniae Species 0.000 description 2
- 241001647378 Chlamydia psittaci Species 0.000 description 2
- 241000606153 Chlamydia trachomatis Species 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- 241000193163 Clostridioides difficile Species 0.000 description 2
- 241000193155 Clostridium botulinum Species 0.000 description 2
- 241000193449 Clostridium tetani Species 0.000 description 2
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 2
- 208000000907 Condylomata Acuminata Diseases 0.000 description 2
- 241000186216 Corynebacterium Species 0.000 description 2
- 241000186227 Corynebacterium diphtheriae Species 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- ATRNZOYKSNPPBF-UHFFFAOYSA-N D-beta-hydroxymyristic acid Natural products CCCCCCCCCCCC(O)CC(O)=O ATRNZOYKSNPPBF-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 241000605314 Ehrlichia Species 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 241000194032 Enterococcus faecalis Species 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000588722 Escherichia Species 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 241000713800 Feline immunodeficiency virus Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 241000224467 Giardia intestinalis Species 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 208000015023 Graves' disease Diseases 0.000 description 2
- 241000606790 Haemophilus Species 0.000 description 2
- 241000589989 Helicobacter Species 0.000 description 2
- 241000700721 Hepatitis B virus Species 0.000 description 2
- 101000669406 Homo sapiens Toll-like receptor 6 Proteins 0.000 description 2
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 2
- 241000701828 Human papillomavirus type 11 Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- 101710198693 Invasin Proteins 0.000 description 2
- 241000710842 Japanese encephalitis virus Species 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- 241000589248 Legionella Species 0.000 description 2
- 208000007764 Legionnaires' Disease Diseases 0.000 description 2
- 241000589902 Leptospira Species 0.000 description 2
- 241000186781 Listeria Species 0.000 description 2
- 241000186779 Listeria monocytogenes Species 0.000 description 2
- 206010058467 Lung neoplasm malignant 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
- 101710085938 Matrix protein Proteins 0.000 description 2
- 101710127721 Membrane protein Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000588621 Moraxella Species 0.000 description 2
- 241000588655 Moraxella catarrhalis Species 0.000 description 2
- 241000186359 Mycobacterium Species 0.000 description 2
- 241000186367 Mycobacterium avium Species 0.000 description 2
- 241000187482 Mycobacterium avium subsp. paratuberculosis Species 0.000 description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 2
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 2
- 241001480233 Paragonimus Species 0.000 description 2
- 241000721454 Pemphigus Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 241000223821 Plasmodium malariae Species 0.000 description 2
- 241001505293 Plasmodium ovale Species 0.000 description 2
- 206010035503 Plasmodium vivax infection Diseases 0.000 description 2
- 201000009976 Plasmodium vivax malaria Diseases 0.000 description 2
- 102100035181 Plastin-1 Human genes 0.000 description 2
- 241000233872 Pneumocystis carinii Species 0.000 description 2
- 108091036414 Polyinosinic:polycytidylic acid Proteins 0.000 description 2
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 2
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 2
- 241000589516 Pseudomonas Species 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 241000725643 Respiratory syncytial virus Species 0.000 description 2
- 241000606701 Rickettsia Species 0.000 description 2
- 241000606695 Rickettsia rickettsii Species 0.000 description 2
- 241000607142 Salmonella Species 0.000 description 2
- 241001138501 Salmonella enterica 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
- 241000242683 Schistosoma haematobium Species 0.000 description 2
- 241000242680 Schistosoma mansoni Species 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 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 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
- 229920002472 Starch Polymers 0.000 description 2
- 241000193985 Streptococcus agalactiae Species 0.000 description 2
- 241000194019 Streptococcus mutans Species 0.000 description 2
- 230000006052 T cell proliferation Effects 0.000 description 2
- 206010043561 Thrombocytopenic purpura Diseases 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 description 2
- 102100039387 Toll-like receptor 6 Human genes 0.000 description 2
- 102100033117 Toll-like receptor 9 Human genes 0.000 description 2
- 241000223997 Toxoplasma gondii Species 0.000 description 2
- 241000589884 Treponema pallidum Species 0.000 description 2
- 241000224526 Trichomonas Species 0.000 description 2
- 241000224527 Trichomonas vaginalis Species 0.000 description 2
- 241000223104 Trypanosoma Species 0.000 description 2
- 241000223109 Trypanosoma cruzi Species 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 241000256856 Vespidae Species 0.000 description 2
- 241000607598 Vibrio Species 0.000 description 2
- 241000607626 Vibrio cholerae Species 0.000 description 2
- 208000005469 Vivax Malaria Diseases 0.000 description 2
- 241000607479 Yersinia pestis Species 0.000 description 2
- 241000607477 Yersinia pseudotuberculosis Species 0.000 description 2
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 2
- 238000003782 apoptosis assay Methods 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- 229960001212 bacterial vaccine Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 239000013060 biological fluid Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 238000001815 biotherapy Methods 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 229940053031 botulinum toxin Drugs 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 229960005084 calcitriol Drugs 0.000 description 2
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000020411 cell activation Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000036755 cellular response Effects 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- QUWFSKKBMDKAHK-SBOJBMMISA-A chembl2103793 Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)CO)[C@@H](O)C1 QUWFSKKBMDKAHK-SBOJBMMISA-A 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 150000002016 disaccharides Chemical group 0.000 description 2
- 231100000676 disease causative agent Toxicity 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 238000003114 enzyme-linked immunosorbent spot assay Methods 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- MSWZFWKMSRAUBD-IVMDWMLBSA-N glucosamine group Chemical group OC1[C@H](N)[C@@H](O)[C@H](O)[C@H](O1)CO MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 102000022382 heparin binding proteins Human genes 0.000 description 2
- 108091012216 heparin binding proteins Proteins 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 235000010181 horse chestnut Nutrition 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 229960001438 immunostimulant agent Drugs 0.000 description 2
- 239000003022 immunostimulating agent Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 238000005462 in vivo assay Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 210000005007 innate immune system Anatomy 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000010829 isocratic elution Methods 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 229940039717 lanolin Drugs 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 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
- 201000001441 melanoma Diseases 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 239000013610 patient sample Substances 0.000 description 2
- QCJWNUNXTZOXCF-UHFFFAOYSA-N pentadecan-4-one Chemical compound CCCCCCCCCCCC(=O)CCC QCJWNUNXTZOXCF-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 150000004713 phosphodiesters Chemical class 0.000 description 2
- 108010049148 plastin Proteins 0.000 description 2
- 201000000317 pneumocystosis Diseases 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 2
- 229940115272 polyinosinic:polycytidylic acid Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000005522 programmed cell death Effects 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000010420 shell particle Substances 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 210000004989 spleen cell Anatomy 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 229940032094 squalane Drugs 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- BGHCVCJVXZWKCC-UHFFFAOYSA-N tetradecane Chemical compound CCCCCCCCCCCCCC BGHCVCJVXZWKCC-UHFFFAOYSA-N 0.000 description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229940021747 therapeutic vaccine Drugs 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 241001529453 unidentified herpesvirus Species 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 238000013022 venting Methods 0.000 description 2
- 239000013603 viral vector Substances 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- PFTAWBLQPZVEMU-DZGCQCFKSA-N (+)-catechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-DZGCQCFKSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- YFESOSRPNPYODN-RSMWSHJLSA-N (2s,3s,4s,5r,6r)-6-[[(4s,6ar,6bs,8r,8ar,9r,10r,14br)-9-acetyloxy-8-hydroxy-4,8a-bis(hydroxymethyl)-4,6a,6b,11,11,14b-hexamethyl-10-[(z)-2-methylbut-2-enoyl]oxy-1,2,3,4a,5,6,7,8,9,10,12,12a,14,14a-tetradecahydropicen-3-yl]oxy]-4-hydroxy-3,5-bis[[(2s,3r,4s, Chemical compound O([C@@H]1[C@H](O[C@H]([C@@H]([C@H]1O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)OC1CC[C@]2(C)C3CC=C4[C@@]([C@@]3(CCC2[C@]1(CO)C)C)(C)C[C@@H](O)[C@@]1(CO)[C@@H](OC(C)=O)[C@@H](C(CC14)(C)C)OC(=O)C(\C)=C/C)C(O)=O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.O([C@@H]1[C@H](O[C@H]([C@@H]([C@H]1O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)OC1CC[C@]2(C)C3CC=C4[C@@]([C@@]3(CCC2[C@]1(CO)C)C)(C)C[C@@H](O)[C@@]1(CO)[C@@H](OC(C)=O)[C@@H](C(CC14)(C)C)OC(=O)C(/C)=C/C)C(O)=O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O YFESOSRPNPYODN-RSMWSHJLSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- IQFYYKKMVGJFEH-OFKYTIFKSA-N 1-[(2r,4s,5r)-4-hydroxy-5-(tritiooxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@@H](CO[3H])O[C@H]1N1C(=O)NC(=O)C(C)=C1 IQFYYKKMVGJFEH-OFKYTIFKSA-N 0.000 description 1
- XFQPQSJDMJVOBN-UHFFFAOYSA-N 1-[4-amino-2-(ethylaminomethyl)imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.C1=CC=CC2=C(N(C(CNCC)=N3)CC(C)(C)O)C3=C(N)N=C21 XFQPQSJDMJVOBN-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- 125000006069 2,3-dimethyl-2-butenyl group Chemical group 0.000 description 1
- GPWNWKWQOLEVEQ-UHFFFAOYSA-N 2,4-diaminopyrimidine-5-carbaldehyde Chemical compound NC1=NC=C(C=O)C(N)=N1 GPWNWKWQOLEVEQ-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- JYZJYKOZGGEXSX-UHFFFAOYSA-N 2-hydroxymyristic acid Chemical compound CCCCCCCCCCCCC(O)C(O)=O JYZJYKOZGGEXSX-UHFFFAOYSA-N 0.000 description 1
- 125000006029 2-methyl-2-butenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- ASCFNMCAHFUBCO-UHFFFAOYSA-N 2-phosphoglycolic acid Chemical compound OC(=O)COP(O)(O)=O ASCFNMCAHFUBCO-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ROYVLWKXIKKQQP-UHFFFAOYSA-N 3-decoxytetradecanoic acid Chemical compound CCCCCCCCCCCC(CC(O)=O)OCCCCCCCCCC ROYVLWKXIKKQQP-UHFFFAOYSA-N 0.000 description 1
- 125000006027 3-methyl-1-butenyl group Chemical group 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 108010068327 4-hydroxyphenylpyruvate dioxygenase Proteins 0.000 description 1
- RVDLHGSZWAELAU-UHFFFAOYSA-N 5-tert-butylthiophene-2-carbonyl chloride Chemical compound CC(C)(C)C1=CC=C(C(Cl)=O)S1 RVDLHGSZWAELAU-UHFFFAOYSA-N 0.000 description 1
- ZMFWTUBNIJBJDB-UHFFFAOYSA-N 6-hydroxy-2-methylquinoline-4-carboxylic acid Chemical compound C1=C(O)C=CC2=NC(C)=CC(C(O)=O)=C21 ZMFWTUBNIJBJDB-UHFFFAOYSA-N 0.000 description 1
- JPFNWUUUXFFWOQ-UHFFFAOYSA-N 7h-purin-6-amine;1-pyridin-3-ylethanone Chemical compound CC(=O)C1=CC=CN=C1.NC1=NC=NC2=C1NC=N2 JPFNWUUUXFFWOQ-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 241000224422 Acanthamoeba 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
- 241000456624 Actinobacteria bacterium Species 0.000 description 1
- AXNVHPCVMSNXNP-GKTCLTPXSA-N Aescin Natural products O=C(O[C@H]1[C@@H](OC(=O)C)[C@]2(CO)[C@@H](O)C[C@@]3(C)[C@@]4(C)[C@@H]([C@]5(C)[C@H]([C@](CO)(C)[C@@H](O[C@@H]6[C@@H](O[C@H]7[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O7)[C@@H](O)[C@H](O[C@H]7[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O7)[C@@H](C(=O)O)O6)CC5)CC4)CC=C3[C@@H]2CC1(C)C)/C(=C/C)/C AXNVHPCVMSNXNP-GKTCLTPXSA-N 0.000 description 1
- 241000157282 Aesculus Species 0.000 description 1
- 241000157280 Aesculus hippocastanum Species 0.000 description 1
- 101000786513 Agrobacterium tumefaciens (strain 15955) Uncharacterized protein outside the virF region Proteins 0.000 description 1
- 208000000884 Airway Obstruction Diseases 0.000 description 1
- 101000618005 Alkalihalobacillus pseudofirmus (strain ATCC BAA-2126 / JCM 17055 / OF4) Uncharacterized protein BpOF4_00885 Proteins 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010001935 American trypanosomiasis Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241001465677 Ancylostomatoidea Species 0.000 description 1
- 241000415078 Anemone hepatica Species 0.000 description 1
- 241000243791 Angiostrongylus Species 0.000 description 1
- 102100020724 Ankyrin repeat, SAM and basic leucine zipper domain-containing protein 1 Human genes 0.000 description 1
- 241000256186 Anopheles <genus> Species 0.000 description 1
- 241000256837 Apidae Species 0.000 description 1
- 101100162403 Arabidopsis thaliana ALEU gene Proteins 0.000 description 1
- 240000005528 Arctium lappa Species 0.000 description 1
- 241000244185 Ascaris lumbricoides Species 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 206010050245 Autoimmune thrombocytopenia 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
- 241000223836 Babesia 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
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 241000335423 Blastomyces Species 0.000 description 1
- 101000641200 Bombyx mori densovirus Putative non-structural protein Proteins 0.000 description 1
- 241000588779 Bordetella bronchiseptica 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
- 241000589969 Borreliella burgdorferi Species 0.000 description 1
- 241001148605 Borreliella garinii Species 0.000 description 1
- 241000589893 Brachyspira hyodysenteriae Species 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 241000244038 Brugia malayi Species 0.000 description 1
- XNXXJJXVPIOUHH-UHFFFAOYSA-N C(CCC)C(C(C(C)(C)Cl)(C)C)CCCCCCC Chemical compound C(CCC)C(C(C(C)(C)Cl)(C)C)CCCCCCC XNXXJJXVPIOUHH-UHFFFAOYSA-N 0.000 description 1
- 102100031092 C-C motif chemokine 3 Human genes 0.000 description 1
- 101710155856 C-C motif chemokine 3 Proteins 0.000 description 1
- 108010074051 C-Reactive Protein Proteins 0.000 description 1
- 102100032752 C-reactive protein Human genes 0.000 description 1
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 1
- 108700012434 CCL3 Proteins 0.000 description 1
- 244000197813 Camelina sativa Species 0.000 description 1
- 241000589875 Campylobacter jejuni Species 0.000 description 1
- 241000222178 Candida tropicalis Species 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241001070941 Castanea Species 0.000 description 1
- 235000014036 Castanea Nutrition 0.000 description 1
- 102100035882 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 102000000013 Chemokine CCL3 Human genes 0.000 description 1
- 102000001326 Chemokine CCL4 Human genes 0.000 description 1
- 108010055165 Chemokine CCL4 Proteins 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 201000006082 Chickenpox Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 108010049048 Cholera Toxin Proteins 0.000 description 1
- 102000009016 Cholera Toxin Human genes 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 101000947633 Claviceps purpurea Uncharacterized 13.8 kDa protein Proteins 0.000 description 1
- 241001508813 Clavispora lusitaniae Species 0.000 description 1
- 241000223203 Coccidioides Species 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- 241000221204 Cryptococcus neoformans Species 0.000 description 1
- 241000223935 Cryptosporidium Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 102000053602 DNA Human genes 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
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 102000011799 Desmoglein Human genes 0.000 description 1
- 108050002238 Desmoglein Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000009007 Diagnostic Kit Methods 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 240000001879 Digitalis lutea Species 0.000 description 1
- QRLVDLBMBULFAL-UHFFFAOYSA-N Digitonin Natural products CC1CCC2(OC1)OC3C(O)C4C5CCC6CC(OC7OC(CO)C(OC8OC(CO)C(O)C(OC9OCC(O)C(O)C9OC%10OC(CO)C(O)C(OC%11OC(CO)C(O)C(O)C%11O)C%10O)C8O)C(O)C7O)C(O)CC6(C)C5CCC4(C)C3C2C QRLVDLBMBULFAL-UHFFFAOYSA-N 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 241000255925 Diptera Species 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 206010014596 Encephalitis Japanese B Diseases 0.000 description 1
- 241000224431 Entamoeba Species 0.000 description 1
- 241000146407 Entamoeba coli Species 0.000 description 1
- 241000204733 Entamoeba dispar Species 0.000 description 1
- 241001133638 Entamoeba equi Species 0.000 description 1
- 241000146401 Entamoeba hartmanni Species 0.000 description 1
- 241000146402 Entamoeba polecki Species 0.000 description 1
- 241000305071 Enterobacterales Species 0.000 description 1
- 101000948901 Enterobacteria phage T4 Uncharacterized 16.0 kDa protein in segB-ipI intergenic region Proteins 0.000 description 1
- 101100373503 Enterobacteria phage T4 y06Q gene Proteins 0.000 description 1
- 241000498255 Enterobius vermicularis Species 0.000 description 1
- 241000194031 Enterococcus faecium Species 0.000 description 1
- 241000991587 Enterovirus C Species 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
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 241000204939 Fasciola gigantica Species 0.000 description 1
- 241000242711 Fasciola hepatica Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 101710154643 Filamentous hemagglutinin Proteins 0.000 description 1
- 108010040721 Flagellin Proteins 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 101000770304 Frankia alni UPF0460 protein in nifX-nifW intergenic region Proteins 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 101000812705 Gallus gallus Endoplasmin Proteins 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
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 101710127404 Glycoprotein 3 Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 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
- 229940033330 HIV vaccine Drugs 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
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 229940124872 Hepatitis B virus vaccine Drugs 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 241000724675 Hepatitis E virus Species 0.000 description 1
- 241000709721 Hepatovirus A Species 0.000 description 1
- 241000282412 Homo 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
- 101000797762 Homo sapiens C-C motif chemokine 5 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
- 101000628547 Homo sapiens Metalloreductase STEAP1 Proteins 0.000 description 1
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 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
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000831496 Homo sapiens Toll-like receptor 3 Proteins 0.000 description 1
- 101000669460 Homo sapiens Toll-like receptor 5 Proteins 0.000 description 1
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- 206010071038 Human anaplasmosis Diseases 0.000 description 1
- 241000341655 Human papillomavirus type 16 Species 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 206010022004 Influenza like illness Diseases 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108090000176 Interleukin-13 Proteins 0.000 description 1
- 101800003050 Interleukin-16 Proteins 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 102000000704 Interleukin-7 Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 201000005807 Japanese encephalitis Diseases 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 101000782488 Junonia coenia densovirus (isolate pBRJ/1990) Putative non-structural protein NS2 Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 101000811523 Klebsiella pneumoniae Uncharacterized 55.8 kDa protein in cps region Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 1
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 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
- 239000005639 Lauric acid Substances 0.000 description 1
- 241000589242 Legionella pneumophila Species 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- 101000878851 Leptolyngbya boryana Putative Fe(2+) transport protein A Proteins 0.000 description 1
- 241000589929 Leptospira interrogans Species 0.000 description 1
- 241000712079 Measles morbillivirus Species 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
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 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
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 1
- 241000711386 Mumps virus Species 0.000 description 1
- 101100369076 Mus musculus Tdgf1 gene Proteins 0.000 description 1
- 206010049565 Muscle fatigue Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 241000187480 Mycobacterium smegmatis Species 0.000 description 1
- 101001055788 Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155) Pentapeptide repeat protein MfpA Proteins 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- BKAYIFDRRZZKNF-VIFPVBQESA-N N-acetylcarnosine Chemical compound CC(=O)NCCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 BKAYIFDRRZZKNF-VIFPVBQESA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 241001644525 Nastus productus Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 241000498270 Necator americanus Species 0.000 description 1
- 241000588650 Neisseria meningitidis Species 0.000 description 1
- 241000244206 Nematoda Species 0.000 description 1
- 208000000291 Nematode infections Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 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
- 208000011623 Obstructive Lung disease Diseases 0.000 description 1
- 241000243985 Onchocerca volvulus Species 0.000 description 1
- 241000133504 Opisthorchis sinensis Species 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
- 238000002944 PCR assay Methods 0.000 description 1
- 108060006580 PRAME Proteins 0.000 description 1
- 102000036673 PRAME Human genes 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 101150111072 Pars2 gene Proteins 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001466532 Pelecanus erythrorhynchos Species 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 108010081690 Pertussis Toxin Proteins 0.000 description 1
- 239000004264 Petrolatum Substances 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
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- 241000235645 Pichia kudriavzevii Species 0.000 description 1
- 101000983333 Plasmodium falciparum (isolate NF54) 25 kDa ookinete surface antigen Proteins 0.000 description 1
- 206010035501 Plasmodium malariae infection Diseases 0.000 description 1
- 206010035502 Plasmodium ovale infection Diseases 0.000 description 1
- 101710183389 Pneumolysin Proteins 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 102100035724 Probable ATP-dependent RNA helicase DDX43 Human genes 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 102100036735 Prostate stem cell antigen Human genes 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 101710132594 Protein E6 Proteins 0.000 description 1
- 101710132604 Protein F7 Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 101710155866 Protein J1 homolog Proteins 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- 108010067787 Proteoglycans 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
- 108010080192 Purinergic Receptors Proteins 0.000 description 1
- 102000000033 Purinergic Receptors Human genes 0.000 description 1
- 101710201576 Putative membrane protein Proteins 0.000 description 1
- 241001454523 Quillaja saponaria Species 0.000 description 1
- 235000009001 Quillaja saponaria Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 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
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 101710203837 Replication-associated protein Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 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
- 235000019774 Rice Bran oil Nutrition 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 101000999689 Saimiriine herpesvirus 2 (strain 11) Transcriptional regulator ICP22 homolog Proteins 0.000 description 1
- 101000790284 Saimiriine herpesvirus 2 (strain 488) Uncharacterized 9.5 kDa protein in DHFR 3'region Proteins 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- 241000607149 Salmonella sp. Species 0.000 description 1
- 241000219287 Saponaria Species 0.000 description 1
- 241001520868 Schistosoma mekongi Species 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 241000607764 Shigella dysenteriae Species 0.000 description 1
- 241000607760 Shigella sonnei Species 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- 102000004598 Small Nuclear Ribonucleoproteins Human genes 0.000 description 1
- 108010003165 Small Nuclear Ribonucleoproteins Proteins 0.000 description 1
- 235000019764 Soybean Meal Nutrition 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 101000936719 Streptococcus gordonii Accessory Sec system protein Asp3 Proteins 0.000 description 1
- 241000193996 Streptococcus pyogenes 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
- 241000244177 Strongyloides stercoralis Species 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 101710137302 Surface antigen S Proteins 0.000 description 1
- 108010002687 Survivin Proteins 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 229940124614 TLR 8 agonist Drugs 0.000 description 1
- 108700012920 TNF Proteins 0.000 description 1
- 241000244159 Taenia saginata Species 0.000 description 1
- 241000244157 Taenia solium Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010043376 Tetanus Diseases 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
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 1
- 102000009843 Thyroglobulin Human genes 0.000 description 1
- 108010034949 Thyroglobulin Proteins 0.000 description 1
- 208000024799 Thyroid disease Diseases 0.000 description 1
- 108090000253 Thyrotropin Receptors Proteins 0.000 description 1
- 102100029337 Thyrotropin receptor Human genes 0.000 description 1
- 241000710771 Tick-borne encephalitis virus Species 0.000 description 1
- 102100024324 Toll-like receptor 3 Human genes 0.000 description 1
- 102100039357 Toll-like receptor 5 Human genes 0.000 description 1
- 102100039390 Toll-like receptor 7 Human genes 0.000 description 1
- 241000223996 Toxoplasma Species 0.000 description 1
- 101710134694 Transcriptional regulator ICP22 homolog Proteins 0.000 description 1
- 102000010912 Transferrin-Binding Proteins Human genes 0.000 description 1
- 241000242541 Trematoda Species 0.000 description 1
- 208000004938 Trematode Infections Diseases 0.000 description 1
- 241000589886 Treponema Species 0.000 description 1
- 241000589892 Treponema denticola Species 0.000 description 1
- 241000243777 Trichinella spiralis Species 0.000 description 1
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 1
- 241001489151 Trichuris Species 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 102000003425 Tyrosinase Human genes 0.000 description 1
- 108060008724 Tyrosinase Proteins 0.000 description 1
- 108010046334 Urease Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 206010046980 Varicella Diseases 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
- 229930003427 Vitamin E Natural products 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 241000244005 Wuchereria bancrofti Species 0.000 description 1
- 241000710772 Yellow fever virus Species 0.000 description 1
- 241000607447 Yersinia enterocolitica Species 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 241000606834 [Haemophilus] ducreyi Species 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 230000000240 adjuvant effect Effects 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229940047712 aluminum hydroxyphosphate Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 208000025009 anogenital human papillomavirus infection Diseases 0.000 description 1
- 201000004201 anogenital venereal wart Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000001355 anti-mycobacterial effect Effects 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 208000037908 antibody-mediated disorder Diseases 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 230000008350 antigen-specific antibody response Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 210000002769 b effector cell Anatomy 0.000 description 1
- 201000008680 babesiosis Diseases 0.000 description 1
- 229940065181 bacillus anthracis Drugs 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 229940055022 candida parapsilosis Drugs 0.000 description 1
- 210000000234 capsid Anatomy 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000000837 carbohydrate group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- ADRVNXBAWSRFAJ-UHFFFAOYSA-N catechin Natural products OC1Cc2cc(O)cc(O)c2OC1c3ccc(O)c(O)c3 ADRVNXBAWSRFAJ-UHFFFAOYSA-N 0.000 description 1
- 235000005487 catechin Nutrition 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 229950001002 cianidanol Drugs 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 201000003278 cryoglobulinemia Diseases 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- VXVVUHQULXCUPF-UHFFFAOYSA-N cycloheptanamine Chemical compound NC1CCCCCC1 VXVVUHQULXCUPF-UHFFFAOYSA-N 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- UVYVLBIGDKGWPX-KUAJCENISA-N digitonin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@H](O[C@H]5[C@@H]([C@@H](O)[C@@H](O[C@H]6[C@@H]([C@@H](O[C@H]7[C@@H]([C@@H](O)[C@H](O)CO7)O)[C@H](O)[C@@H](CO)O6)O[C@H]6[C@@H]([C@@H](O[C@H]7[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O7)O)[C@@H](O)[C@@H](CO)O6)O)[C@@H](CO)O5)O)C[C@@H]4CC[C@H]3[C@@H]2[C@@H]1O)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 UVYVLBIGDKGWPX-KUAJCENISA-N 0.000 description 1
- UVYVLBIGDKGWPX-UHFFFAOYSA-N digitonine Natural products CC1C(C2(CCC3C4(C)CC(O)C(OC5C(C(O)C(OC6C(C(OC7C(C(O)C(O)CO7)O)C(O)C(CO)O6)OC6C(C(OC7C(C(O)C(O)C(CO)O7)O)C(O)C(CO)O6)O)C(CO)O5)O)CC4CCC3C2C2O)C)C2OC11CCC(C)CO1 UVYVLBIGDKGWPX-UHFFFAOYSA-N 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- FOBPTJZYDGNHLR-UHFFFAOYSA-N diphosphorus Chemical compound P#P FOBPTJZYDGNHLR-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 208000008576 dracunculiasis Diseases 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 231100000249 enterotoxic Toxicity 0.000 description 1
- 230000002242 enterotoxic 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
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- 235000020664 gamma-linolenic acid 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
- 229940124670 gardiquimod Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229940085435 giardia lamblia Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 230000002414 glycolytic effect Effects 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 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
- 210000003714 granulocyte Anatomy 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 229940045808 haemophilus influenzae type b Drugs 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 208000005252 hepatitis A Diseases 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 238000007489 histopathology method Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 201000009163 human granulocytic anaplasmosis Diseases 0.000 description 1
- 208000022340 human granulocytic ehrlichiosis Diseases 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- RJTZUHVCZIGJMB-UHFFFAOYSA-N hydron;1h-indole;chloride Chemical class Cl.C1=CC=C2NC=CC2=C1 RJTZUHVCZIGJMB-UHFFFAOYSA-N 0.000 description 1
- FAHBNUUHRFUEAI-UHFFFAOYSA-M hydroxidooxidoaluminium Chemical compound O[Al]=O FAHBNUUHRFUEAI-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 229960002751 imiquimod Drugs 0.000 description 1
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 1
- 230000005965 immune activity Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000003365 immunocytochemistry Methods 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007915 intraurethral administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- VRDLZINLAAZCHM-UHFFFAOYSA-N isosqualene Natural products CC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C VRDLZINLAAZCHM-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000003866 lung sarcoma Diseases 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 101710130522 mRNA export factor Proteins 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- OYHZQJYAAVMDIQ-UHFFFAOYSA-L magnesium;2-methylpropanedioate Chemical compound [Mg+2].[O-]C(=O)C(C)C([O-])=O OYHZQJYAAVMDIQ-UHFFFAOYSA-L 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000005541 medical transmission Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 210000001806 memory b lymphocyte Anatomy 0.000 description 1
- 210000003071 memory t lymphocyte Anatomy 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- ZIYVHBGGAOATLY-UHFFFAOYSA-N methylmalonic acid Chemical compound OC(=O)C(C)C(O)=O ZIYVHBGGAOATLY-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000012569 microbial contaminant Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 235000014571 nuts Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940046166 oligodeoxynucleotide Drugs 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940099789 ospa protein Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 108010021711 pertactin Proteins 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- GWNIPPQZLLOJTO-HXUWFJFHSA-N phenacyl (3r)-3-hydroxytetradecanoate Chemical compound CCCCCCCCCCC[C@@H](O)CC(=O)OCC(=O)C1=CC=CC=C1 GWNIPPQZLLOJTO-HXUWFJFHSA-N 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 229940118768 plasmodium malariae Drugs 0.000 description 1
- 101150106828 pmpD gene Proteins 0.000 description 1
- 229940124733 pneumococcal vaccine Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229940021993 prophylactic vaccine Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 244000000040 protozoan parasite Species 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- BXNMTOQRYBFHNZ-UHFFFAOYSA-N resiquimod Chemical compound C1=CC=CC2=C(N(C(COCC)=N3)CC(C)(C)O)C3=C(N)N=C21 BXNMTOQRYBFHNZ-UHFFFAOYSA-N 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000008165 rice bran oil Substances 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 238000009589 serological test Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000010686 shark liver oil Substances 0.000 description 1
- 229940069764 shark liver oil Drugs 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 238000007390 skin biopsy Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000004455 soybean meal Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940031626 subunit vaccine Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940118376 tetanus toxin Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 229960002175 thyroglobulin Drugs 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 208000021510 thyroid gland disease Diseases 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 230000024664 tolerance induction Effects 0.000 description 1
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229940093609 tricaprylin Drugs 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- NQPHMXWPDCSHTE-UHFFFAOYSA-N trifluoromethanesulfonyl azide Chemical compound FC(F)(F)S(=O)(=O)N=[N+]=[N-] NQPHMXWPDCSHTE-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- 229960001005 tuberculin Drugs 0.000 description 1
- 229960002109 tuberculosis vaccine Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000002477 vacuolizing effect Effects 0.000 description 1
- 229940118696 vibrio cholerae Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000010497 wheat germ oil Substances 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7024—Esters of saccharides
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7016—Disaccharides, e.g. lactose, lactulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/04—Mycobacterium, e.g. Mycobacterium tuberculosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/21—Retroviridae, e.g. equine infectious anemia virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/235—Adenoviridae
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/245—Herpetoviridae, e.g. herpes simplex virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/275—Poxviridae, e.g. avipoxvirus
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
- C07H11/04—Phosphates; Phosphites; Polyphosphates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/12—Acyclic radicals, not substituted by cyclic structures attached to a nitrogen atom of the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55572—Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
- A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
Description
本發明係關於醫藥及疫苗組合物之領域。更具體而言,本文所述實施例係關於醫藥及疫苗組合物、以及相關預防及治療方法,其中該等組合物包含如本文所述葡萄吡喃糖基脂質佐劑(GLA)。
較高等有機體之免疫系統的特徵在於辨別外來試劑(或「非自身」試劑)與熟悉或「自身」組份,以使外來試劑激發免疫應答同時忽略或耐受「自身」組份。傳統上,免疫應答之特徵在於其中由稱作血漿細胞之分化B淋巴細胞產生對抗原具有特異性之抗體的體液應答、或其中各種類型之T淋巴細胞藉由多種機制起作用以消除抗原的細胞調介之應答。舉例而言,能夠辨識特異性抗原之CD4+輔助T細胞可藉由釋放可溶性調介子(例如細胞因子)以募集免疫系統之額外細胞以在免疫應答中沉澱來應答。同時,亦能夠辨識特異性抗原之CD8+細胞毒性T細胞可藉由結合帶有抗原之細胞或顆粒並對其進行破壞或損害來應答。已知在免疫技術中通常出於誘發宿主中之期望免疫應答的目的,根據各種調配物提供某些疫苗。
經由向宿主投與疫苗來激發特異性免疫應答之若干策略包括用熱殺死或活的減毒感染病原體(例如,病毒、細菌或某些真核生物病原體)進行免疫接種;或用能夠引導編碼抗原之遺傳物質表現的非病毒感染劑進行免疫接種,期望對該(等)抗原免疫應答;及用含有來自
特定病原體之分離免疫原(例如蛋白質)的亞單位疫苗進行免疫接種以誘發抵抗病原體之免疫力。(參見,例如,Liu,1998 Nature Medicine 4(增刊5):515)。對於某些抗原而言,可存在一或多種類型之合意的免疫力,其中該等方法均不特別有效,包括有效保護宿主免疫抵抗人類免疫缺陷病毒或其他感染病原體、癌症、自身免疫疾病或其他臨床病況之疫苗的開發。
很早以前就已知腸細菌脂多糖(LPS)係免疫系統之強效刺激劑,但因其毒性效應其在佐劑中之用途受到限制。LPS之非毒性衍生物(藉由自還原端葡萄糖胺去除核心碳水化合物基團及磷酸根產生之單磷醯脂質A(MPL))已由Ribi等人(1986,Immunology and Immunopharmacology of Bacterial Endotoxins,Plenum Publ.公司,NY,p407-419)進行闡述。
MPL之其他去毒形式係由自二糖骨架之3位置去除醯基鏈產生且稱為3-O-去醯基化單磷醯脂質A(3D-MPL)。可藉由GB 2122204B中教示之方法對其進行純化及製備,該參考文獻亦揭示二磷醯脂質A、及其3-O-去醯基化變體之製備。舉例而言,已製備呈具有直徑小於0.2μm之小粒徑的乳液形式的3D-MPL,且其製造方法揭示於WO 94/21292中。包含單磷醯脂質A及表面活性劑之水性調配物已闡述於WO 9843670A2中。
可自細菌來源純化及處理欲調配於佐劑組合中之細菌脂多糖衍生之佐劑,或者另一選擇為其可合成。舉例而言,純化單磷醯脂質A闡述於Ribi等人(1986)(見上文)中,且源自沙門氏菌屬(Salmonella sp.)之3-O-去醯基化單磷醯或二磷醯脂質A闡述於GB 2220211及美國專利第4,912,094號中。3D-MPL及β(1-6)葡萄糖胺二糖以及其他純化及合成脂多糖已進行闡述(WO 98/01139;美國專利第6,005,099號及EP 0 729 473 B1,Hilgers等人,1986 Int.Arch.Allergy Immunol.,
79(4):392-6;Hilgers等人,1987,Immunology,60(1);141-6;及EP 0 549 074 B1)。3D-MPL及源自奎拉雅屬皂樹(Quillaja Saponaria molina)之樹皮之皂苷佐劑的組合已闡述於EP 0 761 231B中。WO 95/17210揭示基於角鯊烯、α-生育酚及聚氧乙烯山梨醇酐單油酸酯(TWEENTM-80)之佐劑乳液系統,其與免疫刺激劑QS21一起調配且視情況包括3D-MPL。儘管存在該等組合之可及性,但使用源自天然產物之佐劑伴有高生產成本、各批次之間不一致性、與大規模生產相關之困難、及在任一給定製劑之組成構成中對於是否存在雜質之不確定性。
因此,需要改良之疫苗、且具體而言需要有利地含有高純度、化學界定佐劑組份之疫苗,該等佐劑組份呈現批次之間一致性且可以工業規模有效率地製造而不引入不期望或化學上未界定之污染物。本發明提供用於該等疫苗之組合物及方法,且提供其他相關優勢。
本發明在其若干態樣中係關於有利地利用某些合成的葡萄吡喃糖基脂質佐劑(GLA)作為免疫調節劑或佐劑的化合物、組合物及方法。因此,根據本文所述本發明之一個態樣,提供具有下式(I)之結構的GLA化合物:
或其醫藥上可接受之鹽,其中L1、L2、L3、L4、L5、L6、L7、L8、L9、L10、Y1、Y2、Y3、Y4、R1、R2、R3、R4、R5、R6係如本文所定義。
本發明之GLA化合物在寬範圍之治療應用中具有效用,其中期望誘發特異性或非特異性免疫應答。舉例而言,在本發明之某些態樣中,提供包含一或多種本文所述GLA化合物與抗原之組合的疫苗組合物。該等疫苗組合物可有利地用於在有需要之個體中刺激抗原特異性免疫應答之方法中。在本發明之其他態樣中,提供包含一或多種本文所述GLA化合物之醫藥組合物,其中該等組合物實質上無抗原。該等醫藥組合物可有利地用於在有需要之個體中刺激非特異性免疫應答之方法中,例如,用於治療感染、季節性鼻炎及諸如此類。
參照下文具體說明及附圖,本發明之該等及其他態樣將顯而易見。另外,本文所述之各種參考文獻更詳細地闡述本發明之某些態樣,且因此其全文以引用方式併入本文中。
圖1證實在小鼠用包含抗原及GLA之本發明組合物免疫接種之後活體內誘發之IFN-γ細胞因子產生;圖2A-2F顯示在小鼠用包含抗原及GLA之本發明組合物免疫接種之後活體內誘發之抗體應答;圖3顯示於本發明闡釋性GLA化合物(化合物IX)之不同濃度下觀察到的NF-kB增強;及圖4A-4D顯示於本發明闡釋性GLA化合物(化合物IX)之不同濃度下免疫刺激細胞因子(MIP-1b及TNFa)的誘發。
已知單磷醯脂質A(MPL)及其他相關佐劑可至少部分地藉由作為類鐸(Toll-like)受體(TLR)之激動劑起作用來調介其效應。基於與TLR
受體刺激有關之3D結構考慮因素合理地設計本發明之葡萄吡喃糖基脂質佐劑(GLA)化合物。更具體而言,根據本發明,藉由選擇性界定本發明GLA化合物之醯基鏈長度以使其在化合物之三維結構中達成「扁平」底部,可在TLR受體之結合位點內達成改良之配合,藉此產生增強之TLR刺激及增強之免疫刺激性質。另外,本發明GLA化合物之溶解度(例如,在水溶液中)由於縮短之醯基鏈長度而有利地得以改良,藉此有利於有效率且有效之化合物調配。此外,由於醯基鏈長度適於使得分子沿分子底部為三維「平的」,故可將化合物更有效地納入囊泡中用於(例如)脂質體調配物。
另外,本發明化合物提供有利之效能對毒性之曲線。舉例而言,本發明化合物可在寬且相對較高劑量範圍內使用以達成期望位準之活性(例如,佐劑活性),同時仍然對人類細胞及人類患者實質上無毒性,如藉由(例如)在一系列濃度內自人類細胞產生之腫瘤壞死因子之含量所分析,其不像其他更具毒性之TLR4激動劑(例如脂多糖)那樣,而是快速升高並趨向於平穩。此基於細胞之分析應可預測人類藥理學中不利事件中涉及之較低炎症標記(如C-反應蛋白)。例如,當將本發明化合物投與給對細胞因子之耐受性可能較低的兒童時,或當該等化合物用於以大群體為目標之調配物中時,本發明化合物的有利之效能對毒性之曲線可尤為重要,其中對於對TLR激動具有不同應答性之人群而言,更平穩的應答將轉化為更一致臨床結果。類似地,當活性醫藥成份之範圍不需嚴格控制於耐受位準時,由於靶向投藥將更具寬容度且製造簡單化,故註冊審批亦將簡單化。
因此,本發明在其許多實施例中提供包括如本文所述合成的GLA化合物之化合物、疫苗組合物、佐劑組合物、醫藥組合物及相關調配物及方法。GLA化合物代表合成的免疫調節劑,相對於現有技術之佐劑且尤其相對於天然產物佐劑,其可有利地以實質上均勻形式製備。
此外,本發明之GLA化合物可經由大規模合成化學製造方法有效率且經濟地製備,不同於天然產物衍生之佐劑。由於自界定起始材料化學合成以獲得化學界定之產物的合成佐劑呈現定性及定量批與批之間一致性,故本發明之GLA化合物提供包括改良之產品品質控制的益處。
如本文所述,在一些實施例中,GLA化合物、組合物及其使用方法包括GLA本身與醫藥上可接受之載劑或賦形劑用於免疫佐劑活性(例如,非特異性免疫刺激活性)之用途,包括其中向個體投與GLA可完全獨立於向個體投與一或多種抗原及/或在時間上及/或空間上與其分離之「輔佐性」,期望激發或增強個體中對該等抗原之免疫應答(例如,抗原特異性應答)。其他實施例包括GLA在疫苗組合物中之用途,該疫苗組合物亦包括期望藉由此疫苗激發或增強免疫應答之一或複數種抗原。
如本文所述,該等疫苗組合物可在某些相關實施例中亦包括一或多種類鐸受體(TLR)激動劑及/或一或多種共佐劑、咪唑并喹啉免疫應答調節劑、及雙莖環免疫調節劑(dSLIM)中之一個或複數個。在其他相關實施例中,本文提供之疫苗組合物可包含GLA及一或多種重組表現構築體,該等構築體各自包含可操作地連接至編碼抗原之核酸序列的啟動子,期望激發或增強個體中對該抗原之免疫應答(例如,抗原特異性應答)。
如上所述,由於GLA係化學合成佐劑,故其可以實質上均勻形式製備,該實質上均勻形式GLA係指就GLA分子而言純度為至少80%、較佳至少85%、更佳至少90%、更佳至少95%且仍更佳至少96%、97%、98%或99%的GLA製劑。
本發明之GLA化合物具有下式(I):
或其醫藥上可接受之鹽,其中:L1、L2、L3、L4、L5及L6相同或不同且獨立地係-O-、-NH-或-(CH2)-;L7、L8、L9及L10相同或不同且獨立地不存在或為-C(=O)-;Y1係酸官能團;Y2及Y3相同或不同且獨立地係-OH、-SH或酸官能團;Y4係-OH或-SH;R1、R3、R5及R6相同或不同且獨立地係C8-13烷基;且R2及R4相同或不同且獨立地係C6-11烷基。
本文所用上述術語具有以下含義:「烷基」意指含有1至20個碳原子、且在某些較佳實施例中含有11至20個碳原子之直鏈或具支鏈、非環狀或環狀、不飽和或飽和脂肪族烴。代表性飽和直鏈烷基包括甲基、乙基、正丙基、正丁基、正戊基、正己基及諸如此類,包括十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基等;而飽和具支鏈烷基包括異丙基、第二丁基、異丁基、第三丁基、異戊基及諸如此類。代表性飽和環狀烷基包括環丙基、環丁基、環戊基、環己基及諸如此類;而不飽和環狀烷基包括環戊烯基及環己烯基及諸如此類。環
狀烷基在本文中亦稱作「同素環」或「同素環狀環」。不飽和烷基在相鄰碳原子間含有至少一個雙鍵或三鍵(分別稱為「烯基」或「炔基」)。代表性直鏈及具支鏈烯基包括乙烯基、丙烯基、1-丁烯基、2-丁烯基、異丁烯基、1-戊烯基、2-戊烯基、3-甲基-1-丁烯基、2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基及諸如此類;而代表性直鏈及具支鏈炔基包括乙炔基、丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-甲基-1-丁炔基及諸如此類。
「C8-13烷基」及「C6-11烷基」意指分別含有8至13或6至11個碳原子之如上文所定義烷基。
「酸官能團」意指能夠在水性介質中提供質子之官能團(即Brønsted-Lowry酸)。在供應質子之後,酸官能團變為帶負電荷之物質(即,酸官能團之共軛鹼)。酸官能團之實例包括(但不限於):-OP(=O)(OH)2(磷酸根)、-OS(=O)(OH)2(硫酸根)、-OS(OH)2(亞硫酸根)、-C(=O)OH(羧酸根)、-OC(=O)CH(NH2)CH2C(=O)OH(天冬胺酸根)、-OC(=O)CH2CH2C(=O)OH(琥珀酸酯根)、及-OC(=O)CH2OP(=O)(OH)2(羧甲基磷酸根)。
在更具體實施例中,本發明提供式(I)之GLA化合物,其中L5及L6二者均係-O-且L7、L8、L9及L10各自係-C(=O)-,且GLA化合物具有下式(II):
(II)
在更具體實施例中,本發明提供式(II)之GLA化合物,其中R1、R3、R5及R6各自係Cx烷基,其中x係恆定的且係選自8至13之整數,且R2及R4二者均係Cx-2烷基,且GLA化合物具有下式(III):
在其他更具體實施例中,本發明提供式(III)之GLA化合物,其中x係選自10至12之整數。
在其他更具體實施例中,本發明提供式(III)之GLA化合物,其中x係11,且GLA化合物具有以下結構(IV):
在又一些具體實施例中,本發明提供式(II)之GLA化合物,其中
Y1係-OP(=O)(OH)2且Y2、Y3及Y4各自係-OH,且GLA化合物具有下式(V):
在其他具體實施例中,本發明提供式(II)之GLA化合物,其中L1及L3二者均係-O-且L2及L4二者均係-NH-,且GLA化合物具有下式(VI):
在再更具體實施例中,本發明提供式(II)之GLA化合物,其中Y1係-OP(O)(OH)2,Y2、Y3及Y4各自係-OH,L1及L3二者均係-O-,且L2及L4二者均係-NH-,且GLA化合物具有下式(VII):
在又一些具體實施例中,本發明提供式(II)之GLA化合物,其中Y1係-OP(O)(OH)2,Y2、Y3及Y4各自係-OH,L1及L3二者均係-O-,L2及L4二者均係-NH-,R1、R3、R5及R6各自係Cx烷基,其中x係恆定的且係選自8至13之整數,且R2及R4二者均係Cx-2烷基,且GLA化合物具有下式(VIII):
在式(VIII)之更具體實施例中,x係11,且本發明提供具有以下結構(IX)之GLA化合物:
(IX)
如上文所提及,本發明提供GLA化合物。本發明之GLA化合物可藉由已知有機合成技術(包括實例中更詳細闡述之方法)製備。一般而言,結構(I)之GLA化合物可藉由以下反應示意圖製備,其中除非另有說明否則所有取代基均係如上文所定義。
代表性GLA化合物之糖骨架通常可根據反應示意圖1製備,其中G1、G2、G3、G4、G5、G6、G7、G8、G9及G10相
同或不同且獨立地係適當保護基團或氫。適當糖(例如(i))可購得或根據彼等熟習此項技術者已知之方法製備。隨後可使用彼等熟習此項技術者已知之方法完全保護糖(i)之官能團以獲得(ii)。就此而言,熟習此項技術者應認識到可採用可使得糖官能團選擇性去保護之適當正交保護基團策略。適宜保護基團包括(但不限於)甲矽烷基醚、苄基醚、烯丙氧基羰基、縮醛、Fmoc、疊氮化物及諸如此類。G1之去保護產生游離醇(iii),隨後可使用適當偶合條件(例如,CCl3CN/NaH)使其與經保護糖(iv)偶合,從而獲得期望糖骨架(v)。
代表性GLA化合物尾片(其中L5及L6二者均係-O-且L7、L8、L9及L10各自係-C(=O)-)通常可根據反應示意圖2製備,其中G11代表適當保護基團。結構(vi)之酸化合物可購得或根據彼等熟習此項技術者已知之方法製備。與適當試劑(例如甲基丙二酸氫)反應,產生酮酯(vii)。還原(vii),產生醇(viii)。熟習此項技術者應認識到可如實例中所例示在適當條件下立體專一還原(vii)之酮基團。(viii)之皂化產生酸(ix),可隨後對其進行保護以產生(x)。用醯氯(xi)處理(x),產生(xii),其在
去保護後產生(xiii)。化合物(ix)及(xiii)二者均可藉由彼等熟習此項技術者已知之方法轉化為適宜保護之醯氯衍生物且附接至GLA化合物糖骨架,如下文反應示意圖3中所示。儘管反應示意圖2繪示包含R1及R2之GLA化合物尾片的合成,但應瞭解亦可藉由類似方法製備包含其他烷基(例如,R3、R4、R5及R6)之其他尾片。亦可藉由類似方法製備具有不同L5、L6、L7、L8、L9及L10基團之其他尾片。
代表性GLA化合物通常可根據反應示意圖3製備,其中G12及G13相同或不同且獨立地代表適當保護基團。去除(v)之G5保護基團,之後與醯氯(xiv)反應,從而生成(xv)。類似地,去除(xv)之G8保護基團,之後與醯氯(xvi)反應,從而產生(xvii)。使(xvii)去保護並與醯氯(xviii)反應,從而產生(xix)。去除G9且與(xx)反應,則生成受保護之GLA化合物(xxi)。使(xxi)整體去保護,從而產生結構(II)之化合物。儘管反應示意圖3繪示結構(II)之化合物的合成,但熟習此項技術者應認識到可採用類似方法生成結構(I)之任一化合物。另外,熟習此項技術者亦應認識到利用適當保護基團之選擇,最終去保護產生期望化合物。
本發明化合物通常可以游離鹼或游離酸形式利用。或者,本發明化合物可以酸或鹼加成鹽形式使用。本發明之游離胺基化合物的酸加成鹽可藉由相關技藝熟知之方法製備且可自有機及無機酸形成。適宜有機酸包括馬來酸、富馬酸、苯甲酸、抗壞血酸、琥珀酸、甲烷磺酸、乙酸、草酸、丙酸、酒石酸、水楊酸、檸檬酸、葡萄糖酸、乳酸、扁桃酸、肉桂酸、天冬胺酸、硬脂酸、棕櫚酸、乙醇酸、麩胺酸及苯磺酸。適宜無機酸包括氫氯酸、氫溴酸、硫酸、磷酸及硝酸。
類似地,本發明之酸化合物的鹼加成鹽可藉由相關技藝熟知之方法製備且可自有機及無機鹼形成。適宜有機鹼包括(但不限於)三乙胺及吡啶。適宜無機鹼包括(但不限於)氫氧化鈉、氫氧化鉀、碳酸鈉、碳酸鉀及氨。因而,術語結構(I)之「醫藥上可接受之鹽」意欲涵蓋任一及所有可接受之鹽形式。
另外,本發明上下文中亦包括前藥。前藥係在將該前藥投與患者時在活體內釋放結構(I)之化合物的任何共價鍵結載劑。前藥通常係以修飾藉由常規操作或在活體內解離而產生母體化合物之方式修飾官能團來製備。前藥包括(例如)本發明化合物,其中羥基、胺或巰基鍵
結至當投與患者時解離形成羥基、胺或巰基之任一基團。因而,前藥之代表性實例包括(但不限於)結構(I)之化合物之醇及胺官能團的乙酸鹽、甲酸鹽及苯甲酸鹽衍生物。此外,在羧酸(COOH)之情形下,可採用酯,例如甲基酯、乙基酯及諸如此類。
就立體異構體而言,結構(I)之化合物可具有對掌性中心且可以外消旋異構體、外消旋混合物及個別對映異構體或非對映異構體形式存在。所有該等同分異構體形式均包括於本發明內,包括其混合物。此外,結構(I)之化合物的一些結晶形式可以多晶型形式存在,其包括於本發明中。另外,一些結構(I)之化合物亦可與水或其他有機溶劑形成溶劑合物。該等溶劑合物類似地包括於本發明範疇內。
用於本文所述疫苗組合物及採用GLA之方法的某些實施例中之抗原可為任一靶向抗原決定基、分子(包括生物分子)、分子複合物(包括含有生物分子之分子複合物)、亞細胞總成、細胞或組織,期望激發或增強個體中對該抗原之免疫反應性。通常,術語抗原應指目標多肽抗原。然而,本文所用抗原亦可指編碼目標多肽抗原之重組構築體(例如,表現構築體)。在某些較佳實施例中,抗原可為、或可源自與以下疾病相關之感染病原體及/或抗原決定基、生物分子、細胞或組織,或可與其免疫交叉反應:感染、癌症、自身免疫疾病、過敏症、哮喘或其中刺激抗原特異性免疫應答可為合意的或有益處之任一其他病況。
較佳地且在某些實施例中,本發明之疫苗調配物含有能夠激發抵抗人類或其他哺乳動物病原體之免疫應答的抗原或抗原性組合物,該抗原或抗原性組合物可包括源自諸如以下等病毒之組合物:HIV-1(例如,tat、nef、gp120或gp160)、人類皰疹病毒(例如,gD或其衍生物)或即刻早期蛋白(例如,來自HSV1或HSV2之ICP27)、巨細胞病
毒((尤其人類)(例如gB或其衍生物)、輪狀病毒(包括活的減毒病毒)、愛潑斯坦巴爾病毒(Epstein Barr virus)(例如,gp350或其衍生物)、水痘-帶狀皰疹病毒(Varicella Zoster Virus)(例如,gpI、II及IE63)、或肝炎病毒(例如,B型肝炎病毒(例如,B型肝炎表面抗原或其衍生物)、A型肝炎病毒、C型肝炎病毒及E型肝炎病毒)、或其他病毒病原體(例如,副黏病毒(paramyxoviruses):呼吸道合胞病毒(例如,F及G蛋白或其衍生物)、副流行性感冒病毒、麻疹病毒、流行性腮腺炎病毒、人類乳頭瘤病毒(例如,HPV6、11、16、18等)、黃病毒(例如,黃熱病病毒、登革熱病毒(Dengue Virus)、蜱傳腦炎病毒(Tick-borne encephalitis virus)、日本腦炎病毒(Japanese Encephalitis Virus)或流行性感冒病毒(全活或滅活病毒、裂解之流行性感冒病毒(生長於蛋或MDCK細胞中)、或全流行性感冒病毒體(如由Gluck,Vaccine,1992,10,915-920所述)或其純化或重組蛋白(例如HA、NP、NA或M蛋白、或其組合))。
在某些其他較佳實施例中,本發明之疫苗調配物含有能夠激發抵抗人類或其他哺乳動物病原體之免疫應答的抗原或抗原性組合物,該抗原或抗原性組合物可包括源自以下之一或多種細菌病原體的組合物:例如,奈瑟菌屬(Neisseria spp),包括淋球菌(N.gonorrhea)及腦膜炎雙球菌(N.meningitidis)(例如,莢膜多糖及其偶聯物、轉鐵蛋白結合蛋白、乳鐵傳遞蛋白結合蛋白、PilC、黏附素);膿鏈球菌(S.pyogenes)(例如,M蛋白或其片段、C5A蛋白酶、脂磷壁酸);無乳鏈球菌(S.agalactiae)、變形鏈球菌(S.mutans);杜克氏嗜血桿菌(H.ducreyi);莫拉菌屬(Moraxella spp),包括卡他莫拉菌(M catarrhalis),亦稱作卡他布蘭漢球菌(Branhamella catarrhalis)(例如,高及低分子量黏附素及侵染素);博德氏桿菌屬(Bordetella spp),包括百日咳博德氏桿菌(B.pertussis)(例如,百日咳桿菌黏附素
(pertactin)、百日咳毒素或其衍生物、絲狀血凝素、腺苷酸環化酶、菌毛)、副百日咳博德氏桿菌(B.parapertussis)及枝氣管敗血鮑特氏菌(B.bronchiseptica);分枝桿菌屬(Mycobacterium spp.),包括結核分枝桿菌(M.tuberculosis)(例如ESAT6、抗原85A、-B或-C)、牛型分枝桿菌(M.bovis)、麻風分枝桿菌(M.leprae)、鳥型分枝桿菌(M.avium)、副結核分枝桿菌(M.paratuberculosis)、齒垢分枝桿菌(M.smegmatis);軍團菌屬(Legionella spp),包括嗜肺軍團菌(L.pneumophila);埃希氏菌屬(Escherichia spp),包括腸毒素大腸桿菌(enterotoxic E.coli)(例如,定居因子、不耐熱毒素或其衍生物、耐熱毒素或其衍生物)、腸出血性大腸桿菌、腸道病原性大腸桿菌(例如,志賀毒素樣毒素(shiga toxin-like toxin)或其衍生物);弧菌屬(Vibrio spp),包括霍亂弧菌(V.cholera)(例如,霍亂毒素或其衍生物);志賀氏桿菌屬(Shigella spp),包括宋內氏志賀桿菌(S.sonnei)、停乳志賀氏桿菌(S.dysenteriae)、福氏志賀氏桿菌(S.flexnerii);耶爾森氏菌屬(Yersinia spp),包括小腸結腸炎耶爾森氏菌(Y.enterocolitica)(例如,Yop蛋白)、鼠疫耶爾森氏菌(Y.pestis)、假結核耶爾森氏菌(Y.pseudotuberculosis);彎曲桿菌屬(Campylobacter spp),包括空腸彎曲桿菌(C.jejuni)(例如,毒素、黏附素及侵染素)及大腸彎曲桿菌(C.coli);沙門氏菌屬,包括傷寒沙門氏菌(S.typhi)、副傷寒沙門氏菌(S.paratyphi)、豬霍亂沙門氏菌(S.choleraesuis)、腸炎沙門氏菌(S.enteritidis);利斯特氏菌屬(Listeria spp.),包括單核細胞增生利斯特菌(L.monocytogenes);螺旋桿菌屬(Helicobacter spp),包括幽門螺旋桿菌(H.pylori)(例如,脲酶、過氧化氫酶、空泡素);假單胞菌屬(Pseudomonas spp),包括銅綠假單胞菌(P.aeruginosa);葡萄球菌屬(Staphylococcus spp.),包括金黃色葡萄球菌(S.aureus)、表皮葡萄球菌(S.epidermidis);腸球菌屬(Enterococcus spp.),包括糞腸球菌(E. faecalis)、屎腸球菌(E.faecium);梭狀芽孢桿菌屬(Clostridium spp.),包括破傷風梭狀芽孢桿菌(C.tetani)(例如,破傷風毒素及其衍生物)、肉毒梭狀芽孢桿菌(C.botulinum)(例如,肉毒毒素及其衍生物)、難辨梭狀芽孢桿菌(C.difficile)(例如,梭狀芽孢桿菌毒素A或B及其衍生物);芽胞桿菌屬(Bacillus spp.),包括炭疽芽孢桿菌(B.anthracis)(例如,肉毒毒素及其衍生物);棒桿菌屬(Corynebacterium spp.),包括白喉棒桿菌(C.diphtheriae)(例如,白喉毒素及其衍生物);疏螺旋體屬(Borrelia spp.),包括布氏疏螺旋體(B.burgdorferi)(例如,OspA、OspC、DbpA、DbpB)、嘎氏疏螺旋體(B.garinii)(例如,OspA、OspC、DbpA、DbpB)、阿氏疏螺旋體(B.afzelii)(例如,OspA、OspC、DbpA、DbpB)、安氏疏螺旋體(B.andersonii)(例如,OspA、OspC、DbpA、DbpB)、赫氏疏螺旋體(B.hermsii);埃裏希氏體屬(Ehrlichia spp.),包括馬埃裏希氏體(E.equi)及人粒細胞埃裏希氏體病(Human Granulocytic Ehrlichiosis)之病因;立克次氏體屬(Rickettsia spp),包括立氏立克次氏體(R.rickettsii);衣原體屬(Chlamydia spp.),包括沙眼衣原體(C.trachomatis)(例如,MOMP、肝素結合蛋白)、肺炎衣原體(C.pneumoniae)(例如,MOMP、肝素結合蛋白)、鸚鵡熱衣原體(C.psittaci);鉤端螺旋體屬(Leptospira spp.),包括問號鉤端螺旋體(L.interrogans);密螺旋體屬(Treponema spp.),包括蒼白密螺旋體(T.pallidum)(例如,稀有外膜蛋白)、齒垢密螺旋體(T.denticola)、豬痢疾密螺旋體(T.hyodysenteriae);或其他細菌病原體。
在某些其他較佳實施例中,本發明之疫苗調配物含有能夠激發抵抗人類或其他哺乳動物病原體之免疫應答的抗原或抗原性組合物,該抗原或抗原性組合物可包括源自以下之一或多者的組合物:寄生蟲(參見,例如,John,D.T.及Petri,W.A.,Markell and Voge's Medical Parasitology-第9版,2006,WB Saunders,Philadelphia;Bowman,D.D.,Georgis' Parasitology for Veterinarians-第8版,2002,WB Saunders,Philadelphia),例如瘧疾原蟲屬(Plasmodium spp.),包括惡性瘧原蟲(P.falciparum);弓形蟲屬(Toxoplasma spp.),包括鼠弓形蟲(T.gondii)(例如,SAG2、SAG3、Tg34);內阿米巴屬(Entamoeba spp.),包括溶組織內阿米巴(E.histolytica);巴貝蟲屬(Babesia spp.),包括果氏巴貝蟲(B.microti);錐蟲屬(Trypanosoma spp.),包括克魯斯錐蟲(T.cruzi);賈第蟲屬(Giardia spp.),包括蘭伯賈第蟲(G.lamblia);利什曼原蟲屬(Leishmania spp.),包括碩大利什曼原蟲(L.major);肺囊蟲屬(Pneumocystis spp.),包括卡氏肺囊蟲(P.carinii);毛滴蟲屬(Trichomonas spp.),包括陰道毛滴蟲(T.vaginalis);或來自能夠感染哺乳動物之蠕蟲,例如:(i)線蟲感染(包括但不限於:蟯蟲(Enterobius vermicularis)、人蛔蟲(Ascaris lumbricoides)、人鞭蟲(Trichuris trichuria)、美洲鉤蟲(Necator americanus)、十二指腸鉤蟲(Ancylostoma duodenalee)、班氏吳策線蟲(Wuchereria bancrofti)、馬來絲蟲(Brugia malayi)、旋盤尾絲蟲(Onchocerca volvulus)、麥地那龍線蟲(Dracanculus medinensis)、旋毛線蟲(Trichinella spiralis)、反糞類圓線蟲(Strongyloides stercoralis));(ii)吸蟲感染(包括但不限於:曼森血吸蟲(Schistosoma mansoni)、埃及血吸蟲(Schistosoma haematobium)、日本血吸蟲(Schistosoma japonicum)、湄公河裂體吸蟲(Schistosoma mekongi)、中華後睾吸蟲(Opisthorchis sinensis)、並殖吸蟲屬(Paragonimus sp)、肝片形吸蟲(Fasciola hepatica)、薑片吸蟲(Fasciola magna)、大片吸蟲(Fasciola gigantica));及(iii)絛蟲感染(包括但不限於:牛肉絛蟲(Taenia saginata)及豬肉絛蟲(Taenia solium))。因此,某些實施例可涵蓋包括源自血吸蟲屬(Schisostoma spp.)(曼森血吸蟲、埃及血吸蟲及/或日本血吸蟲)、或源自酵母(例 如,念珠菌屬(Candida spp.),包括白色念珠菌(C.albicans);隱球菌屬(Cryptococcus spp.),包括新型隱球菌(C.neoformans))之抗原的疫苗組合物。
結核分枝桿菌之其他較佳特異性抗原係(例如)Th Ra12、Tb H9、Tb Ra35、Tb38-1、Erd 14、DPV、MTI、MSL、mTTC2及hTCC1(WO 99/51748)。結核分枝桿菌之蛋白質亦包括融合蛋白質及其變體,其中至少兩種、較佳三種結核分枝桿菌多肽融合成較大蛋白質。較佳之融合體包括Ra12-TbH9-Ra35、Erd14-DPV-MTI、DPV-MTI-MSL、Erd14DPV-MTI-MSL-mTCC2、Erd14-DPV-MTI-MSL、DPV-MTI-MSL-mTCC2、TbH9-DPV-MTI(WO 99151748)。
衣原體之某些較佳抗原包括(例如)高分子量蛋白質(HWMP)(WO 99/17741)、ORF3(EP 366412)、CT622、CT610、pmpD、UVEB及推定之膜蛋白(Pmp)。疫苗調配物之其他衣原體抗原可選自WO 99128475中所述之群。較佳之細菌疫苗包含源自鏈球菌屬(Streptococcus spp)(包括肺炎鏈球菌(S.pneumoniae)(例如,莢膜多糖及其偶聯物、PsaA、PspA、PdB、鏈球菌溶血素、膽鹼結合蛋白)之抗原及蛋白抗原肺炎球菌溶血素(Biochem Biophys Acta,1989,67,1007;Rubins等人,Microbial Pathogenesis,25,337-342)及其突變體脫毒衍生物(WO 90/06951;WO 99/03884)。其他較佳之細菌疫苗包含源自嗜血桿菌屬(Haemophilus spp.)之抗原,該等嗜血桿菌包括B型流感嗜血桿菌(H. influenzae type B)(例如,PRP及其偶聯物)、非定型流感嗜血桿菌(nontypeable H.influenzae)(例如,OMP26)、高分子量黏附素、P5、P6、蛋白D及脂蛋白D、及絲束蛋白及絲束蛋白衍生肽(美國專利第5,843,464號)或其多次拷貝變體或融合蛋白。
B型肝炎表面抗原之衍生物已為相關技藝所熟知且尤其包括歐洲專利申請案EP-A414 374、EP-A-0304 578及EP 198474中所述彼等
PreS1、Pars2 S抗原。在一個較佳態樣中,尤其當在CHO細胞中表現時,本發明之疫苗調配物包含HIV-1抗原、gp120。在又一實施例中,本發明之疫苗調配物包含gD2t,如上文所定義。
在本發明之一較佳實施例中,含有所主張佐劑之疫苗包含源自被視為可造成生殖器疣之人類乳頭瘤病毒(HPV)(HPV 6或HPV 11及其他)、及可造成子宮頸癌之HPV病毒(HPV16、HPV18及其他)的抗原。生殖器疣預防性或治療性疫苗之尤佳形式包含L1粒子或殼粒、及包含選自HPV 6及HPV 11蛋白質E6、E7、L1及L2之一或多種抗原的融合蛋白。融合蛋白之某些較佳形式包括如WO 96/26277中所揭示L2E7、及如GB 9717953.5(PCT/EP98/05285)中所揭示蛋白D(1/3)-E7。較佳HPV子宮頸感染或癌症之預防性或治療性疫苗可包含HPV 16或18抗原。舉例而言,L1或L2抗原單體、或L1或L2抗原一起作為病毒樣粒子(VLP)存在或單獨的L1蛋白單獨存於VLP或殼粒結構中。此等抗原、病毒樣粒子及殼粒本身為已知。參見,例如,WO 94/00152、WO 94/20137、WO 94/05792及WO 93/02184。
舉例而言,額外早期蛋白可單獨包括或以融合蛋白(例如,E7、E2或較佳F5)形式包括;尤佳實施例包括包含L1E7融合蛋白之VLP(WO 96/11272)。尤佳HPV 16抗原包含與蛋白D載體融合以自HPV 16形成蛋白D-E6或E7融合體之早期蛋白E6或F7、或其組合;或E6或E7與L2之組合(WO 96/26277)。或者,HPV 16或18早期蛋白E6及E7可以單一分子(較佳為蛋白D-E6/E7融合體)形式存在。該疫苗可視情況含有來自HPV 18之E6及E7蛋白中的任一種或兩種,較佳地,呈蛋白D-E6或蛋白D-E7融合蛋白或蛋白D E6/E7融合蛋白形式。本發明之疫苗可額外包含來自其他HPV菌株、較佳來自菌株HPV 31或33之抗原。
本發明之疫苗進一步包含源自引發瘧疾之寄生蟲的抗原。舉例而言,來自惡性瘧原蟲之較佳抗原包括RTS,S及TRAP。RTS係一種雜
合蛋白,其實質上包含經由B型肝炎表面抗原preS2部分之四個胺基酸連接至B型肝炎病毒表面(S)抗原的惡性瘧原蟲環子孢子(CS)蛋白之所有C-末端部分。其全結構揭示於國際專利申請案第PCT/EP92/02591中,公開為主張英國專利申請案第9124390.7號之優先權的WO 93/10152。當在酵母中表現時,RTS以脂蛋白粒子形式產生,且當其與來自HBV之S抗原共表現時,其產生稱為RTS,S之混合粒子。
TRAP抗原闡述於公開為WO 90/01496之國際專利申請案第PCT/GB89/00895號中。本發明之一較佳實施例係瘧疾疫苗,其中抗原性製劑包含RTS,S與TRAP抗原之組合。可能為多級瘧疾疫苗之組份的候選物的其他瘧原蟲抗原係惡性瘧原蟲MSP1、AMA1、MSP3、EBA、GLURP、RAP1、RAP2、鉗合蛋白、PfEMP1、Pf332、LSA1、LSA3、STARP、SALSA、PfEXP1、Pfs25、Pfs28、PFS27125、Pfs16、Pfs48/45、Pfs230及其在瘧原蟲屬中之相似物。
因此,某些本文所揭示實施例涵蓋源自至少一種感染病原體之抗原,該等病原體係例如細菌、病毒或真菌,包括放線細菌(Actinobacterium),例如結核分枝桿菌或麻風分枝桿菌或另一分枝桿菌;細菌,例如屬沙門氏菌、奈瑟菌、疏螺旋體、衣原體或博德氏桿菌之一員;病毒,例如單純皰疹病毒、人類免疫缺陷病毒(HIV)、貓免疫缺陷病毒(FIV)、巨細胞病毒、水痘-帶狀皰疹病毒、肝炎病毒、愛潑斯坦巴爾病毒(EBV)、呼吸道合胞病毒、人類乳頭瘤病毒(HPV)及巨細胞病毒;HIV,例如HIV-1或HIV-2;真菌,例如曲黴菌屬(Aspergillus)、芽生菌屬(Blastomyces)、球孢菌屬(Coccidioides)及肺囊蟲屬或酵母,包括念珠菌物種,例如白色念珠菌、光滑球念珠茵(C.glabrata)、克柔念珠菌(C.krusei)、魯希特念珠菌(C.lusitaniae)、熱帶念珠菌(C.tropicalis)及近平滑假絲酵母(C.parapsilosis);寄生蟲,例如原蟲,例如,瘧原蟲物種,包括惡性瘧原蟲、間日瘧原蟲
(P.vivax)、三日瘧原蟲(P.malariae)及卵形瘧原蟲(P.ovale);或另一寄生蟲,例如棘阿米巴屬(Acanthamoeba)、溶組織內阿米巴、管圓線蟲屬(Angiostrongylus)、曼森血吸蟲、埃及血吸蟲、日本血吸蟲、隱孢子蟲屬(Cryptosporidium)、鉤口線蟲屬(Ancylostoma)、溶組織內阿米巴、結腸內阿米巴(Entamoeba coli)、迪斯帕內阿米巴(Entamoeba dispar)、哈氏內阿米巴(Entamoeba hartmanni)、波氏內阿米巴(Entamoeba polecki)、班氏吳策線蟲、賈第蟲及利什曼原蟲中之一或多者。
舉例而言,在含有源自疏螺旋體屬之抗原的含GLA之疫苗實施例中,抗原可包括核酸、病原體衍生之抗原或抗原性製劑、重組製造之蛋白或肽、及嵌合融合蛋白。一種此抗原係OspA。OspA由於其在宿主細胞(Lipo-OspA)中生物合成可為呈脂質化形式之完全成熟蛋白或另一選擇可為非脂質化衍生物。該等非脂質化衍生物包括非脂質化NS1-OspA融合蛋白,其具有流行性感冒病毒之非結構蛋白(NS1)的前81個N-端胺基酸、及完全OspA蛋白,且另一MDP-OspA係攜帶3個額外N-端胺基酸之OspA的非脂質化形式。
鑒定患有或懷疑處於感染如本文所述感染病原體之風險的個體之組合物及方法已為相關技藝所知。
舉例而言,細菌結核分枝桿菌引起結核病(TB)。細菌通常襲擊肺但亦可襲擊腎、脊柱及腦。若不經適當治療,則TB疾病可為致命的。當感染者打噴嚏或咳嗽時,該疾病通過空氣在人之間傳播。2003年,美國報告了14,000例以上TB病例。
儘管通常可使用長期抗生素療法控制結核病,但該治療不足以防止疾病傳播且存在關於抗生素抗性菌株之有效選擇的問題。感染個體可無症狀,但有時有傳染性。另外,儘管與治療方案之順應性至關重要,但難以監測患者行為。一些患者未完成治療過程,此可導致無
效治療並形成藥物抗性。(例如,美國專利第7,087,713號)
目前,利用活細菌疫苗接種係誘發抵抗結核病之保護性免疫力的最有效方法。出於此目的採用之最常見分枝桿菌係卡介苗(Bacillus Calmette-Guerin)(BCG),一種牛分枝桿菌(Mycobacterium bovis)之無毒性菌株。然而,BCG之安全及功效係爭論之來源且一些國家(例如美國)不對普通大眾進行接種。通常使用皮膚測試達成診斷,該測試涉及皮內暴露於結核菌素PPD(蛋白純化衍生物)。抗原特異性T細胞應答在注射後48至72小時於注射位點處產生可量測之硬結,此指示暴露於分枝桿菌抗原中。然而,敏感性及特異性已經成為此測試之問題,且不能將接種BCG之個體與感染個體區分開。(例如,美國專利第7,087,713號)
儘管已顯示巨噬細胞可起結核分枝桿菌免疫之主要效應劑的作用,但T細胞係該免疫之重要誘發劑。T細胞在抵抗結核分枝桿菌感染中之基本作用係藉由AIDS患者中結核分枝桿菌之頻繁出現闡釋,此頻繁出現係由於與人類免疫缺陷病毒(HIV)感染相關之CD4 T細胞耗盡。已顯示分枝桿菌反應性CD4 T細胞為干擾素-γ(IFN-γ)之強效產生者,已顯示其進而觸發小鼠中巨噬細胞之抗分枝桿菌效應。儘管干擾素-γ在人類中之作用尚較不清楚,但研究已顯示1,25-二羥基-維他命D3單獨或與IFN-γ或腫瘤壞死因子-α組合可活化人類巨噬細胞以抑制結核分枝桿菌感染。此外,已知IFN-γ刺激人類巨噬細胞以產生1,25-二羥基-維他命D3。類似地,已顯示IL-12在刺激對結核分枝桿菌感染之抗性中起作用。關於結核分枝桿菌感染之免疫學的綜述,參見Chan及Kaufmann,Tuberculosis:Pathogenesis,Protection and Control,Bloom(編輯),ASM Press.Washington,D.C.(1994)。
用於診斷結核病或誘發抵抗結核病之保護免疫力的現有化合物及方法包括使用含有一或多種分枝桿菌蛋白之至少一免疫原性部分及
編碼該等多肽之DNA分子的多肽。含有該等多肽或DNA序列及適宜檢測試劑之診斷套組可用於檢測患者及生物試樣中之分枝桿菌感染。亦提供針對該等多肽之抗體。另外,可將該等化合物調配成用於抵抗分枝桿菌感染之免疫的疫苗及/或醫藥組合物。(美國專利第6,949,246號及第6,555,653號)。
20世紀60年代,瘧疾曾在世界的許多地方銷聲匿跡,但現在此疾病仍然存在且出現了此疾病抗現有藥物之新菌株。在90個以上國家中,瘧疾係主要公共健康問題。瘧疾之十分之九的病例發生於撒哈拉以南非洲。三分之一以上之世界人口處於風險中,且每年3.5億與5億之間之人受瘧疾感染。今年有4500萬妊娠女性處於感染瘧疾之風險中。在彼等已感染之個體中,每年有100萬以上彼等感染者死於此可預防性疾病。大多數彼等死亡者係非洲之兒童。
當人被已感染之雌性按蚊(Anopheles mosquito)叮咬時,通常會傳播瘧疾。為了傳染,蚊必須自已感染瘧疾之人體吸取血液而被感染。瘧疾係由寄生蟲引發且該疾病之臨床症狀包括發熱及流感樣疾病,例如寒戰、頭痛、肌肉酸痛及疲勞。該等症狀可能伴有噁心、嘔吐及腹瀉。瘧疾由於紅血細胞之損失亦可引發貧血及黃疸。感染一種類型瘧疾(惡性瘧原蟲)若不及時治療可引發腎衰竭、癲癇發作、精神錯亂、昏迷及死亡。
已知一種活體外診斷個體瘧疾之方法,其包括由取自個體之組織或生物體液與分子或多肽組合物在可使該組合物與可能存在於組織或生物體液中之抗體之間發生活體外免疫反應的條件下接觸,其中該分子或多肽組合物包含帶有由惡性瘧原蟲之感染活性所產生蛋白質之一或多個T抗原決定基之所有或一部分的一或多種肽序列,並於活體外檢測所形成抗原-抗體複合物(參見,例如,美國專利第7,087,231號)。
已闡述重組惡性瘧原蟲(3D7)AMA-1胞外結構域之表現及純化。先前方法已產生高度純化蛋白質,其保留天然分子之摺疊及二硫鍵橋。重組AMA-1適用為診斷試劑且適用於生產抗體,並可單獨作為蛋白質或作為疫苗之一部分用於預防瘧疾。(美國專利第7,029,685號)
相關技藝曾闡述編碼物種特異性間日瘧原蟲瘧疾肽抗原之聚核苷酸,其係易感性哺乳動物宿主在感染後分泌至血漿中之蛋白質或蛋白質片段,因為其具有針對該等抗原之單株或多株抗體。在用於診斷瘧疾、以及確定間日瘧原蟲是否為造成感染之物種之分析法中利用肽抗原、單株抗體、及/或多株抗體。(美國專利第6,706,872號)。亦已報告物種特異性間日瘧原蟲瘧疾肽抗原,其係易感性哺乳動物宿主在感染後分泌至血漿中之蛋白質或蛋白質片段,因為其具有針對該等抗原之單株或多株抗體。在用於診斷瘧疾、以及確定間日瘧原蟲是否是造成感染之物種之分析中利用肽抗原、單株抗體、及/或多株抗體(參見,例如,美國專利第6,231,861號)。
重組惡性瘧原蟲(3D7)AMA-1胞外結構域亦藉由產生高度純化蛋白質之方法表現,該蛋白質保留天然分子之摺疊及二硫鍵橋。重組AMA-1用作診斷試劑用於抗體生產且用作疫苗。(美國專利第7,060,276號)。類似已知重組惡性瘧原蟲(3D7)MSP-142之表現及純化,其保留天然分子之摺疊及二硫鍵橋。重組MSP-142用作診斷試劑用於抗體生產且用作疫苗。(美國專利第6,855,322號)
因而,根據該等及相關揭示內容,已知檢測人類瘧疾感染以鑒定患有或懷疑處於感染瘧疾感染病原體之風險的個體之診斷方法。具體而言,例如,組合血樣與含有3-乙醯基吡啶腺嘌呤二核苷酸(APAD)、基質(例如,乳酸鹽或乳酸)及緩衝液之試劑。試劑經設計以檢測由瘧疾寄生蟲產生之獨特糖酵解酶的存在性。此酶稱為寄生蟲乳酸脫氫酶(PLDH)。使用上述試劑可容易區別PLDH與宿主LDH。試劑
與寄生蟲化血樣組合可還原APAD。然而,APAD不被宿主LDH還原。隨後可藉由各種技術(包括光譜、螢光、電泳、或比色分析)檢測經還原APAD。以上述方式檢測經還原APAD會提供瘧疾感染之陽性指示(例如,美國專利第5,124,141號)。在診斷瘧疾之另一方法中,在測試試樣中藉由抗多肽或與多肽反應之特異性抗體辨識包含源自惡性瘧原蟲抗原GLURP之特徵胺基酸序列的多肽。(美國專利第5,231,168號)
利什曼病係在印度半島、非洲及拉丁美洲廣泛傳播之寄生蟲疾病與頻發流行病且具有疫苗開發之世界衛生組織(World Health Organization)優先權。併發不同疾病時,利什曼原蟲寄生蟲會引發內臟器官之致命感染以及嚴重皮膚疾病。利什曼病之一種最具破壞性形式係鼻及口之毀損面容感染。利什曼病之病例數正逐步增加,且現在在許多地區失去控制。利什曼病由於HIV感染亦在一些發達國家(尤其南歐洲)上升。可用之藥物具有毒性、昂貴且需要長期每日注射。
利什曼原蟲係棲息於免疫系統之巨噬細胞或白血細胞之原蟲寄生蟲。該等寄生蟲藉由小吸血昆蟲(白蛉)之叮咬傳播,該等昆蟲由於棲息於行星之廣大區域而難以控制。
內臟利什曼病係三種疾病表現之最危險者。估計每年出現約500,000內臟形式新病例(黑熱病(kala-azar)或「殺人疾病」)。目前2億以上人處於感染內臟利什曼病之風險。90%以上內臟利什曼病病例出現於印度、孟加拉國、蘇丹、巴西及尼泊爾。大多數死亡出現於兒童中。彼等具有皮膚形式者經常永久性毀損面部。
利什曼原蟲感染難以診斷且通常涉及活組織檢查樣本之組織病理分析。然而,已開發若干血清學及免疫診斷分析。(美國專利第7,008,774號;Senaldi等人,(1996)J.Immunol.Methods 193:9 5;Zijlstra等人,(1997)Trans.R.Soc.Trop.Med.Hyg.91:671 673;Badaro等人,(1996)J.Inf.Dis.173:758 761;Choudhary,S.等人,
(1992)J.Comm.Dis.24:32 36;Badaro,R.等人,(1986)Am.J.Trop.Med.Hyg.35:72 78;Choudhary,A.等人,(1990)Trans.R.Soc.Trop.Med.Hyg.84:363 366;及Reed,S.G.等人,(1990)Am.J.Trop.Med.Hyg.43:632 639)。前鞭毛體釋放代謝產物至培養基中以產生條件培養基。該等代謝產物對宿主具有免疫原性。參見Schnur,L.F.等人,(1972)Isrl.J.Med.Sci.8:932 942;Sergeiev,V.P.等人,(1969)Med.Parasitol.38:208 212;El-On,J.等人,(1979)Exper.Parasitol.47:254 269;及Bray,R.S.等人,(1966)Trans.R.Soc.Trop.Med.Hyg.60:605 609;美國專利第6,846,648號;美國專利第5,912,166號;美國專利第5,719,263號;美國專利第5,411,865)。
全世界約有4000萬人感染HIV,其係一種引發AIDS之病毒。每年約300萬人死於此疾病,其中95%在發展中國家。每年,接近500萬人感染HIV。目前,撒哈拉以南非洲負擔最高疾病負荷,但其快速傳播至其他國家,例如印度、中國及俄羅斯。流行病在少數人群中最快速生長。在美國,自1981年以來已報告950,000例以上AIDS。AIDS在人最具生產年期間擊中其。女性出於生物及社會原因具有HIV/AIDS之增大風險。
AIDS係由人類免疫缺陷病毒(HIV)引發,其殺死並損害身體免疫系統之細胞並漸進性破壞身體對抗感染及某些癌症之能力。HIV最常見係藉由與感染伴侶無預防措施之性交傳播。此問題之最有力解決方案係防止病毒傳播。製備安全、有效且負擔的起之HIV疫苗係達成此目的之一種方式。在全世界,處於HIV感染之高風險的五分之一以下人獲得有效預防。
診斷HIV感染之方法已知,包括藉由病毒培養、自患者樣品PCR限定核酸序列、及抗體測試患者血清中抗-HIV抗體之存在性(參見,例如,美國專利第6,979,535號、第6,544,728號、第6,316,183號、第
6,261,762號、第4,743,540號)。
根據本文所揭示某些其他實施例,疫苗組合物及相關調配物及使用方法可包括源自癌症細胞之抗原,如同可用於癌症之免疫療法治療一樣。舉例而言,發現佐劑調配物可與腫瘤排斥抗原(例如,彼等對於前列腺癌、乳癌、結腸直腸癌、肺癌、胰腺癌、腎癌或黑素瘤癌之抗原)一起使用。例示性癌症或癌症細胞衍生之抗原包括MAGE 1、3及MAGE 4或其他MAGE抗原(例如彼等揭示於WO99/40188中者)、PRAME、BAGE、Lage(亦稱作NY Eos 1)SAGE及HAGE(WO 99/53061)或GAGE(Robbins及Kawakami,1996 Current Opinions in Immunology 8,第628-636頁;Van den Eynde等人,International Journal of Clinical & Laboratory Research(1997及1998);Correale等人(1997),Journal of the National Cancer Institute 89,第293頁)。癌症抗原之該等非限制性實例在多種腫瘤類型(例如,黑素瘤、肺癌、肉瘤及膀胱癌)中表現。參見,例如,美國專利第6,544,518號。
適於與某些本發明所揭示實施例之GLA一起使用之其他腫瘤特異性抗原包括(但不限於)腫瘤特異性或腫瘤相關性神經節苷脂,例如GM2、及GM3或其與載體蛋白之偶聯物;或用於GLA疫苗組合物以激發或增強抗癌免疫應答之抗原可為自體肽激素,例如全長促性腺激素釋放激素(GnRH,WO 95/20600),其為10個胺基酸長之短肽,且可用於多種癌症治療。在另一實施例中,使用前列腺抗原,例如前列腺特異性抗原(PSA)、PAP、PSCA(例如,Proc.Nat.Acad.Sci.USA 95(4)1735-1740 1998)、PSMA,或在一較佳實施例中為稱作前列腺酶之抗原。(例如,Nelson等人,Proc.Natl.Acad.Sci.USA(1999)96:3114-3119;Ferguson等人,Proc.Natl.Acad.Sci.USA 1999.96,3114-3119;WO 98/12302;美國專利第5,955,306號;WO 98/20117;美國專利第5,840,871號及第5,786,148號;WO 00/04149。其他前列腺特異
性抗原自WO 98/137418及WO/004149已知。另一者係STEAP(PNAS 96 14523 14528 7-12 1999)。
可用於本發明上下文中之其他腫瘤相關抗原包括:Plu-1(J Biol.Chem 274(22)15633-15645,1999)、HASH-1、HasH-2、Cripto(Salomon等人,Bioessays 199,21:61-70,美國專利第5,654,140號)及Criptin(美國專利第5,981,215號)。另外,與癌症療法中之疫苗尤其相關之抗原亦包含酪胺酸酶及存活素。
關於含有GLA且包含癌症抗原之疫苗組合物的本文所揭示實施例可用於抵抗任一癌症,其特徵在於腫瘤相關抗原表現,例如HER-2/neu表現或其他癌症特異性或癌症相關性抗原。
患有癌症或懷疑處於患有癌症之風險之個體的診斷可藉由多種相關技藝接受之方法的任一者來完成,該等方法可端視包括臨床表現、癌症進程程度、癌症類型及其他因素之多種因素有所變化。癌症診斷之實例包括患者試樣(例如,血液、皮膚活檢、其他組織活檢、手術樣品等)之組織病理學、組織細胞化學、免疫組織細胞化學及免疫組織病理學檢驗、界定基因(例如,核酸)標記之PCR測試、循環癌症相關性抗原或帶有該等抗原之細胞、或界定特異性之抗體的血清學測試、或彼等熟習此項技術者熟悉之其他方法。參見,例如,美國專利第6,734,172號;第6,770,445號;第6,893,820號;第6,979,730號;第7,060,802號;第7,030,232號;第6,933,123號;第6,682,901號;第6,587,792號;第6,512,102號;第7,078,180號;第7,070,931號;JP5-328975;Waslylyk等人,1993 Eur.J Bioch.211(7):18。
本發明某些實施例之疫苗組合物及方法亦可用於自身免疫疾病之預防或治療,該等疾病包括其中宿主或個體之免疫系統有害地調介免疫應答之疾病、病況或病症,該免疫應答係針對「自身」組織、細胞、生物分子(例如,肽、多肽、蛋白質、糖蛋白、脂蛋白、蛋白
脂、脂質、糖脂、核酸(例如RNA及DNA)、寡糖、多糖、蛋白多糖、葡糖胺聚糖、或諸如此類、及個體細胞及組織之其他分子組份)或抗原決定基(例如,特異性免疫界定辨識結構,例如彼等藉由抗體可變區互補決定區(CDR)或T細胞受體CDR辨識者)。
因而,自身免疫疾病之特徵在於涉及細胞或抗體之異常免疫應答,其在任一情形下係針對正常自身組織。哺乳動物中之自身免疫疾病通常可以兩種不同類別中之一者來分類:細胞調介之疾病(即,T細胞)或抗體調介之病症。細胞調介之自身免疫疾病的非限制性實例包括多發性硬化、類風濕性關節炎、橋本甲狀腺炎(Hashimoto thyroiditis)、I型糖尿病(青少年型糖尿病)及自身免疫性葡萄膜視網膜炎。抗體調介之自身免疫病症包括(但不限於)重症肌無力、全身性紅斑狼瘡(或SLE)、格雷夫斯氏病(Graves' disease)、自身免疫性溶血性貧血、自身免疫性血小板減少症、自身免疫性哮喘、冷球蛋白血症、血小板減少性紫斑症、原發性膽道硬化及惡性貧血。與以下相關之該(等)抗原:全身性紅斑狼瘡係小核糖核酸蛋白(snRNP);格雷夫斯氏病係促甲狀腺受體、甲狀腺球蛋白及甲狀腺上皮細胞之其他組份(Akamizu等人,1996;Kellerman等人,1995;Raju等人,1997;及Texier等人,1992);天皰瘡係鈣依黏連蛋白樣天皰瘡抗原,例如橋粒核心糖蛋白3及其他黏著分子(Memar等人,1996:Stanley,1995;Plott等人,1994;及Hashimoto,1993);且血小板減少性紫斑症係血小板之抗原。(參見,例如,美國專利第6,929,796號;Gorski等人(編輯),Autoimmunity,2001,Kluwer Academic Publishers,Norwell,MA;Radbruch及Lipsky,P.E.(編輯)Current Concepts in Autoimmunity and Chronic Inflammation(Curr.Top.Microbiol.and Immunol.)2001,Springer,NY)。
自身免疫在80種以上不同疾病(包括1型糖尿病、多發性硬化、狼
瘡、類風濕性關節炎、硬皮病及甲狀腺疾病)中起作用。缺乏對大多數自身免疫疾病之發病率的強烈定量估計。20世紀90年代後期實施之最近研究揭示,在美國,自身免疫疾病係第三大最常見主要疾病;且最常見自身免疫疾病影響850萬以上美國人。當前估計該疾病之患病率在5%至8%美國人群範圍內。大多數自身免疫疾病對女性之影響特別嚴重。女性獲得自身免疫疾病之可能比男性大2.7倍。女性更易受自身免疫疾病之影響;男性似乎比女性具有較高位準之天然殺傷細胞活性。(Jacobsen等人,Clinical Immunology and Immunopathology,84:223-243,1997)。
當免疫系統將自身組織誤以為非自身組織且發動不適當攻擊時,發生自身免疫疾病。身體可以不同方式受自身免疫疾病之影響,包括(例如)腸(克羅恩氏病(Crohn's disease))及腦(多發性硬化)。已知自身抗體攻擊自身細胞或自身組織而損傷其功能且結果引發自身免疫疾病,且可在自身免疫疾病實際發生(例如,出現臨床跡象及症狀)之前在患者血清中檢測到自身抗體。因而,自身抗體之檢測使得可早期發現或辨識自身免疫疾病之存在或其發育之風險。基於該等發現,已發現各種抵抗自身抗原之自身抗體且已在臨床測試中量測抵抗自身抗原之自身抗體(例如,美國專利第6,919,210號、第6,596,501號、第7,012,134號、第6,919,078號),同時其他自身免疫診斷可涉及相關代謝產物(例如,美國專利第4,659,659號)或免疫反應性(例如,美國專利第4,614,722號及第5,147,785號、第4,420,558號、第5,298,396號、第5,162,990號、第4,420,461號、第4,595,654號、第5,846,758號、第6,660,487)之檢測。
在某些實施例中,本發明組合物尤其適用於老年人及/或免疫抑制(包括進行腎透析之個體、進行化學療法及/或放射療法之個體、移植接受者及諸如此類)的治療。該等個體通常對疫苗呈現減少之免疫
應答,且因此使用本發明組合物可增強該等個體中達成之免疫應答。
在其他實施例中,本發明組合物中所用該(等)抗原包括與呼吸性疾病(例如彼等由細菌感染(例如,肺炎球菌)引發或加劇之疾病)相關之抗原,其用於諸如慢性阻塞性肺病(COPD)等病況的預防及治療。COPD係藉由患有慢性枝氣管炎及/或肺氣腫之患者中存在不可逆或部分可逆氣道阻塞而在生理上加以定義(Am J Respir Crit Care Med.1995 Nov;152(5 Pt 2):S77-121)。COPD之惡化經常係由細菌(例如,肺炎球菌)感染引發(Clin Microbiol Rev.2001 Apr;14(2):336-63)。在一特定實施例中,本發明組合物包含如本文所述GLA佐劑、與肺炎球菌疫苗Prevnar®(Wyeth)之組合。
在又一些實施例中,包含本文所述GLA之本發明組合物用於過敏病況之治療。舉例而言,在一特定實施例中,組合物用於過敏症脫敏療法。該療法涉及利用逐漸增大劑量之使人過敏之物質刺激免疫系統,其中該等物質調配於包含GLA之組合物中。在具體實施例中,組合物用於治療對食品、花粉、蟎蟲、貓或有刺的昆蟲(例如,蜜蜂、大黃蜂、黃色胡蜂、黃蜂、蟻蜂、火蟻)之過敏症。
如本文所述,本發明之某些實施例涵蓋包括醫藥組合物在內之疫苗組合物及免疫佐劑組合物,該等組合物除本發明之該(等)GLA化合物外,亦包括一或多種類鐸受體激動劑(TLR激動劑)。類鐸受體(TLR)包括先天免疫系統之細胞表面跨膜受體,其賦予宿主細胞早期辨識各種保守微生物分子結構(例如可存在於大量感染病原體中或其上)之能力。(例如,Armant等人,2002 Genome Biol.3(8):reviews3011.1-3011.6;Fearon等人,1996 Science 272:50;Medzhitov等人,1997 Curr.Opin.Immunol.9:4;Luster 2002 Curr.Opin.Immunol.14:129;Lien等人2003 Nat.Immunol.4:1162;
Medzhitov,2001 Nat.Rev.Immunol.1:135;Takeda等人,2003 Ann Rev Immunol.21:335;Takeda等人2005 Int.Immunol.17:1;Kaisho等人,2004 Microbes Infect.6:1388;Datta等人2003 J. Immunol.170:4102)。
誘發TLR調介之信號轉導以經由先天免疫系統強化免疫應答的起始可由TLR激動劑實施,該等TLR激動劑接合細胞表面TLR。舉例而言,脂多糖(LPS)可為經由TLR2或TLR4之TLR激動劑(Tsan等人,2004 J.Leuk.Biol.76:514;Tsan等人,2004 Am.J.Physiol.Cell Physiol.286:C739;Lin等人,2005 Shock 24:206);聚(肌苷-胞苷)(聚I:C)可為經由TLR3之TLR激動劑(Salem等人,2006 Vaccine 24:5119);CpG序列(含有未甲基化胞嘧啶-鳥嘌呤或「CpG」二核苷酸基元(例如CpG 7909)之寡聚去氧核苷酸,Cooper等人,2005 AIDS 19:1473;CpG 10101 Bayes等人,Methods Find Exp Clin Pharmacol 27:193;Vollmer等人Expert Opinion on Biological Therapy 5:673;Vollmer等人,2004 Antimicrob.Agents Chemother.48:2314;Deng等人,2004 J.Immunol.173:5148)可為經由TLR9之TLR激動劑(Andaloussi等人,2006 Glia 54:526;Chen等人,2006 J.Immunol.177:2373);肽多糖可為TLR2及/或TLR6激動劑(Soboll等人,2006 Biol.Reprod.75:131;Nakao等人,2005 J.Immunol.174:1566);3M003(4-胺基-2-(乙氧基甲基)-α,α-二甲基-6,7,8,9-四氫-1H-咪唑并[4,5-c]喹啉-1-乙醇水合物,Mol.Wt.318 Da,來自3M Pharmaceuticals,St.Paul,MN,其亦係相關化合物3M001及3M002之來源;Gorden等人,2005 J.Immunol.174:1259)可為TLR7激動劑(Johansen 2005 Clin.Exp.Allerg.35:1591)及/或TLR8激動劑(Johansen 2005);鞭毛蛋白可為TLR5激動劑(Feuillet等人,2006 Proc.Nat.Acad.Sci.USA 103:12487);且C型肝炎抗原可經由TLR7及/或TLR9起TLR激動劑之作用(Lee等人,2006
Proc.Nat.Acad.Sci.USA 103:1828;Horsmans等人,2005 Hepatol.42:724)。已知其他TLR激動劑(例如,Schirmbeck等人,2003 J.Immunol.171:5198)且可根據某些本發明所述實施例使用。
舉例而言,且藉助背景(參見,例如,美國專利第6,544,518號),含有未甲基化CpG二核苷酸(「CpG」)之免疫刺激性寡核苷酸在藉由全身及黏膜途徑投與時稱作佐劑(WO 96/02555,EP 468520,Davis等人,J.Immunol,1998,160(2):870-876;McCluskie及Davis,J.Immunol.,1998,161(9):4463-6)。CpG係存於DNA中之胞嘧啶-鳥嘌呤二核苷酸基元之縮寫。CG基元在免疫刺激中之主要作用由Krieg(Nature 374,第546頁,1995)闡明。詳細分析已顯示CG基元必須處於某一序列文本中且該等序列在細菌DNA中常見但在脊椎動物DNA中罕見。免疫刺激序列通常為:嘌呤、嘌呤、C、G、嘧啶、嘧啶;其中二核苷酸CG基元未經甲基化,但已知其他未甲基化CpG序列具有免疫刺激性且可用於本發明之某些實施例中。當將CpG調配於疫苗中時,其可於游離溶液中與游離抗原一起投與(WO 96/02555;McCluskie及Davis,如上文所述),或共價結合至抗原(PCT公開案第WO 98/16247號)或與諸如氫氧化鋁等載劑一起調配(例如,Davis等人,如上文所述,Brazolot-Millan等人,Proc.Natl.Acad.Sci.,USA,1998,95(26),15553-8)。
用於本發明佐劑或疫苗中之較佳寡核苷酸較佳含有由至少三個、更佳至少6個或更多個核苷酸分離之兩個或更多個二核苷酸CpG基元。本發明寡核苷酸通常為去氧核苷酸。在一較佳實施例中,寡核苷酸中之間核苷酸係二硫代磷酸酯、或更佳硫代磷酸酯鍵,但磷酸二酯及其他核苷酸間鍵(包括具有混合核苷酸間鍵合之寡核苷酸鍵)屬於本發明範疇,。製造硫代磷酸酯寡核苷酸或二硫代磷酸酯之方法闡述於美國專利第5,666,153號、第5,278,302號及WO 95/26204中。
較佳寡核苷酸之實例具有揭示於以下公開案中之序列;對於某些本文所揭示實施例而言,序列較佳含有經硫代磷酸酯修飾之核苷酸間鍵合:CPG 7909:Cooper等人,「CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-treated HIV-infected adults」。AIDS,2005年9月23日;19(14):1473-9。
CpG 10101:Bayes等人,「Gateways to clinical trials.」Methods Find.Exp.Clin.Pharmacol.2005年4月;27(3):193-219。
Vollmer J.,「Progress in drug development of immunostimulatory CpG oligodeoxynucleotide ligands for TLR9.」Expert Opinion on Biological Therapy.2005年5月;5(5):673-682。
替代CpG寡核苷酸可包含上文所列舉公開案中所述較佳序列的變體,不同之處在於其中具有不連貫核苷酸序列取代、插入、缺失及/或添加。用於本發明之某些實施例的CpG寡核苷酸可藉由相關技藝已知之任一方法來合成(例如EP 468520)。為方便起見,該等寡核苷酸可利用自動合成器來合成。寡核苷酸通常為去氧核苷酸。在一較佳實施例中,寡核苷酸中之核苷酸間鍵係二硫代磷酸酯、更佳硫代磷酸酯鍵,但磷酸二酯亦屬於本發明涵蓋之實施例的範疇。本發明亦涵蓋包含不同核苷酸間鍵合(例如混合硫代磷酸酯磷酸二酯鍵)之寡核苷酸。亦可使用穩定寡核苷酸之其他核苷酸間鍵。
本文所提供某些實施例包括含有醫藥組合物在內之疫苗組合物及免疫佐劑組合物,該等醫藥組合物除該(等)GLA化合物外,亦含有至少一種共佐劑,該佐劑係指具有除GLA外之佐劑活性的該等組合物之組份。具有該佐劑活性之共佐劑包括當投與具有辨識免疫系統的個體(例如,人類(例如,人類患者)、非人靈長類、哺乳動物或另一較高
等真核有機體)時能夠改變(即,以統計學顯著方式增加或降低,且在某些較佳實施例中,增強或增加)免疫應答之效能及/或壽命的組合物。(參見,例如,Powell及Newman,「Vaccine design-The Subunit and Adjuvant Approach」,1995,Plenum Press,New York)。在本文所揭示某些實施例中,GLA及期望抗原及視情況一或多種共佐劑可如此改變(例如,激發或增強)免疫應答,其針對可與GLA同時投與或可在投與時有時間及/或空間間隔(例如,在不同解剖位點處)的期望抗原,但某些本發明實施例並不意欲限於此且因而亦涵蓋組合物中之GLA的投與,該組合物並不包括指定抗原但亦可包括一或多種TLR激動劑、共佐劑、咪唑并喹啉免疫應答調節劑、及雙莖環免疫調節劑(dSLIM)。
因此且如上文所述,共佐劑包括不為GLA且具有佐劑效應之組合物,例如皂苷及皂苷模擬物,包括QS21及QS21模擬物(參見,例如,美國專利第5,057,540號;EP 0 362 279 B1;WO 95/17210)、明礬、植物生物鹼(例如,蕃茄素)、洗滌劑(例如但不限於,皂苷、聚山梨醇酯80、Span 85及硬脂基酪胺酸)、一或多種細胞因子(例如,GM-CSF、IL-2、IL-7、IL-12、TNF-α、IFN-γ)、咪唑并喹啉免疫應答調節劑、及雙莖環免疫調節劑(dSLIM,例如,Weeratna等人,2005 Vaccine 23:5263)。
包括皂苷之洗滌劑教示於(例如)美國專利第6,544,518號;Lacaille-Dubois,M及Wagner H.(1996 Phytomedicine 2:363-386),美國專利第5,057,540號,Kensil,Crit Rev Ther Drug Carrier Syst,1996,12(1-2):1-55、及EP 0 362 279 B1中。包含Quil A(皂苷)流份之顆粒結構(稱為免疫刺激複合物(ISCOMS))具有溶血性且已用於疫苗之生產(Morein,B.,EP 0 109 942 B1)。已報告該等結構具有佐劑活性(EP 0 109942 B1;WO 96/11711)。溶血性皂苷QS21及QS17(經HPLC純化之
Quil A流份)已被闡述為強效全身性佐劑,且其生產方法揭示於美國專利第5,057,540號及EP 0 362 279 B1中。在該等參考文獻中亦闡述了用作全身疫苗強效佐劑之QS7(Quil-A之非溶血性流份)的用途。QS21之用途進一步闡述於Kensil等人(1991.J.Immunology 146:431-437)中。QS21與聚山梨醇酯或環糊精之組合亦已知(WO 99/10008)。包含QuilA流份(例如QS21及QS7)之顆粒佐劑系統闡述於WO 96/33739及WO 96/11711中。用於全身性疫苗接種研究之其他皂苷包括彼等源自其他植物物種(例如絲石竹屬(Gypsophila)及肥皂草屬(Saponaria))者(Bomford等人,Vaccine,10(9):572-577,1992)。
七葉素(escin)係與用於本文所揭示實施例之佐劑組合物中之皂苷相關的另一洗滌劑。七葉素作為出現於西洋栗樹(horse chestnut tree)、歐洲七葉樹(Aesculus hippocastanum)之種子中之皂苷混合物闡述於Merck index(第12版,條目3737)中。藉由層析及純化(Fiedler,Arzneimittel-Forsch.4,213(1953))、及離子交換樹脂(Erbring等人,美國專利第3,238,190號)對其分離進行闡述。七葉素(亦稱作七葉皂苷(aescin))之流份經純化且顯示具有生物活性(Yoshikawa M,等人(Chem Pharm Bull(Tokyo)1996年8月;44(8):1454-1464))。洋地黃皂苷(digitonin)係另一洗滌劑,亦作為皂苷闡述於Merck index(第12版,條目3204)中,其源自毛地黃(Digitalis purpurea)之種子且根據由Gisvold 等人,J.Am.Pharm.Assoc.,1934,23,664;及Rubenstroth-Bauer,Physiol.Chem.,1955,301,621闡述之程序進行純化。
根據某些本文所揭示實施例使用之其他共佐劑包括嵌段共聚物或生物可降解聚合物,其係指彼等相關技術中者熟悉之聚合化合物的類別。可包括於GLA疫苗組合物或GLA免疫佐劑中之嵌段共聚物或生物可降解聚合物的實例包括Pluronic® L121(BASF公司,Mount Olive,NJ;參見,例如,Yeh等人,1996 Pharm.Res.13:1693;美國專利第
5,565,209號)、CRL1005(例如,Triozzi等人,1997 Clin Canc.Res.3:2355)、聚(乳酸-共-乙醇酸)(PLGA)、聚(乳酸)(PLA)、聚-(D,L-乳酸-共-乙醇酸)(PLG)、及聚I:C.(參見,例如,Powell and Newman,「Vaccine design-The Subunit and Adjuvant Approach」,1995,Plenum Press,New York)。
某些實施例涵蓋包括油之GLA疫苗及GLA免疫佐劑,該油在一些該等實施例中可有利於共佐劑活性且在其他該等實施例中可額外或另一選擇為提供醫藥上可接受之載劑或賦形劑。任一數量之適宜油已知且可基於本發明經選擇以納入疫苗組合物及免疫佐劑組合物中。該等油之實例以闡釋性而非限制性方式包括角鯊烯、角鯊烷、礦物油、橄欖油、膽固醇、及二縮甘露醇單油酸酯。
免疫應答調節劑(例如咪唑并喹啉免疫應答調節劑)亦為相關技藝已知且在某些本發明揭示之實施例中亦可作為共佐劑包括於其中。某些較佳咪唑并喹啉免疫應答調節劑以非限制性實例方式包括瑞喹莫德(resiquimod)(R848)、咪喹莫德(imiquimod)及格敵喹莫德(gardiquimod)(Hemmi等人,2002 Nat.Immunol.3:196;Gibson等人,2002 Cell.Immunol.218:74;Gorden等人,2005 J.Immunol.174:1259);該等及其他咪唑并喹啉免疫應答調節劑在適當條件下亦可具有如本文所述TLR激動劑活性。其他免疫應答調節劑係基於核酸之雙莖環免疫調節劑(dSLIM)。涵蓋用於某些本發明所揭示實施例中之dSLIM的具體實例可參見Schmidt等人,2006 Allergy 61:56;Weihrauch等人2005 Clin Cancer Res.11(16):5993-6001;Modern Biopharmaceuticals,J.Knäblein(編輯)。John Wiley & Sons,2005年12月6日。(dSLIM論述於第183至約200頁),及來自Mologen AG(Berlin,FRG:[在8/18/06於http://www.mologen.com/English/04.20-dSLIM.shtm1上線上檢索]。
亦如上文所述,與本文所述GLA一起使用之一種類型的共佐劑可為鋁共佐劑,其通常稱作「明礬」。明礬共佐劑係基於以下:羥基氧化鋁;羥基磷酸鋁;或各種專有鹽。使用明礬共佐劑之疫苗可包括用於破傷風菌株、HPV、A型肝炎、滅活脊髓灰質炎病毒及如本文所述其他抗原之疫苗。明礬共佐劑由於具有良好安全記錄、加強抗體應答、穩定抗原且對於大規模生產相對簡單而較為有利的。(Edelman 2002 Mol.Biotechnol.21:129-148;Edelman,R.1980 Rev.Infect.Dis.2:370-383)。
可與GLA組合用於有效免疫刺激之其他共佐劑包括皂苷及皂苷模擬物,包括QS21及賦予類似效應且在本文中稱作QS21模擬物之結構上相關之化合物。QS21被視為較佳共佐劑。QS21可包含源自奎拉雅屬皂樹之樹皮的經HPLC純化之無毒性流份。QS21之生成揭示於美國專利第5,057,540號中。(亦參見美國專利第6,936,255號、第7,029,678號及第6,932,972號中)。
在某些實施例中,GLA亦可與稱作ISCOMS之「免疫刺激性複合物」(例如,美國專利第6,869,607號、第6,846,489號、第6,027,732號、第4,981,684號)(包括皂苷衍生之ISCOMATRIX®,其可自(例如)Iscotec(Stockholm,Sweden)及CSL有限公司(Parkville,Victoria,Australia)購得)組合。
根據某些本文所揭示實施例,GLA疫苗組合物可含有至少一種重組表現構築體,其包含可操作地連接至編碼抗原之核酸序列的啟動子。在某些其他實施例中,病毒載體(例如,腺病毒、腺相關病毒、皰疹病毒、慢病毒、痘病毒或逆轉錄病毒載體)中存在重組表現構築體。對於本文所提供多肽抗原之表現,製備及使用該等表現構築體及載體之組合物及方法已為相關技藝已知,根據(例如)Ausubel等人(編
輯),Current Protocols in Molecular Biology,2006 John Wiley & Sons,NY。重組表現構築體之非限制性實例通常可參見(例如)美國專利第6,844,192號;第7,037,712號;第7,052,904號;第7,001,770號;第6,106,824號;第5,693,531號;第6,613,892號;第6,875,610號;第7,067,310號;第6,218,186號;第6,783,981號;第7,052,904號;第6,783,981號;第6,734,172號;第6,713,068號;第5,795,577號及第6,770,445號及別處,其中教示可適於如本文所提供多肽抗原之表現,其用於某些本發明所揭示實施例中。
本發明由此提供用於改變(即,例如,相對於熟習此項技術者熟知之適當對照,以統計學顯著方式增加或降低)能夠發動免疫應答之宿主中之免疫應答的組合物。如熟習此項技術者已知,免疫應答可為宿主之免疫狀態的任一活性改變,其可包括參與宿主免疫狀態之維持及/或調控的一或多種組織、器官、細胞或分子之結構或功能的任一改變。通常,可藉由多種熟知參數中之任一者檢測免疫應答,該等參數包括但不限於以下之活體內或活體外測定:可溶性免疫球蛋白或抗體;可溶性調介子,例如細胞因子、淋巴因子、趨化因子、激素、生長因子及諸如此類以及其他可溶性小肽、碳水化合物、核苷酸及/或脂質調介子;細胞活化狀態變化,如由免疫系統之細胞的改變功能或結構性質所測定,例如,細胞增生、改變之運動、誘發特定活性,例如特異性基因表現或細胞溶解行為;由免疫系統之細胞的細胞分化,包括改變之表面抗原表現曲線或細胞凋亡(程序性細胞死亡)之起始;或可檢測免疫應答之存在性之任一其他標準。
免疫應答經常可被視為(例如)於分子及細胞層面下由宿主免疫系統之細胞及組織識別自身結構與非自身結構,但本發明不應限於此。舉例而言,免疫應答亦可包括免疫系統狀態變化,其係由自身分子、
細胞或組織之免疫辨識產生,同時可伴隨任一數量之正常狀況(例如免疫系統組份之典型調控),或可存在於病理狀況(例如,自身免疫及退化性疾病中觀察到之不適當自身免疫應答)中。作為另一實例,除藉由上調特定免疫系統活性(例如,抗體及/或細胞因子產生、或細胞調介之免疫力的活化)誘發外,免疫應答亦可包括可檢測免疫力之抑制、衰減或任一其他下調,其可為所選抗原、抗原投與路徑、特異性耐受力誘發或其他因素之結果。
由本發明疫苗誘發免疫應答之測定可由彼等熟習此項技術者容易熟悉之許多熟知免疫分析中之任一者來建立。該等分析包括(但無需限於)以下之活體內或活體外測定:可溶性抗體;可溶性調介子,例如細胞因子、淋巴因子、趨化因子、激素、生長因子及諸如此類以及其他可溶性小肽、碳水化合物、核苷酸及/或脂質調介子;細胞活化狀態變化,如由免疫系統之細胞的改變功能或結構性質所測定,例如,細胞增生、改變之運動、誘發特定活性,例如特異性基因表現或細胞溶解行為;由免疫系統之細胞的細胞分化,包括改變之表面抗原表現曲線或細胞凋亡(程序性細胞死亡)之起始。實施該等及類似分析之程序廣為人知且可參見(例如)Lefkovits(Immunology Methods Manual:The Comprehensive Sourcebook of Techniques,1998;亦參見Current Protocols in Immunology;亦參見,例如,Weir,Handbook of Experimental Immunology,1986 Blackwell Scientific,Boston,MA;Mishell及Shigii(編輯)Selected Methods in Cellular Immunology,1979 Freeman Publishing,San Francisco,CA;Green及Reed,1998 Science 281:1309及其中所引用之參考文獻)。
可藉由各種已知技術完成抗原反應性T細胞之增生的檢測。舉例而言,可藉由量測DNA合成速率檢測T細胞增生,且可藉由控制於其中暴露候選抗原反應性T細胞之刺激素(例如,特異性期望抗原或對照
抗原脈衝之抗原呈遞細胞)來測定抗原特異性。經刺激以增生之T細胞呈現增大之DNA合成速率。量測DNA合成速率之典型方式係(例如)藉由用經氚標記之胸苷脈衝標記T細胞之培養物,該經氚標記之胸苷係納入新合成DNA中之核苷前體。可使用液態閃爍分光光度計測定所納入經氚標記之胸苷的量。檢測T細胞增生之其他方式包括量測介白素-2(IL-2)產生、Ca2+通量、或染劑吸收(例如,3-(4,5-二甲基噻唑-2-基)-2,5-二苯基-四唑鎓)之增加。或者,可量測淋巴因子(例如,干擾素-γ)之合成或可對可響應特定抗原之相對量之T細胞進行定量。
抗原特異性抗體產生之檢測可藉由以下達成:(例如)使用活體外方法(例如,放射免疫分析(RIA)、酶聯免疫吸附分析(ELISA)、平衡透析法或固相免疫印記法(包括西方印記法(Western blotting))分析來自經本發明疫苗處理之宿主的試樣(例如,含有免疫球蛋白之試樣,例如血清、血漿或血液)。在較佳實施例中,ELISA分析可進一步包括目標抗原與對抗原具有特異性之固相單株抗體的抗原-捕獲固定以(例如)增強分析之敏感性。可溶性調介子(例如,細胞因子、趨化因子、淋巴因子、前列腺素等)之分泌亦可藉由酶聯免疫吸附分析(ELISA)使用(例如)容易自市售來源(例如,Sigma,St.Louis,MO;亦參見R & D Systems 2006 Catalog,R & D Systems,Minneapolis,MN)獲得之方法、設備及試劑容易地測定。
任何數量之其他免疫參數可使用相關技藝熟知之常規分析進行監測。該等分析可包括(例如)抗體依賴性細胞調介之細胞毒性(ADCC)分析、活體外二級抗體應答、使用已建立良好之標記抗原系統的各種外周血液或淋巴單核細胞子群之流式免疫細胞螢光分析、免疫組織化學或其他相關分析。該等及其他分析可參見(例如)Rose等人(編輯),Manual of Clinical Laboratory Immunology,第5版,1997 American Society of Microbiology,Washington,DC。
因此,預計本文所提供疫苗及佐劑組合物能夠激發或增強宿主中之至少一種免疫應答,其係選自TH1-型T淋巴細胞應答、TH2-型T淋巴細胞應答、細胞毒性T淋巴細胞(CTL)應答、抗體應答、細胞因子應答、淋巴因子應答、趨化因子應答、及炎症應答。在某些實施例中,免疫應答可包含以下之至少一種:其中細胞因子係選自干擾素-γ(IFN-γ)、腫瘤壞死因子-α(TNF-α)之一或複數個細胞因子的產生、其中介白素係選自IL-1、IL-2、IL-3、IL-4、IL-6、IL-8、IL-10、IL-12、IL-13、IL-16、IL-18及IL-23之一或複數個介白素的產生、其中趨化因子係選自MIP-1α、MIP-1β、RANTES、CCL4及CCL5之一或複數個趨化因子的產生、及選自記憶T細胞應答、記憶B細胞應答、效應T細胞應答、細胞毒性T細胞應答及效應B細胞應答之淋巴細胞應答。參見,例如,WO 94/00153;WO 95/17209,WO 96/02555,U.S.6,692,752;U.S.7,084,256;U.S.6,977,073;U.S.6,749,856;U.S.6,733,763;U.S.6,797,276;U.S.6,752,995;U.S.6,057,427;U.S.6,472,515;U.S.6,309,847;U.S.6,969,704;U.S.6,120,769;U.S.5,993,800;U.S.5,595,888;Smith等人,1987 J Biol Chem.262:6951;Kriegler等人,1988 Cell 53:45 53;Beutler等人,1986 Nature 320:584;U.S.6,991,791;U.S.6,654,462;U.S.6,375,944。
醫藥組合物通常包含至少一種本發明GLA化合物,且可進一步包含一或多種本文所提供組份,其選自(例如)抗原、TLR激動劑、共佐劑(視情況包括細胞因子、咪唑并喹啉免疫應答調節劑及/或dSLIM)、及/或重組表現構築體、與醫藥上可接受之載劑、賦形劑或稀釋劑之組合。
因此,在某些態樣中,本發明涉及GLA「單一療法」,其中將如本文所述GLA調配於實質上無其他抗原之組合物中,且出於治療或預
防疾病或其他病況之目的(例如,用於治療被有機體感染,用於治療季節性鼻炎,或諸如此類)投與個體以刺激免疫應答(例如,非特異性免疫應答)。舉例而言,在一個實施例中,本發明之組合物及方法採用GLA化合物用於刺激個體中之免疫應答。在另一實施例中,GLA係呈噴霧、視情況提供於套組中之形式。
可較佳將GLA調配於穩定乳液中。舉例而言,在一特定實施例中,提供包含存於實質上無其他抗原之穩定乳液中的本發明GLA化合物之組合物。
在某些其他實施例中,醫藥組合物係包含GLA及抗原二者之疫苗組合物,且可進一步包含一或多種本文所提供組份,其選自TLR激動劑、共佐劑(包括(例如)細胞因子、咪唑并喹啉免疫應答調節劑及/或dSLIM)及諸如此類、及/或重組表現構築體、與醫藥上可接受之載劑、賦形劑或稀釋劑之組合。
闡釋性載劑在所用劑量及濃度下應對接受者無毒性。對於基於GLA-加-核酸之疫苗或對於包含GLA加上抗原之疫苗而言,通常藉由皮內、皮下、肌內或靜脈內路徑或藉由其他路徑一般投與約0.001μg/kg至約100mg/kg體重。
在一更具體實施例中,劑量係約0.001μg/kg至約1mg/kg。在另一具體實施例中,劑量係約0.001μg/kg至約50μg/kg。在另一具體實施例中,劑量係約0.001μg/kg至約15μg/kg。
在另一具體實施例中,所投與GLA之量係約0.01μg/劑量至約5mg/劑量。在另一具體實施例中,所投與GLA之量係約0.1μg/劑量至約1mg/劑量。在另一具體實施例中,所投與GLA之量係約0.1μg/劑量至約100μg/劑量。在另一具體實施例中,所投與GLA係約0.1μg/劑量至約10μg/劑量。
熟習此項技術者應明瞭,投與之數量及頻率應端視宿主之反應
而定。用於治療用途之「醫藥上可接受之載劑」已為醫藥技術所熟知且闡述於(例如)Remingtons Pharmaceutical Sciences,Mack Publishing公司(A.R.Gernaro編輯,1985)中。舉例而言,可使用生理pH下之無菌鹽水及磷酸鹽緩衝鹽水。醫藥組合物中可提供防腐劑、穩定劑、染劑及甚至矯味劑。舉例而言,可添加苯甲酸鈉、山梨酸及對羥基苯甲酸之酯作為防腐劑。同一出處,於1449處。另外,可使用抗氧化劑及懸浮劑。同一出處。
「醫藥上可接受之鹽」係指源自該等化合物與有機酸或無機酸(酸加成鹽)或有機鹼或無機鹼(鹼加成鹽)之組合的本發明化合物之鹽。本發明組合物可以游離鹼或鹽形式使用,兩種形式均視為屬於本發明範疇。
醫藥組合物可呈可將組合物投與患者之任一形式。舉例而言,組合物可呈固體、液體或氣體(氣溶膠)形式。典型投與路徑包括(但不限於)經口、局部、非經腸(例如,經舌下或含服)、經舌下、經直腸、經陰道及經鼻內(例如,以噴霧形式)。本文所用術語非經腸包括離子導入(例如,U.S.7,033,598;7,018,345;6,970,739)、超音波泳動(sonophoretic)(例如,U.S.4,780,212;4,767,402;4,948,587;5,618,275;5,656,016;5,722,397;6,322,532;6,018,678)、熱(例如,U.S.5,885,211;6,685,699)、主動經皮(例如,U.S.3,598,122;3,598,123;4,286,592;4,314,557;4,379,454;4,568,343;5,464,387;英國專利說明書第2232892號;U.S.6,871,477;6,974,588;6,676,961)、微型針(例如,U.S.6,908,453;5,457,041;5,591,139;6,033,928)投與亦及皮下注射、靜脈內、肌內、胸骨內、海綿竇內、鞘內、壁內、尿道內注射或輸注技術。在一特定實施例中,藉由選自離子導入、微小細胞形成、超音波泳動或微型針之技術經皮內投與本文所述組合物(包括疫苗及醫藥組合物)。
調配醫藥組合物以便在將組合物投與患者時其中含有之活性成份生物可用。可投與患者之組合物採取一或多個劑量單元之形式,其中(例如)錠劑可為單一劑量單元,且呈氣溶膠形式之一或多種本發明化合物的容器可容納複數個劑量單元。
經口投與時,可存在賦形劑及/或黏合劑。其實例係蔗糖、高嶺土、甘油、澱粉糊精、海藻酸鈉、羧甲基纖維素及乙基纖維素。可存在著色劑及/或矯味劑。可採用外層包衣。
組合物可呈液體(例如,酏劑、糖漿、溶液、乳液或懸浮液)形式。其中兩個實例為可經口投與液體或藉由注射遞送液體。當意欲經口投與時,較佳組合物含有甜味劑、防腐劑、染劑/著色劑及香味增強劑中之一或多者。在計畫注射投與之組合物中,可包括表面活性劑、防腐劑、潤濕劑、分散劑、懸浮劑、緩衝劑、穩定劑及等滲劑中之一或多者。
本文所用液體醫藥組合物不論呈溶液、懸浮液形式還是其他類似形式,均可包括以下一種或多種載劑或賦形劑:無菌稀釋劑(例如,注射用水)、鹽水溶液(較佳生理食鹽水、林格氏(Ringer's)溶液、等滲氯化鈉)、不揮發油(例如,角鯊烯、角鯊烷、礦物油、二縮甘露醇單油酸酯、膽固醇、及合成的甘油單酯或甘油二酯(其可用作溶劑或懸浮介質)、聚乙二醇、甘油、丙二醇或其他溶劑);抗細菌劑,例如苄醇或對羥基苯甲酸甲酯;抗氧化劑,例如,抗壞血酸或亞硫酸氫納;螯合劑,例如,乙二胺四乙酸;緩衝劑,例如,乙酸鹽、檸檬酸鹽或磷酸鹽及用於調節滲透性之試劑,例如氯化鈉或右旋糖。非經腸製劑可封裝於由玻璃或塑膠製成的安瓿、可棄式注射器或多劑量小瓶中。可注射醫藥組合物為無菌較佳。
在特定實施例中,本發明之醫藥或疫苗組合物包含小於0.2μm之穩定水性懸浮液且進一步包含至少一種選自由磷脂、脂肪酸、表面活
性劑、洗滌劑、皂苷、氟化脂質及諸如此類組成之群中之組份。
在另一實施例中,以可氣溶膠方式調配本發明組合物。
亦可期望疫苗或醫藥組合物中包括其他組份,例如遞送媒劑,其包括但不限於鋁鹽、油包水乳液、生物可降解油媒劑、水包油乳液、生物可降解微膠囊及脂質體。用於該等媒劑中之額外免疫刺激性物質(共佐劑)之實例亦如上文所述且可包括N-乙醯基胞壁醯基-L-丙胺酸-D-異麩胺醯胺(MDP)、葡聚糖、IL-12、GM-CSF、γ干擾素及IL-12。
儘管本發明醫藥組合物中可採用彼等熟習此項技術者已知之任一適宜載劑,但載劑之類型可端視投與模式及是否期望持續釋放而有所變化。對於非經腸投與(例如,皮下注射)而言,載劑較佳包含水、鹽水、醇、脂肪、蠟或緩衝液。對於經口投與而言,可採用上述載劑或固體載劑中之任一者,例如,甘露醇、乳糖、澱粉、硬脂酸鎂、糖精鈉、滑石粉、纖維素、葡萄糖、蔗糖及碳酸鎂。亦可採用生物可降解微球體(例如,聚丙交酯-乙交酯丙交酯(polylactic galactide))作為載劑用於本發明醫藥組合物中。適宜生物可降解微球體揭示於(例如)美國專利第4,897,268號及第5,075,109號中。就此而言,微球體較佳大於約25微米。
醫藥組合物(包括GLA疫苗及GLA免疫佐劑)亦可含有稀釋劑(例如緩衝液)、抗氧化劑(例如,抗壞血酸)、低分子量(小於約10個殘基)多肽、蛋白質、胺基酸、碳水化合物(包括葡萄糖、蔗糖或糊精)、螯合劑(例如,EDTA、麩胱甘肽)及其他穩定劑及賦形劑。中性緩衝鹽水或混有非特異性血清白蛋白之鹽水係例示性適當稀釋劑。較佳地,可使用適當賦形劑溶液(例如,蔗糖)作為稀釋劑將產物調配為低壓凍乾物。
如上文所述,在某些實施例中,本發明包括能夠遞送編碼期望
抗原之核酸分子的組合物。該等組合物包括重組病毒載體(例如,逆轉錄病毒(參見WO 90/07936、WO 91/02805、WO 93/25234、WO 93/25698及WO 94/03622)、腺病毒(參見Berkner,Biotechniques 6:616-627,1988;Li等人,Hum.Gene Ther.4:403-409,1993;Vincent等人,Nat.Genet.5:130-134,1993;及Kolls等人,Proc.Natl.Acad.Sci.USA 91:215-219,1994)、痘病毒(參見美國專利第4,769,330號;美國專利第5,017,487號;及WO 89/01973))、與聚陽離子分子複合之重組表現構築體核酸分子(參見WO 93/03709)、及與脂質體相關之核酸(參見Wang等人,Proc.Natl.Acad.Sci.USA 84:7851,1987)。在某些實施例中,可將DNA連接至殺死或滅活腺病毒(參見Curiel等人,Hum.Gene Ther.3:147-154,1992;Cotton等人,Proc.Natl.Acad.Sci.USA 89:6094,1992)。其他適宜組合物包括DNA-配體(參見Wu等人,J.Biol.Chem.264:16985-16987,1989)及脂質-DNA組合(參見Felgner等人,Proc.Natl.Acad.Sci.USA 84:7413-7417,1989)。
除實施活體內程序外,亦可使用離體程序,其中自宿主移出細胞、對其進行修飾並放置於同一或另一宿主動物中。顯而易見,在離體環境下可利用上述組合物中之任一者用於將編碼核酸分子之抗原引入組織細胞中。用於病毒、物理及化學方法之方案已為相關技藝所熟知。
因此,本發明用於增強或激發宿主、患者或細胞培養物中之免疫應答。本文所用術語「患者」係指任一溫血動物、較佳人類。患者可患有感染病、癌症(例如乳癌)、或自身免疫疾病,或可正常(即,無可檢測到之疾病及/或感染)。「細胞培養物」係含有免疫活性細胞或免疫系統之分離細胞(包括但不限於T細胞、巨噬細胞、單核細胞、B細胞及樹突細胞)之任一製劑。可藉由彼等熟習此項技術者熟知之多種技術中之任一者(例如,Ficoll-hypaque密度離心)分離該等細胞。細
胞可(但不必須)分離自患有癌症之患者,且可在治療後再引入患者中。
在某些實施例中,意欲用於非經腸或經口投與之液體組合物應含有可獲得適宜劑量之量的GLA疫苗組合物。通常,組合物中之此量係至少0.01wt%抗原。當意欲經口投與時,此量可在組合物之0.1重量%與70重量%之間變化。較佳口服組合物含有約4%與約50%之間之抗原。製備較佳組合物及製劑以使非經腸劑量單元含有0.01重量%至1重量%活性組合物。
醫藥組合物可意欲局部投與,在此情形下載劑可適宜地包含溶液、乳液、軟膏或凝膠基質。舉例而言,該基質可包含以下之一或多者:礦脂、羊毛脂、聚乙二醇、蜂臘、礦物油、稀釋劑(例如,水及醇)、及乳化劑及穩定劑。用於局部投與之醫藥組合物中可存在增稠劑。若意欲經皮投與,則組合物可包括經皮貼片或離子導入裝置。局部調配物可含有濃度為約0.1 w/v至約10% w/v(重量/單位體積)之抗原(例如,GLA-抗原疫苗組合物)或GLA(例如,免疫佐劑組合物;GLA係自Avanti Polar Lipids公司,Alabaster,AL購得;例如,產品號699800)。
組合物可意欲以(例如)在直腸中融化並釋放藥物之栓劑形式經直腸投與。用於經直腸投與之組合物可含有油狀基質作為適宜非刺激性賦形劑。該等基質包括(但不限於)羊毛脂、可可脂及聚乙二醇。在本發明方法中,疫苗組合物/佐劑可經由使用插入物、珠粒、定時釋放調配物、貼片或快速釋放調配物來投與。
在某些實施例中,亦涵蓋包含本文所述GLA疫苗組合物及/或GLA免疫佐劑組合物之套組,其可提供於一或多個容器中。在一個實施例中,GLA疫苗組合物及/或GLA免疫佐劑組合物之所有組份均一起存在於單一容器中,但本發明實施例並不意欲限於此且亦涵蓋兩個
或更多個容器,其中(例如)GLA免疫佐劑組合物與抗原組份分離且並不接觸。藉助非限制性理論,據信,在某些情形下可有利地實施僅GLA免疫佐劑組合物之投與,同時在其他情形下該投與可有利地與抗原之投與在時間上及/或空間上(例如,於不同解剖位點處)分離,同時在又一些情形下有利地向個體投與如本文所述且含有抗原及GLA二者、及視情況以及本文所述其他組份之GLA疫苗組合物。
該套組實施例之容器可為任一適宜容器、器皿、小瓶、安瓿、管、杯子、盒子、瓶、燒瓶、大口瓶、盤、單孔或多孔設備之孔、槽、罐或諸如此類、或其中可將本文所揭示組合物於其中放置、儲存及/或運輸、及存取以移除內容物之其他裝置。通常,該容器可由與期望用途一致及可容易地達成所含內容物之回收的材料製得。該等容器之較佳實例包括玻璃及/或塑膠密封或可重複密封之管及安瓿,其包括彼等具有橡膠隔片或與使用針及注射器之內容物的抽取一致之其他密封構件者。舉例而言,該等容器可由玻璃或化學上相容之塑膠或樹脂製得,其可由允許物質自容器有效回收及/或保護物質免受(例如)降解條件(例如,紫外光或溫度極端)、或免於引入不期望污染物(包括微生物污染物)的材料製得或經其塗佈。容器較佳無菌或消毒,且由可與任一載劑、賦形劑、溶劑、媒劑或諸如此類相容之材料製得,例如可用於懸浮或溶解本文所述疫苗組合物及/或免疫佐劑組合物及/或抗原及/或重組表現構築體等。
本發明調配組合物中亦可使用乳液系統。舉例而言,已闡述許多單一或多相乳液系統。已建議水包油乳液佐劑本身用作佐劑組合物(EP 0 399 843B),同時水包油乳液及其他活性試劑之組合已闡述為用於疫苗之佐劑(WO 95/17210;WO 98/56414;WO 99/12565;WO 99/11241)。已闡述其他油乳液佐劑,例如油包水乳液(美國專利第5,422,109號;EP 0 480 982 B2)及水包油包水乳液(美國專利第
5.424,067號;EP 0 480 981 B)。用於本發明中之油乳液佐劑可為天然或合成的,且可為無機或有機的。熟習此項技術者將容易地明瞭無機及有機油之實例。
在一特定實施例中,本發明組合物包含水包油乳液,其中將GLA納入油相中。在另一實施例中,本發明組合物包含水包油乳液,其中將GLA納入油相中且其中存在額外組份,例如共佐劑、TLR激動劑、或諸如此類,如本文所述。
為使任一水包油組合物適於人類投與,乳液系統之油相較佳包含可代謝油。術語可代謝油之含義已為相關技藝所熟知。可代謝可定義為「能夠藉由代謝轉化」(Dorland's illustrated Medical Dictionary,W.B.Saunders公司,第25版(1974))。該油可為任一植物油、魚油、動物油或合成油,其對接受者無毒性且能夠藉由代謝轉化。堅果(例如花生油)、種子及穀物係植物油之常見來源。合成油亦係本發明之部分且可包括市售油,例如NEOBEE®及其他。
舉例而言,角鯊烯(2,6,10,15,19,23-六甲基-2,6,10,14,18,22-二十四碳六烯)係不飽和油,其在鯊魚肝油大量發現,且在橄欖油、麥胚芽油、米糠油及酵母中發現較少量,且係用於本發明中之尤佳油。由於角鯊烯係膽固醇生物合成中之中間體的事實,故其係可代謝油(Merck index,第10版,條目號8619)。尤佳油乳液係水包油乳液,且具體而言係存於水乳液中之角鯊烯。另外,本發明之最佳油乳液佐劑包含抗氧化劑,其較佳係油α-生育酚(維他命E,EP 0 382 271 B1)。WO 95/17210及WO 99/11241揭示基於角鯊烯、α-生育酚、及TWEEN® 80之乳液佐劑,其視情況與免疫刺激劑QS21及/或3D-MPL一起調配(上文對其進行論述)。WO 99/12565揭示利用向油相中添加類固醇對該等角鯊烯乳液之改良。另外,為穩定乳液,可向油相中添加甘油三酸酯(例如,三辛酸甘油酯(C27H50O6))(WO 98/56414)。
穩定的水包油乳液中發現之油滴的大小較佳小於1微米,其可在實質上30-600nm範圍內、較佳實質上直徑為約30-500nm、且最佳實質上直徑為150-500nm、且具體而言直徑為約150nm,如由光子相關光譜來量測。就此而言,80數量%之油滴應在較佳範圍內,更佳90數量%以上且最佳95數量%以上油滴在界定尺寸範圍內。本發明油乳液中存在之組份之量傳統上係在2%至10%油(例如角鯊烯)、及2%至10%α-生育酚(若存在)、及0.3%至3%表面活性劑(例如聚氧乙烯山梨醇酐單油酸酯)範圍內。較佳地,油:α-生育酚之比率等於或小於1,此時提供更穩定乳液。Span 85亦可以約1%之含量存在。在一些情形下,本發明疫苗進一步含有穩定劑可較為有利。
生產水包油乳液之方法已為熟習此項技術者熟知。通常,該方法包含混合油相與表面活性劑(例如PBS/TWEEN80®乳液),之後使用均質器進行均質化。舉例而言,包含將混合物通過注射器針頭一次、兩次或更多次之方法可適於均質化小體積之液體。相同地,微射流機(M110S微流體化機器,最大50次通過,於6巴最大輸入壓力(輸出壓力為約850巴)下持續2分鐘之時間)中之乳化製程可適用於產生較小或較大體積之乳液。此適應可藉由常規實驗達成,其包含量測所得乳液直至獲得具有所需直徑之油滴的製劑為止。
提供下列實例以舉例說明而非加以限制。
將疊氮化鈉(2.78g,42.7mmol)溶解於水(7mL)及甲苯(7mL)中。在劇烈攪拌下將混合物冷卻至0℃。逐滴添加三氟甲磺酸酐(Triflic anhydride)(4.57mL,27.2mmol),且於0℃下將混合物攪拌30min。將溫度升高至10℃,且將兩相混合物攪拌2h。逐滴添加碳酸氫鈉飽和水溶液直至停止氣體釋放為止。分離兩相,且用甲苯(2×7mL)萃取水層。合併之有機層用於後續重氮基轉移反應中。
將葡萄糖胺1(2.04g,9.45mmol)、碳酸氫鈉(3.21g,38.22mmol)及五水硫酸銅(II)(90.5mg,0.362mmol)溶解於水(12.3mL)中。添加上文製備之三氟甲磺酸疊氮化物儲備溶液(21mL),之後添加甲醇(81mL),從而產生均相系統。將藍色混合物於室溫下劇烈攪拌。藉由TLC(茚三酮染色法)監測胺之完全消耗且其亦由混合物自藍色至綠色之顏色變化來指示。在真空中利用旋轉蒸發器去除溶劑,將溫度嚴格保持於25℃下。藉由矽膠上層析(120g RediSep管柱,用0%至40%甲醇/二氯甲烷之梯度洗脫,經50min,85mL/min)純化殘留物,從而得到無色液體狀產物2(1.93g,99%)。1H NMR(300MHz,CD3OD)(非對映異構體之混合物1/1)δ 5.18(d,J=3.4Hz,0.5H),4.51(d,J=8.0Hz,0.5H),3.89-3.63(m,3H),3.32-3.26(m,2H),3.11-3.06(m,1H)。
向化合物2(2.00g,9.75mmol)存於DMF(40mL)中之溶液中添加苯甲醛二甲縮醛(1.65g,10.8mmol)及樟腦磺酸(90mg)。將燒瓶連接至真空系統,且於50℃下在油浴中加熱混合物。3h後,使用旋轉蒸發器濃縮混合物。將殘留物重新溶解於二乙醚(50mL)及Et3N(2mL)
中,之後重新溶解於飽和碳酸氫鈉(50mL)中。用二乙醚(3×50mL)萃取水層。將合併之有機萃取物經硫酸鈉乾燥並過濾。在使用旋轉蒸發器去除溶劑之後,藉由矽膠上層析(120g RediSep管柱,用0%至100%乙酸乙酯/己烷之梯度洗脫,經50min,85mL/min)純化殘留物,從而得到無色液體狀產物3(2.58g,90%)。1H NMR(300MHz,CD3OD)δ 7.49-7.32(m,5H),5.58(s,1H),4.64(d,J=3.8Hz,1H),4.25-341(m,5H),3.23-3.20(m,1H)。
於0℃下向化合物3(1.45g,4.94mmol)及咪唑(768mg,11.3mmol)存於CH2Cl2(40mL)中之混合物中添加第三丁基二甲基甲矽烷基氯(820mg,5.44mmol)。在將溶液攪拌過夜之後,添加飽和碳酸氫鈉(20mL),且用二乙醚(3×30mL)萃取混合物。將合併之有機層經Na2SO4乾燥、過濾並在真空中濃縮。藉由急驟管柱層析(80g RediSep管柱,用0%至70%乙酸乙酯/己烷之梯度洗脫,經40min,60mL/min)純化殘留物,從而得到無色固體狀產物4(1.5g,74%)。1H NMR(300MHz,CDCl3)δ 7.46-7.43(m,2H),7.35-7.32(m,3H),5.48(s,1H),4.59(d,J=7.6Hz,1H),4.23(dd,J=10.2,5.0Hz,1H),3.73(t,J=10.2Hz,1H),3.56-3.51(m,2H),3.31-3.28(m,2H),2.72(d,J=2.2Hz,1H),0.91(s,9H),0.14(s,3H),0.13(s,3H)。
於0℃下向化合物4(1.50g,3.68mmol)及四甲基乙二胺(TMEDA)(0.78mL,5.2mmol)存於二氯甲烷(DCM)(50mL)中之溶液中逐滴添加氯甲酸烯丙酯(0.78mL,7.3mmol)。將混合物升溫至室溫,且將混合物於室溫下攪拌10h。將混合物用DCM(50mL)稀釋並用飽和NaHCO3水溶液(2×100mL)及鹽水(2×50mL)洗滌。將合併之有機層經Na2SO4乾燥、過濾並在真空中濃縮。藉由急驟管柱層析(80g RediSep管柱,用0%至50%乙酸乙酯/己烷之梯度洗脫,經40min,60mL/min)純化殘留物,從而得到無色固體狀產物5(1.57g,87%)。R f =0.40(己烷/乙酸乙酯,3/1,v/v)。1H NMR(300MHz,CDCl3)δ 7.44-7.41(m,2H),7.35-7.32(m,3H),5.98-5.85(m,1H),5.48(s,1H),5.38-5.22(m,2H),4.88(t,J=11.4Hz,1H),4.72-4.64(m,3H),4.32-4.27(m,1H),3.81-3.65(m,2H),3.50-3.42(m,2H),0.94(s,9H),0.18(s,3H),0.17(s,3H)。
將化合物5(320mg,0.651mmol)及分子篩(4Å,200mg)存於THF
(5mL)中之懸浮液於室溫下攪拌1h,且隨後添加NaCNBH3(246mg,3.91mmol)。向此混合物中逐滴添加氯化氫溶液(2M,存於二乙醚中)直至混合物變為酸性(~5mL,pH=5)。在再攪拌0.5h後,將反應混合物用固體NaHCO3淬滅,用二乙醚(100mL)稀釋,並用飽和NaHCO3水溶液(2×100mL)及鹽水(2×50mL)洗滌。將有機層經Na2SO4乾燥,過濾,在真空中濃縮,且藉由急驟管柱層析(40g RediSep管柱,用0%至100%乙酸乙酯/己烷之梯度洗脫,經40min,40mL/min)純化殘留物,從而得到無色固體狀產物6(273mg,85%)。R f =0.42(己烷/乙酸乙酯,4/1,v/v)。1H NMR(300MHz,CDCl3)δ 7.39-7.34(m,5H),5.99-5.89(m,1H),5.40-5.26(m,2H),4.67-4.56(m,5H),3.72-3.70(m,3H),3.48-3.46(m,2H),3.37(dd,J=9.6,8.4Hz,1H),3.01(寬s,1H),0.94(s,9H),0.17(s,6H)。
向化合物6(5.47g,11.1mmol)及1H-四唑(3wt%,存於乙腈中,35.5mmol,104mL)之溶液中添加N,N-二乙基-1,5-二氫-3H-2,4,3-苯并二噁磷環庚烷-3-胺(5.3g,22mmol)。在將反應混合物於室溫下攪拌15min後,將其冷卻至-20℃,於該溫度下再攪拌10min,且隨後添加mCPBA(8.40g,50-55wt%,24.4mmol)。將反應混合物於-20℃下攪拌20min,並在真空中濃縮。將殘留物重新溶解於DCM(30mL)中並
用飽和NaHCO3水溶液(40mL)洗滌。用DCM(3×50mL)萃取水層。將合併之有機層經Na2SO4乾燥、過濾並在真空中濃縮。藉由急驟管柱層析(120g RediSep管柱,用0%至100%乙酸乙酯/己烷之梯度洗脫,經60min,85mL/min)純化殘留物,從而得到淺黃色油狀產物7(4.85g,65%)。R f =0.40(己烷/乙酸乙酯,1/1,v/v)。1H NMR(300MHz,CDCl3)δ 7.35-7.18(m,9H),5.98-5.85(m,1H),5.41-5.05(m,6H),4.64(t,J=10.1Hz,1H),4.58-4.52(m,6H),3.83(d,J=9.0Hz,1H),3.72-3.61(m,2H),3.41(dd,J=10.5,7.4Hz,1H),0.92(s,9H),0.16(s,3H),0.15(s,3H)。
向7(700mg,1.04mmol)及鋅粉(676mg,10.4mmol)存於DCM(15mL)中之攪拌懸浮液中逐滴添加乙酸(0.30mL,5.2mmol)。將反應混合物於室溫下攪拌4h,此後用乙酸乙酯(50mL)對其進行稀釋。藉由過濾移出固體並用乙酸乙酯(2×10mL)洗滌。將合併之濾液用飽和NaHCO3水溶液(2×40mL)及鹽水(2×40mL)洗滌。乾燥(MgSO4)並過濾有機相,且在真空中濃縮濾液,從而獲得淺黃色油狀粗製中間體胺。R f =0.21(己烷/乙酸乙酯,1/1,v/v)。於0℃下向粗製胺及二異丙基乙基胺(DIPEA)(0.22mL,1.3mmol)存於DCM(15mL)中之攪拌溶液中添加9-茀基甲基氧基羰基氯(Fmoc-Cl)(323mg,1.25mmol)。使反應混
合物升溫並於室溫下攪拌5h,此後將其用DCM(40mL)稀釋並用鹽水(2×50mL)洗滌。乾燥(MgSO4)有機相並加以過濾。於真空中濃縮濾液。藉由矽膠管柱層析(40g RediSep管柱,用0%至100%乙酸乙酯/己烷之梯度洗脫,經30min,40mL/min)純化殘留物,從而得到白色固體狀產物8(337mg,73%,經兩個步驟)。R f =0.54(己烷/乙酸乙酯,1/1,v/v)。1H NMR(300MHz,CDCl3)δ 7.78-7.20(m,17H),5.92-5.82(m,1H),5.49-5.16(m,8H),4.69-4.06(m,5H),4.49-4.28(m,2H),3.88-3.61(m,3H),3.60-3.51(m,2H),3.32(寬s,1H),0.94(s,9H),0.14(s,3H),0.10(s,3H)。
向8(6.00g,6.88mmol)存於THF(50mL)中之攪拌溶液中逐滴添加氟化氫/吡啶(6mL,0.2mol)。將反應混合物於室溫下攪拌12h,此後將其用二乙醚(100mL)稀釋,且隨後用飽和NaHCO3水溶液(2×40mL)及鹽水(2×40mL)洗滌。乾燥(MgSO4)有機相並加以過濾。於真空中濃縮濾液。藉由矽膠管柱層析(120g RediSep管柱,用0%至80%乙酸乙酯/己烷之梯度洗脫,經60min,85mL/min)純化殘留物,從而得到淺黃色油狀產物9(4.34g,83%)。1H NMR(300MHz,CDCl3)δ 7.75-7.20(m,17H),5.92-5.82(m,1H),5.27-5.06(m,9H),4.59-4.55(m,5H),4.41-4.39(m,1H),4.25-4.01(m,5H),3.85-3.65(m,2H)。
將10(參見下文製備)(350mg,0.172mmol)、鋅(1.3g,21mmol)及乙酸(0.70mL,12mmol)存於DCM(20mL)中之懸浮液於室溫下攪拌12h。用二乙醚稀釋混合物。藉由過濾去除固體,且用二乙醚(2×10mL)洗滌殘留物。用飽和NaHCO3水溶液(2×15mL)及鹽水(2×15mL)洗滌合併之濾液。乾燥(MgSO4)有機相並加以過濾。在真空中濃縮濾液,且藉由矽膠管柱層析(12g RediSep管柱,用0%至60%乙酸乙酯/己烷之梯度洗脫,經35min,30mL/min)純化殘留物,從而獲得淺黃色糖漿狀產物11(220mg,64%)。R f =0.29(己烷/乙酸乙酯,5/2,v/v)。1H NMR(300MHz,CDCl3)δ 7.37-7.24(m,20H),6.20(d,J=7.2Hz,1H),5.59(t,J=9.6Hz,1H),5.31(m,1H),5.12-4.97(m,6H),4.62-4.44(m,7H),4.05-3.24(m,9H),2.68-2.12(m,9H),1.64-1.59(m,13H),1.27(寬m,95H),0.94(m,25H),0.13(s,6H)。HRMS(m/z)(正)計算值C117H193N2O20PSi,2005.37;實驗值2006.3729[M+H]+。
於室溫下向胺11(93mg,0.046mmol)存於DCM(10mL)中之溶液中添加吡啶(21mg,0.27mmol)、(R)-3-(4-甲氧基苄基氧基)十四烷醯基氯(參見下文製備,化合物35)(40mg,0.12mmol)及4-二甲基胺基吡啶(DMAP)(1mg),且將混合物攪拌過夜。將混合物轉移至分液漏斗中並用二乙醚(20mL)及飽和碳酸氫鈉(20mL)稀釋。用二乙醚(3×20mL)萃取水層。將合併之有機萃取物經硫酸鈉乾燥,過濾並在降低之壓力下濃縮。藉由矽膠上層析(12g RediSep管柱,用0%至80%乙酸乙酯/己烷之梯度洗脫,經35min,30mL/min)純化殘留物,從而得到無色液體狀產物12(81mg,74%)。R f =0.34(己烷/乙酸乙酯,3/2,v/v)。1H NMR(300MHz,CDCl3)δ 7.34-7.20(m,20H),6.89-6.86(m,4H),6.15(t,J=9.0Hz,1H),5.57-5.55(m,1H),5.31-4.99(m,8H),4.57-4.44(m,11H),4.06-3.33(m,15H),2.63-2.57(m,5H),2.33-2.27(m,9H),1.57(m,8H),1.27(寬m,112H),0.88-0.82(m,27H),0.08(s,3H),0.04
(s,3H)。HRMS(m/z)(正)計算值C139H227N2O23PSi,2351.62;實驗值2352.6343[M+H]+。
於室溫下將12(10mg,0.0042mmol)及Pd-黑(15.0mg)存於無水THF(5mL)中之懸浮液在H2(50psi)氛圍下振盪30h。藉由過濾移出觸媒。用THF(2×1mL)洗滌殘留物。將溶液冷卻至-40℃並用存於甲醇中之氨(0.1mL,7M)中和且濃縮而並不在真空中加熱。藉由層析(12g RediSep管柱,用氯仿/甲醇/水8/2/0.1洗脫30min,30mL/min)純化殘留物,從而獲得無色膜狀物13a(4mg,54%)。將產物重新溶解於水及甲醇(v/v,1/1,2mL)中並凍乾,從而獲得白色粉末狀產物13a。1H NMR(500MHz,CDCl3)δ 6.00-5.00(m,1H),4.50-3.50(m,2H),3.00-2.00(m,3H),2.00-1.00(m,50H),0.81(m,18H)。MS(多模式,負)計算值C96H181N2O22P,1745.28;實驗值1745.0[M-H]-。
於室溫下將12(27mg,0.011mmol)及Pd-黑(41.0mg)存於無水THF(12mL)中之懸浮液在H2(50psi)氛圍下振盪30h。藉由過濾移出觸媒。用THF(2×3mL)洗滌殘留物。用三乙胺(TEA)(0.1mL)中和溶液並濃縮而不在真空中加熱。將合併之濾液在真空中濃縮並藉由氧化矽上層析(12g RediSep管柱,用氯仿/甲醇/水8/2/0.1洗脫30min,30mL/min)純化,從而獲得無色膜狀物13b(5mg,25%)。將產物重新溶解於水及甲醇(v/v,1/1,2mL)中並凍乾,從而獲得白色粉末狀產物13b。1H NMR(500MHz,CDCl3)δ 5.17(寬,2H),4.23-3.62(m,5H),3.11-3.07(q,J=2.8Hz,2H),2.51-2.12(m,6H),1.56-1.00(m,69H),0.92-0.84(m,18H)。MS(多模式,負)計算值C96H181N2O22P,1745.28;實驗值1744.1[M-H]-。
將化合物9(89mg,0.12mmol)溶解於無水DMF(3mL)中。先後添加三氯乙腈(1.0mL)及氫化鈉(1.0mg,60%,存於礦物油中)。15min後,TLC指示存在9,因此添加額外量之氫化鈉(1mg,60%,存於礦物油中)。15min後,TLC指示反應完成。將混合物在真空下濃縮並裝載於用Et3N預處理且用50%乙酸乙酯/己烷洗脫之SiO2管柱上,從而提供三氯乙醯亞胺酯中間體(76.9mg,71%),其未經進一步純化即使用。將三氯乙醯亞胺酯(76.9mg,0.0852mmol)、受體14(參見下文製備)(52.34mg,0.1277mmol)及分子篩(4Å,500mg)存於DCM(5.0mL)中之懸浮液攪拌1h。冷卻混合(-60℃)並添加TMSOTf(1.54μL,0.0851mmol)。在將反應混合物攪拌30min後,將其用固體NaHCO3淬滅。藉由過濾去除固體,並在真空中濃縮濾液。藉由矽膠管柱層析(己烷/乙酸乙酯,2:1(v/v))純化殘留物,從而得到無色固體狀物15(55mg,40%)。1H NMR(500MHz,CD3COCD3)δ 7.86-7.22(m,22H),6.98(d,J=9.0Hz,1H),5.85(m,1H),5.41(t,J=9.0Hz,1H),5.38-5.21(m,3H),5.10-5.02(m,3H),4.91(d,J=11.0Hz,2H),4.72-4.46(m,7H),4.23-4.15(m,4H),3.93-3.80(m,4H),3.69-3.66(m,1H),3.54(br s,3H),3.20(dd,J 1=8.0Hz,J 2=8.0Hz,1H),0.95(s,9H),0.17(s,6H);13C NMR(125MHz,CD3COCD3)δ 207.00,156.61,155.51,145.22,144.82,142.06,142.01,139.98,139.57,136.68,136.62,133.02,132.94,129.85,129.83,129.15,129.05,128.95,128.91,128.82,128.61,128.49,128.41,128.21,128.17,128.0,127.92,126.19,126.09,125.98,120.79,118.60,118.52,101.41,97.57,78.78,78.10,76.84,75.98,75.88,75.43,75.30,75.17,74.70,74.07,70.63,69.76,69.64,69.27,69.15,69.10,69.02,68.97,67.73,67.17,57.29,54.94,26.11,18.51;;HR MS(m/z)計算值C59H69N4O16PSi[M+H]+,1149.4293;實驗值1149.4238。
向15(800mg,0.696mmol)存於DCM(10mL)中之溶液中逐滴添加1,8-二氮雜二環[5.4.0]十一-7-烯(220μL,1.47mmol)。將該反應混合物在室溫下攪拌1h,此後將其在真空中濃縮。藉由矽膠管柱層析(DCM/甲醇,100:1至100:3(v/v))純化殘留物,從而獲得無色糖漿狀游離胺(648mg,99%)。1H NMR(500MHz,CDCl3)δ 7.36-7.17(m,14H),5.96-5.88(m,1H),5.40-5.06(m,7H),4.84-4.50(m,9H),4.21(d,J=13.5Hz,1H),4.15-4.11(m,1H),3.82(m,1H),3.79-3.42(m,5H),3.34-3.19(m,2H),2.96-2.90(m,1H),2.34(d,J=4.5Hz,1H),0.90(s,9H),0.13(s,6H)。HRMS(m/z)計算值C44H59N4O14PSi[M+H]+,927.3613;實驗值927.3569。
向(R)-3-十二烷醯基-十四烷酸(參見下文製備,化合物40)(381mg,0.81mmol)存於DCM(10mL)中之攪拌溶液中添加N,N-二環己基碳化二亞胺(DCC)(230mg,1.11mmol)。在將反應混合物攪拌10min後,添加存於DCM(10mL)中之游離胺(648mg,0.699mmol),且再繼續攪拌12h。藉由過濾去除不可溶物質,且用DCM(2×2mL)洗滌殘
留物。在真空中濃縮合併之濾液,且藉由矽膠管柱層析(己烷/乙酸乙酯,2:1(v/v))純化殘留物,從而得到白色固體狀物16(450mg,47%)。1H NMR(500MHz,CDCl3)δ 7.35-7.17(m,14H),5.94-5.86(m,2H),5.47(t,J=9.0,10.5Hz,1H),5.37(d,J=2.5Hz,1H),5.34(d,J=2.5Hz,1H),5.24(d,J=13.5Hz,1H),5.13-4.97(m,6H),4.75(d,J=11.0Hz,1H),4.66-4.49(m,7H),4.00(d,J=17.0Hz,2H),3.83(d,J=10.5Hz,1H),3.75-3.56(m,4H),3.49-3.36(m,5H),3.20(m,1H),2.42-2.17(m,4H),1.93(d,J=11.5Hz,1H),1.70(m,2H),1.23(br s,36H),0.92(s,9H),0.89-0.86(m,6H),0.14(s,6H);HRMS(m/z)計算值C72H111N4O17PSi[M+H]+,1363.7529;實驗值1363.7487。
將(R)-3-苄基氧基十四烷酸(參見下文製備,化合物33)(120mg,0.540mmol)及DCC(171mg,0.830mmol)存於DCM(5mL)中之混合物於室溫下攪拌10min,且隨後添加存於DCM(5mL)中之二糖16(451
mg,0.331mmol)及DMAP(25mg,0.21mmol)。將反應混合物於室溫下攪拌14h,此後藉由過濾去除固體。用DCM(2×4mL)洗滌殘留物。在真空中濃縮合併之濾液,且藉由矽膠管柱層析(己烷/乙酸乙酯,4:1(v/v))純化殘留物,從而得到白色固體狀物17(540mg,97%)。R f =0.41(己烷/乙酸乙酯,2:1(v/v))。1H NMR(500MHz,CDCl3)δ 7.33-7.15(m,19H),5.94-5.85(m,2H),5.47(t,J=9.5Hz,1H),5.37(d,J=17.5Hz,1H),5.22(d,J=10.0Hz,1H),5.10-4.95(m,7H),4.62-4.43(m,10H),4.0-3.96(m,3H),3.90-3.81(m,2H),3.74-3.67(m,3H),3.56-3.42(m,6H),3.33-3.27(m,1H),2.60-2.21(m,6H),1.24(br s,54H),0.91(s,9H),0.87-0.84(m,9H),0.14(s,6H)。HRMS(m/z)計算值C93H143N4O19PSi[M+H]+,1679.9931;實驗值1679.9934。
向17(1.66g,0.980mmol)、n-BuNH2(0.19mL,1.97mmol)及HCOOH(74.5μL,1.98mmol)存於THF(20mL)中之溶液中添加肆(三苯基膦)鈀(228mg,0.198mmol)。在將反應混合物於室溫下攪拌20
min後,將其用DCM(40mL)稀釋,且連續用水(40mL)、飽和NaHCO3水溶液(2×40mL)及鹽水(40mL)洗滌。乾燥(MgSO4)有機相並加以過濾。於真空中濃縮濾液。藉由矽膠管柱層析(己烷/乙酸乙酯,4:3(v/v))純化殘留物,從而得到化合物18(1.43g,91%)。R f =0.5(己烷/乙酸乙酯,1:1(v/v))。1H NMR(500MHz,CDCl3)δ 7.33-7.11(m,19H),6.2(d,J=7.5Hz,1H),5.46(t,J=9.0Hz,1H),5.04-4.90(m,9H),4.55-4.38(m,8H),3.92(d,J=10.0Hz,1H),3.84-3.76(m,1H),3.75-3.7(m,4H),3.53-3.44(m,2H),3.43-3.32(m,2H),3.25-3.20(m,1H),2.61-2.10(m,12H),1.23(br s,54H),0.90(s,9H),0.88-0.84(m,9H),0.12(s,6H)。HRMS(m/z)計算值C89H139N4O17PSi[M+H]+,1595.972;實驗值1595.9713。
將(R)-3-(對甲氧基)苄基氧基-十四烷酸(參見下文製備,化合物34,424mg,1.16mmol)及DCC(369mg,1.79mmol)存於DCM(15mL)中之溶液於室溫下攪拌10min,且添加存於DCM(10mL)中之醇
18(1.43g,0.896mmol)及DMAP(54.72mg,0.4479mmol)。將反應混合物再攪拌14h,此後藉由過濾移出固體並用DCM(2×5mL)洗滌。於真空中濃縮合併之濾液。藉由矽膠管柱層析(己烷/乙酸乙酯,4:1(v/v))純化殘留物,從而獲得白色固體狀物19(1.15g,66%)。R f =0.46(己烷/乙酸乙酯,2:1(v/v))。1H NMR(500MHz,CDCl3)δ 7.38-6.79(m,23H),5.73(d,J=8.0Hz,1H),5.55(t,J=9.5Hz,1H),5.20-4.88(m,8H),4.66-4.47(m,12H),4.33(d,J=12.5Hz,1H),4.0-3.66(m,12H),3.61-3.40(m,5H),3.36-3.27(m,3H),2.67(d,J=6.0Hz,2H),2.60-2.22(m,6H),1.27(br s,72H),0.93(s,9H),0.92-0.87(m,12H),0.16(s,6H)。HRMS(m/z)計算值C111H173N4O20PSi[M+H]+,1942.2228;實驗值1942.2289。
向19(1.15g,0.592mmol)存於DCM與H2O混合物(11mL,10:1(v/v))中之攪拌溶液中添加2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)(202
mg,0.890mmol)。將該反應混合物在室溫下攪拌1h,此後將其用DCM稀釋。將混合物用鹽水(20mL)洗滌,乾燥(MgSO4)並在真空中濃縮。藉由矽膠管柱層析(己烷/乙酸乙酯,3:1(v/v))純化殘留物,從而得到無色糖漿狀醇(1.01g,94%)。R f =0.50(己烷/乙酸乙酯,5:3(v/v))。向醇(1.01g,0.554mmol)及吡啶(0.35mL,4.33mmol)存於DCM(20mL)中之溶液中添加肉豆蔻醯氯(0.74mL,2.7mmol)。將將反應混合物於室溫下攪拌12h後,將其用DCM稀釋並用飽和NaHCO3水溶液(2×40mL)及鹽水(40mL)洗滌。乾燥(MgSO4)有機相並加以過濾。於真空中濃縮濾液。藉由矽膠管柱層析(己烷/乙酸乙酯,4:1(v/v))純化殘留物,從而獲得白色固體狀物10(680mg,57%)。R f =0.46(己烷/乙酸乙酯,5:2(v/v))。1H NMR(500MHz,CDCl3)δ 7.37-7.24(m,19H),6.23(d,J=7.5Hz,1H),5.58(t,J 1=J 2=9.5Hz,1H),5.32-5.27(m,1H),5.16-4.99(m,6H),4.78-4.44(m,7H),4.03(d,J=10.5Hz,1H),3.99-3.20(m,10H),2.65-2.21(m,10H),1.61-1.51(m,10H),1.27(br s,94H),1.21(br s,25H),0.12(s,6H)。
化合物15(1.23g,1.07mmol)以類似於化合物16(實例14)之合成
方式使用(DCC,430mg,2.08mmol)、所需脂質(化合物40,實例36,630mg,1.59mmol)及三乙胺(161mg,1.59mmol)醯基化,從而提供無色油狀物20(1.05g,81%)。1H NMR(500MHz,CDCl3)δ 7.35-7.17(m,14H),5.91-5.86(m,2H),5.47(t,J=9.0,10.5Hz,1H),5.34(d,J=17Hz,1H),5.24(d,J=10.5Hz,1H),5.10-4.98(m,8H),4.75(d,J=11.5Hz,1H),4.66-4.49(m,8H),4.00(d,J=11.0Hz,2H),3.83(d,J=11.0Hz,1H),3.75-3.69(m,2H),3.49-3.36(m,4H),3.20(m,1H),2.40-2.26(m,4H),1.24(br s,32H),0.92(s,9H),0.89-0.86(m,6H),0.14(s,6H);MS(多模式,正)m/z=1307[M+H]+。
化合物20(1.43g,1.18mmol)以類似於化合物17(實例15)之合成方式使用(DCC,453mg,2.20mmol)、所需脂質(477mg,1.43mmol)及N,N-二甲基-4-胺基吡啶(67mg,0.548mmol)醯基化,從而提供無色油狀物21(1.60g,83%)。1H NMR(500MHz,CDCl3)δ 7.33-7.15(m,
19H),5.94-5.85(m,2H),5.48(t,J=9.0Hz,1H),5.34(d,J=17.5Hz,1H),5.22(d,J=10.0Hz,1H),5.12-4.96(m,7H),4.63-4.46(m,11H),3.97(d,J=10.5Hz,1H),3.89-3.85(m,2H),3.74-3.68(m,3H),3.55-3.52(m,2H),3.47-3.41(m,1H),3.28(m,1H),2.61-2.22(m,8H),1.59-1.52(m,6H),1.98(m,2H),1.23(br s,44H),0.90(s,9H),0.88-0.84(m,9H),0.12(s,6H);MS(多模式,正)m/z=1625[M+H]+。
以類似於化合物18(實例16)之合成方式使化合物21(1.60g,0.985mmol)反應。因此,使用肆(三苯基膦)鈀(227mg,0.196mmol)、甲酸(74μL,1.97mmol)及正丁基胺(144mg,1.97mmol),得到黃色固體22(1.25g,82%)。1H NMR(500MHz,CDCl3)δ 7.33-7.15(m,19H),6.20(d,J=7.5Hz,1H),5.38-4.95(m,6H),4.86(d,J=8.0Hz,1H),4.60-4.46(m,10H),3.97-3.71(m,8H),3.68-3.48(m,5H),3.31-3.27(m,3H),2.62-2.55(m,2H),2.50-2.42(m,3H),2.40-2.22(m,5H),1.23(br s,44H),0.90(s,9H),0.88-0.84(m,9H),0.12(s,6H);MS(多模式,正)
m/z=1539[M+H]+。
化合物22(1.25g,0.811mmol)以類似於化合物19(實例17)之合成方式使用(DCC,335mg,1.62mmol)、所需脂質(化合物34,實例32,386mg,1.06mmol)及N,N-二甲基-4-胺基吡啶(50mg,0.41mmol)醯基化,從而提供無色油狀物23(440mg,29%)。1H NMR(500MHz,CDCl3)δ 7.38-6.79(m,23H),5.71(d,J=7.5Hz,1H),5.55(t,J=9.5Hz,1H),5.06-4.85(m,9H),4.66-4.45(m,12H),3.97(d,J=11.0Hz,1H),3.90-3.69(m,9H),3.60-3.55(m,3H),3.37-3.29(m,2H),2.65(d,J=7.5Hz,2H),2.61-2.55(m,1H),2.48-2.42(m,1H),2.35-2.21(m,3H),2.11-2.05(m,1H),1.62-1.59(m,8H),1.27(br s,62H),0.93(s,9H),0.92-0.87(m,12H),0.16(s,6H);MS(多模式,正)m/z=1886[M+H]+。
首先遵循中間體10針對目標A之程序使用DDQ(80mg,0.35mmol)使化合物23(446mg,0.236mmol)去保護。隨後此中間體(343mg,0.194mmol)以類似於化合物10針對目標A之合成方式使用癸醯氯(185mg,0.970mmol)及吡啶(123mg,1.55mmol)醯基化,從而提供無色油狀物24(343mg,76%)。1H NMR(500MHz,CDCl3)δ 7.39-7.22(m,14H),6.15(d,J=7.5Hz,1H),5.54(t,J=9.5Hz,1H),5.28-5.24(m,1H),5.14-4.96(m,8H),4.60-4.45(m,10H),3.99(d,J=10.5Hz,1H),3.90-3.85(m,1H),3.80-3.65(m,4H),3.55(m,3H),3.46-3.39(m,1H),3.32-3.27(m,1H),2.66-2.53(m,3H),2.46-2.41(m,1H),2.35-2.18(m,7H),1.61-1.51(m,10H),1.26(br s,78H),0.95(s,9H),0.92-0.90(m,15H),0.19(s,3H),0.18(s,3H)。
將24(296mg,0.154mmol)、鋅(100mg,1.52mmol)及乙酸(53μL,0.93mmol)存於DCM(10mL)中之懸浮液於室溫下攪拌12h,此後將其用乙酸乙酯(25mL)稀釋。藉由過濾移出固體並用乙酸乙酯(2×25mL)洗滌,且用飽和NaHCO3水溶液(2×100mL)及鹽水(200mL)洗滌合併之濾液。乾燥(Na2SO4)有機相並加以過濾。於真空中濃縮濾液。藉由矽膠管柱層析(己烷/乙酸乙酯,2.5:1(v/v))純化殘留物,從而獲得淺黃色糖漿狀胺(245mg,84%)。1H NMR(500MHz,CDCl3)δ 7.39-7.22(m,14H),6.15(d,J=7.5Hz,1H),5.54(t,J=9.5Hz,1H),5.29-5.23(m,1H),5.13-4.93(m,8H),4.62-4.30(m,9H),4.00(d,J=10.5Hz,1H),3.88-3.65(m,6H),3.56-3.53(m,2H),3.46-3.41(m,1H),2.66-2.58(m,4H),2.54-2.45(m,2H),2.35-2.17(m,7H),1.64-1.42(m,12H),1.26(br s,78H),0.87(s,24H),0.13(s,6H)。
向(R)-3-苄基氧基十四烷醯基氯(228mg,0.646mmol)、DMAP
(15.79mg,0.1292mmol)及吡啶(83μL,1.0mmol)存於DCM(5.0mL)中之攪拌溶液中添加胺。將反應混合物攪拌14h。將混合物用CH2Cl2稀釋並用飽和NaHCO3/鹽水洗滌,在Na2SO4下乾燥並在真空下濃縮。藉由矽膠TLC層析(己烷/乙酸乙酯,3.5:1(v/v))純化殘留物,從而得到白色固體狀物25(450mg,>100%)。R f =0.54(己烷/乙酸乙酯,2:1(v/v))。1H NMR(500MHz,CDCl3)δ 7.39-7.22(m,19H),6.14-6.10(m,2H),5.57(t,J=9.5Hz,1H),5.29-5.24(m,1H),5.13-4.93(m,7H),4.61-4.41(m,10H),4.00(d,J=10.5Hz,1H),3.89-3.79(m,8H),3.72-3.66(m,4H),3.57-3.35(m,3H),2.73-2.57(m,10H),2.39-2.15(m,10H),1.71-1.64(m,7H),1.26(br s,93H),0.88(s,24H),0.83(s,9H)。
向25(450mg,0.204mmol)存於THF(5mL)中之攪拌溶液中逐滴添加氟化氫/吡啶(1.12mL,43.1mmol)。將反應混合物於室溫下攪拌14h。將混合物用乙酸乙酯(100mL)稀釋,並用飽和NaHCO3水溶液
(2×80mL)及鹽水洗滌。乾燥(Na2SO4)有機相並加以過濾。於真空中濃縮濾液。藉由矽膠管柱層析(己烷/乙酸乙酯,3:1至4:3(v/v))純化殘留物,從而得到白色固體狀物26(180mg,42%)。1H NMR(500MHz,CDCl3)δ 7.39-7.19(m,19H),6.31(d,J=7.0Hz,1H),6.24(d,J=9.5Hz,1H),5.57-5.48(m,2H),5.40(t,J=9.5Hz,1H),5.28-5.21(m,1H),5.14-4.96(m,8H),4.68-4.41(m,12H),4.23-4.19(m,1H),4.13-4.06(m,1H),3.94-3.66(m,9H),3.38-3.28(m,2H),2.67-2.58(m,3H),2.44-2.20(m,11H),1.58(br s,12H),1.26(br s,93H),0.91-0.81(m,18H)。
將化合物26(180mg,0.0858mmol)溶解於無水THF(15mL)中。向混合物中添加鈀黑(0.225g)且在50psi氫氛圍下氫化過夜。經由矽藻土床過濾混合物。將濾液冷卻至-40℃並添加存於甲醇(1.8mL,4M)中之氨溶液。在真空下濃縮混合物而不加熱。藉由矽膠層析用氯仿/甲醇/水(80:20:1(v/v))之混合物洗脫純化殘留物,從而得到期望化合物(IX)(102mg,73%)。藉由TLC及1H NMR之分析顯示存在油脂及
不明顯密集運行之斑點(TLC,存於CH2Cl2/CMA中,4:1)。使殘留物經受層析(12g RediSep管柱,用等梯度CH2Cl2之梯度洗脫,5管柱體積(CV);至25% CMA之梯度洗脫,10 CV;等梯度10 CV洗脫;至100% CMA之梯度洗脫,10 CV;於100% CMA下等梯度洗脫,10 CV,20mL/min),從而得到期望產物(57mg,25%)。合併並濃縮部分之TLC分析仍指示僅在期望產物上有極少量雜質流動。藉由矽膠層析(兩個串聯12g RediSep管柱,與上文相同梯度)再純化殘留物,從而在溶解於甲醇/水/氯仿中並冷凍乾燥後提供8.9mg期望產物(由TLC顯示純淨)及11.9mg稍微不純產物。總產率(20.8mg,14%),呈灰白色固體狀。R f =0.40CMA。1H NMR(500MHz,CDCl3)δ 5.40-5.30(br s,2H),4.10-4.00(m,4H),3.70-3.60(m,4H),2.83-2.76(m,1H),2.75-2.20(m,13H),2.10-1.90(寬,9H),1.40-1.00(寬,106H),0.90-0.70(寬,18H)。MS(多模式,負)m/z=1632[M-H]-。
向乙醇鎂(10.82g,94.61mmol)存於1,4-二噁烷(100mL)中之懸浮液中添加存於1,4-二噁烷(100mL)中之甲基丙二酸氫(25.0g,189mmol)。將所得漿液攪拌過夜。在真空中濃縮混合物。在單獨燒瓶中,將月桂酸(28,20.85g,104.1mmol)溶解於1,4-二噁烷(50mL)中且於室溫下添加CDI(16.88g,104.1mmol)存於1,4-二噁烷(150mL)中之溶液。將所得溶液攪拌過夜。隨後將混合物轉移至甲基丙二酸鎂燒瓶中。將所得懸浮液回流過夜。在真空中濃縮混合物。將殘留物重新溶解於DCM(300mL)中並經由氧化矽塞(10g)過濾。在降低之壓力下蒸
發溶劑。藉由矽膠管柱層析(360g RediSep管柱,用0%至30%乙酸乙酯/己烷之梯度洗脫,經80min,100mL/min)純化殘留物,從而獲得淺黃色糖漿狀產物29(17g,61%)。
將3-側氧基十四烷酸甲酯(29,29.0g,113mmol)存於甲醇(120mL)中之漿液在300mL高壓反應器玻璃套管中用N2吹掃10分鐘。添加二氯-R-2,2'-雙(二苯基膦基)-1,1'-聯萘基釕(897mg,1.10mmol)。將混合物放置於Parr 5500系列集成反應器中。向反應器中充入H2(60psi)且通風3次。向反應器中充入H2(60psi)並攪拌(1200rpm)並加熱至50℃並保持20h。將反應器冷卻至室溫,且在真空中濃縮所得橙色溶液。藉由矽膠層析(120g RediSep管柱,用0%至40%乙酸乙酯/己烷之梯度洗脫,經60min,85mL/min)純化殘留物,從而提供白色固體狀產物30(28.5g,97%產率)。
於0℃下向化合物30(2.8g,10.83mmol)及三氯乙醯亞胺苄酯(3.4g,14mmol)存於DCM(100mL)中之溶液中逐滴添加三氟甲烷磺酸(0.24mL,2.7mmol)。將所得混合物於0℃下攪拌6h並升溫至室溫。
將混合物用飽和NaHCO3溶液(300mL)及水(300mL)洗滌並經Na2SO4乾燥有機層。藉由過濾去除乾燥劑,且使用旋轉蒸發器去除溶劑。藉由矽膠上層析(80g RediSep管柱,用0%至30%乙酸乙酯/己烷之梯度洗脫,經60min,60mL/min)純化殘留物,從而得到無色液體狀產物31(1.2g,32%)。1H NMR(300MHz,CDCl3)δ 7.30-7.05(m,5H),4.51(s,2H),3.90-3.80(m,1H),3.70(s,3H),2.58-2.45(m,2H),1.80-1.60(m,2H),1.50-1.20(m,18H),0.85(t,J=5.8Hz,3H)。
將酯31(1.3g,3.73mmol)溶解於THF/MeOH/CH3CN混合物(v/v/v,1/1/1,90mL)中。添加存於水(30mL)中之溶液形式之氫氧化鋰單水合物(235mg,5.6mmol),且將混合物攪拌過夜。在真空中將溶劑量減少為約30mL。向剩餘水溶液中添加1M氫氯酸以使pH降低至3。用二乙醚(3×40mL)萃取水層。將合併之有機萃取物經硫酸鈉乾燥。藉由過濾去除乾燥劑,且使用旋轉蒸發器去除溶劑。藉由矽膠上層析(40g RediSep管柱,用0%至50%乙酸乙酯/己烷之梯度洗脫,經40min,40mL/min)純化殘留物,從而得到無色液體狀產物33(990mg,79%)。1H NMR(300MHz,CDCl3)δ 7.30-7.05(m,5H),4.51(s,2H),3.90-3.80(m,1H),2.58-2.45(m,2H),1.80-1.60(m,2H),1.50-1.20(m,18H),0.85(t,J=5.8Hz,3H)。
向化合物30(3.50g,12.9mmol)及三氯乙醯亞胺4-甲氧基苄基酯(4.65g,17.3mmol)存於DCM(100mL)中之溶液中添加樟腦磺酸(450mg,1.92mmol)。將混合物在室溫下攪拌過夜。將混合物用飽和NaHCO3溶液(300mL)及水(300mL)洗滌並經Na2SO4乾燥。藉由過濾去除乾燥劑,且使用旋轉蒸發器去除溶劑。藉由矽膠上層析(120g RediSep管柱,用0%至30%乙酸乙酯/己烷之梯度洗脫,經70min,85mL/min)純化殘留物,從而得到無色液體狀產物32(4.01g,81%)。
將酯32(4.01g,10.4mmol)溶解於THF/MeOH/CH3CN混合物(v/v/v,1/1/1,90mL)中。添加存於水(30mL)中之溶液形式之氫氧化鋰單水合物(874mg,20.8mmol),且將混合物攪拌過夜。在真空中將溶劑量減少為約30mL。向剩餘水溶液中添加氫氯酸(1M)以使pH降低至3。用二乙醚(3×40mL)萃取水層。將合併之有機萃取物經硫酸鈉乾燥。藉由過濾去除乾燥劑,且使用旋轉蒸發器去除溶劑。藉由矽膠上層析(120g RediSep管柱,用0%至50%乙酸乙酯/己烷之梯度洗脫,經
60min,85mL/min)純化殘留物,從而得到無色液體狀產物34(3.37g,89%)。1H NMR(300MHz,CDCl3)δ 7.22(d,J=6.1Hz,2H),6.82(d,J=6.1Hz,2H),4.46(s,2H),3.81(m,1H),3.75(s,3H),2.65-2.49(m,2H),1.80-1.60(m,2H),1.50-1.20(m,18H),0.85(t,J=5.8Hz,3H)。
向酸34(500mg,1.37mmol)存於DCM(5mL)中之溶液中添加二甲基甲醯胺(DMF)(100mg,1.37mmol),且將所得混合物冷卻至-10℃。逐滴添加存於DCM(5mL)中之草醯氯(174mg,1.37mmol)。經1h將溶液升溫室溫。在TLC分析顯示不存在酸之後,在真空中濃縮混合物且其未經進一步純化即使用。
於室溫下向(R)-3-羥基十四烷酸(36,參見下文製備)(9.55g,39.1mmol)及三乙胺(5.90g,58.6mmol)存於乙酸乙酯(500mL)中之溶液中添加2-溴苯乙酮(7.90g,39.1mmol)。將混合物於室溫下攪拌14h。藉由過濾去除沉澱,且在真空中濃縮濾液。藉由矽膠層析(120g RediSep管柱,用0%至30%乙酸乙酯/己烷之梯度洗脫,經50min,85
mL/min)純化殘留物,從而得到白色固體狀產物37(10.2g,72%產率)。
於0℃下向37(4.80g,13.2mmol)及吡啶(2.10g,26.5mmol)存於DCM(100mL)中之溶液中添加癸醯氯(38,2.8g,4.8mmol)。將混合物攪拌14h,使混合物之溫度升高至室溫。將混合物用飽和NaHCO3溶液(100mL)及鹽水(100mL)洗滌並經Na2SO4乾燥。藉由過濾去除乾燥劑,且使用旋轉蒸發器去除溶劑。藉由矽膠上層析(120g RediSep管柱,用0%至40%乙酸乙酯/己烷之梯度洗脫,經50min,85mL/min)純化殘留物,從而得到無色液體狀產物39(6.68g,97%)。
將酯39(10.15g,20.77mmol)溶解於乙酸(100mL)中。添加鋅(15.5g,237mmol),且將混合物加熱回流4h。在真空下去除乙酸且使殘留物與甲苯共沸至乾燥。藉由矽膠上層析(120g RediSep管柱,用0%至60%乙酸乙酯/己烷之梯度洗脫,經50min,85mL/min)純化殘
留物,從而得到無色液體狀產物40(7.2g,89%)。1H NMR(300MHz,CDCl3)δ 5.23-5.19(m,1H),2.62-2.55(m,2H),2.34-2.25(m,2H),1.65-1.58(m,2H),1.28-1.20(m,32H),0.85(m,6H)。
向300mL高壓反應器玻璃套管中之存於甲醇(30mL)中的3-側氧基十四烷酸甲酯(41,5.27g,20.6mmol)的漿液中通N2 10分鐘。添加二氯-R-2,2'-雙(二苯基膦基)-1,1'-聯萘基釕(142mg,1.1mmol)且將混合物放置於Parr 5500系列集成反應器中。向反應器中充入H2(60psi)且通風3次。隨後向反應器中充入H2(60psi)之最後部分,攪拌(600rpm)並加熱至50℃並保持20h。隨後將反應器冷卻至室溫且在真空中濃縮混合物。藉由矽膠層析用0%至50%乙酸乙酯/己烷之梯度洗脫純化所得殘留物,從而提供灰白色固體狀物42(3.97g,74%)。1H NMR(CDCl3)δ 4.00-3.98(m,1H),3.71(s,3H),2.82(d,J=6.5Hz,1H),2.62-2.30(m,2H),1.54-1.39(m,3H),1.27(br s,17H),(m,20H),0.86(t,J=7.0Hz,3H)。
向(R)-3-羥基十四烷酸甲酯(42,8.17g,31.5mmol)存於THF(66mL)及水(66mL)中之溶液中添加氫氧化鋰單水合物(1.98g,47.2mmol)並於室溫下攪拌2h。隨後用二乙醚(1L)稀釋混合物且用氫氯酸溶液(1N)將pH調節至約3。隨後用二乙醚(200mL)萃取溶液,且合併有機部分並經Na2SO4乾燥。藉由過濾去除Na2SO4且在真空中濃縮濾液,從而提供灰白色固體狀(R)-3-羥基十四烷酸(36,7.59g,98%)。1H NMR(CDCl3)δ 3.99-3.94(m,1H),2.45-2.39(m,2H),1.47(br s,3H),1.29(br s,17H),0.89(t,J=7.0Hz,3H)。
向3-羥基十四烷酸(R)-2-側氧基-2-苯乙基酯(37,根據實例34製備,10.8g,29.8mmol)存於吡啶(40mL)中之溶液中添加肉豆蔻醯氯(45,8.83g,35.8mmol)。將反應混合物於室溫下攪拌14h。隨後在真空中濃縮混合物,且藉由將殘留物溶解於甲苯(100mL)中並在真空中濃縮去除殘留吡啶。藉由矽膠層析用0%至20%乙酸乙酯/己烷之梯度洗脫純化所得殘留物,從而提供無色油狀物46(16.31g,83%)。1H NMR(CDCl3)δ 7.90(m,2H),7.64-7.57(m,1H),7.50-7.45(m,2H),5.33(s,2H),5.31-5.27(m,1H),2.80-2.70(m,2H),2.33-2.26(t,J=4.5Hz,2H),1.65-1.58(m,2H),1.31-1.21(m,40 H),0.85(t,J=10.0Hz,6H)。
向46(16.28g,28.42mmol)存於乙酸(150mL)中之溶液中添加鋅粉(24.42g,373.3mmol)。隨後將混合物加熱至回流溫度(115℃)並保持3h。隨後在真空中濃縮混合物,且藉由將殘留物溶解於甲苯(100mL)中並在真空中濃縮去除殘留吡啶。藉由矽膠層析用0%至30%乙酸乙酯/己烷之梯度洗脫純化所得殘留物,從而提供無色油狀(R)-苄基3-(十四烷醯基氧基)十四烷酸(47,11.14g,86%產率)。1H NMR(CDCl3)δ 5.29-5.18(m,1H),2.62-2.55(m,2H),2.34-2.25(m,2H),1.65-1.58(m,3H),1.28-1.20(m,40H),0.85(m,6H)。
將化合物4(根據實例3製備,1.32g,3.36mmol)溶解於BH3(1M)存於THF(18.1mL,18.1mmol)中之溶液中。在將混合物於0℃下攪拌5min後,逐滴添加三氟甲磺酸二丁硼(1M,存於DCM中,3.62mL,3.62mmol),且將反應混合物於0℃下再攪拌1h。隨後,添加三乙胺(0.5mL)及甲醇(~0.5mL)直至停止釋放H2氣體為止。在真空中蒸發溶劑,且將殘留物與甲醇(3×50mL)一起共蒸發。藉由矽膠管柱層析(己烷/乙酸乙酯,8:1(v/v))純化殘留物,從而得到無色油狀物14(0.67g,
49%)。R f =0.40(己烷/乙酸乙酯,3:1(v/v))。1H NMR(500MHz,CDCl3)δ 7.32-7.31(m,5H),4.81(d,J=11.4Hz,1H),4.70(d,J=11.4Hz,1H),4.55(d,J=7.5Hz,1H),3.84(m,1H),3.70(dd,1H,J=12.0,1.5Hz,1H),3.49-3.43(m,2H),3.33(br s,1H),3.22-3.17(m,1H),0.92(s,9H),0.14(s,6H)。
此實例證實本發明之闡釋性GLA化合物的活體內Th1-型免疫刺激劑活性,該化合物具有以下結構(IX):
化合物IX用於含有結核分枝桿菌抗原性多肽(稱作ID83)之疫苗中。採用標準免疫方法及試劑(Current Protocols in Immunology,Coligan等人(編輯)2006 John Wiley & Sons,NY)。將小鼠(四隻C57BL/6動物/組)用存於水中之ID83抗原(每次接種免疫8μg/動物)、調配於穩定乳液媒劑中之ID83抗原(每次接種免疫8μg/動物)、或調配於含有(i)GLA-SE(每次接種免疫10μg/動物)或(ii)化合物IX(每次接種免疫10μg/動物)之穩定乳液中的ID83抗原(每次接種免疫8μg/動物)以三周之間隔接種免疫三次。
在每次注射一周後,對小鼠實施取血以評價抗原特異性抗體(IgG1及IgG2c)應答。在最後一次接種免疫三周後,將小鼠處死且採集脾以根據已公開方法(同一出處)藉由ELISPOT分析對活體外抗原刺
激之T細胞依賴性IFN-γ細胞因子應答。IFN-γ細胞因子應答與抵抗結核分枝桿菌感染之TH1保護性表現型相關。
圖1顯示在使用與10μg化合物IX之穩定乳液(SE)一起調配之ID83抗原及ID83組份抗原(Rv2608、Rv1813及Rv3620)與調配於GLA-SE、SE或水中之ID83相比第三次接種免疫後三周在小鼠中誘發之抗-ID83 IFN-γ細胞因子產生的ELISPOT數據。顯示各組中之IFN-γ分泌細胞/百萬脾細胞的平均值及SEM。本文實例中所用「GLA-SE」係指如共同擁有之美國專利公開案第20080131466號中所述化合物之穩定乳液,其中R1、R3、R5及R6係C11直鏈烷基;且R2及R4係C13直鏈烷基。
所有動物均對ConA、強效細胞活化劑及分裂素等效地應答。ID83+化合物IX疫苗接種誘發有力ID83抗原特異性細胞因子應答,而在ID83+水或ID83+SE對照組中觀察到極少或未觀察到該等應答。在用ID83組份抗原、Rv2608、Rv1813及Rv3620重新刺激時,自用ID83+化合物IX或ID83+GLA-SE免疫接種之小鼠純化之脾細胞中激發IFN-γ分泌細胞之類似位準。
總之,具有結核分枝桿菌疫苗抗原候選物ID83之穩定油調配物中的化合物IX主要誘發與保護性TH1表現型相關之細胞類型(T細胞)的抗原特異性免疫應答。
此實例證實含有結核分枝桿菌抗原(稱作ID83)之疫苗中的化合物IX之活體內Th1-及Th2-型免疫刺激劑活性。採用標準免疫方法及試劑(Current Protocols in Immunology,Coligan等人(編輯)2006 John Wiley & Sons,NY)。
將小鼠(四隻C57BL/6動物/組)用單獨使用或調配於含有化合物IX(每次免疫接種10μg/動物)之穩定乳液中的ID83抗原(每次免疫接種
8μg/動物)以三周間隔免疫接種三次。藉由在每次免疫接種一周後使動物流血採集血清,且藉由ELISA根據已公開方法(同一出處)檢驗對ID83具有特異性之IgG1及IgG2c抗體的血清含量。IgG1或IgG2c抗體同型物之優勢分別與TH2或TH1應答相關。已證實保護抵抗結核分枝桿菌感染必需TH1應答。
如圖2中所示,用存於水中之ID83疫苗接種來主要誘發抗原特異性IgG1抗體。相反,ID83+SE、ID83+化合物IX-SE或ID83+GLA-SE疫苗接種誘發較高IgG2c抗體效價,並將表現型轉化為混合IgG1:IgG2c抗原特異性抗體應答。
此實例證實化合物IX在人類細胞中之免疫刺激活性。在活體外使用具有編碼1)TLR4、MD-2及CD14、或2)TLR2及TLR6之表現載體的HEK 293細胞(InvivoGen)測試化合物IX以界定化合物活性及對TLR4之依賴性並排除TLR2之活化。該等HEK 293細胞系進一步經NF-kB報告載體pNifty-2穩定轉染以使在活化TLR信號傳導途徑時鹼性磷酸酶分泌至生長介質中。將經轉染細胞系以5x104個細胞/孔平鋪於96孔板中並刺激16-24小時,在含有一系列稀釋之化合物IX及其他佐劑的培養基中培養。在培養基中使用QUANTIBlue®分析(InvivoGen)量測所分泌鹼性磷酸酶活性。數據量測為超出PBS陰性對照之NF-kB增強。使用此分析,化合物IX顯示於低達0.1μg/ml之濃度下NF-kB增強兩倍以上(圖3)。該等實驗之結果證實化合物IX之清晰TLR4激動劑活性,其似乎不與TLR2之誘發相關。基於MD2及TLR4之報告原子結構的結構考慮因素設計化合物IX。因此,其結合並激發類似於商業批准之TLR4激動劑(MPL®)之曲線的曲線之事實係令人驚訝且意想不到的結果。更具體而言,在預計細胞因子位準升至其自身可施加不良副作
用之程度之前,化合物IX之曲線隨濃度增大有利地快速地趨於平穩。因而,預期本發明之化合物IX及其他闡釋性化合物可寬濃度範圍內安全地投與,此在患者中臨床結果的重現性的情形下及對於變化成人及兒童之劑量的安全性係高度合意的。就此而言,化合物IX之較低細胞因子活性係將進一步有利於其在臨床調配物中之安全使用之令人吃驚且合意的結果。
在此實例中,用化合物IX刺激人類全血細胞且實施ELISA分析以檢測免疫刺激細胞因子之誘發。用磷酸鹽緩衝鹽水在96孔板中實施化合物IX及其他佐劑之一系列稀釋(1:5),總共稀釋7次。混合自兩個不同供體新鮮採取之100μl人類血液並與100μl佐劑稀釋物一起培育。在培育20小時後,對板進行離心並收集上清液(~70μl),避免收集紅血細胞,且儲存於-20℃下,之後使用標準生物化學程序實施MIP-1-α及TNF-α ELISA。該等實驗結果進一步證明化合物IX在主要人類血細胞中具有免疫刺激活性(圖4)。因此,該等主要供體結果模擬人類細胞系中觀察到之結果且擴大與可能劑量範圍及此化合物之安全曲線有關之該等重要發現。
本說明書中所提及及/或本申請案資料清單中所列示之所有上述美國專利、美國專利申請公開案、美國專利申請案、外國專利、外國專利申請案及非專利出版物之全部內容皆以引用方式併入本文中。
自上文應瞭解,儘管本文出於闡釋之目的已對本發明之具體實施例予以闡述,但可對其實施各種修改,此並不背離本發明之精神及範疇。因此,除隨附申請專利範圍外,本發明不受其他限制。
Claims (9)
- 一種包含具有以下結構(I)之GLA化合物或其醫藥上可接受鹽的組合物之用途,
- 如請求項1之用途,其中L5及L6二者均係-O-,L7、L8、L9及L10各 自係-C(=O)-,且該GLA化合物具有下式(II):
- 如請求項1之用途,其中該GLA化合物具有以下結構(IV):
- 如請求項2之用途,其中Y1係-OP(=O)(OH)2且Y2、Y3及Y4各自係-OH,且該GLA化合物具有下式(V):
- 如請求項2之用途,其中L1及L3二者均係-O-且L2及L4二者均係-NH-,且該GLA化合物具有下式(VI):
- 如請求項2之用途,其中Y1係-OP(O)(OH)2,Y2、Y3及Y4各自係-OH,L1及L3二者均係-O-,且L2及L4二者均係-NH-,且該GLA化合物具有下式(VII):
- 一種包含具有以下結構(IX)之GLA化合物或其醫藥上可接受鹽的組合物之用途,
- 如請求項1至7中任一項之用途,其中該組合物實質上無抗原。
- 如請求項1至7中任一項之用途,其中該組合物進一步包含抗原或編碼抗原之重組表現構築體。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18470309P | 2009-06-05 | 2009-06-05 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201544120A TW201544120A (zh) | 2015-12-01 |
TWI549688B true TWI549688B (zh) | 2016-09-21 |
Family
ID=43298190
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW099118278A TWI494125B (zh) | 2009-06-05 | 2010-06-04 | 合成的葡萄吡喃糖基脂質佐劑 |
TW104113418A TWI549688B (zh) | 2009-06-05 | 2010-06-04 | 合成的葡萄吡喃糖基脂質佐劑 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW099118278A TWI494125B (zh) | 2009-06-05 | 2010-06-04 | 合成的葡萄吡喃糖基脂質佐劑 |
Country Status (22)
Country | Link |
---|---|
US (4) | US8722064B2 (zh) |
EP (2) | EP2437753B1 (zh) |
JP (3) | JP5830015B2 (zh) |
CN (2) | CN105131051B (zh) |
AU (1) | AU2010256461B2 (zh) |
BR (1) | BRPI1011072B1 (zh) |
CA (1) | CA2764374C (zh) |
CY (1) | CY1118347T1 (zh) |
DK (1) | DK2437753T3 (zh) |
ES (1) | ES2606563T3 (zh) |
HR (1) | HRP20161585T1 (zh) |
HU (1) | HUE031051T2 (zh) |
IL (2) | IL216669A (zh) |
LT (1) | LT2437753T (zh) |
MX (2) | MX2011012836A (zh) |
PL (1) | PL2437753T3 (zh) |
PT (1) | PT2437753T (zh) |
RU (3) | RU2732574C2 (zh) |
SI (1) | SI2437753T1 (zh) |
SM (1) | SMT201600437B (zh) |
TW (2) | TWI494125B (zh) |
WO (1) | WO2010141861A1 (zh) |
Families Citing this family (77)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090181078A1 (en) | 2006-09-26 | 2009-07-16 | Infectious Disease Research Institute | Vaccine composition containing synthetic adjuvant |
SI2068918T1 (sl) | 2006-09-26 | 2012-09-28 | Infectious Disease Res Inst | Si - ep sestavek za cepljenje, ki vsebuje sintetiäśna pomagala |
KR101881596B1 (ko) | 2008-12-02 | 2018-07-24 | 웨이브 라이프 사이언시스 재팬 인코포레이티드 | 인 원자 변형된 핵산의 합성 방법 |
EP2437753B1 (en) | 2009-06-05 | 2016-08-31 | Infectious Disease Research Institute | Synthetic glucopyranosyl lipid adjuvants and vaccine compositions containing them |
IN2012DN00720A (zh) | 2009-07-06 | 2015-06-19 | Ontorii Inc | |
BR112012022939A2 (pt) | 2010-03-11 | 2016-08-02 | Immune Design Corp | composição farmacêutica para uso em um método de imunização de um indivíduo em necessidade do mesmo contra um vírus influenza |
US10428019B2 (en) | 2010-09-24 | 2019-10-01 | Wave Life Sciences Ltd. | Chiral auxiliaries |
US20120263754A1 (en) | 2011-02-15 | 2012-10-18 | Immune Design Corp. | Methods for Enhancing Immunogen Specific Immune Responses by Vectored Vaccines |
EA027236B1 (ru) | 2011-04-08 | 2017-07-31 | Иммьюн Дизайн Корп. | Иммуногенные композиции и способы применения таких композиций для индукции гуморального и клеточного иммунного ответа |
US20120288515A1 (en) | 2011-04-27 | 2012-11-15 | Immune Design Corp. | Synthetic long peptide (slp)-based vaccines |
BR112014001244A2 (pt) | 2011-07-19 | 2017-02-21 | Wave Life Sciences Pte Ltd | métodos para a síntese de ácidos nucléicos funcionalizados |
WO2013072768A2 (en) | 2011-11-18 | 2013-05-23 | Variation Biotechnologies, Inc. | Synthetic derivatives of mpl and uses thereof |
WO2013082500A2 (en) * | 2011-12-02 | 2013-06-06 | Rhode Island Hospital | Vaccine for falciparum malaria |
CN110339160A (zh) * | 2012-02-07 | 2019-10-18 | 传染性疾病研究院 | 包含tlr4激动剂的改进佐剂制剂及其使用方法 |
JP5650780B2 (ja) | 2012-04-04 | 2015-01-07 | 日東電工株式会社 | ワクチン組成物 |
MX350274B (es) | 2012-05-16 | 2017-08-31 | Immune Design Corp | Vacunas para hsv-2. |
CA2876150A1 (en) | 2012-06-08 | 2013-12-12 | The Johns Hopkins University | Compostions and methods for cancer immunotherapy |
EP2872147B1 (en) | 2012-07-13 | 2022-12-21 | Wave Life Sciences Ltd. | Method for making chiral oligonucleotides |
EP2873674B1 (en) * | 2012-07-13 | 2020-05-06 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant |
BR112015000784A8 (pt) | 2012-07-13 | 2018-04-03 | Wave Life Sciences Japan | Grupo auxiliar assimétrico |
AU2013358892B2 (en) | 2012-12-13 | 2018-06-21 | Aduro Biotech, Inc. | Compositions comprising cyclic purine dinucleotides having defined stereochemistries and methods for their preparation and use |
BR112015025709A2 (pt) | 2013-04-18 | 2017-07-18 | Immune Design Corp | monoterapia com gla para uso em tratamento de câncer |
CN112386604A (zh) | 2013-04-29 | 2021-02-23 | 纪念斯隆-凯特琳癌症中心 | cGAS的调节剂 |
WO2014179760A1 (en) | 2013-05-03 | 2014-11-06 | The Regents Of The University Of California | Cyclic di-nucleotide induction of type i interferon |
US9549944B2 (en) | 2013-05-18 | 2017-01-24 | Aduro Biotech, Inc. | Compositions and methods for inhibiting “stimulator of interferon gene”—dependent signalling |
RS59500B1 (sr) | 2013-05-18 | 2019-12-31 | Aduro Biotech Inc | Sastavi i metode za aktiviranje signaliziranja koje je zavisno od „stimulatora gena za interferon“ |
US9463198B2 (en) * | 2013-06-04 | 2016-10-11 | Infectious Disease Research Institute | Compositions and methods for reducing or preventing metastasis |
US10176292B2 (en) | 2013-07-31 | 2019-01-08 | Memorial Sloan-Kettering Cancer Center | STING crystals and modulators |
WO2015035010A1 (en) * | 2013-09-05 | 2015-03-12 | Immune Design Corp. | Vaccine compositions for drug addiction |
US9504743B2 (en) | 2013-09-25 | 2016-11-29 | Sequoia Sciences, Inc | Compositions of vaccines and adjuvants and methods for the treatment of urinary tract infections |
US9149522B2 (en) | 2013-09-25 | 2015-10-06 | Sequoia Sciences, Inc. | Compositions of vaccines and adjuvants and methods for the treatment of urinary tract infections |
US20150086592A1 (en) * | 2013-09-25 | 2015-03-26 | Sequoia Sciences, Inc | Compositions of vaccines and adjuvants and methods for the treatment of urinary tract infections |
US9149521B2 (en) | 2013-09-25 | 2015-10-06 | Sequoia Sciences, Inc. | Compositions of vaccines and adjuvants and methods for the treatment of urinary tract infections |
MX2016003325A (es) | 2013-10-03 | 2016-07-06 | Nitto Denko Corp | Composicion de vacuna para mucosa. |
US9962439B2 (en) | 2013-10-03 | 2018-05-08 | Nitto Denko Corporation | Injectable vaccine composition |
WO2015050180A1 (ja) | 2013-10-03 | 2015-04-09 | 日東電工株式会社 | 粘膜ワクチン組成物 |
CA2923026A1 (en) | 2013-10-03 | 2015-04-09 | Nitto Denko Corporation | Nasal mucosal vaccine composition |
CN106163551A (zh) | 2013-12-31 | 2016-11-23 | 传染性疾病研究院 | 单瓶疫苗制剂 |
JPWO2015108046A1 (ja) | 2014-01-15 | 2017-03-23 | 株式会社新日本科学 | 抗アレルギー作用を有するキラル核酸アジュバンド及び抗アレルギー剤 |
WO2015108047A1 (ja) | 2014-01-15 | 2015-07-23 | 株式会社新日本科学 | 免疫誘導活性を有するキラル核酸アジュバンド及び免疫誘導活性剤 |
JPWO2015108048A1 (ja) | 2014-01-15 | 2017-03-23 | 株式会社新日本科学 | 抗腫瘍作用を有するキラル核酸アジュバンド及び抗腫瘍剤 |
KR20230152178A (ko) | 2014-01-16 | 2023-11-02 | 웨이브 라이프 사이언시스 리미티드 | 키랄 디자인 |
WO2015112485A1 (en) * | 2014-01-21 | 2015-07-30 | Immune Design Corp. | Compositions for use in the treatment of allergic conditions |
ES2738582T3 (es) | 2014-02-14 | 2020-01-23 | Immune Design Corp | Inmunoterapia del cáncer a través de combinación de inmunoestimulación local y sistémica |
CA2955015A1 (en) | 2014-07-15 | 2016-01-21 | Immune Design Corp. | Prime-boost regimens with a tlr4 agonist adjuvant and a lentiviral vector |
JP6692826B2 (ja) | 2015-03-10 | 2020-05-13 | アドゥロ バイオテック,インク. | 「インターフェロン遺伝子刺激因子」依存性シグナル伝達の活性化のための組成物及び方法 |
TW201722472A (zh) | 2015-11-27 | 2017-07-01 | Nitto Denko Corp | 口腔內投與用疫苗醫藥組合物及口腔內投與用疫苗醫藥組合物之製造方法 |
KR102392974B1 (ko) | 2016-05-16 | 2022-05-02 | 인펙셔스 디지즈 리서치 인스티튜트 (아이디알아이) | Tlr 작용제를 함유하는 제제 및 사용 방법 |
WO2017200957A1 (en) | 2016-05-16 | 2017-11-23 | Infectious Disease Research Institute | Pegylated liposomes and methods of use |
EP3458088A2 (en) | 2016-05-21 | 2019-03-27 | Infectious Disease Research Institute | Compositions and methods for treating secondary tuberculosis and nontuberculous mycobacterium infections |
MX2021010105A (es) | 2016-06-01 | 2022-06-16 | Infectious Disease Res Inst | Particulas de nanoalumbre que contienen un agente de dimensionamiento. |
WO2018009466A1 (en) | 2016-07-05 | 2018-01-11 | Aduro Biotech, Inc. | Locked nucleic acid cyclic dinucleotide compounds and uses thereof |
EP3522893A4 (en) * | 2016-10-04 | 2020-08-26 | University Of Maryland, Baltimore | METHODS OF TREATMENT OF SEPTICEMIA USING LIPID A-BASED THERAPEUTIC AGENTS (ASLA) ANTISEPSY |
KR102028463B1 (ko) * | 2016-11-25 | 2019-10-04 | 재단법인 목암생명과학연구소 | 바리셀라 조스터 바이러스 백신 |
EA038864B1 (ru) * | 2016-12-26 | 2021-10-29 | Могам Инститьют Фор Байомедикал Рисерч | Вакцинная композиция против опоясывающего герпеса |
UY37695A (es) | 2017-04-28 | 2018-11-30 | Novartis Ag | Compuesto dinucleótido cíclico bis 2’-5’-rr-(3’f-a)(3’f-a) y usos del mismo |
CN111315362A (zh) | 2017-06-15 | 2020-06-19 | 传染病研究所 | 纳米结构脂质载剂和稳定乳剂以及其用途 |
US20200276299A1 (en) * | 2017-09-08 | 2020-09-03 | Infectious Disease Research Institute | Liposomal formulations comprising saponin and methods of use |
EP3681534A1 (en) | 2017-09-13 | 2020-07-22 | Sanofi Pasteur | Human cytomegalovirus immunogenic composition |
MX2020008417A (es) | 2018-02-12 | 2020-11-11 | Inimmune Corp | Ligandos de receptores de tipo toll. |
TW201946650A (zh) | 2018-03-12 | 2019-12-16 | 美商詹森藥物公司 | 針對腹內感染之疫苗 |
SG11202110303XA (en) | 2019-03-18 | 2021-10-28 | Janssen Pharmaceuticals Inc | Methods of producing bioconjugates of e. coli o-antigen polysaccharides, compositions thereof, and methods of use thereof |
PE20212265A1 (es) | 2019-03-18 | 2021-11-30 | Janssen Pharmaceuticals Inc | Bioconjugados de antigenos-polisacaridos de e. coli, metodos de produccion y metodos de utilizacion de los mismos |
US20220249646A1 (en) | 2019-05-25 | 2022-08-11 | Infectious Disease Research Institute | Composition and method for spray drying an adjuvant vaccine emulsion |
US11679163B2 (en) | 2019-09-20 | 2023-06-20 | Hdt Bio Corp. | Compositions and methods for delivery of RNA |
EP4038091A1 (en) | 2019-10-02 | 2022-08-10 | Janssen Vaccines & Prevention B.V. | Staphylococcus peptides and methods of use |
WO2021097347A1 (en) | 2019-11-15 | 2021-05-20 | Infectious Disease Research Institute | Rig-i agonist and adjuvant formulation for tumor treatment |
JP2023500749A (ja) | 2020-01-16 | 2023-01-10 | ヤンセン ファーマシューティカルズ,インコーポレーテッド | FimH変異体、その組成物、及びその使用 |
EP4126021A1 (en) | 2020-03-23 | 2023-02-08 | HDT Bio Corp. | Compositions and methods for delivery of rna |
US10973908B1 (en) | 2020-05-14 | 2021-04-13 | David Gordon Bermudes | Expression of SARS-CoV-2 spike protein receptor binding domain in attenuated salmonella as a vaccine |
WO2022051022A1 (en) | 2020-09-04 | 2022-03-10 | Infectious Disease Research Institute | Co-lyophilized rna and nanostructured lipid carrier |
PE20231385A1 (es) | 2020-09-17 | 2023-09-12 | Janssen Pharmaceuticals Inc | Composiciones de vacunas multivalentes y usos de las mismas |
IL303195A (en) | 2020-11-25 | 2023-07-01 | Akagera Medicines Inc | Lipid nanoparticles for delivery of nucleic acids and related methods of use |
CN117120087A (zh) | 2020-12-23 | 2023-11-24 | 高级健康研究所 | 茄尼醇疫苗助剂及其制备方法 |
KR20230125842A (ko) | 2021-01-12 | 2023-08-29 | 얀센 파마슈티칼즈, 인코포레이티드 | FimH 돌연변이체, 이를 포함하는 조성물 및 이의 용도 |
IL307247A (en) | 2021-04-01 | 2023-11-01 | Janssen Pharmaceuticals Inc | Production of E. Coli O18 bioconjugates |
WO2022256740A1 (en) | 2021-06-04 | 2022-12-08 | Curia Ip Holdings, Llc | Polymeric fusion proteins and compositions for inducing an immune response against infection |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0172581A2 (en) * | 1984-08-24 | 1986-02-26 | Daiichi Seiyaku Co., Ltd. | Disaccharide derivatives |
WO2009035528A2 (en) * | 2007-09-07 | 2009-03-19 | University Of Georgia Research Foundation, Inc. | Synthetic lipid a derivative |
Family Cites Families (242)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3238190A (en) * | 1963-10-23 | 1966-03-01 | Madaus & Co K G Fa Dr | Aescin recovery |
US3598123A (en) | 1969-04-01 | 1971-08-10 | Alza Corp | Bandage for administering drugs |
US3598122A (en) | 1969-04-01 | 1971-08-10 | Alza Corp | Bandage for administering drugs |
US4029762A (en) * | 1971-11-17 | 1977-06-14 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. | Lipid A-preparation |
US4286592A (en) | 1980-02-04 | 1981-09-01 | Alza Corporation | Therapeutic system for administering drugs to the skin |
US4314557A (en) | 1980-05-19 | 1982-02-09 | Alza Corporation | Dissolution controlled active agent dispenser |
US4420558A (en) | 1981-02-12 | 1983-12-13 | Janssen Pharmaceutica N.V. | Bright field light microscopic method of enumerating and characterizing subtypes of white blood cells and their precursors |
US4379454A (en) | 1981-02-17 | 1983-04-12 | Alza Corporation | Dosage for coadministering drug and percutaneous absorption enhancer |
US4769330A (en) | 1981-12-24 | 1988-09-06 | Health Research, Incorporated | Modified vaccinia virus and methods for making and using the same |
US4436727A (en) | 1982-05-26 | 1984-03-13 | Ribi Immunochem Research, Inc. | Refined detoxified endotoxin product |
US4420461A (en) | 1982-05-26 | 1983-12-13 | Ortho Diagnostic Systems Inc. | Agglutination-inhibition test kit for detecting immune complexes |
SE8205892D0 (sv) | 1982-10-18 | 1982-10-18 | Bror Morein | Immunogent membranproteinkomplex, sett for framstellning och anvendning derav som immunstimulerande medel och sasom vaccin |
US4987237A (en) * | 1983-08-26 | 1991-01-22 | Ribi Immunochem Research, Inc. | Derivatives of monophosphoryl lipid A |
US4743540A (en) | 1983-09-27 | 1988-05-10 | Memorial Sloan-Kettering Cancer Center | Method for diagnosis of subclassifications of common varied immunodeficiency disease group |
US5147785A (en) | 1983-11-01 | 1992-09-15 | Amtl Corporation | Method and apparatus for measuring the degree of reaction between a foreign entity and white blood cells |
US4614722A (en) | 1983-11-01 | 1986-09-30 | Pasula Mark J | Method and apparatus for measuring the degree of reaction between antigens and leukocyte cellular antibodies |
US4595654A (en) * | 1983-11-07 | 1986-06-17 | Immunomedics Inc. | Method for detecting immune complexes in serum |
US4855238A (en) | 1983-12-16 | 1989-08-08 | Genentech, Inc. | Recombinant gamma interferons having enhanced stability and methods therefor |
US4629722A (en) | 1984-07-12 | 1986-12-16 | Ribi Immunochem Research, Inc. | Method of inhibiting the onset of acute radiation syndrome |
US4844894A (en) * | 1984-07-12 | 1989-07-04 | Ribi Immunochem Research Inc. | Method of inhibiting the onset of septicemia and endotoxemia |
US5612041A (en) * | 1984-07-17 | 1997-03-18 | Chiron Corporation | Recombinant herpes simplex gD vaccine |
US5066794A (en) * | 1984-08-24 | 1991-11-19 | Daiichi Pharmaceutical Co., Ltd. | Process for preparing a disaccharide derivative |
US4568343A (en) | 1984-10-09 | 1986-02-04 | Alza Corporation | Skin permeation enhancer compositions |
US4659659A (en) | 1985-01-22 | 1987-04-21 | Monsanto Company | Diagnostic method for diseases having an arthritic component |
GB8508845D0 (en) | 1985-04-04 | 1985-05-09 | Hoffmann La Roche | Vaccinia dna |
FI861417A0 (fi) | 1985-04-15 | 1986-04-01 | Endotronics Inc | Hepatitis b ytantigen framstaelld med rekombinant-dna-teknik, vaccin, diagnostiskt medel och cellinjer samt foerfaranden foer framstaellning daerav. |
US4746742A (en) | 1985-11-28 | 1988-05-24 | Toho Yakuhin Kogyo Kabushiki Kaisha | Analogs of nonreducing monosaccharide moiety of lipid A |
US5310651A (en) | 1986-01-22 | 1994-05-10 | Institut Pasteur | DNA probes of human immunodeficiency virus type 2 (HIV-2), and methods employing these probes for dectecting the presence of HIV-2 |
US6514691B1 (en) | 1986-01-22 | 2003-02-04 | Institut Pasteur | Peptides of human immunodeficiency virus type 2 (HIV-2), antibodies against peptides of HIV-2, and methods and kits for detecting HIV-2 |
US6544728B1 (en) * | 1986-01-22 | 2003-04-08 | Institut Pasteur | Methods and kits for diagnosing human immunodeficiency virus type 2 (HIV-2), proteins of HIV-2, and vaccinating agents for HIV-2 |
US6054565A (en) * | 1986-03-03 | 2000-04-25 | Institut Pasteur | Nucleic Acids of HIV-2, Diagnostic Test Kit and Method using Nucleic Acid Probes of HIV-2 |
US5169763A (en) | 1986-04-08 | 1992-12-08 | Transgene S.A., Institut Pasteur | Viral vector coding glycoprotein of HIV-1 |
US4877611A (en) | 1986-04-15 | 1989-10-31 | Ribi Immunochem Research Inc. | Vaccine containing tumor antigens and adjuvants |
JPH0755906B2 (ja) | 1986-07-01 | 1995-06-14 | 第一製薬株式会社 | ジサツカライド誘導体含有鎮痛剤 |
US4767402A (en) | 1986-07-08 | 1988-08-30 | Massachusetts Institute Of Technology | Ultrasound enhancement of transdermal drug delivery |
US4948587A (en) | 1986-07-08 | 1990-08-14 | Massachusetts Institute Of Technology | Ultrasound enhancement of transbuccal drug delivery |
US5075109A (en) | 1986-10-24 | 1991-12-24 | Southern Research Institute | Method of potentiating an immune response |
FR2672290B1 (fr) | 1991-02-05 | 1995-04-21 | Pasteur Institut | Sequences peptidiques specifiques des stades hepatiques de p. falciparum porteuses d'epitopes capables de stimuler les lymphocytes t. |
US5565209A (en) | 1987-03-17 | 1996-10-15 | Akzo Nobel N.V. | Adjuvant mixture |
US5057540A (en) | 1987-05-29 | 1991-10-15 | Cambridge Biotech Corporation | Saponin adjuvant |
CA1331443C (en) | 1987-05-29 | 1994-08-16 | Charlotte A. Kensil | Saponin adjuvant |
EP0304578B1 (en) | 1987-06-22 | 2001-10-24 | Medeva Holdings Bv | Peptide comprising hepatitis B surface antigen |
US4780212A (en) | 1987-07-31 | 1988-10-25 | Massachusetts Institute Of Technology | Ultrasound enchancement of membrane permeability |
US4897268A (en) * | 1987-08-03 | 1990-01-30 | Southern Research Institute | Drug delivery system and method of making the same |
WO1989001973A2 (en) | 1987-09-02 | 1989-03-09 | Applied Biotechnology, Inc. | Recombinant pox virus for immunization against tumor-associated antigens |
EP0324455A3 (en) | 1988-01-15 | 1991-03-27 | Hans O. Ribi | Novel polymeric immunological adjuvants |
GB2232892B (en) | 1988-02-23 | 1991-07-24 | John Mark Tucker | Occlusive body for administering a physiologically active substance |
US5278302A (en) * | 1988-05-26 | 1994-01-11 | University Patents, Inc. | Polynucleotide phosphorodithioates |
US5888519A (en) | 1988-06-02 | 1999-03-30 | The United States Of America As Represented By The Secretary Of The Army | Encapsulated high-concentration lipid a compositions as immunogenic agents to produce human antibodies to prevent or treat gram-negative bacterial infections |
US4912094B1 (en) | 1988-06-29 | 1994-02-15 | Ribi Immunochem Research Inc. | Modified lipopolysaccharides and process of preparation |
GB8819209D0 (en) | 1988-08-12 | 1988-09-14 | Research Corp Ltd | Polypeptide & dna encoding same |
US5231168A (en) * | 1988-09-16 | 1993-07-27 | Statens Seruminstitut | Malaria antigen |
US4999403A (en) | 1988-10-28 | 1991-03-12 | Exxon Chemical Patents Inc. | Graft polymers of functionalized ethylene-alpha-olefin copolymer with polypropylene, methods of preparation, and use in polypropylene compositions |
CA2005704C (en) | 1988-12-16 | 2003-02-11 | James C. Paton | Pneumolysin mutants and pneumococcal vaccines made therefrom |
EP0454781B1 (en) | 1989-01-23 | 1998-12-16 | Chiron Corporation | Recombinant cells for therapies of infection and hyperproliferative disorders and preparation thereof |
DE69015222T2 (de) | 1989-02-04 | 1995-05-04 | Akzo Nv | Tocole als Impfstoffadjuvans. |
WO1990014837A1 (en) | 1989-05-25 | 1990-12-13 | Chiron Corporation | Adjuvant formulation comprising a submicron oil droplet emulsion |
FR2649013B1 (fr) | 1989-07-03 | 1991-10-25 | Seppic Sa | Vaccins et vecteurs de principes actifs fluides contenant une huile metabolisable |
FR2649012B1 (fr) | 1989-07-03 | 1991-10-25 | Seppic Sa | Emulsions multiphasiques injectables |
SG48175A1 (en) | 1989-07-25 | 1998-04-17 | Smithkline Beecham Biolog | Novel antigens and method for their preparation |
EP1001032A3 (en) | 1989-08-18 | 2005-02-23 | Chiron Corporation | Recombinant retroviruses delivering vector constructs to target cells |
US4981684A (en) * | 1989-10-24 | 1991-01-01 | Coopers Animal Health Limited | Formation of adjuvant complexes |
US6120769A (en) | 1989-11-03 | 2000-09-19 | Immulogic Pharmaceutical Corporation | Human T cell reactive feline protein (TRFP) isolated from house dust and uses therefor |
US5298396A (en) | 1989-11-15 | 1994-03-29 | National Jewish Center For Immunology And Respiratory Medicine | Method for identifying T cells disease involved in autoimmune disease |
US5256643A (en) | 1990-05-29 | 1993-10-26 | The Government Of The United States | Human cripto protein |
US5124141A (en) * | 1990-06-14 | 1992-06-23 | Flow Incorporated | Method for diagnosing malaria |
US5162990A (en) | 1990-06-15 | 1992-11-10 | The United States Of America As Represented By The United States Navy | System and method for quantifying macrophage phagocytosis by computer image analysis |
EP0468520A3 (en) | 1990-07-27 | 1992-07-01 | Mitsui Toatsu Chemicals, Inc. | Immunostimulatory remedies containing palindromic dna sequences |
US6277969B1 (en) | 1991-03-18 | 2001-08-21 | New York University | Anti-TNF antibodies and peptides of human tumor necrosis factor |
GB9105992D0 (en) * | 1991-03-21 | 1991-05-08 | Smithkline Beecham Biolog | Vaccine |
ES2279020T3 (es) | 1991-07-19 | 2007-08-16 | The University Of Queensland | Vacuna contra el papilomavirus humano. |
US5464387A (en) | 1991-07-24 | 1995-11-07 | Alza Corporation | Transdermal delivery device |
RO116459B1 (ro) | 1991-07-25 | 2001-02-28 | Idec Pharma Corp | Compozitie imunogena |
US6197311B1 (en) | 1991-07-25 | 2001-03-06 | Idec Pharmaceuticals Corporation | Induction of cytotoxic T-lymphocyte responses |
AU2143992A (en) | 1991-08-16 | 1993-03-16 | Vical, Inc. | Composition and method for treating cystic fibrosis |
AU660325B2 (en) * | 1991-10-11 | 1995-06-22 | Eisai Co. Ltd. | Anti-endotoxin compounds and related molecules and methods |
US5530113A (en) * | 1991-10-11 | 1996-06-25 | Eisai Co., Ltd. | Anti-endotoxin compounds |
EP0614465B1 (en) | 1991-11-16 | 1999-03-17 | SMITHKLINE BEECHAM BIOLOGICALS s.a. | HYBRID PROTEIN BETWEEN CS FROM PLASMODIUM AND HBsAG |
US6057427A (en) * | 1991-11-20 | 2000-05-02 | Trustees Of Dartmouth College | Antibody to cytokine response gene 2(CR2) polypeptide |
JP3723231B2 (ja) | 1991-12-23 | 2005-12-07 | ディミナコ アクチェンゲゼルシャフト | アジュバント |
US5286718A (en) | 1991-12-31 | 1994-02-15 | Ribi Immunochem Research, Inc. | Method and composition for ameliorating tissue damage due to ischemia and reperfusion |
JPH05328975A (ja) | 1992-06-02 | 1993-12-14 | Takara Shuzo Co Ltd | E1a−f遺伝子 |
WO1993025234A1 (en) | 1992-06-08 | 1993-12-23 | The Regents Of The University Of California | Methods and compositions for targeting specific tissue |
EP0644946A4 (en) | 1992-06-10 | 1997-03-12 | Us Health | VECTOR PARTICLES RESISTANT TO HUMAN SERUM INACTIVATION. |
UA40597C2 (uk) | 1992-06-25 | 2001-08-15 | Смітклайн Бічем Байолоджікалс С.А. | Вакцинна композиція,спосіб лікування ссавців, що страждають або сприйнятливі до інфекції, спосіб лікування ссавців, що страждають на рак, спосіб одержання вакцинної композиції, композиція ад'ювантів |
PT647140E (pt) | 1992-06-25 | 2007-12-27 | Univ Georgetown | Vacinas de papilomavírus |
US5786148A (en) | 1996-11-05 | 1998-07-28 | Incyte Pharmaceuticals, Inc. | Polynucleotides encoding a novel prostate-specific kallikrein |
GB2269175A (en) | 1992-07-31 | 1994-02-02 | Imperial College | Retroviral vectors |
US5437951A (en) | 1992-09-03 | 1995-08-01 | The United States Of America As Represented By The Department Of Health And Human Services | Self-assembling recombinant papillomavirus capsid proteins |
US5411865A (en) * | 1993-01-15 | 1995-05-02 | Iasys Corporation | Method of detecting anti-leishmania parasite antibodies |
EP1588713B1 (en) | 1993-03-09 | 2010-12-22 | The University Of Rochester | Production of human papillomavirus HBV-11 capsid protein L1 and virus-like particles |
ATE204762T1 (de) * | 1993-03-23 | 2001-09-15 | Smithkline Beecham Biolog | 3-0-deazylierte monophosphoryl lipid a enthaltende impfstoff-zusammensetzungen |
US5532133A (en) * | 1993-06-02 | 1996-07-02 | New York University | Plasmodium vivax blood stage antigens, PvESP-1, antibodies, and diagnostic assays |
US6106824A (en) | 1993-08-13 | 2000-08-22 | The Rockefeller University | Expression of growth associated protein B-50/GAP-43 in vitro and in vivo |
US5961970A (en) | 1993-10-29 | 1999-10-05 | Pharmos Corporation | Submicron emulsions as vaccine adjuvants |
DE69433695T2 (de) | 1993-11-02 | 2004-08-12 | Matsushita Electric Industrial Co., Ltd., Kadoma | Halbleiterbauelement mit Aggregat von Mikro-Nadeln aus Halbleitermaterial |
US5458140A (en) | 1993-11-15 | 1995-10-17 | Non-Invasive Monitoring Company (Nimco) | Enhancement of transdermal monitoring applications with ultrasound and chemical enhancers |
US5814599A (en) * | 1995-08-04 | 1998-09-29 | Massachusetts Insitiute Of Technology | Transdermal delivery of encapsulated drugs |
US5885211A (en) | 1993-11-15 | 1999-03-23 | Spectrix, Inc. | Microporation of human skin for monitoring the concentration of an analyte |
RU2154068C2 (ru) | 1993-11-17 | 2000-08-10 | Лаборатуар Ом С.А. | Глюкозаминовые дисахариды, способ их получения, фармацевтическая композиция |
US5693531A (en) | 1993-11-24 | 1997-12-02 | The United States Of America As Represented By The Department Of Health And Human Services | Vector systems for the generation of adeno-associated virus particles |
GB9326253D0 (en) | 1993-12-23 | 1994-02-23 | Smithkline Beecham Biolog | Vaccines |
US5688506A (en) | 1994-01-27 | 1997-11-18 | Aphton Corp. | Immunogens against gonadotropin releasing hormone |
US5457041A (en) | 1994-03-25 | 1995-10-10 | Science Applications International Corporation | Needle array and method of introducing biological substances into living cells using the needle array |
WO1995026204A1 (en) | 1994-03-25 | 1995-10-05 | Isis Pharmaceuticals, Inc. | Immune stimulation by phosphorothioate oligonucleotide analogs |
US5591139A (en) | 1994-06-06 | 1997-01-07 | The Regents Of The University Of California | IC-processed microneedles |
CA2560114A1 (en) | 1994-07-15 | 1996-02-01 | The University Of Iowa Research Foundation | Immunomodulatory oligonucleotides |
US7037712B2 (en) | 1994-07-26 | 2006-05-02 | Commonwealth Scientific And Industrial Research Organisation | DNA encoding ovine adenovirus (OAV287) and its use as a viral vector |
GB9415319D0 (en) | 1994-07-29 | 1994-09-21 | Medical Res Council | HSV viral vector |
SE9403137D0 (sv) | 1994-09-20 | 1994-09-20 | Perstorp Ab | Derivatives of carbohydrates and compositions containing them |
EP1728800A1 (de) | 1994-10-07 | 2006-12-06 | Loyola University Of Chicago | Papillomavirusähnliche Partikel, Fusionsproteine sowie Verfahren zu deren Herstellung |
AUPM873294A0 (en) | 1994-10-12 | 1994-11-03 | Csl Limited | Saponin preparations and use thereof in iscoms |
FR2727689A1 (fr) | 1994-12-01 | 1996-06-07 | Transgene Sa | Nouveau procede de preparation d'un vecteur viral |
DE69633272T2 (de) | 1995-02-08 | 2005-09-08 | Takara Bio Inc., Otsu | Methoden zur Krebsbehandlung und -kontrolle |
WO1996026277A1 (en) | 1995-02-24 | 1996-08-29 | Cantab Pharmaceuticals Research Limited | Polypeptides useful as immunotherapeutic agents and methods of polypeptide preparation |
US5912166A (en) | 1995-04-21 | 1999-06-15 | Corixa Corporation | Compounds and methods for diagnosis of leishmaniasis |
UA56132C2 (uk) | 1995-04-25 | 2003-05-15 | Смітклайн Бічем Байолоджікалс С.А. | Композиція вакцини (варіанти), спосіб стабілізації qs21 відносно гідролізу (варіанти), спосіб приготування композиції вакцини |
US6846489B1 (en) | 1995-04-25 | 2005-01-25 | Smithkline Beecham Biologicals S.A. | Vaccines containing a saponin and a sterol |
US5718904A (en) * | 1995-06-02 | 1998-02-17 | American Home Products Corporation | Adjuvants for viral vaccines |
US5843464A (en) | 1995-06-02 | 1998-12-01 | The Ohio State University | Synthetic chimeric fimbrin peptides |
US5993800A (en) | 1995-06-05 | 1999-11-30 | Bristol-Myers Squibb Company | Methods for prolonging the expression of a heterologous gene of interest using soluble CTLA4 molecules and an antiCD40 ligand |
US6417172B1 (en) * | 1995-06-05 | 2002-07-09 | Eisai Co., Ltd. | Prevention and treatment of pulmonary bacterial infection or symptomatic pulmonary exposure to endotoxin by inhalation of antiendotoxin drugs |
US5981215A (en) | 1995-06-06 | 1999-11-09 | Human Genome Sciences, Inc. | Human criptin growth factor |
US6309847B1 (en) | 1995-07-05 | 2001-10-30 | Yeda Research And Development Co. Ltd. | Method for detecting or monitoring the effectiveness of treatment of T cell mediated diseases |
US6458366B1 (en) | 1995-09-01 | 2002-10-01 | Corixa Corporation | Compounds and methods for diagnosis of tuberculosis |
WO1997011708A1 (en) | 1995-09-29 | 1997-04-03 | Eisai Research Institute | Method for treating alcoholic liver disease |
US5666153A (en) | 1995-10-03 | 1997-09-09 | Virtual Shopping, Inc. | Retractable teleconferencing apparatus |
US5618275A (en) | 1995-10-27 | 1997-04-08 | Sonex International Corporation | Ultrasonic method and apparatus for cosmetic and dermatological applications |
US5843462A (en) | 1995-11-30 | 1998-12-01 | Regents Of The University Of Minnesota | Diphtheria toxin epitopes |
US5846758A (en) | 1995-11-30 | 1998-12-08 | His Excellency Ghassan I. Shaker | Method for diagnosing autoimmune diseases |
SE9600648D0 (sv) | 1996-02-21 | 1996-02-21 | Bror Morein | Receptorbimdande enhet |
US5656016A (en) | 1996-03-18 | 1997-08-12 | Abbott Laboratories | Sonophoretic drug delivery system |
ES2242226T3 (es) * | 1996-07-03 | 2005-11-01 | Eisai Co., Ltd. | Composiciones que contienen analogos del lipido a y procedimiento parasu preparacion. |
ATE229073T1 (de) | 1996-09-06 | 2002-12-15 | Univ California | Protein e25a, methoden zu dessen herstellung und anwendung |
US5955306A (en) | 1996-09-17 | 1999-09-21 | Millenium Pharmaceuticals, Inc. | Genes encoding proteins that interact with the tub protein |
ES2241042T3 (es) | 1996-10-11 | 2005-10-16 | The Regents Of The University Of California | Conjugados de polinucleotido inmunoestimulador/ molecula inmunomoduladora. |
JPH10131046A (ja) | 1996-10-29 | 1998-05-19 | Nikka Chem Co Ltd | 繊維の耐久性pH緩衝加工方法 |
US6797276B1 (en) | 1996-11-14 | 2004-09-28 | The United States Of America As Represented By The Secretary Of The Army | Use of penetration enhancers and barrier disruption agents to enhance the transcutaneous immune response |
US7033598B2 (en) * | 1996-11-19 | 2006-04-25 | Intrabrain International N.V. | Methods and apparatus for enhanced and controlled delivery of a biologically active agent into the central nervous system of a mammal |
DE19654221B4 (de) | 1996-12-23 | 2005-11-24 | Telefonaktiebolaget Lm Ericsson (Publ) | Leitungsanschlußschaltkreis |
US5840871A (en) | 1997-01-29 | 1998-11-24 | Incyte Pharmaceuticals, Inc. | Prostate-associated kallikrein |
US6977073B1 (en) | 1997-02-07 | 2005-12-20 | Cem Cezayirli | Method for stimulating an immune response |
DE69831222T2 (de) | 1997-02-25 | 2006-07-13 | Corixa Corp., Seattle | Verbindungen zur immundiagnose von prostatakrebs und deren verwendung |
WO2000004149A2 (en) | 1998-07-14 | 2000-01-27 | Corixa Corporation | Compositions and methods for therapy and diagnosis of prostate cancer |
US6541212B2 (en) | 1997-03-10 | 2003-04-01 | The Regents Of The University Of California | Methods for detecting prostate stem cell antigen protein |
US6491919B2 (en) | 1997-04-01 | 2002-12-10 | Corixa Corporation | Aqueous immunologic adjuvant compostions of monophosphoryl lipid A |
AU743114B2 (en) | 1997-04-01 | 2002-01-17 | Corixa Corporation | Aqueous immunologic adjuvant compositions of monophosphoryl lipid A |
US7037510B2 (en) | 1997-04-18 | 2006-05-02 | Statens Serum Institut | Hybrids of M. tuberculosis antigens |
US6555653B2 (en) | 1997-05-20 | 2003-04-29 | Corixa Corporation | Compounds for diagnosis of tuberculosis and methods for their use |
US6358508B1 (en) | 1997-06-11 | 2002-03-19 | Human Genome Sciences, Inc. | Antibodies to human tumor necrosis factor receptor TR9 |
GB9711990D0 (en) | 1997-06-11 | 1997-08-06 | Smithkline Beecham Biolog | Vaccine |
WO1998058956A2 (en) | 1997-06-23 | 1998-12-30 | Ludwig Institute For Cancer Research | Methods for inducing an immune response involving prime-boost protocols |
US6764686B2 (en) | 1997-07-21 | 2004-07-20 | Baxter International Inc. | Modified immunogenic pneumolysin compositions as vaccines |
GB9717953D0 (en) | 1997-08-22 | 1997-10-29 | Smithkline Beecham Biolog | Vaccine |
WO1999010008A1 (en) | 1997-08-29 | 1999-03-04 | Aquila Biopharmaceuticals, Inc. | Compositions comprising the adjuvant qs-21 and polysorbate or cyclodextrin as excipient |
GB9718901D0 (en) | 1997-09-05 | 1997-11-12 | Smithkline Beecham Biolog | Vaccine |
EP1009382B1 (en) | 1997-09-05 | 2003-06-18 | GlaxoSmithKline Biologicals S.A. | Oil in water emulsions containing saponins |
US6749856B1 (en) * | 1997-09-11 | 2004-06-15 | The United States Of America, As Represented By The Department Of Health And Human Services | Mucosal cytotoxic T lymphocyte responses |
US6368604B1 (en) * | 1997-09-26 | 2002-04-09 | University Of Maryland Biotechnology Institute | Non-pyrogenic derivatives of lipid A |
US7459524B1 (en) | 1997-10-02 | 2008-12-02 | Emergent Product Development Gaithersburg Inc. | Chlamydia protein, sequence and uses thereof |
EP2228384A1 (en) | 1997-11-28 | 2010-09-15 | Merck Serono Biodevelopment | Chlamydia trachomatis genomic sequence and polypeptides, fragments thereof and uses thereof, in particular for the diagnosis, prevention and treatment of infection |
US7012134B2 (en) | 1998-01-26 | 2006-03-14 | Human Genome Sciences, Inc. | Dendritic enriched secreted lymphocyte activation molecule |
DE19803453A1 (de) * | 1998-01-30 | 1999-08-12 | Boehringer Ingelheim Int | Vakzine |
BR9907691B1 (pt) | 1998-02-05 | 2011-05-31 | derivado de antìgeno e antìgeno da famìlia mage associado a tumor, seqüência de ácido nucléico, codificando os mesmos, seus usos na preparação de vacina, processo para produção de vacina e vacina. | |
JP2002502884A (ja) | 1998-02-12 | 2002-01-29 | アメリカン・サイアナミド・カンパニー | インターロイキン−12および単純ヘルペスウイルス抗原を含んでなるワクチン |
US6596501B2 (en) | 1998-02-23 | 2003-07-22 | Fred Hutchinson Cancer Research Center | Method of diagnosing autoimmune disease |
FR2775601B1 (fr) * | 1998-03-03 | 2001-09-21 | Merial Sas | Vaccins vivants recombines et adjuves |
ATE339223T1 (de) | 1998-03-09 | 2006-10-15 | Glaxosmithkline Biolog Sa | Kombinierte impfstoffzusammensetzungen |
IL138809A0 (en) | 1998-04-07 | 2001-10-31 | Corixa Corp | Fusion proteins of mycobacterium tuberculosis antigens and pharmaceutical compositions containing the same |
GB2336310B (en) | 1998-04-14 | 2003-09-10 | Stowic Resources Ltd | Method of manufacturing transdermal patches |
AU3560399A (en) | 1998-04-15 | 1999-11-01 | Ludwig Institute For Cancer Research | Tumor associated nucleic acids and uses therefor |
US6680175B2 (en) | 1998-05-05 | 2004-01-20 | Adherex Technologies, Inc. | Methods for diagnosing and evaluating cancer |
CA2330610A1 (en) | 1998-05-07 | 1999-11-11 | Corixa Corporation | Adjuvant composition and methods for its use |
US6322532B1 (en) | 1998-06-24 | 2001-11-27 | 3M Innovative Properties Company | Sonophoresis method and apparatus |
AU766994B2 (en) | 1998-08-25 | 2003-10-30 | Ronald J. Gallenberg | Beach cleaning apparatus and method |
WO2000013029A1 (fr) | 1998-09-01 | 2000-03-09 | Eisai Co., Ltd | Procede pour evaluer des injections contenant des analogues de lipide a |
US6692752B1 (en) | 1999-09-08 | 2004-02-17 | Smithkline Beecham Biologicals S.A. | Methods of treating human females susceptible to HSV infection |
JP2000095694A (ja) * | 1998-09-24 | 2000-04-04 | Sankyo Co Ltd | 新規な医療用薬剤 |
US6375944B1 (en) * | 1998-09-25 | 2002-04-23 | The Wistar Institute Of Anatomy And Biology | Methods and compositions for enhancing the immunostimulatory effect of interleukin-12 |
WO2000018929A2 (en) | 1998-09-25 | 2000-04-06 | Smithkline Beecham Biologicals S.A. | Paramyxovirus vaccines |
US7001770B1 (en) * | 1998-10-15 | 2006-02-21 | Canji, Inc. | Calpain inhibitors and their applications |
KR100629028B1 (ko) * | 1998-10-16 | 2006-09-26 | 글락소스미스클라인 바이오로지칼즈 에스.에이. | 애쥬번트 시스템 및 백신 |
US6261573B1 (en) | 1998-10-30 | 2001-07-17 | Avant Immunotherapeutics, Inc. | Immunoadjuvants |
US6734172B2 (en) | 1998-11-18 | 2004-05-11 | Pacific Northwest Research Institute | Surface receptor antigen vaccines |
US6512102B1 (en) * | 1998-12-31 | 2003-01-28 | Chiron Corporation | Compositions and methods of diagnosis and treatment using casein kinase I |
WO2000042994A2 (en) | 1999-01-21 | 2000-07-27 | North Shore-Long Island Jewish Research Institute | Inhibition of bacterial dissemination |
AU769539B2 (en) * | 1999-01-29 | 2004-01-29 | Zoetis Services Llc | Adjuvants for use in vaccines |
US20030170249A1 (en) | 1999-02-19 | 2003-09-11 | Hakomori Sen-Itiroh | Vaccines directed to cancer-associated carbohydrate antigens |
US6770445B1 (en) | 1999-02-26 | 2004-08-03 | Pacific Northwest Research Institute | Methods and compositions for diagnosing carcinomas |
US6599710B1 (en) | 1999-03-10 | 2003-07-29 | The General Hospital Corporation | Treatment of autoimmune disease |
GB9906177D0 (en) | 1999-03-17 | 1999-05-12 | Oxford Biomedica Ltd | Anti-viral vectors |
WO2000062066A1 (fr) | 1999-04-07 | 2000-10-19 | Hitachi Chemical Co., Ltd. | PROCEDE D'EVALUATION DE MALADIES AUTO-IMMUNES, PROCEDE DE DETECTION D'ANTICORPS DE PROTEINE ANTI-Reg ET DIAGNOSTICS POUR MALADIES AUTO-IMMUNES |
WO2000062800A2 (en) | 1999-04-19 | 2000-10-26 | Smithkline Beecham Biologicals Sa | Adjuvant composition comprising saponin and an immunostimulatory oligonucleotide |
US6685699B1 (en) | 1999-06-09 | 2004-02-03 | Spectrx, Inc. | Self-removing energy absorbing structure for thermal tissue ablation |
EP1206533A1 (en) | 1999-08-26 | 2002-05-22 | Pharmacia AB | Novel response element |
GB9921146D0 (en) | 1999-09-07 | 1999-11-10 | Smithkline Beecham Biolog | Novel composition |
US7084256B2 (en) | 1999-09-24 | 2006-08-01 | Large Scale Biology Corporation | Self antigen vaccines for treating B cell lymphomas and other cancers |
JP4162813B2 (ja) | 1999-10-28 | 2008-10-08 | 久光製薬株式会社 | イオントフォレーシス装置 |
US6218186B1 (en) | 1999-11-12 | 2001-04-17 | Trustees Of The University Of Pennsylvania | HIV-MSCV hybrid viral vector for gene transfer |
JP2003514824A (ja) | 1999-11-15 | 2003-04-22 | ビオミラ,インコーポレーテッド | 合成脂質−a類似体およびその使用 |
US20020064801A1 (en) * | 1999-12-01 | 2002-05-30 | Ryan Jeffrey R. | Novel and practical serological assay for the clinical diagnosis of leishmaniasis |
US6974588B1 (en) | 1999-12-07 | 2005-12-13 | Elan Pharma International Limited | Transdermal patch for delivering volatile liquid drugs |
US6587792B1 (en) * | 2000-01-11 | 2003-07-01 | Richard A. Thomas | Nuclear packing efficiency |
GB0000891D0 (en) | 2000-01-14 | 2000-03-08 | Allergy Therapeutics Ltd | Formulation |
AU2001233132A1 (en) * | 2000-01-31 | 2001-08-07 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services, The National Institutes Of Health | Hybrid adeno-retroviral vector for the transfection of cells |
EP1122542A1 (en) | 2000-02-01 | 2001-08-08 | Anda Biologicals S.A. | Method for the rapid detection of whole microorganisms on retaining membranes by use of chaotropic agents |
AU2001241738A1 (en) | 2000-02-25 | 2001-09-03 | Corixa Corporation | Compounds and methods for diagnosis and immunotherapy of tuberculosis |
KR100829674B1 (ko) | 2000-05-19 | 2008-05-16 | 코릭사 코포레이션 | 단당류 또는 이당류계 화합물을 이용한 전염성 및 다른질병의 예방 및 치료 방법 |
WO2001092550A2 (en) * | 2000-05-31 | 2001-12-06 | Human Gene Therapy Research Institute | Methods and compositions for efficient gene transfer using transcomplementary vectors |
DE10041515A1 (de) | 2000-08-24 | 2002-03-14 | Gerold Schuler | Verfahren zur Herstellung gebrauchsfertiger, Antigen-beladener oder -unbeladener, kryokonservierter reifer dendritischer Zellen |
US6969704B1 (en) | 2000-08-25 | 2005-11-29 | The Trustees Of Columbia University In The City Of New York | Methods for suppressing early growth response—1protein (Egr-1) to reduce vascular injury in a subject |
US7060802B1 (en) | 2000-09-18 | 2006-06-13 | The Trustees Of Columbia University In The City Of New York | Tumor-associated marker |
WO2002028424A2 (en) | 2000-10-06 | 2002-04-11 | Paradies H Henrich | Kyberdrug as autovaccines with immune-regulating effects |
JP2004511527A (ja) | 2000-10-18 | 2004-04-15 | グラクソスミスクライン バイオロジカルズ ソシエテ アノニム | ワクチン |
WO2003004525A2 (en) | 2001-01-26 | 2003-01-16 | Walter Reed Army Institute Of Research | Isolation and purification of plasmodium falciparum merozoite protein-142 |
US6893820B1 (en) | 2001-01-31 | 2005-05-17 | The Ohio State University Research Foundation | Detection of methylated CpG rich sequences diagnostic for malignant cells |
US7029685B2 (en) | 2001-03-26 | 2006-04-18 | The United States Of America As Represented By The Secretary Of The Army | Plasmodium falciparum AMA-1 protein and uses thereof |
WO2002077195A2 (en) | 2001-03-26 | 2002-10-03 | Walter Reed Army Institute Of Research | Plasmodium falciparum ama-1 protein and uses thereof |
US6933123B2 (en) | 2001-04-05 | 2005-08-23 | Yao Xiong Hu | Peptides from the E2, E6, and E7 proteins of human papilloma viruses 16 and 18 for detecting and/or diagnosing cervical and other human papillomavirus associated cancers |
US6844192B2 (en) * | 2001-06-29 | 2005-01-18 | Wake Forest University | Adenovirus E4 protein variants for virus production |
US7727974B2 (en) * | 2001-08-10 | 2010-06-01 | Eisai R & D Management Co., Ltd. | Methods of reducing the severity of mucositis |
WO2003021227A2 (en) | 2001-09-05 | 2003-03-13 | The Children's Hospital Of Philadelphia | Methods and compositions useful for diagnosis, staging, and treatment of cancers and tumors |
US20040161776A1 (en) | 2001-10-23 | 2004-08-19 | Maddon Paul J. | PSMA formulations and uses thereof |
US6752995B2 (en) | 2002-04-15 | 2004-06-22 | Board Of Regents, The University Of Texas System | Nucleic acid and polypeptide sequences useful as adjuvants |
US6908453B2 (en) | 2002-01-15 | 2005-06-21 | 3M Innovative Properties Company | Microneedle devices and methods of manufacture |
CN101138566B (zh) | 2002-02-04 | 2012-05-23 | 科里克萨有限公司 | 用免疫效应化合物对感染性疾病和其它疾病的预防和治疗处理 |
US6911434B2 (en) * | 2002-02-04 | 2005-06-28 | Corixa Corporation | Prophylactic and therapeutic treatment of infectious and other diseases with immunoeffector compounds |
RU2288723C2 (ru) * | 2002-02-04 | 2006-12-10 | Корикса Корпорейшн | Профилактическое и терапевтическое лечение инфекционных и других заболеваний с помощью иммуноэффективных соединений |
US6676961B1 (en) | 2002-03-06 | 2004-01-13 | Automated Carrier Technologies, Inc. | Transdermal patch assembly |
US7820627B2 (en) | 2002-05-09 | 2010-10-26 | Oncothyreon Inc. | Lipid A and other carbohydrate ligand analogs |
US7018345B2 (en) | 2002-12-06 | 2006-03-28 | Hisamitsu Pharmaceutical Co., Inc. | Iontophoresis system |
US20050123550A1 (en) * | 2003-05-12 | 2005-06-09 | Laurent Philippe E. | Molecules enhancing dermal delivery of influenza vaccines |
FR2862062B1 (fr) | 2003-11-06 | 2005-12-23 | Oreal | Lipide a et composition topique, notamment cosmetique, le comprenant |
SI2068918T1 (sl) * | 2006-09-26 | 2012-09-28 | Infectious Disease Res Inst | Si - ep sestavek za cepljenje, ki vsebuje sintetiäśna pomagala |
US20090181078A1 (en) * | 2006-09-26 | 2009-07-16 | Infectious Disease Research Institute | Vaccine composition containing synthetic adjuvant |
KR101064518B1 (ko) | 2007-09-21 | 2011-09-19 | 주식회사 운화 | 저장근을 가지는 초본식물의 형성층 유래 식물줄기세포주 및 이의 분리방법 |
WO2009083014A1 (en) | 2007-12-27 | 2009-07-09 | Nokia Corporation | Maintaining the integrity of configuration information of a network of access points for use in positioning an apparatus |
EP2437753B1 (en) | 2009-06-05 | 2016-08-31 | Infectious Disease Research Institute | Synthetic glucopyranosyl lipid adjuvants and vaccine compositions containing them |
CN110339160A (zh) | 2012-02-07 | 2019-10-18 | 传染性疾病研究院 | 包含tlr4激动剂的改进佐剂制剂及其使用方法 |
JP5328975B2 (ja) | 2012-12-19 | 2013-10-30 | ルネサスエレクトロニクス株式会社 | Rfパワーモジュール |
BR112015025709A2 (pt) * | 2013-04-18 | 2017-07-18 | Immune Design Corp | monoterapia com gla para uso em tratamento de câncer |
US9463198B2 (en) | 2013-06-04 | 2016-10-11 | Infectious Disease Research Institute | Compositions and methods for reducing or preventing metastasis |
-
2010
- 2010-06-04 EP EP10784178.5A patent/EP2437753B1/en active Active
- 2010-06-04 RU RU2015129468A patent/RU2732574C2/ru active
- 2010-06-04 CN CN201510353412.8A patent/CN105131051B/zh active Active
- 2010-06-04 MX MX2011012836A patent/MX2011012836A/es active IP Right Grant
- 2010-06-04 PT PT107841785T patent/PT2437753T/pt unknown
- 2010-06-04 SI SI201031333A patent/SI2437753T1/sl unknown
- 2010-06-04 BR BRPI1011072-0A patent/BRPI1011072B1/pt active IP Right Grant
- 2010-06-04 WO PCT/US2010/037466 patent/WO2010141861A1/en active Application Filing
- 2010-06-04 JP JP2012514187A patent/JP5830015B2/ja active Active
- 2010-06-04 CN CN201080034214.0A patent/CN102481312B/zh active Active
- 2010-06-04 ES ES10784178.5T patent/ES2606563T3/es active Active
- 2010-06-04 DK DK10784178.5T patent/DK2437753T3/en active
- 2010-06-04 US US12/794,336 patent/US8722064B2/en active Active
- 2010-06-04 EP EP16186377.4A patent/EP3124491B1/en active Active
- 2010-06-04 MX MX2014009221A patent/MX360448B/es unknown
- 2010-06-04 LT LTEP10784178.5T patent/LT2437753T/lt unknown
- 2010-06-04 PL PL10784178T patent/PL2437753T3/pl unknown
- 2010-06-04 AU AU2010256461A patent/AU2010256461B2/en active Active
- 2010-06-04 TW TW099118278A patent/TWI494125B/zh active
- 2010-06-04 CA CA2764374A patent/CA2764374C/en active Active
- 2010-06-04 HU HUE10784178A patent/HUE031051T2/en unknown
- 2010-06-04 TW TW104113418A patent/TWI549688B/zh active
- 2010-06-04 RU RU2011152602/04A patent/RU2560182C2/ru active
-
2011
- 2011-11-29 IL IL216669A patent/IL216669A/en active IP Right Grant
-
2014
- 2014-03-21 US US14/222,481 patent/US9480740B2/en active Active
-
2015
- 2015-08-19 JP JP2015162164A patent/JP2016028042A/ja active Pending
- 2015-12-09 IL IL242992A patent/IL242992B/en active IP Right Grant
-
2016
- 2016-10-04 US US15/285,378 patent/US9814772B2/en active Active
- 2016-10-05 CY CY20161100990T patent/CY1118347T1/el unknown
- 2016-11-29 SM SM201600437T patent/SMT201600437B/it unknown
- 2016-11-29 HR HRP20161585TT patent/HRP20161585T1/hr unknown
-
2017
- 2017-03-03 JP JP2017040574A patent/JP6251431B2/ja active Active
- 2017-10-10 US US15/729,512 patent/US10632191B2/en active Active
-
2020
- 2020-09-10 RU RU2020129844A patent/RU2020129844A/ru unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0172581A2 (en) * | 1984-08-24 | 1986-02-26 | Daiichi Seiyaku Co., Ltd. | Disaccharide derivatives |
WO2009035528A2 (en) * | 2007-09-07 | 2009-03-19 | University Of Georgia Research Foundation, Inc. | Synthetic lipid a derivative |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI549688B (zh) | 合成的葡萄吡喃糖基脂質佐劑 | |
ES2673046T3 (es) | Composición de vacuna que contiene un adyuvante sintético |