JP2019519504A - Tlrアゴニストを含有する製剤及び使用方法 - Google Patents
Tlrアゴニストを含有する製剤及び使用方法 Download PDFInfo
- Publication number
- JP2019519504A JP2019519504A JP2018560185A JP2018560185A JP2019519504A JP 2019519504 A JP2019519504 A JP 2019519504A JP 2018560185 A JP2018560185 A JP 2018560185A JP 2018560185 A JP2018560185 A JP 2018560185A JP 2019519504 A JP2019519504 A JP 2019519504A
- Authority
- JP
- Japan
- Prior art keywords
- composition
- agonist
- antigen
- aluminum
- tlr7
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 322
- 239000000556 agonist Substances 0.000 title claims abstract description 151
- 238000000034 method Methods 0.000 title claims abstract description 61
- 238000009472 formulation Methods 0.000 title claims abstract description 47
- 150000002632 lipids Chemical class 0.000 claims abstract description 144
- 102100039360 Toll-like receptor 4 Human genes 0.000 claims abstract description 94
- 229940124613 TLR 7/8 agonist Drugs 0.000 claims abstract description 62
- FBFJOZZTIXSPPR-UHFFFAOYSA-N 1-(4-aminobutyl)-2-(ethoxymethyl)imidazo[4,5-c]quinolin-4-amine Chemical compound C1=CC=CC2=C(N(C(COCC)=N3)CCCCN)C3=C(N)N=C21 FBFJOZZTIXSPPR-UHFFFAOYSA-N 0.000 claims abstract description 58
- 239000013011 aqueous formulation Substances 0.000 claims abstract description 49
- 230000028993 immune response Effects 0.000 claims abstract description 39
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 claims abstract 15
- 239000000427 antigen Substances 0.000 claims description 279
- 102000036639 antigens Human genes 0.000 claims description 279
- 108091007433 antigens Proteins 0.000 claims description 279
- 239000006070 nanosuspension Substances 0.000 claims description 107
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 103
- 239000002245 particle Substances 0.000 claims description 98
- 102000002689 Toll-like receptor Human genes 0.000 claims description 68
- 108020000411 Toll-like receptor Proteins 0.000 claims description 68
- 229960005486 vaccine Drugs 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 58
- FAHBNUUHRFUEAI-UHFFFAOYSA-M hydroxidooxidoaluminium Chemical compound O[Al]=O FAHBNUUHRFUEAI-UHFFFAOYSA-M 0.000 claims description 48
- 239000008194 pharmaceutical composition Substances 0.000 claims description 34
- 241000700605 Viruses Species 0.000 claims description 29
- 206010028980 Neoplasm Diseases 0.000 claims description 26
- 101001000212 Rattus norvegicus Decorin Proteins 0.000 claims description 26
- FVJZSBGHRPJMMA-UHFFFAOYSA-N distearoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-UHFFFAOYSA-N 0.000 claims description 26
- 201000008827 tuberculosis Diseases 0.000 claims description 26
- -1 quaternary ammonium salt lipid Chemical class 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 24
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 claims description 22
- 102100039390 Toll-like receptor 7 Human genes 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 21
- 241000282414 Homo sapiens Species 0.000 claims description 20
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 claims description 20
- 201000011510 cancer Diseases 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 20
- 206010022000 influenza Diseases 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 17
- 208000004881 Amebiasis Diseases 0.000 claims description 16
- 206010001980 Amoebiasis Diseases 0.000 claims description 16
- 102000004127 Cytokines Human genes 0.000 claims description 16
- 108090000695 Cytokines Proteins 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 208000002672 hepatitis B Diseases 0.000 claims description 12
- 229940035032 monophosphoryl lipid a Drugs 0.000 claims description 12
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 claims description 10
- 125000000524 functional group Chemical group 0.000 claims description 10
- 239000012528 membrane Substances 0.000 claims description 10
- 150000003904 phospholipids Chemical class 0.000 claims description 10
- 230000015788 innate immune response Effects 0.000 claims description 9
- 101710154606 Hemagglutinin Proteins 0.000 claims description 7
- 208000005176 Hepatitis C Diseases 0.000 claims description 7
- 101710093908 Outer capsid protein VP4 Proteins 0.000 claims description 7
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 claims description 7
- 101710176177 Protein A56 Proteins 0.000 claims description 7
- 239000000185 hemagglutinin Substances 0.000 claims description 7
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 7
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 7
- 229940068968 polysorbate 80 Drugs 0.000 claims description 7
- 229920000053 polysorbate 80 Polymers 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 claims description 6
- 229940047712 aluminum hydroxyphosphate Drugs 0.000 claims description 6
- 208000037797 influenza A Diseases 0.000 claims description 6
- 208000037798 influenza B Diseases 0.000 claims description 6
- 208000037799 influenza C Diseases 0.000 claims description 6
- 101000831567 Homo sapiens Toll-like receptor 2 Proteins 0.000 claims description 5
- 206010020751 Hypersensitivity Diseases 0.000 claims description 5
- 229940124614 TLR 8 agonist Drugs 0.000 claims description 5
- 102100024333 Toll-like receptor 2 Human genes 0.000 claims description 5
- 208000026935 allergic disease Diseases 0.000 claims description 5
- 230000007815 allergy Effects 0.000 claims description 5
- 230000016784 immunoglobulin production Effects 0.000 claims description 5
- 238000001990 intravenous administration Methods 0.000 claims description 5
- GRLPQNLYRHEGIJ-UHFFFAOYSA-J potassium aluminium sulfate Chemical compound [Al+3].[K+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O GRLPQNLYRHEGIJ-UHFFFAOYSA-J 0.000 claims description 5
- 101000831496 Homo sapiens Toll-like receptor 3 Proteins 0.000 claims description 4
- 101000669460 Homo sapiens Toll-like receptor 5 Proteins 0.000 claims description 4
- 101000669406 Homo sapiens Toll-like receptor 6 Proteins 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- 102100024324 Toll-like receptor 3 Human genes 0.000 claims description 4
- 102100039357 Toll-like receptor 5 Human genes 0.000 claims description 4
- 102100039387 Toll-like receptor 6 Human genes 0.000 claims description 4
- 230000004936 stimulating effect Effects 0.000 claims description 4
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 claims description 4
- RREGISFBPQOLTM-UHFFFAOYSA-N alumane;trihydrate Chemical compound O.O.O.[AlH3] RREGISFBPQOLTM-UHFFFAOYSA-N 0.000 claims description 3
- 238000009097 single-agent therapy Methods 0.000 claims description 3
- 238000007920 subcutaneous administration Methods 0.000 claims description 3
- 229940044655 toll-like receptor 9 agonist Drugs 0.000 claims description 3
- 230000003844 B-cell-activation Effects 0.000 claims description 2
- 208000005374 Poisoning Diseases 0.000 claims description 2
- 230000006044 T cell activation Effects 0.000 claims description 2
- 230000005784 autoimmunity Effects 0.000 claims description 2
- 231100000572 poisoning Toxicity 0.000 claims description 2
- 230000000607 poisoning effect Effects 0.000 claims description 2
- QVLTXCYWHPZMCA-UHFFFAOYSA-N po4-po4 Chemical compound OP(O)(O)=O.OP(O)(O)=O QVLTXCYWHPZMCA-UHFFFAOYSA-N 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 abstract description 84
- 229910052782 aluminium Inorganic materials 0.000 abstract description 29
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 abstract description 26
- 108010060804 Toll-Like Receptor 4 Proteins 0.000 description 79
- 239000003446 ligand Substances 0.000 description 56
- 210000004027 cell Anatomy 0.000 description 50
- 238000001179 sorption measurement Methods 0.000 description 45
- 230000000694 effects Effects 0.000 description 36
- 241000699670 Mus sp. Species 0.000 description 35
- 230000003053 immunization Effects 0.000 description 34
- 238000002649 immunization Methods 0.000 description 32
- 241000725303 Human immunodeficiency virus Species 0.000 description 31
- 230000004044 response Effects 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 108090000765 processed proteins & peptides Proteins 0.000 description 27
- 210000001744 T-lymphocyte Anatomy 0.000 description 24
- 102000004196 processed proteins & peptides Human genes 0.000 description 23
- 108090000623 proteins and genes Proteins 0.000 description 22
- 229920001184 polypeptide Polymers 0.000 description 21
- 235000018102 proteins Nutrition 0.000 description 20
- 102000004169 proteins and genes Human genes 0.000 description 20
- 239000000523 sample Substances 0.000 description 20
- 108020001507 fusion proteins Proteins 0.000 description 18
- 102000037865 fusion proteins Human genes 0.000 description 18
- 102000007863 pattern recognition receptors Human genes 0.000 description 18
- 108010089193 pattern recognition receptors Proteins 0.000 description 18
- 241000701806 Human papillomavirus Species 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 239000003795 chemical substances by application Substances 0.000 description 17
- 238000002474 experimental method Methods 0.000 description 17
- 230000014509 gene expression Effects 0.000 description 16
- 230000027455 binding Effects 0.000 description 15
- 102000040430 polynucleotide Human genes 0.000 description 15
- 108091033319 polynucleotide Proteins 0.000 description 15
- 239000002157 polynucleotide Substances 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 13
- 108010074328 Interferon-gamma Proteins 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 230000006698 induction Effects 0.000 description 12
- 239000000546 pharmaceutical excipient Substances 0.000 description 12
- 210000002966 serum Anatomy 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- 229940037003 alum Drugs 0.000 description 11
- 238000002296 dynamic light scattering Methods 0.000 description 11
- 208000015181 infectious disease Diseases 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 11
- 230000000153 supplemental effect Effects 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 238000002965 ELISA Methods 0.000 description 10
- 102100037850 Interferon gamma Human genes 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 10
- 239000006228 supernatant Substances 0.000 description 10
- 239000012646 vaccine adjuvant Substances 0.000 description 10
- 229940124931 vaccine adjuvant Drugs 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000013459 approach Methods 0.000 description 9
- 239000003085 diluting agent Substances 0.000 description 9
- 210000000987 immune system Anatomy 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 230000007935 neutral effect Effects 0.000 description 9
- 102100033110 Toll-like receptor 8 Human genes 0.000 description 8
- 238000009826 distribution Methods 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 201000004792 malaria Diseases 0.000 description 8
- 244000045947 parasite Species 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 7
- RHKWIGHJGOEUSM-UHFFFAOYSA-N 3h-imidazo[4,5-h]quinoline Chemical class C1=CN=C2C(N=CN3)=C3C=CC2=C1 RHKWIGHJGOEUSM-UHFFFAOYSA-N 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 description 7
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 7
- 108700006640 OspA Proteins 0.000 description 7
- 230000005867 T cell response Effects 0.000 description 7
- 230000005875 antibody response Effects 0.000 description 7
- 239000007900 aqueous suspension Substances 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 210000005087 mononuclear cell Anatomy 0.000 description 7
- 239000002953 phosphate buffered saline Substances 0.000 description 7
- 238000003259 recombinant expression Methods 0.000 description 7
- 210000004988 splenocyte Anatomy 0.000 description 7
- 108010002350 Interleukin-2 Proteins 0.000 description 6
- 102000000588 Interleukin-2 Human genes 0.000 description 6
- 241001467552 Mycobacterium bovis BCG Species 0.000 description 6
- 241000223960 Plasmodium falciparum Species 0.000 description 6
- 241000242677 Schistosoma japonicum Species 0.000 description 6
- 229960000190 bacillus calmette–guérin vaccine Drugs 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 230000018109 developmental process Effects 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 230000001571 immunoadjuvant effect Effects 0.000 description 6
- 239000000568 immunological adjuvant Substances 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 210000004698 lymphocyte Anatomy 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 150000007523 nucleic acids Chemical class 0.000 description 6
- 238000000527 sonication Methods 0.000 description 6
- 241000894007 species Species 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 5
- 229940124957 Cervarix Drugs 0.000 description 5
- 108010012236 Chemokines Proteins 0.000 description 5
- 102000019034 Chemokines Human genes 0.000 description 5
- 241000606161 Chlamydia Species 0.000 description 5
- 241000224432 Entamoeba histolytica Species 0.000 description 5
- 108010034145 Helminth Proteins Proteins 0.000 description 5
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 241000242678 Schistosoma Species 0.000 description 5
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 description 5
- 102100033117 Toll-like receptor 9 Human genes 0.000 description 5
- 102100040247 Tumor necrosis factor Human genes 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 5
- 210000003719 b-lymphocyte Anatomy 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 230000036755 cellular response Effects 0.000 description 5
- 238000005119 centrifugation Methods 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- 238000000604 cryogenic transmission electron microscopy Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000009881 electrostatic interaction Effects 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 244000000013 helminth Species 0.000 description 5
- 210000001165 lymph node Anatomy 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 102000039446 nucleic acids Human genes 0.000 description 5
- 108020004707 nucleic acids Proteins 0.000 description 5
- 235000021317 phosphate Nutrition 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000003053 toxin Substances 0.000 description 5
- 231100000765 toxin Toxicity 0.000 description 5
- 108700012359 toxins Proteins 0.000 description 5
- FVXDQWZBHIXIEJ-LNDKUQBDSA-N 1,2-di-[(9Z,12Z)-octadecadienoyl]-sn-glycero-3-phosphocholine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC FVXDQWZBHIXIEJ-LNDKUQBDSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 208000023275 Autoimmune disease Diseases 0.000 description 4
- 102100037840 Dehydrogenase/reductase SDR family member 2, mitochondrial Human genes 0.000 description 4
- 102000008072 Lymphokines Human genes 0.000 description 4
- 108010074338 Lymphokines Proteins 0.000 description 4
- 241000186359 Mycobacterium Species 0.000 description 4
- 108700023315 OspC Proteins 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
- 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
- 125000002252 acyl group Chemical group 0.000 description 4
- 229940024545 aluminum hydroxide Drugs 0.000 description 4
- 125000000129 anionic group Chemical group 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 238000003114 enzyme-linked immunosorbent spot assay Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000036039 immunity Effects 0.000 description 4
- 230000005847 immunogenicity Effects 0.000 description 4
- 230000000977 initiatory effect Effects 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 210000005007 innate immune system Anatomy 0.000 description 4
- 239000007927 intramuscular injection Substances 0.000 description 4
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical class 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 4
- 210000000822 natural killer cell Anatomy 0.000 description 4
- 244000052769 pathogen Species 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- DSNRWDQKZIEDDB-SQYFZQSCSA-N 1,2-dioleoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC DSNRWDQKZIEDDB-SQYFZQSCSA-N 0.000 description 3
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 241000589968 Borrelia Species 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 3
- 241000222122 Candida albicans Species 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- 230000006820 DNA synthesis Effects 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 102100025137 Early activation antigen CD69 Human genes 0.000 description 3
- 241000588724 Escherichia coli 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
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 3
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 3
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 description 3
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 3
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 3
- 102100022338 Integrin alpha-M Human genes 0.000 description 3
- 102000008070 Interferon-gamma Human genes 0.000 description 3
- 108010002352 Interleukin-1 Proteins 0.000 description 3
- 102000000589 Interleukin-1 Human genes 0.000 description 3
- 241000222722 Leishmania <genus> Species 0.000 description 3
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 3
- 241000588653 Neisseria Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- 241000607142 Salmonella Species 0.000 description 3
- 241000194017 Streptococcus Species 0.000 description 3
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000004442 acylamino group Chemical group 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 101150078331 ama-1 gene Proteins 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000000890 antigenic effect Effects 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 238000000149 argon plasma sintering Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000008901 benefit Effects 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
- 210000001185 bone marrow Anatomy 0.000 description 3
- KQNZDYYTLMIZCT-KQPMLPITSA-N brefeldin A Chemical compound O[C@@H]1\C=C\C(=O)O[C@@H](C)CCC\C=C\[C@@H]2C[C@H](O)C[C@H]21 KQNZDYYTLMIZCT-KQPMLPITSA-N 0.000 description 3
- JUMGSHROWPPKFX-UHFFFAOYSA-N brefeldin-A Natural products CC1CCCC=CC2(C)CC(O)CC2(C)C(O)C=CC(=O)O1 JUMGSHROWPPKFX-UHFFFAOYSA-N 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 230000007969 cellular immunity Effects 0.000 description 3
- 230000000139 costimulatory effect Effects 0.000 description 3
- BPHQZTVXXXJVHI-UHFFFAOYSA-N dimyristoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 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 3
- 239000000975 dye Substances 0.000 description 3
- 229940007078 entamoeba histolytica Drugs 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- 231100000283 hepatitis Toxicity 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 229940124669 imidazoquinoline Drugs 0.000 description 3
- 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 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000010255 intramuscular injection Methods 0.000 description 3
- 238000012737 microarray-based gene expression Methods 0.000 description 3
- 230000000813 microbial effect Effects 0.000 description 3
- 239000004005 microsphere Substances 0.000 description 3
- 238000012243 multiplex automated genomic engineering Methods 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 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 3
- 239000012723 sample buffer Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 229960002109 tuberculosis vaccine Drugs 0.000 description 3
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 3
- 241000701161 unidentified adenovirus Species 0.000 description 3
- 241000712461 unidentified influenza virus Species 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 241000224422 Acanthamoeba Species 0.000 description 2
- 241000224489 Amoeba Species 0.000 description 2
- 206010059313 Anogenital warts Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102100030009 Azurocidin Human genes 0.000 description 2
- 101710154607 Azurocidin Proteins 0.000 description 2
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 2
- 241000335423 Blastomyces Species 0.000 description 2
- 108030001720 Bontoxilysin Proteins 0.000 description 2
- 241000588807 Bordetella Species 0.000 description 2
- 241000495356 Borrelia microti Species 0.000 description 2
- 241000589972 Borrelia sp. Species 0.000 description 2
- 241001148604 Borreliella afzelii Species 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 102100032912 CD44 antigen Human genes 0.000 description 2
- 241000589877 Campylobacter coli Species 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 241000193163 Clostridioides difficile Species 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 208000000907 Condylomata Acuminata Diseases 0.000 description 2
- 241000186227 Corynebacterium diphtheriae Species 0.000 description 2
- 241000223935 Cryptosporidium Species 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 2
- 102100020743 Dipeptidase 1 Human genes 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
- 238000011510 Elispot assay Methods 0.000 description 2
- 241000204733 Entamoeba dispar Species 0.000 description 2
- 241000713800 Feline immunodeficiency virus Species 0.000 description 2
- 108010040721 Flagellin Proteins 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 241000224466 Giardia Species 0.000 description 2
- 241000606768 Haemophilus influenzae Species 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 2
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 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
- 102000013462 Interleukin-12 Human genes 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- 108010002616 Interleukin-5 Proteins 0.000 description 2
- 102100034872 Kallikrein-4 Human genes 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- 241000589929 Leptospira interrogans Species 0.000 description 2
- 108090001030 Lipoproteins Proteins 0.000 description 2
- 102000004895 Lipoproteins Human genes 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
- 241000124008 Mammalia Species 0.000 description 2
- 101710085938 Matrix protein Proteins 0.000 description 2
- 101710127721 Membrane protein Proteins 0.000 description 2
- 241000588655 Moraxella catarrhalis Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000186366 Mycobacterium bovis Species 0.000 description 2
- 241000186362 Mycobacterium leprae Species 0.000 description 2
- 241000187480 Mycobacterium smegmatis Species 0.000 description 2
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 2
- MXRIRQGCELJRSN-UHFFFAOYSA-N O.O.O.[Al] Chemical compound O.O.O.[Al] MXRIRQGCELJRSN-UHFFFAOYSA-N 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 241000235645 Pichia kudriavzevii Species 0.000 description 2
- 102100035181 Plastin-1 Human genes 0.000 description 2
- 241000233870 Pneumocystis Species 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 2
- 102100038358 Prostate-specific antigen Human genes 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 241000725643 Respiratory syncytial virus Species 0.000 description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 2
- 241000191963 Staphylococcus epidermidis Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 241000193996 Streptococcus pyogenes Species 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
- 241000223996 Toxoplasma Species 0.000 description 2
- 241000242541 Trematoda Species 0.000 description 2
- 241000589892 Treponema denticola Species 0.000 description 2
- 241000589884 Treponema pallidum Species 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- YGPZYYDTPXVBRA-RTDBHSBRSA-N [(2r,3s,4r,5r,6s)-2-[[(2r,3r,4r,5s,6r)-3-[[(3r)-3-dodecanoyloxytetradecanoyl]amino]-6-(hydroxymethyl)-5-phosphonooxy-4-[(3r)-3-tetradecanoyloxytetradecanoyl]oxyoxan-2-yl]oxymethyl]-3,6-dihydroxy-5-[[(3r)-3-hydroxytetradecanoyl]amino]oxan-4-yl] (3r)-3-hydr 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](O)O1 YGPZYYDTPXVBRA-RTDBHSBRSA-N 0.000 description 2
- 230000033289 adaptive immune response Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 210000000628 antibody-producing cell Anatomy 0.000 description 2
- 210000000612 antigen-presenting cell Anatomy 0.000 description 2
- 238000003782 apoptosis assay Methods 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 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 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
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 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 2
- 239000003086 colorant Substances 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 230000001461 cytolytic effect Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- BFMYDTVEBKDAKJ-UHFFFAOYSA-L disodium;(2',7'-dibromo-3',6'-dioxido-3-oxospiro[2-benzofuran-1,9'-xanthene]-4'-yl)mercury;hydrate Chemical compound O.[Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(Br)=C([O-])C([Hg])=C1OC1=C2C=C(Br)C([O-])=C1 BFMYDTVEBKDAKJ-UHFFFAOYSA-L 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 238000012395 formulation development Methods 0.000 description 2
- 239000012634 fragment Substances 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
- 150000004676 glycans Chemical class 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 229960002751 imiquimod Drugs 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000012678 infectious agent Substances 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 108010024383 kallikrein 4 Proteins 0.000 description 2
- 229940039717 lanolin Drugs 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 239000002502 liposome Substances 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
- 201000001441 melanoma Diseases 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 244000000010 microbial pathogen Species 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 230000004899 motility Effects 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 108010049148 plastin Proteins 0.000 description 2
- 229940068917 polyethylene glycols Drugs 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 230000005522 programmed cell death Effects 0.000 description 2
- 239000001294 propane Substances 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 229950010550 resiquimod Drugs 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 229930182490 saponin Natural products 0.000 description 2
- 150000007949 saponins Chemical class 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000009897 systematic effect Effects 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- 241001529453 unidentified herpesvirus Species 0.000 description 2
- 238000002255 vaccination Methods 0.000 description 2
- 239000013603 viral vector Substances 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 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 description 1
- BIABMEZBCHDPBV-BEBVUIBBSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-BEBVUIBBSA-N 0.000 description 1
- 229940012999 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol) Drugs 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 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
- FHJATBIERQTCTN-UHFFFAOYSA-N 1-[4-amino-2-(ethylaminomethyl)imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol Chemical compound C1=CC=CC2=C(N(C(CNCC)=N3)CC(C)(C)O)C3=C(N)N=C21 FHJATBIERQTCTN-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
- 125000006069 2,3-dimethyl-2-butenyl group Chemical group 0.000 description 1
- ZLGYVWRJIZPQMM-HHHXNRCGSA-N 2-azaniumylethyl [(2r)-2,3-di(dodecanoyloxy)propyl] phosphate Chemical compound CCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCC ZLGYVWRJIZPQMM-HHHXNRCGSA-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
- 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
- 125000006027 3-methyl-1-butenyl group Chemical group 0.000 description 1
- 125000000972 4,5-dimethylthiazol-2-yl group Chemical group [H]C([H])([H])C1=C(N=C(*)S1)C([H])([H])[H] 0.000 description 1
- IMCUVBSHZXQITN-UHFFFAOYSA-N 4-[[4-(4-chlorophenyl)-5-(2-methoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino]-4-oxobutanoic acid Chemical compound S1C(NC(=O)CCC(O)=O)=NC(C=2C=CC(Cl)=CC=2)=C1CC(=O)OC IMCUVBSHZXQITN-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 210000002925 A-like Anatomy 0.000 description 1
- 102100024643 ATP-binding cassette sub-family D member 1 Human genes 0.000 description 1
- 101000787132 Acidithiobacillus ferridurans Uncharacterized 8.2 kDa protein in mobL 3'region Proteins 0.000 description 1
- 101000827262 Acidithiobacillus ferrooxidans Uncharacterized 18.9 kDa protein in mobE 3'region Proteins 0.000 description 1
- 241001156739 Actinobacteria <phylum> Species 0.000 description 1
- 208000000884 Airway Obstruction 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
- 241001147657 Ancylostoma Species 0.000 description 1
- 241000243791 Angiostrongylus Species 0.000 description 1
- 101000811747 Antithamnion sp. UPF0051 protein in atpA 3'region Proteins 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 101100162403 Arabidopsis thaliana ALEU gene Proteins 0.000 description 1
- 208000002109 Argyria Diseases 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 102100035526 B melanoma antigen 1 Human genes 0.000 description 1
- 241000223836 Babesia Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 101000827607 Bacillus phage SPP1 Uncharacterized 8.5 kDa protein in GP2-GP6 intergenic region Proteins 0.000 description 1
- 101000961975 Bacillus thuringiensis Uncharacterized 13.4 kDa protein 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
- 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
- 235000018185 Betula X alpestris Nutrition 0.000 description 1
- 235000018212 Betula X uliginosa Nutrition 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 241000588779 Bordetella bronchiseptica Species 0.000 description 1
- 241000588780 Bordetella parapertussis Species 0.000 description 1
- 241000588832 Bordetella pertussis Species 0.000 description 1
- 241000589978 Borrelia hermsii 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
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- 108700012434 CCL3 Proteins 0.000 description 1
- 241000244203 Caenorhabditis elegans Species 0.000 description 1
- 101000964407 Caldicellulosiruptor saccharolyticus Uncharacterized 10.7 kDa protein in xynB 3'region Proteins 0.000 description 1
- 244000197813 Camelina sativa Species 0.000 description 1
- 241000589876 Campylobacter Species 0.000 description 1
- 241000222173 Candida parapsilosis Species 0.000 description 1
- 241000222178 Candida tropicalis Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102100035882 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 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
- 102000001327 Chemokine CCL5 Human genes 0.000 description 1
- 241001647372 Chlamydia pneumoniae Species 0.000 description 1
- 241000606153 Chlamydia trachomatis Species 0.000 description 1
- 108010049048 Cholera Toxin Proteins 0.000 description 1
- 102000009016 Cholera Toxin Human genes 0.000 description 1
- 101710164918 Choline-binding protein Proteins 0.000 description 1
- 241000193403 Clostridium Species 0.000 description 1
- 241000193155 Clostridium botulinum Species 0.000 description 1
- 241000193449 Clostridium tetani Species 0.000 description 1
- 241000223203 Coccidioides Species 0.000 description 1
- 241000255749 Coccinellidae Species 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 241000207892 Convolvulus Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000186249 Corynebacterium sp. Species 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- 241000221204 Cryptococcus neoformans Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 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
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 241000605314 Ehrlichia Species 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 241000224431 Entamoeba Species 0.000 description 1
- 241000146407 Entamoeba coli 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
- 241000194033 Enterococcus Species 0.000 description 1
- 241000194031 Enterococcus faecium Species 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 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
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 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
- 241000239183 Filaria Species 0.000 description 1
- 241000710831 Flavivirus Species 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
- 101710177291 Gag polyprotein Proteins 0.000 description 1
- 101000812705 Gallus gallus Endoplasmin Proteins 0.000 description 1
- 241001427367 Gardena Species 0.000 description 1
- 241000224467 Giardia intestinalis Species 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 1
- 108010024636 Glutathione Proteins 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
- 208000031886 HIV Infections Diseases 0.000 description 1
- 229940033330 HIV vaccine Drugs 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 101100406392 Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) omp26 gene Proteins 0.000 description 1
- 101000768777 Haloferax lucentense (strain DSM 14919 / JCM 9276 / NCIMB 13854 / Aa 2.2) Uncharacterized 50.6 kDa protein in the 5'region of gyrA and gyrB Proteins 0.000 description 1
- 241000589989 Helicobacter Species 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 241000724675 Hepatitis E virus Species 0.000 description 1
- 241000709721 Hepatovirus A Species 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 241000238631 Hexapoda Species 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
- 101000874141 Homo sapiens Probable ATP-dependent RNA helicase DDX43 Proteins 0.000 description 1
- 101001136592 Homo sapiens Prostate stem cell antigen Proteins 0.000 description 1
- 101001130441 Homo sapiens Ras-related protein Rap-2a Proteins 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- 241000701828 Human papillomavirus type 11 Species 0.000 description 1
- 101000607404 Infectious laryngotracheitis virus (strain Thorne V882) Protein UL24 homolog Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100022297 Integrin alpha-X Human genes 0.000 description 1
- 102000013691 Interleukin-17 Human genes 0.000 description 1
- 108050003558 Interleukin-17 Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 102000004890 Interleukin-8 Human genes 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 101710198693 Invasin Proteins 0.000 description 1
- 241000710842 Japanese encephalitis virus Species 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 101000735632 Klebsiella pneumoniae Uncharacterized 8.8 kDa protein in aacA4 3'region Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 231100000111 LD50 Toxicity 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
- 241000589248 Legionella Species 0.000 description 1
- 241000589242 Legionella pneumophila Species 0.000 description 1
- 208000004554 Leishmaniasis Diseases 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- 241000186781 Listeria Species 0.000 description 1
- 241000186779 Listeria monocytogenes Species 0.000 description 1
- 208000016604 Lyme disease Diseases 0.000 description 1
- 101710125418 Major capsid protein Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000712079 Measles morbillivirus Species 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102100026712 Metalloreductase STEAP1 Human genes 0.000 description 1
- 108700011259 MicroRNAs Proteins 0.000 description 1
- 241000588621 Moraxella Species 0.000 description 1
- 241000711386 Mumps virus Species 0.000 description 1
- MSFSPUZXLOGKHJ-UHFFFAOYSA-N Muraminsaeure Natural products OC(=O)C(C)OC1C(N)C(O)OC(CO)C1O MSFSPUZXLOGKHJ-UHFFFAOYSA-N 0.000 description 1
- 101100369076 Mus musculus Tdgf1 gene Proteins 0.000 description 1
- 241000186367 Mycobacterium avium Species 0.000 description 1
- 241000187482 Mycobacterium avium subsp. paratuberculosis Species 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- 241000588650 Neisseria meningitidis Species 0.000 description 1
- 208000000291 Nematode infections Diseases 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 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
- 241000133504 Opisthorchis sinensis Species 0.000 description 1
- 101710116435 Outer membrane protein Proteins 0.000 description 1
- 108060006580 PRAME Proteins 0.000 description 1
- 102000036673 PRAME Human genes 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108010013639 Peptidoglycan Proteins 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 108010081690 Pertussis Toxin Proteins 0.000 description 1
- 239000004264 Petrolatum Substances 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
- 240000009188 Phyllostachys vivax Species 0.000 description 1
- 244000010922 Plantago major Species 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 101000983333 Plasmodium falciparum (isolate NF54) 25 kDa ookinete surface antigen Proteins 0.000 description 1
- 241000223821 Plasmodium malariae Species 0.000 description 1
- 206010035501 Plasmodium malariae infection Diseases 0.000 description 1
- 241001505293 Plasmodium ovale Species 0.000 description 1
- 206010035502 Plasmodium ovale infection Diseases 0.000 description 1
- 241000233872 Pneumocystis carinii Species 0.000 description 1
- 101710183389 Pneumolysin Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 102100035724 Probable ATP-dependent RNA helicase DDX43 Human genes 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
- 101710155866 Protein J1 homolog Proteins 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000508269 Psidium Species 0.000 description 1
- 101710201576 Putative membrane protein Proteins 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102100022851 Rab5 GDP/GTP exchange factor Human genes 0.000 description 1
- 102100031420 Ras-related protein Rap-2a Human genes 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 101710203837 Replication-associated protein Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 241000606695 Rickettsia rickettsii Species 0.000 description 1
- 241000606651 Rickettsiales Species 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- 241001138501 Salmonella enterica Species 0.000 description 1
- 241001354013 Salmonella enterica subsp. enterica serovar Enteritidis Species 0.000 description 1
- 241000531795 Salmonella enterica subsp. enterica serovar Paratyphi A Species 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- 241000242680 Schistosoma mansoni Species 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 241000607764 Shigella dysenteriae Species 0.000 description 1
- 241000607760 Shigella sonnei Species 0.000 description 1
- 101710084578 Short neurotoxin 1 Proteins 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 101000818100 Spirochaeta aurantia Uncharacterized 12.7 kDa protein in trpE 5'region Proteins 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000193985 Streptococcus agalactiae Species 0.000 description 1
- 241000194019 Streptococcus mutans Species 0.000 description 1
- 108010011834 Streptolysins Proteins 0.000 description 1
- 101001037658 Streptomyces coelicolor (strain ATCC BAA-471 / A3(2) / M145) Glucokinase Proteins 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 108010002687 Survivin Proteins 0.000 description 1
- 108010008038 Synthetic Vaccines Proteins 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 108010055044 Tetanus Toxin Proteins 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 241000710771 Tick-borne encephalitis virus Species 0.000 description 1
- 108010060825 Toll-Like Receptor 7 Proteins 0.000 description 1
- 108010060752 Toll-Like Receptor 8 Proteins 0.000 description 1
- 229940123384 Toll-like receptor (TLR) agonist Drugs 0.000 description 1
- 101710182223 Toxin B Proteins 0.000 description 1
- 101710182532 Toxin a Proteins 0.000 description 1
- 101710134694 Transcriptional regulator ICP22 homolog Proteins 0.000 description 1
- 108020004566 Transfer RNA Proteins 0.000 description 1
- 102000010912 Transferrin-Binding Proteins Human genes 0.000 description 1
- 241000869417 Trematodes Species 0.000 description 1
- 241000589886 Treponema Species 0.000 description 1
- 241000224526 Trichomonas Species 0.000 description 1
- 241000224527 Trichomonas vaginalis Species 0.000 description 1
- 241001489151 Trichuris Species 0.000 description 1
- 241000223104 Trypanosoma Species 0.000 description 1
- 241000223109 Trypanosoma cruzi Species 0.000 description 1
- 102100039094 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
- 241000607598 Vibrio Species 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- 241000244005 Wuchereria bancrofti Species 0.000 description 1
- 208000024177 X-Linked immunodeficiency 74 Diseases 0.000 description 1
- 241000710772 Yellow fever virus Species 0.000 description 1
- 241000607734 Yersinia <bacteria> Species 0.000 description 1
- 241000607447 Yersinia enterocolitica Species 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 241000607477 Yersinia pseudotuberculosis Species 0.000 description 1
- 208000025087 Yersinia pseudotuberculosis infectious disease Diseases 0.000 description 1
- FVJZSBGHRPJMMA-DHPKCYQYSA-N [(2r)-3-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-2-octadecanoyloxypropyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-DHPKCYQYSA-N 0.000 description 1
- LUXUAZKGQZPOBZ-SAXJAHGMSA-N [(3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] (Z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O LUXUAZKGQZPOBZ-SAXJAHGMSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 241000222126 [Candida] glabrata Species 0.000 description 1
- 241000606834 [Haemophilus] ducreyi Species 0.000 description 1
- 150000001242 acetic acid derivatives 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
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 230000000274 adsorptive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940060265 aldara Drugs 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- RZJRJXONCZWCBN-UHFFFAOYSA-N alpha-octadecene Natural products CCCCCCCCCCCCCCCCCC RZJRJXONCZWCBN-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000011126 aluminium potassium sulphate Nutrition 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229940024546 aluminum hydroxide gel Drugs 0.000 description 1
- SMYKVLBUSSNXMV-UHFFFAOYSA-K aluminum;trihydroxide;hydrate Chemical compound O.[OH-].[OH-].[OH-].[Al+3] SMYKVLBUSSNXMV-UHFFFAOYSA-K 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 239000003708 ampul 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
- 230000002605 anti-dotal effect Effects 0.000 description 1
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000000231 atomic layer deposition Methods 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 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 1
- 210000002769 b effector cell Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 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
- 229940092738 beeswax Drugs 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
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000006406 biphasic response Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940053031 botulinum toxin Drugs 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 208000032343 candida glabrata infection Diseases 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000008004 cell lysis buffer Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000003837 chick embryo Anatomy 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 231100001102 clostridial toxin Toxicity 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000012937 correction Methods 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
- 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
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 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 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 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
- 241001493065 dsRNA viruses Species 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000000369 enteropathogenic effect Effects 0.000 description 1
- 231100000249 enterotoxic Toxicity 0.000 description 1
- 230000002242 enterotoxic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 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
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000005469 ethylenyl group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 230000002550 fecal effect Effects 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 229940124670 gardiquimod Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 150000002327 glycerophospholipids 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
- 238000000227 grinding Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 108010037896 heparin-binding hemagglutinin Proteins 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 102000045715 human TLR7 Human genes 0.000 description 1
- 229940124866 human papillomavirus vaccine Drugs 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000005965 immune activity Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008073 immune recognition Effects 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 230000009851 immunogenic response Effects 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000010324 immunological assay Methods 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 108091005434 innate immune receptors Proteins 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000005651 interleukin-17A production Effects 0.000 description 1
- 230000022023 interleukin-5 production Effects 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010212 intracellular staining Methods 0.000 description 1
- 238000007915 intraurethral administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 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
- 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
- 201000010982 kidney cancer Diseases 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229940115932 legionella pneumophila Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000002809 long lived plasma cell Anatomy 0.000 description 1
- 201000003866 lung sarcoma Diseases 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 101710130522 mRNA export factor Proteins 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940124735 malaria vaccine Drugs 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 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
- 239000003550 marker Substances 0.000 description 1
- 210000001806 memory b lymphocyte Anatomy 0.000 description 1
- 210000003071 memory t lymphocyte Anatomy 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 229940042472 mineral oil Drugs 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 125000001421 myristyl 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])[H] 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 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
- 239000002105 nanoparticle Substances 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 108091027963 non-coding RNA Proteins 0.000 description 1
- 102000042567 non-coding RNA Human genes 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 230000009871 nonspecific binding Effects 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
- 229940038384 octadecane Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229940099789 ospa protein Drugs 0.000 description 1
- 229960003126 other bacterial vaccines in atc Drugs 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 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
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 238000005453 pelletization Methods 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
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 235000020030 perry Nutrition 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
- 239000012071 phase Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 238000013379 physicochemical characterization Methods 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 201000000317 pneumocystosis Diseases 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000002516 postimmunization Effects 0.000 description 1
- 229940050271 potassium alum Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000005470 propylenyl group Chemical group 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229940124551 recombinant vaccine Drugs 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000002924 silencing RNA Substances 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 150000003384 small molecules Chemical class 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
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000003046 sporozoite Anatomy 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007619 statistical method Methods 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
- 238000011146 sterile filtration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent 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
- 230000002123 temporal effect Effects 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
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 230000024664 tolerance induction Effects 0.000 description 1
- 239000003970 toll like receptor agonist Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000009495 transient activation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 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
- 238000004879 turbidimetry Methods 0.000 description 1
- 238000007492 two-way ANOVA Methods 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
- 229940125575 vaccine candidate Drugs 0.000 description 1
- 210000003934 vacuole Anatomy 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
- 210000000605 viral structure Anatomy 0.000 description 1
- 239000000277 virosome Substances 0.000 description 1
- 239000012905 visible particle Substances 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 238000005406 washing Methods 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
- 238000011816 wild-type C57Bl6 mouse Methods 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
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/04—Amoebicides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
-
- 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
- A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
- A61K2039/552—Veterinary vaccine
-
- 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
- A61K2039/55505—Inorganic adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
-
- 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
- A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
- C12N2740/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cell Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- Pulmonology (AREA)
- Oncology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
【選択図】なし
Description
この出願は、2016年5月16日出願の米国仮出願第62/337,322号の利益を主張し、その全体を参照することによりここに組み入れられたものとする。
連邦政府委託研究又は開発に関する記載
又は薬剤的に許容できるその塩を含むものであって、式中、
L1、L2、L3、L4、L5及びL6は、同一であるか又は異なるものであり、独立に−O−、−NH−又は−(CH2)−であり、
L7、L8、L9及びL10は、同一であるか又は異なるものであり、独立に、存在しないか又は−C(=O)−であり、
Y1は、酸官能基であり、
Y2及びY3は、同一であるか又は異なるものであり、独立に−OH、−SH又は酸官能基であり、
Y4は、−OH又は−SHであり、
R1、R3、R5及びR6は、同一であるか又は異なるものであり、独立に炭素数8〜13のアルキルであり、
R2及びR4は、同一であるか又は異なるものであり、独立に炭素数6〜11のアルキルである。
又は薬剤的に許容できるその塩を含むものであって、式中、
R1、R3、R5及びR6は、炭素数11〜20のアルキルであり、R2及びR4は、炭素数12〜20のアルキルである。
組成物
TLRアゴニスト
TLR7/8アゴニスト
又は薬剤的に許容できるその塩であって、式中、
R10は、水素及び炭素数1〜6のアルキルからなる群から選択され、
R11bは、ハロ、ヒドロキシル、炭素数1〜6のアルキル及びアシルアミノからなる群から選択される1つ又は複数の群で置換されていてもよい炭素数1〜6のアルキルである。
或る好ましい実施形態では、本明細書の組成物において用いられるTLR7/8アゴニストは、米国特許第9,242,980号に記載されるN−(4−{[4−アミノ−2−ブチル−1H−イミダゾ[4,5−c]キノリン−1−イル]オキシ}ブチル)オクタデカンアミド)、3M−052を含む。
TLR4アゴニスト
又は薬剤的に許容できるその塩であって、式中、
L1、L2、L3、L4、L5及びL6は、同一であるか又は異なるものであり、独立に−O−、−NH−又は−(CH2)−であり、
L7、L8、L9及びL10は、同一であるか又は異なるものであり、独立に、存在しないか又は−C(=O)−であり、
Y1は、酸官能基であり、
Y2及びY3は、同一であるか又は異なるものであり、独立に−OH、−SH又は酸官能基であり、
Y4は、−OH又は−SHであり、
R1、R3、R5及びR6は、同一であるか又は異なるものであり、独立に炭素数8〜13のアルキルであり、
R2及びR4は、同一であるか又は異なるものであり、独立に炭素数6〜11のアルキルである。
補助脂質
アルミニウム塩
TLRアゴニスト及び補助脂質の水性製剤
サイズ
安定性
TLRアゴニスト、補助脂質及びアルミニウム塩の組み合わせ
リガンド交換
静電相互作用
組成物の製造方法
(a)TLRアゴニスト(例えば、TLR7/8アゴニスト又はTLR4アゴニスト)及び補助脂質を溶媒中で混合して溶液を作製することと、
(b)ステップ(a)の溶液から溶媒を除去して膜組成物を作製することと、
(c)ステップ(c)の膜組成物を再水和して再水和組成物を作製することと、
(d)再水和組成物を高エネルギー源に晒してナノ懸濁液剤組成物を作製することとを含む。
(a)TLRアゴニスト(例えば、TLR7/8アゴニスト又はTLR4アゴニスト)及び補助脂質を溶媒中で混合して溶液を作製することと、
(b)ステップ(a)の溶液から溶媒を除去して膜組成物を作製することと、
(c)ステップ(c)の膜組成物を再水和して再水和組成物を作製することと、
(d)再水和組成物を高エネルギー源に晒してナノ懸濁液剤組成物を作製することと、によって作製されたナノ懸濁液剤組成物を提供する。
薬剤
ポリペプチド
抗原
ポリヌクレオチド
アジュバント
有機体
TLRアゴニスト
組換え発現コンストラクト
免疫応答
医薬組成物
概要
材料及び方法
合成の1,2−ジラウロイル−sn−グリセロ−3−phosphcocholine(DLPC)、1,2−ジミリストイル−sn−グリセロ−3−ホスホコリン(phosphocholine)(DMPC)、1,2−ジパルミトイル−sn−グリセロ−3−ホスホコリン(DPPC)、1,2−ジステアロイル−sn−グリセロ−3−ホスホコリン(DSPC)、1,2−ジオレオイル−sn−グリセロ−3−ホスホコリン(DOPC)、1,2−ジラウロイル−sn−グリセロ−3−ホスホ−(1’−rac−グリセロール)(DLPG)、1,2−dimyrsitoyl−sn−グリセロ−3−ホスホ−(1’−rac−グリセロール)(DMPG)、1,2−ジパルミトイル−sn−グリセロ−3−ホスホ−(1’−rac−グリセロール)(DPPG),1,2−ジステアロイル−sn−グリセロ−3−ホスホ−(1’−rac−グリセロール)(DSPG)、1,2−ジオレオイル−sn−グリセロ−3−ホスホ−(1’−rac−グリセロール)(DOPG)、1,2−ジステアロイル−3−トリメチルアンモニウム−プロパン(DSTAP)、1,2−ジパルミトイル−3−トリメチルアンモニウム−プロパン(DPTAP)、及びグルコピラノシルリピドアジュバント(GLA、PHAD(登録商標)としても知られる)を、Avanti Polar Lipids社(アラバマ州アラバスター)より購入した。ポリソルベート80は、J.T. Baker社(カリフォルニア州サンフランシスコ)より購入した。ポロクサマー188は、Spectrum Chemical社(カリフォルニア州ガーデナ)より購入した。食塩水(0.9%w/v)は、Teknova社(カリフォルニア州ホリスター)より購入した。TLR9 CpGコントロールは、Avecia社(マサチューセッツ州ミルフォード)より得た。Alhydrogel(登録商標)‘85’及びAdjuPhos(登録商標)は、E.M. Sergeant Pulp & Chemical社(ニュージャージー州クリフトン)より購入した。HIV gp120抗原は、Fouts et al.(Expression and Characterization of a Single-Chain Polypeptide Analogue of the Human Immunodeficiency Virus Type 1 gp120-CD4 Receptor Complex” Virol. vol. 74, no. 24, December 2000, 11427-11436)に参照される。実施例で用いたGLAは一般式(III)の構造を有し、式中、R1、R3、R5及びR6は炭素数11のアルキルであり、R2及びR4は炭素数13のアルキルである。
水性ナノ懸濁液剤は、3M−052又はGLAを脂質賦形剤と共にモル比1:2(アジュバント:脂質)で、クロロホルム中にもしくは、クロロホルム、メタノール及び水の混合液中に分散させることで製造した。その後溶媒を、Genevac EZ−2遠心エバポレーター(ニューヨーク州ストーンリッジ(Stone Ridge))を用いて蒸発させた。乾燥させた膜を超純水で再水和して、その後最大数時間又は調製物が視認できる粒子のない半透明になるまで、超音波処理の水浴を約60℃にしてCrest powersonic CP230D(ニュージャージー州トレントン)で超音波処理した。アルミニウム含有組成物を調製するために、水性ナノ懸濁液剤をAlhydrogel(登録商標)又はAdjuPhos(登録商標)と混合した。免疫原性試験のために、組換えワクチン抗原(ID93又はHIV gp120の抗原)を、ナノ懸濁液、アルミニウム及び上記した希釈剤と共に混合した。
水性ナノ懸濁液剤は、Malvern Instruments社(英国ウスターシャー)のゼータサイザーナノ(Zetasizer Nano)−S又は−ZSを用いて動的光散乱(DLS)によって粒子サイズについて特性決定した。水性ナノ懸濁液剤は、Z−平均(Z-ave)として報告される、分散強度バイアスの平均直径値が得られる3回の測定からなる分析の前に、ポリスチレンキュベット中で1:10又は1:100倍に水で希釈した。ゼータサイザーナノ−ZSにより、水での1:10希釈で調製した各サンプルから回収した9回の連続測定で、使い捨てキャピラリーセルを用いてゼータ電位を測定した。通常、3M−052濃度は、調製物をエタノール:HCl(98:2v:v)で1:20に希釈した後322.5nmのUV吸光度より測定し、検量線と比較した。有機溶媒での希釈により、ナノ懸濁液剤粒子の光分散から干渉可能性が除去される。しかしながら、3M−052の結合等温線については、最大感度が望まれる場合には、サンプル又は標準に対して希釈を行わなかった。あるいは、3M−052の濃度は、荷電化粒子検出器を備えた逆相HPLCで決定した。TLR9 CpGコントロールの濃度は、エタノール:HClで1:20に希釈後、260nmのUV吸光度より測定した。GLA濃度は、C18カラム(Atlantis T3又はAgilent XBridge)及び荷電化粒子検出器(CAD)を備えた逆相HPLCを用いて、先に記載したように、メタノール:クロロホルム:水の移動相のグラジエントで測定した(6)。非結合TLRリガンドを検出するために、アルミニウム含有製剤を上記に示すように短時間遠心分離し、上清をUV吸光度又はHPLC−CADでアッセイした。遠心分離時間は、実験に応じて、2,000〜16,000×gで2〜5分とした。一部の実験では(図2D及び表4)、アルミニウム塩製剤中のTLRアゴニストの沈降作用における食塩水又はバッファーの塩の影響を除去するために、はじめにアルミニウム塩を遠心分離して、上清を取り出し、水で置き換えたが、この処理は、結合試験においてアルミニウム塩を用いる前の別の洗浄で繰り返した。
サンプルを、400メッシュの銅製グリッドに載せた穴開き炭素フィルムで支持したガラス状の氷中に保持した。3μL滴のサンプル懸濁液を、洗浄したグリッドに塗布し、ろ紙で汚れを除去して直ぐに液体エタン中でガラス化を行うことによって、サンプルを調製した。グリッドは、イメージングのために電子顕微鏡に移動するまで、液体窒素下で保存した。電子顕微鏡解析は、FEI社のTecnai T12電子顕微鏡を用いて実行し、FEI Eagle4K×4KCCDカメラを設置して120keVで操作した。ガラス状の氷のグリッドは、−170℃以下の温度でグリッドを維持するクライオステージを用いて、電子顕微鏡に移動させた。各グリッドの画像を、試料の分布全体を評価するために多重スケールで取得した。イメージングに好適でありそうな標的箇所を低倍率で特定したら、高倍率画像を110,000×(0.10nm/ピクセル)、52,000×(0.21nm/ピクセル)及び21,000×(0.50nm/ピクセル)の公称倍率で取得した。この画像は、−2μm(110,000×)、−3μm〜−2μm(52,000×)及び−5μm(21,000×)の公称アンダーフォーカス及び電子照射量約9〜42e/Å2で取得した。
3M−052及びID93又はHIV gp120抗原のAlhydrogel(登録商標)及びAdjuPhos(登録商標)への結合効率を、UV−Vis分光法と、銀染色のSDS−PAGEとにより決定した。1mLの製剤を、食塩希釈液、抗原、3M−052−AF及び/又はアルミニウム塩を混合することによって調製した。HIV gp120抗原の吸着性を決定するために、30μlのサンプル上清を10μlのLDSサンプルバッファー,reducing(4X)又はLDSサンプルバッファー,non−reducing(4X)と混合し、次いでその20〜25μlを15μlのSeeBlue2 Prestained Standardと共に10レーンのSDS−PAGEゲルに加えた。ID93の吸着性を決定するために、45μlのサンプル上清を15μlのLDSサンプルバッファー,reducing(4X)と混合し、次いでその25μlを15μlのSeeBlue2 Prestained Standardと共に10レーンのSDS−PAGEゲルに加えた。該ゲルを190Vで55分間走査し、その後固定液、50:40:10のEtOH:CH3COOH:H2O中に一晩置いた。その後、Sigma-Aldrich社(ミズーリ州セントルイス)のProteoSilver Plus Silver Stainキットの指示に従って、ゲルを染色した。
C57Bl/6及びB6.129S1−TLR7tm1Flv/J(TLR7−/−)を、Jackson Laboratories社(メーン州バー・ハーバー)より購入した。AdjuPhos、Alhydrogel(登録商標)で、3M−052+Alhydrogel(登録商標)で、3M−052+AdjuPhosもしくはGLA+Alhydrogel(登録商標)でのアジュバントを含む、組換え型TBワクチン抗原ID93(0.5μg/用量)又はHIV gp120抗原(10μg/用量)での筋肉内注射により、マウスを免疫した。最終的なアジュバント投与量は、100μL中200μgのAdjuPhos又はAlhydrogel(登録商標)と共に、5μgのGLA又は0.1〜10μgの3M−052とした。マウスは初回免疫後3週目に追加免疫した。全てのマウスを、特定病原体未感染条件下で維持した。全ての手順が、IDRI Institutional Animal Care and Use Committeeで承認された。
マウスの血清(N=5/群)は、免疫後21日目に、眼窩後方血液を、microtainer血清回収チューブ(VWRインターナショナル社(VWR International)、ペンシルベニア州ウェストチェスター)に回収して、次いで遠心分離することによって調製した。その後各血清サンプルを、抗体捕捉ELISAによって分析した。簡潔には、ELISAプレート(Nunc社、ニューヨーク州ロチェスター)を、0.1M重炭酸塩緩衝液中2μg/mlの免疫抗原でコーティングし、1%BSA−PBSでブロッキングした。その後、PBS/Tween20で洗浄後に、連続希釈した血清サンプル、抗マウスIgG、IgG1又はIgG2c−HRP(Southern Biotech社、アラバマ州バーミンガム)、及び、ABTS−H2O2(Kirkegaard and Perry Laboratories社、メリーランド州ゲイザースバーグ)をこの順序通りにプレートに加えた。プレートを、405nm(ELX808、Bio-Tek Instruments社、バーモント州ウィヌースキー)で分析した。エンドポイント力価は、Prismソフトウェアバージョン6(GraphPad(グラフパッド))を用いて計算した。あるいは、膣洗浄液をHIV gp120抗原での第3回免疫後3週目に回収し、同じ方法で抗体力価を分析した。
最終免疫後1週目に、脾細胞を単離した。赤血球を、Red Blood Cell Lysisバッファー(eBioscience社)を用いて溶解し、RPMI 1640及び10%FBS中で再懸濁した。細胞を2×106細胞/ウェルで96ウェルプレートに入れて、免疫抗原(10μg/mL)で2時間刺激するか、又は37℃で無刺激とした。GolgiPlug(BD Biosciences社)を添加し、細胞を37℃でさらに8時間インキュベートした。細胞を洗浄し、抗CD16/32(クローン2.4G2)の存在中で20分間、CD4(クローンGK1.5)、CD44(クローンIM7)及びCD8(クローン53−6.7)(BioLegend社及びeBioscience社)に対する蛍光色素標識した抗体で表面染色した。細胞を洗浄して、Cytofix/Cytoperm(BD Biosciences社)で20分間透過処理した。細胞をPerm/Wash(BD Biosciences社)で2回洗浄して、20分間室温で、CD154(クローンMR1)、IFN−γ(クローンXMG−1.2)、IL−2(クローンJES6−5H4)、TNF(クローンMP6−XT22)、GM−CSF(クローンMP1−22E9、IL−5(クローンTRFK5)及びIL−17A(クローンTC11−18H10.1)(BioLegend社及びeBioscience社)に対する蛍光色素標識した抗体で細胞内染色した。細胞を洗浄して、PBS中で再懸濁した。最大106の事象を、LSRFortessaフローサイトメーター(BD Biosciences社)で収集した。データはFlowJo(TreeStar社)で分析した。細胞を、シングレット>リンパ球>CD4+CD8−>サイトカイン陽性又はCD44hi>サイトカイン陽性としてゲートした。抗原特異的応答頻度は、応答陽性の非刺激細胞の頻度を抗原刺激細胞から減算することによって決定した。
骨髄中に存在する抗原特異的抗体の分泌細胞を、ELISPOTアッセイにより定量した。アッセイ開始の1日前に、マルチスクリーンELISPOTプレート(Millipore社)を1ugの抗原/ウェルでコーティングし、一晩インキュベートした。ブロッキングしたプレートを、洗浄用緩衝液(PBS+0.5%Tween20)で3回洗浄し、回収用培地で2時間ブロッキングし、3回洗浄した。免疫後21日目に、10%ウシ胎児血清(FBS)を添加したRPMI培地に骨髄を回収して、Guava自動細胞計数器(Millipore社)を用いて定量し、そして1×106細胞/mLに再懸濁した。細胞は3倍に連続希釈し、プレートに加えて、37℃で5時間インキュベートした。ホースラディッシュペルオキシダーゼ(HRP)と複合化したヤギ抗マウスIgG抗体(Southern Biotech社)の1:100希釈の添加によって、分泌抗体を検出した。AECペルオキシダーゼ基質キット(Vector Labs社)により製造元の指示に従って、スポットを可視化した。スポットはCTLバイオアナライザーで定量した。
腓腹筋への筋肉内免疫18時間後に、膝窩の流入領域リンパ節を回収して、プロテアーゼ阻害剤を含有するPBS(Thermo Fisher Scientific社)中で分離した。細胞は、CD8、CD90.2(クローン53−2.1)、CD19(クローン1D3)、NK1.1(クローンPK136)、CD11c(クローンN418)、CD11b(クローンM1/70)、Ly6G(クローン1A8)、Ly6C(HK1.4)、CD69(クローンH1.2F3)及びCD86(クローンGL1)に関して、20分間氷上で表面染色した。細胞を洗浄して、Cytofix/Cytoperm(BD Biosciences社)で20分間透過処理した。細胞をPerm/Wash(BD Biosciences社)で2回洗浄して、20分間室温で、IFN−γ及びproIL−1β(クローンNJTEN3)(BioLegend及びeBioscience社)に対する蛍光色素標識した抗体で細胞内染色した。細胞を洗浄して、PBS中で再懸濁した。最大106の事象を、LSRFortessaフローサイトメーター(BD Biosciences社)で収集した。データはFlowJo(TreeStar社)で分析した。細胞を、シングレット>細胞>CD19+CD90.2−(B細胞)、CD8+CD90.2+(CD8 T細胞)、CD8−CD90.2+(CD4 T細胞)、CD8−CD19−NK1.1+(NK細胞)、CD8−CD19−CD11c+(DCs)、CD8−CD19−CD11b+Ly6C+(炎症系単核細胞)又はCD19−CD11b+Ly6G+(PMN)としてゲートした。
抗体及びT細胞の応答を、Prismバージョン5又はそれ以降(GraphPad(グラフパッド))を用いて、チューキーの多重比較修正で2元配置分散分析(two-way ANOVA)によって分析した。p値<0.05を与えた比較が重要であると考えた。有意義な比較のみを図面に示している(アジュバントを含む群対抗原単独;3M−052−Alhydrogel(登録商標)、対Alhydrogel(登録商標)、3M−052−AF又は3M−052−AdjuPhos(登録商標);3M−052−AdjuPhos、対AdjuPhos(登録商標)又は3M−052−AF)。
結果
製剤開発及び物理化学的特性決定
表1 PG系ナノ懸濁液剤のサイズ及び吸着性における、アシル鎖及び飽和による影響
値は、粒子サイズとサイズの多分散性とに関しては同一サンプル、又は、Alhydrogel(登録商標)に対する吸着実験に関してはデュプリケートサンプルでの、3回測定の平均±標準偏差を表している。
表2 共吸着TLRリガンドの存在中での時間経過による3M−052−AFの吸着の安定性
3M−052−AFはDSPGを含有し、一方GLA−AFはDPPGを含有する。TLR9 CpGコントロールは可溶性であり、ゆえに補助脂質を含有しない。非結合TLRリガンドを、UV吸光度(3M−052、TLR9 CpGコントロール)で又は荷電化粒子検出器を備えたHPLC(GLA)でアッセイした。値は、デュプリケートサンプルの平均±標準偏差を表している。
表3 3M−052−AFのAlhydrogel(登録商標)に対する吸着性における食塩水濃度の影響
サンプルは、2000×gで10秒間遠心分離した。値は、デュプリケートサンプルの平均±標準偏差を表している。
アジュバントの生物活性
議論
実施例2 アルミニウムに対する合成TLR4リガンドの吸着
表4 GLAの水性ナノ懸濁液剤のAlhydrogel(登録商標)又はAdjuPhos(登録商標)に対する吸着性
1.Glenny AT, Pope CG, Waddington H, Wallace U. The antigenic value of toxoid precipitated by potassium alum.J Pathol Bacteriol.1926;29:31-40.
2.Hem SL, HogenEsch H. Aluminum-containing adjuvants: properties, formulation, and use.In: Singh M, editor.Vaccine Adjuvants and Delivery Systems.Hoboken, NJ: John Wiley & Sons; 2007. p. 81-114.
3.Didierlaurent AM, Morel S, Lockman L, Giannini SL, Bisteau M, Carlsen H, Kielland A, Vosters O, Vanderheyde N, Schiavetti F, Larocque D, Van Mechelen M, Garcon N. AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune resopnse leading to enhanced adaptive immunity.J Immunol. 2009;10:6186-97.
4.Mullen GED, Aebig JA, Dobrescu G, Rausch K, Lambert L, Long CA, Miles AP, Saul A. Enhanced antibody production in mice to the malaria antigen AMA1 by CPG 7909 requires physical association of CpG and antigen.Vaccine.2007;25(29):5343-7.
5.Smirnov D, Schmidt JJ, Capecchi JT, Wightman PD.Vaccine adjuvant activity of 3M-052: an imidazoquinoline designed for local activity without systemic cytokine induction.Vaccine.2011;29:5434-42.
6.Misquith A, Fung M, Dowling QM, Guderian JA, Vedvick TS, Fox CB.In vitro evaluation of TLR4 agonist activity: formulation effects.Coll Surf B: Biointerfaces.2014;113:312-9.
7.Fung HWM, Mikasa TJT, Vergara J, Sivananthan SJ, Guderian JA, Duthie MS, Vedvick TS.Optimizing manufacturing and composition of a TLR4 nanosuspension: physicochemical stability and vaccine adjuvant activity.J Nanobiotechnology.2013;11:43.
8.Fox CB.Characterization of TLR4 agonist effects on Alhydrogel sedimentation: a novel application of laser scattering optical profiling.J Pharm Sci. 2012;101:4357-64.
9.Chollet JL, Jozwiakowski MJ, Phares KR, Reiter MJ, Roddy PJ, Schultz HJ, Ta QV, Tomai MA.Development of a topically active imiquimod formulation.Pharm Dev Technol.1999;4:35-43.
10.Iyer S, Robinett RSR, HogenEsch H, Hem SL.Mechanism of adsorption of hepatitis B surface antigen by aluminum hydroxide adjuvant.Vaccine.2004;22(11-12):1475-9.
11.Bertholet S, Ireton GC, Ordway DJ, Windish HP, Pine SO, Kahn M, Phan T, Orme IM, Vedvick TS, Baldwin SL, Coler RN, Reed SG.A defined tuberculosis vaccine candidate boosts BCG and protects against multidrug-resistant Mycobacterium tuberculosis.Sci Transl Med. 2010;2:53ra74.
12.Dowling QM, Sivananthan SJ, Guderian JA, Moutaftsi M, Chesko JD, Fox CB, Vedvick TS, Kramer RM.Modulating Potency: Physicochemical Characteristics are a Determining Factor of TLR4-Agonist Nanosuspension Activity.Journal of Pharmaceutical Sciences.2014;103(3):879-89.
13.Fouts TR, Tuskan R, Godfrey K, Reitz M, Hone D, Lewis GK, DeVico AL.Expression and Characterization of a Single-Chain Polypeptide Analogue of the Human Immunodeficiency Virus Type 1 gp120-CD4 Receptor Complex.Journal of Virology.2000;74(24):11427-36.
14.Desbien AL, Reed SJ, Bailor HR, Cauwelaert ND, Laurance JD, Orr MT, Fox CB, Carter D, Reed SG, Duthie MS.Squalene emulsion potentiates the adjuvant activity of the TLR4 agonist, GLA, via inflammatory caspases, IL-18, and IFN-γ.European Journal of Immunology.2015;45(2):407-17.
15.Vasilakos JP, Tomai MA.The use of Toll-like receptor 7/8 agonists as vaccine adjuvants.Expert Review of Vaccines.2013;12(7):809-19.
16.Schwenk R, DeBot M, Porter M, Nikki J, Rein L, Spaccapelo R, Crisanti A, Wightman PD, Ockenhouse CF, Dutta S. IgG2 Antibodies against a Clinical Grade <italic>Plasmodium falciparum</italic> CSP Vaccine Antigen Associate with Protection against Transgenic Sporozoite Challenge in Mice.PLoS ONE.2014;9(10):e111020.
17.Reed SG, Orr MT, Fox CB.Key roles of adjuvants in modern vaccines.Nat Med. 2013;19:1597-608.
18.Fox C, Sivananthan S, Duthie M, Vergara J, Guderian J, Moon E, Coblentz D, Reed S, Carter D. A nanoliposome delivery system to synergistically trigger TLR4 AND TLR7.Journal of Nanobiotechnology.2014;12(1):17.
19.Kasturi SP, Skountzou I, Albrecht RA, Koutsonanos D, Hua T, Nakaya HI, Ravindran R, Stewart S, Alam M, Kwissa M, Villinger F, Murthy N, Steel J, Jacob J, Hogan RJ, Garcia-Sastre A, Compans R, Pulendran B. Programming the magnitude and persistence of antibody responses with innate immunity.Nature.2011;470:543-7.
20.Wille-Reece U, Wu C-y, Flynn BJ, Kedl RM, Seder RA.Immunization with HIV-1 Gag Protein Conjugated to a TLR7/8 Agonist Results in the Generation of HIV-1 Gag-Specific Th1 and CD8+ T Cell Responses.The Journal of Immunology.2005;174(12):7676-83.
21.Wu TY-H, Singh M, Miller AT, De Gregorio E, Doro F, D’Oro U, Skibinski DAG, Mbow ML, Bufali S, Herman AE, Cortez A, Li Y, Nayak BP, Tritto E, Filippi CM, Otten GR, Brito LA, Monaci E, Li C, Aprea S, Valentini S, Calabro S, Laera D, Brunelli B, Caproni E, Malyala P, Panchal RG, Warren TK, Bavari S, O’Hagan DT, Cooke MP, Valiante NM.Rational design of small molecules as vaccine adjuvants.Science Translational Medicine.2014;6(263):263ra160
Claims (80)
- (a)TLRアゴニストと、
(b)補助脂質とを含む、TLR水性製剤。 - 前記TLRアゴニストは、TLR2アゴニスト、TLR3アゴニスト、TLR4アゴニスト、TLR5アゴニスト、TLR6アゴニスト、TLR7アゴニスト、TLR8アゴニスト、TLR7/8アゴニスト、又はTLR9アゴニストを含む、請求項1記載の水性製剤。
- アルミニウム塩をさらに含む、請求項1又は2に記載の水性製剤。
- (a)TLR7/8アゴニストと、
(b)補助脂質とを含む、TLR7/8水性製剤。 - 水性製剤は、400nm以下の粒子サイズを有する安定なナノ懸濁液剤である、請求項4記載の水性製剤。
- (a)TLR7/8アゴニストと、
(b)補助脂質と、
(c)アルミニウム塩とを含む、組成物。 - 前記TLR7/8アゴニストは、前記アルミニウム塩に吸着する、請求項6記載の組成物。
- 前記TLR7/8アゴニストは、前記アルミニウム塩の25パーセントで、前記アルミニウム塩に吸着する、請求項6記載の組成物。
- 前記アルミニウム塩は、水酸化アルミニウム、アルミニウム三水和物(aluminum trihydrate)、オキシ水酸化アルミニウム(aluminum oxyhydroxide)、リン酸アルミニウム(aluminum phosphate)、水酸化リン酸アルミニウム(aluminum hydroxyphosphate)、水酸化リン酸アルミニウム硫酸塩(aluminum hydroxyphosphate sulfate)及び硫酸アルミニウムカリウム(potassium aluminum sulfate)からなる群から選択される、請求項6から8のいずれか一項に記載の組成物。
- 前記アルミニウム塩は、Alhydrogel(登録商標)を含む、請求項9記載の組成物。
- 前記アルミニウム塩は、AdjuPhos(登録商標)を含む、請求項9記載の組成物。
- 前記TLR7/8アゴニストは、3M−052を含む、請求項4から11のいずれか一項に記載の組成物。
- 前記補助脂質は、リン脂質又は第四級アンモニウム塩脂質(quaternary ammonium salt lipid)である、請求項4から12のいずれか一項に記載の組成物。
- 前記補助脂質は、炭素数10〜20のアルキル鎖を含む、請求項4から13のいずれか一項に記載の組成物。
- 前記補助脂質は、DOPC、DSPG、DSTAP及びポリソルベート80から選択される、請求項4から14のいずれか一項に記載の組成物。
- 前記補助脂質は、DSPG及びDSTAPから選択される、請求項4から14のいずれか一項に記載の組成物。
- 3M−052、Alhydrogel(登録商標)及びDSPGを含む、請求項6記載の組成物。
- 3M−052、AdjuPhos(登録商標)及びDSTAPを含む、請求項6記載の組成物。
- 抗原をさらに含む、請求項1から18のいずれか一項に記載の組成物。
- 前記抗原は、結核関連抗原、インフルエンザ関連抗原、赤血球凝集素関連抗原、癌関連抗原、ウイルス関連抗原及びアメーバ症関連抗原から選択される、請求項19記載の組成物。
- 前記結核関連抗原は、ID93、ID91及びBCGからなる群から選択される、請求項20記載の組成物。
- 前記インフルエンザ関連抗原は、H5N1、インフルエンザA、インフルエンザB及びインフルエンザCからなる群から選択される、請求項20記載の組成物。
- アメーバ症関連抗原は、LecAである、請求項20記載の組成物。
- 前記ウイルス関連抗原は、B型肝炎及びC型肝炎からなる群から選択される、請求項20記載の組成物。
- 前記組成物は安定である、請求項4から24のいずれか一項に記載の組成物。
- 前記組成物は、少なくとも約6ヶ月間安定である、請求項25記載の組成物。
- 前記組成物は、少なくとも約1年間安定である、請求項25記載の組成物。
- 前記組成物は、2〜8℃で、少なくとも6ヶ月間安定である、請求項25記載の組成物。
- 前記組成物は、2〜8℃で、少なくとも1年間安定である、請求項25記載の組成物。
- (a)TLR4アゴニストと、
(b)DPTAPである補助脂質とを含む、TLR4水性製剤。 - 水性製剤は、400nm以下の粒子サイズを有する安定なナノ懸濁液剤である、請求項30記載の水性製剤。
- (a)TLR4アゴニストと、
(b)DPTAPである補助脂質と、
(c)AdjuPhos(登録商標)であるアルミニウム塩とを含む、組成物。 - 前記TLR4アゴニストは、前記アルミニウム塩に吸着する、請求項32記載の組成物。
- TLR7/8アゴニストは、前記アルミニウム塩の25パーセントで、アルミニウム塩に吸着する、請求項32又は33に記載の組成物。
- 前記TLR4アゴニストは、リン酸アルミニウム(aluminum phosphate)に吸着する、請求項30から34のいずれか一項に記載の組成物。
- 前記TLR4アゴニストは、3D−モノホスホリルリピドA(MPL)を含む、請求項30から35のいずれか一項に記載の組成物。
- 前記TLR4アゴニストは、GLAを含む、請求項30から35のいずれか一項に記載の組成物。
- 前記TLR4アゴニストは、一般式(IV)の合成GLA、
又は薬剤的に許容できるその塩を含むものであって、式中、
L1、L2、L3、L4、L5及びL6は、同一であるか又は異なるものであり、独立に−O−、−NH−又は−(CH2)−であり、
L7、L8、L9及びL10は、同一であるか又は異なるものであり、独立に、存在しないか又は−C(=O)−であり、
Y1は、酸官能基であり、
Y2及びY3は、同一であるか又は異なるものであり、独立に−OH、−SH又は酸官能基であり、
Y4は、−OH又は−SHであり、
R1、R3、R5及びR6は、同一であるか又は異なるものであり、独立に、炭素数8〜13のアルキルであり、
R2及びR4は、同一であるか又は異なるものであり、独立に、炭素数6〜11のアルキルである、請求項37記載の組成物。 - 前記TLR4アゴニストは、一般式(V)の合成GLA、
又は薬剤的に許容できるその塩を含むものであって、式中、
R1、R3、R5及びR6は、炭素数11〜20のアルキルであり、R2及びR4は、炭素数12〜20のアルキルである、請求項37記載の組成物。 - 前記TLR4アゴニストは、以下の一般式の合成GLA:
- 抗原をさらに含む、請求項30から40のいずれか一項に記載の組成物。
- 前記抗原は、結核関連抗原、インフルエンザ関連抗原、赤血球凝集素関連抗原、癌関連抗原、ウイルス関連抗原及びアメーバ症関連抗原から選択される、請求項41記載の組成物。
- 前記結核関連抗原は、ID93、ID91及びBCGからなる群から選択される、請求項41記載の組成物。
- 前記インフルエンザ関連抗原は、H5N1、インフルエンザA、インフルエンザB及びインフルエンザCからなる群から選択される、請求項41記載の組成物。
- 前記アメーバ症関連抗原は、LecAである、請求項41記載の組成物。
- 前記ウイルス関連抗原は、B型肝炎及びC型肝炎からなる群から選択される、請求項41記載の組成物。
- 前記組成物は安定である、請求項30から46のいずれか一項に記載の組成物。
- 前記組成物は、少なくとも約6ヶ月間安定である、請求項47記載の組成物。
- 前記組成物は、少なくとも約1年間安定である、請求項47記載の組成物。
- 前記組成物は、2〜8℃で、少なくとも6ヶ月間安定である、請求項47記載の組成物。
- 前記組成物は、2〜8℃で、少なくとも1年間安定である、請求項47記載の組成物。
- 請求項1から51のいずれか一項に記載の製剤又は組成物を含む、医薬組成物。
- 前記医薬組成物はワクチンである、請求項52記載の医薬組成物。
- 抗原をさらに含む、請求項52又は53に記載の組成物。
- 前記抗原は、結核関連抗原、インフルエンザ関連抗原、赤血球凝集素関連抗原、癌関連抗原、ウイルス関連抗原及びアメーバ症関連抗原から選択される、請求項54記載の組成物。
- 前記結核関連抗原は、ID93、ID91及びBCGからなる群から選択される、請求項55記載の組成物。
- 前記インフルエンザ関連抗原は、H5N1、インフルエンザA、インフルエンザB及びインフルエンザCからなる群から選択される、請求項55記載の組成物。
- 前記アメーバ症関連抗原は、LecAである、請求項55記載の組成物。
- 前記ウイルス関連抗原は、B型肝炎及びC型肝炎からなる群から選択される、請求項55記載の組成物。
- 前記組成物は安定である、請求項52から59のいずれか一項に記載の医薬組成物。
- 組成物は、少なくとも約6ヶ月間安定である、請求項60記載の医薬組成物。
- 組成物は、少なくとも約1年間安定である、請求項60記載の医薬組成物。
- 組成物は、2〜8℃で、少なくとも6ヶ月間安定である、請求項60記載の医薬組成物。
- 組成物は、2〜8℃で、少なくとも1年間安定である、請求項60記載の医薬組成物。
- 対象において免疫応答を刺激する方法であって、該方法が、前記対象に請求項1から64のいずれか一項に記載の製剤又は組成物を投与することによって、前記対象において免疫応答を刺激することを含む、方法。
- 前記免疫応答は、非特異的免疫応答である、請求項65記載の方法。
- 前記免疫応答は、抗原特異的免疫応答である、請求項65記載の方法。
- 前記免疫応答は、B細胞の活性化、T細胞の活性化、抗体の産生又はサイトカインの放出に関与する、請求項65記載の方法。
- 前記組成物は、単剤療法に用いられる、請求項65記載の方法。
- 前記組成物は、アレルギー、中毒、癌又は自己免疫の治療に用いられる、請求項65記載の方法。
- 前記組成物は、ワクチンに用いられる、請求項65記載の方法。
- 前記組成物の投与経路は、経口、静脈、皮内、経皮、経鼻、皮下又は経肛門である、請求項65から71のいずれか一項に記載の方法。
- 前記対象は、ヒトである、請求項65から72のいずれか一項に記載の方法。
- 前記対象は、非ヒト哺乳動物である、請求項65から72のいずれか一項に記載の方法。
- 前記非ヒト哺乳動物は、イヌ、ウシ又はウマである、請求項74記載の方法。
- TLR7/8アゴニスト又はTLR4アゴニスト及び補助脂質を含む水性製剤を調製する方法であって、前記TLR7/8アゴニスト又はTLR4アゴニスト及び前記補助脂質を含む組成物が、1nmから約450nmの範囲にある粒子を含み、前記方法が、
(a)TLR7/8アゴニスト又はTLR4アゴニスト及び補助脂質を溶媒中で混合して溶液を作製することと、
(b)ステップ(a)の前記溶液から溶媒を除去して膜組成物を作製することと、
(c)ステップ(c)の前記膜組成物を再水和して再水和組成物を作製することと、
(d)前記再水和組成物を高エネルギー源に晒してナノ懸濁液剤組成物を作製することとを含む、方法。 - 前記高エネルギー源は、マイクロフルイダイザー、エクストルーダー、超音波処理器、シルバーソンミキサー(silverson mixer)又はホモジナイザーより発生する、請求項76記載の方法。
- 抗原を前記ナノ懸濁液剤組成物と混合することをさらに含む、請求項76記載の方法。
- アルミニウム塩を前記ナノ懸濁液剤組成物と混合することをさらに含む、請求項76記載の方法。
- アルミニウム塩及び抗原を前記ナノ懸濁液剤組成物と混合することをさらに含む、請求項76記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662337322P | 2016-05-16 | 2016-05-16 | |
US62/337,322 | 2016-05-16 | ||
PCT/US2017/032287 WO2017200852A1 (en) | 2016-05-16 | 2017-05-11 | Formulation containing tlr agonist and methods of use |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2019519504A true JP2019519504A (ja) | 2019-07-11 |
JP2019519504A5 JP2019519504A5 (ja) | 2020-04-09 |
JP7195148B2 JP7195148B2 (ja) | 2022-12-23 |
Family
ID=58765966
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018560185A Active JP7195148B2 (ja) | 2016-05-16 | 2017-05-11 | Tlrアゴニストを含有する製剤及び使用方法 |
Country Status (16)
Country | Link |
---|---|
US (3) | US11344619B2 (ja) |
EP (2) | EP3458475B1 (ja) |
JP (1) | JP7195148B2 (ja) |
KR (1) | KR102392974B1 (ja) |
CN (1) | CN109310773B (ja) |
AU (1) | AU2017268144B2 (ja) |
BR (1) | BR112018073690B1 (ja) |
CA (1) | CA3023968A1 (ja) |
DK (1) | DK3458475T3 (ja) |
ES (1) | ES2929054T3 (ja) |
HU (1) | HUE059605T2 (ja) |
IL (2) | IL299285A (ja) |
MX (1) | MX2018014086A (ja) |
RU (1) | RU2761870C2 (ja) |
WO (1) | WO2017200852A1 (ja) |
ZA (1) | ZA201807497B (ja) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108096576B (zh) * | 2017-12-28 | 2021-09-03 | 中国医学科学院医学实验动物研究所 | Tlr8激活剂在制备结核疫苗佐剂中的用途及其制备的结核疫苗 |
SG11202112870WA (en) * | 2019-05-23 | 2021-12-30 | The Univ Of Montana | Vaccine adjuvants based on tlr receptor ligands |
US11679163B2 (en) | 2019-09-20 | 2023-06-20 | Hdt Bio Corp. | Compositions and methods for delivery of RNA |
CN114667193A (zh) | 2019-12-20 | 2022-06-24 | 本田金属技术株式会社 | 透气性盐芯及其制造方法 |
CA3172489A1 (en) | 2020-03-23 | 2021-09-30 | Amit KHANDHAR | Nanoemulsion compositions and methods for delivery of nra |
CA3173408A1 (en) | 2020-12-23 | 2022-06-30 | Access To Advanced Health Institute | Solanesol vaccine adjuvants and methods of preparing same |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008530021A (ja) * | 2005-02-08 | 2008-08-07 | アイディー バイオメディカル コーポレイション オブ ケベック シー.オー.ビー. アズ グラクソスミスクライン バイオロジカルズ ノース アメリカ | 医薬組成物 |
JP2013534248A (ja) * | 2010-08-17 | 2013-09-02 | スリーエム イノベイティブ プロパティズ カンパニー | 脂質付加された免疫反応調節化合物の組成物、製剤及び方法 |
JP2014506916A (ja) * | 2011-03-02 | 2014-03-20 | ノバルティス アーゲー | より低用量の抗原および/またはアジュバントを有する混合ワクチン |
JP2015509522A (ja) * | 2012-03-08 | 2015-03-30 | ノバルティス アーゲー | 追加免疫ワクチンのアジュバント化された処方物 |
WO2015144653A1 (en) * | 2014-03-26 | 2015-10-01 | Glaxosmithkline Biologicals S.A. | Mutant staphylococcal antigens |
Family Cites Families (127)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US669275A (en) | 1897-08-06 | 1901-03-05 | John H Watts | Means for transmitting power. |
US3598122A (en) | 1969-04-01 | 1971-08-10 | Alza Corp | Bandage for administering drugs |
US3598123A (en) | 1969-04-01 | 1971-08-10 | Alza Corp | Bandage for administering drugs |
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 |
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 |
IL73534A (en) | 1983-11-18 | 1990-12-23 | Riker Laboratories Inc | 1h-imidazo(4,5-c)quinoline-4-amines,their preparation and pharmaceutical compositions containing certain such compounds |
US4855238A (en) | 1983-12-16 | 1989-08-08 | Genentech, Inc. | Recombinant gamma interferons having enhanced stability and methods therefor |
US4568343A (en) | 1984-10-09 | 1986-02-04 | Alza Corporation | Skin permeation enhancer compositions |
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. |
US5169763A (en) | 1986-04-08 | 1992-12-08 | Transgene S.A., Institut Pasteur | Viral vector coding glycoprotein of HIV-1 |
US4948587A (en) | 1986-07-08 | 1990-08-14 | Massachusetts Institute Of Technology | Ultrasound enhancement of transbuccal drug delivery |
US4767402A (en) | 1986-07-08 | 1988-08-30 | Massachusetts Institute Of Technology | Ultrasound enhancement of transdermal drug delivery |
US5075109A (en) | 1986-10-24 | 1991-12-24 | Southern Research Institute | Method of potentiating an immune response |
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 |
GB2232892B (en) | 1988-02-23 | 1991-07-24 | John Mark Tucker | Occlusive body for administering a physiologically active substance |
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 |
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 |
WO1990006951A1 (en) | 1988-12-16 | 1990-06-28 | De Staat Der Nederlanden Vertegenwoordigd Door De Minister Van Welzijn, Volksgezondheid En Cultuur | Pneumolysin mutants and pneumococcal vaccines made therefrom |
EP0832980B1 (en) | 1989-01-23 | 2002-06-19 | Chiron Corporation | Recombinant therapies for infection and hyperproliferative disorders |
DE69031556T2 (de) | 1989-07-25 | 1998-05-14 | Smithkline Beecham Biolog | Antigene sowie Verfahren zu deren Herstellung |
EP0487587A1 (en) | 1989-08-18 | 1992-06-03 | Chiron Corporation | Recombinant retroviruses delivering vector constructs to target cells |
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 |
US5256643A (en) | 1990-05-29 | 1993-10-26 | The Government Of The United States | Human cripto protein |
GB9106048D0 (en) | 1991-03-21 | 1991-05-08 | Smithkline Beecham Biolog | Vaccines |
US6277969B1 (en) | 1991-03-18 | 2001-08-21 | New York University | Anti-TNF antibodies and peptides of human tumor necrosis factor |
DE122007000018I1 (de) | 1991-07-19 | 2007-05-24 | Univ Queensland | Polynukleotidabschnitt des HPV16-Genoms |
US5464387A (en) | 1991-07-24 | 1995-11-07 | Alza Corporation | Transdermal delivery device |
US6197311B1 (en) | 1991-07-25 | 2001-03-06 | Idec Pharmaceuticals Corporation | Induction of cytotoxic T-lymphocyte responses |
WO1993003709A1 (en) | 1991-08-16 | 1993-03-04 | Vical, Inc. | Composition and method for treating cystic fibrosis |
ES2129461T3 (es) | 1991-11-16 | 1999-06-16 | Smithkline Beecham Biolog | Proteina hibrida entre cs de plasmodium y hbsag. |
US6057427A (en) | 1991-11-20 | 2000-05-02 | Trustees Of Dartmouth College | Antibody to cytokine response gene 2(CR2) polypeptide |
JPH07507689A (ja) | 1992-06-08 | 1995-08-31 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 特定組織のターゲティング方法及び組成物 |
JPH09507741A (ja) | 1992-06-10 | 1997-08-12 | アメリカ合衆国 | ヒト血清による不活性化に耐性のあるベクター粒子 |
ES2294778T3 (es) | 1992-06-25 | 2008-04-01 | Georgetown University | Vacunas para el virus del papiloma. |
JP3755890B2 (ja) | 1992-06-25 | 2006-03-15 | スミスクライン・ビーチャム・バイオロジカルス(ソシエテ・アノニム) | アジュバント含有ワクチン組成物 |
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 |
DE69435331D1 (de) | 1993-03-09 | 2011-02-03 | Univ Rochester | Herstellung von menschlichen papillomavirus HBV-11 Kapsidprotein L1 und Virus-ähnliche Partikeln |
EP0708772B1 (en) | 1993-07-15 | 2000-08-23 | Minnesota Mining And Manufacturing Company | IMIDAZO [4,5-c]PYRIDIN-4-AMINES |
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 |
EP0887866B1 (en) | 1993-11-02 | 2004-04-07 | Matsushita Electric Industrial Co., Ltd | Semiconductor device comprising an aggregate of semiconductor micro-needles |
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 |
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 |
US5591139A (en) | 1994-06-06 | 1997-01-07 | The Regents Of The University Of California | IC-processed microneedles |
EP1167379A3 (en) | 1994-07-15 | 2004-09-08 | 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 |
US6066324A (en) | 1994-10-07 | 2000-05-23 | Loyola University Of Chicago | Carboxyl terminal of papilloma virus L1 region is not required for formation of virus-like particles |
FR2727689A1 (fr) | 1994-12-01 | 1996-06-07 | Transgene Sa | Nouveau procede de preparation d'un vecteur viral |
AU4727296A (en) | 1995-02-24 | 1996-09-11 | Cantab Pharmaceuticals Research Limited | Polypeptides useful as immunotherapeutic agents and methods of polypeptide preparation |
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 |
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 |
US5618275A (en) | 1995-10-27 | 1997-04-08 | Sonex International Corporation | Ultrasonic method and apparatus for cosmetic and dermatological applications |
US5656016A (en) | 1996-03-18 | 1997-08-12 | Abbott Laboratories | Sonophoretic drug delivery system |
US5955306A (en) | 1996-09-17 | 1999-09-21 | Millenium Pharmaceuticals, Inc. | Genes encoding proteins that interact with the tub protein |
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 |
DK0972201T3 (da) | 1997-02-25 | 2006-01-02 | Corixa Corp | Forbindelser til immundiagnosticering af prostatacancer og fremgangsmåder til anvendelse heraf |
JP2001510031A (ja) | 1997-07-21 | 2001-07-31 | ノース・アメリカン・ヴァクシン・インコーポレーテッド | ワクチンとしての修飾された免疫原ニューモリシン組成物 |
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 |
US7459524B1 (en) | 1997-10-02 | 2008-12-02 | Emergent Product Development Gaithersburg Inc. | Chlamydia protein, sequence and uses thereof |
KR100735653B1 (ko) | 1997-11-28 | 2007-07-06 | 세로노 제네틱스 인스티튜트 에스.에이. | 클라미디아 트라코마티스 게놈 서열과 폴리펩티드, 이의단편 및 이의 용도, 특히, 감염의 진단, 예방 및 치료 용도 |
UA67760C2 (uk) | 1997-12-11 | 2004-07-15 | Міннесота Майнінг Енд Мануфакчурінг Компані | Імідазонафтиридин та тетрагідроімідазонафтиридин, фармацевтична композиція, спосіб індукування біосинтезу цитокінів та спосіб лікування вірусної інфекції, проміжні сполуки |
DE69929310T2 (de) | 1998-02-05 | 2006-08-03 | Glaxosmithkline Biologicals S.A. | Tumorassoziierte antigenderivate der mage-familie, nukleinsäuresequenzen die dafür kodieren, zur herstellung von fusionsproteinen und zusammensetzungen zur impfung |
FR2775601B1 (fr) | 1998-03-03 | 2001-09-21 | Merial Sas | Vaccins vivants recombines et adjuves |
CN1629185B (zh) | 1998-04-07 | 2011-11-02 | 科里克萨公司 | 结核杆菌抗原融合蛋白及其应用 |
GB2336310B (en) | 1998-04-14 | 2003-09-10 | Stowic Resources Ltd | Method of manufacturing transdermal patches |
JP2002511266A (ja) | 1998-04-15 | 2002-04-16 | ルードヴィッヒ インスティテュート フォー キャンサー リサーチ | 腫瘍関連核酸及びその使用 |
US6322532B1 (en) | 1998-06-24 | 2001-11-27 | 3M Innovative Properties Company | Sonophoresis method and apparatus |
AU762812B2 (en) | 1998-07-14 | 2003-07-03 | Corixa Corporation | Compositions and methods for therapy and diagnosis of prostate cancer |
US6110929A (en) | 1998-07-28 | 2000-08-29 | 3M Innovative Properties Company | Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof |
US6692752B1 (en) | 1999-09-08 | 2004-02-17 | Smithkline Beecham Biologicals S.A. | Methods of treating human females susceptible to HSV infection |
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 |
US7001770B1 (en) | 1998-10-15 | 2006-02-21 | Canji, Inc. | Calpain inhibitors and their applications |
US6734172B2 (en) | 1998-11-18 | 2004-05-11 | Pacific Northwest Research Institute | Surface receptor antigen vaccines |
US6770445B1 (en) | 1999-02-26 | 2004-08-03 | Pacific Northwest Research Institute | Methods and compositions for diagnosing carcinomas |
GB9906177D0 (en) | 1999-03-17 | 1999-05-12 | Oxford Biomedica Ltd | Anti-viral vectors |
DE60014076T2 (de) | 1999-04-19 | 2005-10-13 | Glaxosmithkline Biologicals S.A. | Adjuvans-zusammensetzung, enthaltend saponin und ein immunstimulatorisches oligonukleotid |
US6685699B1 (en) | 1999-06-09 | 2004-02-03 | Spectrx, Inc. | Self-removing energy absorbing structure for thermal tissue ablation |
CA2380865A1 (en) | 1999-08-26 | 2001-03-01 | Biovitrum Ab | Novel response element |
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 |
US6974588B1 (en) | 1999-12-07 | 2005-12-13 | Elan Pharma International Limited | Transdermal patch for delivering volatile liquid drugs |
WO2001055362A2 (en) | 2000-01-31 | 2001-08-02 | The Governement Of The United States Of America, As Represented By The Secretary, Departement Of Health & Human Services, The National Institutes Of Health | Hybrid adeno-retroviral vector for the transfection of cells |
US6875610B2 (en) | 2000-05-31 | 2005-04-05 | Human Gene Therapy Research Institute | Methods and compositions for efficient gene transfer using transcomplementary vectors |
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 |
US6844192B2 (en) | 2001-06-29 | 2005-01-18 | Wake Forest University | Adenovirus E4 protein variants for virus production |
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 |
US6676961B1 (en) | 2002-03-06 | 2004-01-13 | Automated Carrier Technologies, Inc. | Transdermal patch assembly |
US7018345B2 (en) | 2002-12-06 | 2006-03-28 | Hisamitsu Pharmaceutical Co., Inc. | Iontophoresis system |
NZ546274A (en) | 2003-10-03 | 2009-12-24 | 3M Innovative Properties Co | Pyrazolopyridines and analags thereof |
DE102005032175A1 (de) | 2005-07-09 | 2007-01-18 | Krones Ag | Behälter-Behandlungsmaschine und Verfahren zum Laden und Entladen einer Behälter-Behandlungsmaschine |
EP1611926B1 (de) | 2005-07-19 | 2008-01-16 | Gebrüder Holzapfel GmbH & Co. KG | Auftriebshilfe |
US20090181078A1 (en) * | 2006-09-26 | 2009-07-16 | Infectious Disease Research Institute | Vaccine composition containing synthetic adjuvant |
WO2008057696A2 (en) * | 2006-10-10 | 2008-05-15 | Juvaris Biotherapeutics, Inc. | Compositions of pattern recognition receptor-ligand: lipid complexes and methods of use thereof |
MX351247B (es) | 2007-04-04 | 2017-10-05 | Infectious Disease Res Institute Star | Composiciones inmunogenicas que comprenden polipeptidos de mycobacterium tuberculosis y fusiones de los mismos. |
US8709445B2 (en) * | 2007-07-31 | 2014-04-29 | Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center | Vaccination with killed but metabolically active (KBMA) protozoans with toll-like receptor agonists |
US8793881B2 (en) | 2008-08-15 | 2014-08-05 | Stanley Black & Decker, Inc. | Utility knife with blade lock |
PT2437753T (pt) | 2009-06-05 | 2016-11-23 | Infectious Disease Res Inst | Adjuvantes lipídicos de glucopiranosilo sintéticos e composições de vacina contendo os mesmos |
BR112012004806B8 (pt) * | 2009-09-02 | 2022-10-04 | Novartis Ag | composições imunogênicas que incluem moduladores da atividade de tlr, método para aumento da eficácia da referida composição e uso |
BR112013032675A2 (pt) * | 2011-06-19 | 2017-08-08 | Vaxine Pty Ltd | composição adjuvante de vacina compreendendo partículas de inulina |
WO2013139744A1 (en) * | 2012-03-18 | 2013-09-26 | Glaxosmithkline Biologicals S.A. | Method of vaccination against human papillomavirus |
EP3065829B1 (en) | 2013-11-08 | 2021-05-19 | University of Virginia Patent Foundation | Compositions and methods for treating melanoma |
EP3131579A4 (en) | 2014-04-18 | 2017-10-25 | The Children's Medical Center Corporation | Vaccine adjuvant compositions |
WO2016010788A1 (en) | 2014-07-15 | 2016-01-21 | The United States Of America, As Represented By The Secretary, Dept. Of Health And Human Services | Polyketal particles including a cpg oligodeoxynucleotide for the treatment of lung cancer |
CN104800843B (zh) * | 2015-04-02 | 2017-07-04 | 中国农业科学院兰州兽医研究所 | 一种用于弓形虫感染预防的药剂及应用 |
-
2017
- 2017-05-11 WO PCT/US2017/032287 patent/WO2017200852A1/en unknown
- 2017-05-11 CA CA3023968A patent/CA3023968A1/en active Pending
- 2017-05-11 DK DK17725451.3T patent/DK3458475T3/da active
- 2017-05-11 RU RU2018139999A patent/RU2761870C2/ru active
- 2017-05-11 BR BR112018073690-2A patent/BR112018073690B1/pt active IP Right Grant
- 2017-05-11 KR KR1020187035495A patent/KR102392974B1/ko active IP Right Grant
- 2017-05-11 MX MX2018014086A patent/MX2018014086A/es unknown
- 2017-05-11 IL IL299285A patent/IL299285A/en unknown
- 2017-05-11 AU AU2017268144A patent/AU2017268144B2/en active Active
- 2017-05-11 EP EP17725451.3A patent/EP3458475B1/en active Active
- 2017-05-11 US US16/098,615 patent/US11344619B2/en active Active
- 2017-05-11 HU HUE17725451A patent/HUE059605T2/hu unknown
- 2017-05-11 JP JP2018560185A patent/JP7195148B2/ja active Active
- 2017-05-11 ES ES17725451T patent/ES2929054T3/es active Active
- 2017-05-11 CN CN201780035091.4A patent/CN109310773B/zh active Active
- 2017-05-11 EP EP22170931.4A patent/EP4112638A1/en active Pending
-
2018
- 2018-11-08 ZA ZA2018/07497A patent/ZA201807497B/en unknown
- 2018-11-15 IL IL263028A patent/IL263028B2/en unknown
-
2022
- 2022-04-28 US US17/731,671 patent/US20220280640A1/en active Pending
- 2022-04-28 US US17/731,718 patent/US20220257754A1/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008530021A (ja) * | 2005-02-08 | 2008-08-07 | アイディー バイオメディカル コーポレイション オブ ケベック シー.オー.ビー. アズ グラクソスミスクライン バイオロジカルズ ノース アメリカ | 医薬組成物 |
JP2013534248A (ja) * | 2010-08-17 | 2013-09-02 | スリーエム イノベイティブ プロパティズ カンパニー | 脂質付加された免疫反応調節化合物の組成物、製剤及び方法 |
JP2014506916A (ja) * | 2011-03-02 | 2014-03-20 | ノバルティス アーゲー | より低用量の抗原および/またはアジュバントを有する混合ワクチン |
JP2015509522A (ja) * | 2012-03-08 | 2015-03-30 | ノバルティス アーゲー | 追加免疫ワクチンのアジュバント化された処方物 |
WO2015144653A1 (en) * | 2014-03-26 | 2015-10-01 | Glaxosmithkline Biologicals S.A. | Mutant staphylococcal antigens |
Non-Patent Citations (4)
Title |
---|
DRUG DELIVERY SYSTEM, vol. 25, no. 1, JPN6022002220, 2010, pages 29 - 36, ISSN: 0004866972 * |
DRUG DELIVERY SYSTEM, vol. 27, no. 1, JPN6022002221, 2012, pages 19 - 27, ISSN: 0004866971 * |
JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 103, JPN6021005431, 2014, pages 879 - 889, ISSN: 0004866969 * |
YAKUGAKU ZASSHI, vol. 131, no. 12, JPN6022002222, 2011, pages 1723 - 1731, ISSN: 0004866970 * |
Also Published As
Publication number | Publication date |
---|---|
JP7195148B2 (ja) | 2022-12-23 |
US20190142935A1 (en) | 2019-05-16 |
KR102392974B1 (ko) | 2022-05-02 |
AU2017268144B2 (en) | 2021-07-22 |
IL299285A (en) | 2023-02-01 |
WO2017200852A1 (en) | 2017-11-23 |
ZA201807497B (en) | 2019-06-26 |
RU2018139999A (ru) | 2020-06-17 |
IL263028B1 (en) | 2023-03-01 |
EP4112638A1 (en) | 2023-01-04 |
BR112018073690A2 (pt) | 2019-02-26 |
IL263028A (en) | 2018-12-31 |
MX2018014086A (es) | 2019-09-18 |
EP3458475B1 (en) | 2022-07-27 |
KR20190008545A (ko) | 2019-01-24 |
ES2929054T3 (es) | 2022-11-24 |
RU2018139999A3 (ja) | 2020-11-26 |
CN109310773B (zh) | 2022-04-26 |
US11344619B2 (en) | 2022-05-31 |
IL263028B2 (en) | 2023-07-01 |
US20220280640A1 (en) | 2022-09-08 |
BR112018073690B1 (pt) | 2022-05-24 |
US20220257754A1 (en) | 2022-08-18 |
RU2761870C2 (ru) | 2021-12-13 |
CA3023968A1 (en) | 2017-11-23 |
DK3458475T3 (da) | 2022-09-12 |
HUE059605T2 (hu) | 2022-11-28 |
EP3458475A1 (en) | 2019-03-27 |
AU2017268144A1 (en) | 2018-11-29 |
CN109310773A (zh) | 2019-02-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20220280640A1 (en) | Formulation containing tlr agonist and methods of use | |
JP7439171B2 (ja) | サイジング剤含有ナノアラム粒子 | |
JP7339942B2 (ja) | サポニンを含むリポソーム製剤および使用方法 | |
KR102483033B1 (ko) | 페길화된 리포솜 및 이의 용도 | |
RU2796539C2 (ru) | Пегилированные липосомы и способы их применения |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200227 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20200227 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210217 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210514 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210817 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220120 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20220418 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220720 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220722 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220906 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221124 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20221206 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20221213 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7195148 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |