CN1235609A - 免疫刺激性核酸分子 - Google Patents
免疫刺激性核酸分子 Download PDFInfo
- Publication number
- CN1235609A CN1235609A CN97199352A CN97199352A CN1235609A CN 1235609 A CN1235609 A CN 1235609A CN 97199352 A CN97199352 A CN 97199352A CN 97199352 A CN97199352 A CN 97199352A CN 1235609 A CN1235609 A CN 1235609A
- Authority
- CN
- China
- Prior art keywords
- cpg
- cell
- odn
- dna
- nucleotide sequence
- 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
- 150000007523 nucleic acids Chemical class 0.000 title claims abstract description 105
- 102000039446 nucleic acids Human genes 0.000 title claims description 103
- 108020004707 nucleic acids Proteins 0.000 title claims description 103
- 230000003308 immunostimulating effect Effects 0.000 title description 51
- 210000003719 b-lymphocyte Anatomy 0.000 claims abstract description 106
- 230000004663 cell proliferation Effects 0.000 claims abstract description 14
- 230000005934 immune activation Effects 0.000 claims abstract description 14
- 230000016396 cytokine production Effects 0.000 claims abstract description 5
- 239000002773 nucleotide Substances 0.000 claims description 84
- 125000003729 nucleotide group Chemical group 0.000 claims description 83
- 108090001005 Interleukin-6 Proteins 0.000 claims description 80
- 102000004889 Interleukin-6 Human genes 0.000 claims description 80
- 230000004913 activation Effects 0.000 claims description 74
- 238000001994 activation Methods 0.000 claims description 74
- 238000000034 method Methods 0.000 claims description 52
- 102000004127 Cytokines Human genes 0.000 claims description 47
- 108090000695 Cytokines Proteins 0.000 claims description 47
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 41
- 210000001541 thymus gland Anatomy 0.000 claims description 41
- 230000000638 stimulation Effects 0.000 claims description 37
- 108010065805 Interleukin-12 Proteins 0.000 claims description 35
- 102000013462 Interleukin-12 Human genes 0.000 claims description 35
- 230000005764 inhibitory process Effects 0.000 claims description 35
- 210000004698 lymphocyte Anatomy 0.000 claims description 35
- 238000012986 modification Methods 0.000 claims description 27
- 230000004048 modification Effects 0.000 claims description 25
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims description 24
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 24
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 24
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims description 24
- 229960003677 chloroquine Drugs 0.000 claims description 24
- 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 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 150000004713 phosphodiesters Chemical class 0.000 claims description 22
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 19
- 108010074328 Interferon-gamma Proteins 0.000 claims description 18
- 210000001163 endosome Anatomy 0.000 claims description 17
- 238000011282 treatment Methods 0.000 claims description 17
- 102100037850 Interferon gamma Human genes 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 16
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 10
- 208000006673 asthma Diseases 0.000 claims description 10
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 10
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 9
- 229940104302 cytosine Drugs 0.000 claims description 9
- 206010025135 lupus erythematosus Diseases 0.000 claims description 9
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 9
- 230000009885 systemic effect Effects 0.000 claims description 8
- 208000023275 Autoimmune disease Diseases 0.000 claims description 6
- 229930191564 Monensin Natural products 0.000 claims description 6
- GAOZTHIDHYLHMS-UHFFFAOYSA-N Monensin A Natural products O1C(CC)(C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CCC1C(O1)(C)CCC21CC(O)C(C)C(C(C)C(OC)C(C)C(O)=O)O2 GAOZTHIDHYLHMS-UHFFFAOYSA-N 0.000 claims description 6
- 229960005358 monensin Drugs 0.000 claims description 6
- GAOZTHIDHYLHMS-KEOBGNEYSA-N monensin A Chemical compound C([C@@](O1)(C)[C@H]2CC[C@@](O2)(CC)[C@H]2[C@H](C[C@@H](O2)[C@@H]2[C@H](C[C@@H](C)[C@](O)(CO)O2)C)C)C[C@@]21C[C@H](O)[C@@H](C)[C@@H]([C@@H](C)[C@@H](OC)[C@H](C)C(O)=O)O2 GAOZTHIDHYLHMS-KEOBGNEYSA-N 0.000 claims description 6
- XDHNQDDQEHDUTM-UHFFFAOYSA-N bafliomycin A1 Natural products COC1C=CC=C(C)CC(C)C(O)C(C)C=C(C)C=C(OC)C(=O)OC1C(C)C(O)C(C)C1(O)OC(C(C)C)C(C)C(O)C1 XDHNQDDQEHDUTM-UHFFFAOYSA-N 0.000 claims description 5
- 239000011782 vitamin Substances 0.000 claims description 5
- 229930003231 vitamin Natural products 0.000 claims description 5
- 235000013343 vitamin Nutrition 0.000 claims description 5
- 229940088594 vitamin Drugs 0.000 claims description 5
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 5
- 229930192649 bafilomycin Natural products 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 3
- 206010040047 Sepsis Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims 2
- 208000015023 Graves' disease Diseases 0.000 claims 2
- 208000023328 Basedow disease Diseases 0.000 claims 1
- 208000004232 Enteritis Diseases 0.000 claims 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 claims 1
- 208000003807 Graves Disease Diseases 0.000 claims 1
- 201000004681 Psoriasis Diseases 0.000 claims 1
- 206010039361 Sacroiliitis Diseases 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 230000004936 stimulating effect Effects 0.000 abstract description 18
- 230000028993 immune response Effects 0.000 abstract description 3
- 239000002671 adjuvant Substances 0.000 abstract 1
- 230000002101 lytic effect Effects 0.000 abstract 1
- 229940046166 oligodeoxynucleotide Drugs 0.000 description 236
- 108020004414 DNA Proteins 0.000 description 227
- 210000004027 cell Anatomy 0.000 description 188
- 241000699666 Mus <mouse, genus> Species 0.000 description 83
- 108091034117 Oligonucleotide Proteins 0.000 description 79
- 230000000694 effects Effects 0.000 description 74
- 230000001939 inductive effect Effects 0.000 description 63
- 229940046168 CpG oligodeoxynucleotide Drugs 0.000 description 52
- 238000002474 experimental method Methods 0.000 description 49
- 108090000623 proteins and genes Proteins 0.000 description 46
- 241000894006 Bacteria Species 0.000 description 40
- 102000004169 proteins and genes Human genes 0.000 description 40
- 102000005636 Cyclic AMP Response Element-Binding Protein Human genes 0.000 description 37
- 108010045171 Cyclic AMP Response Element-Binding Protein Proteins 0.000 description 37
- 230000028327 secretion Effects 0.000 description 37
- 239000002158 endotoxin Substances 0.000 description 36
- 229920006008 lipopolysaccharide Polymers 0.000 description 36
- 229940117681 interleukin-12 Drugs 0.000 description 34
- 239000002585 base Substances 0.000 description 33
- 241000588724 Escherichia coli Species 0.000 description 32
- 210000004681 ovum Anatomy 0.000 description 30
- 230000004044 response Effects 0.000 description 30
- 108010000912 Egg Proteins Proteins 0.000 description 28
- 102000002322 Egg Proteins Human genes 0.000 description 28
- 235000019633 pungent taste Nutrition 0.000 description 26
- 239000000427 antigen Substances 0.000 description 25
- 102000036639 antigens Human genes 0.000 description 25
- 108091007433 antigens Proteins 0.000 description 25
- 241000282414 Homo sapiens Species 0.000 description 24
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 24
- 244000309466 calf Species 0.000 description 24
- 238000004519 manufacturing process Methods 0.000 description 24
- 210000001616 monocyte Anatomy 0.000 description 24
- 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 23
- 210000004072 lung Anatomy 0.000 description 23
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 22
- 230000014509 gene expression Effects 0.000 description 22
- 229910052760 oxygen Inorganic materials 0.000 description 22
- 239000001301 oxygen Substances 0.000 description 22
- 238000011160 research Methods 0.000 description 22
- 238000002347 injection Methods 0.000 description 21
- 239000007924 injection Substances 0.000 description 21
- 210000004988 splenocyte Anatomy 0.000 description 21
- 210000001744 T-lymphocyte Anatomy 0.000 description 19
- 210000000952 spleen Anatomy 0.000 description 19
- 101710163270 Nuclease Proteins 0.000 description 18
- 238000002965 ELISA Methods 0.000 description 17
- 230000007246 mechanism Effects 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 241000700605 Viruses Species 0.000 description 15
- 238000001514 detection method Methods 0.000 description 15
- 230000001976 improved effect Effects 0.000 description 15
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 14
- 230000000692 anti-sense effect Effects 0.000 description 14
- 238000009395 breeding Methods 0.000 description 14
- 230000001488 breeding effect Effects 0.000 description 14
- 230000008859 change Effects 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 210000002966 serum Anatomy 0.000 description 14
- -1 cationic lipid Chemical class 0.000 description 13
- 210000000822 natural killer cell Anatomy 0.000 description 13
- 238000005457 optimization Methods 0.000 description 13
- 229960005486 vaccine Drugs 0.000 description 13
- 108091081548 Palindromic sequence Proteins 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 12
- 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 11
- 206010028980 Neoplasm Diseases 0.000 description 11
- 241000242678 Schistosoma Species 0.000 description 11
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 11
- 210000003979 eosinophil Anatomy 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 229940104230 thymidine Drugs 0.000 description 11
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
- 238000010521 absorption reaction Methods 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 238000013459 approach Methods 0.000 description 10
- 238000004113 cell culture Methods 0.000 description 10
- 230000000527 lymphocytic effect Effects 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 230000003844 B-cell-activation Effects 0.000 description 9
- 238000011765 DBA/2 mouse Methods 0.000 description 9
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
- 230000022534 cell killing Effects 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- 230000036039 immunity Effects 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- 206010061218 Inflammation Diseases 0.000 description 8
- 101001076414 Mus musculus Interleukin-6 Proteins 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 8
- 230000027455 binding Effects 0.000 description 8
- 230000001900 immune effect Effects 0.000 description 8
- 210000000987 immune system Anatomy 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 210000004969 inflammatory cell Anatomy 0.000 description 8
- 230000004054 inflammatory process Effects 0.000 description 8
- 231100000344 non-irritating Toxicity 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- 230000002103 transcriptional effect Effects 0.000 description 8
- 206010020751 Hypersensitivity Diseases 0.000 description 7
- 102000004388 Interleukin-4 Human genes 0.000 description 7
- 108090000978 Interleukin-4 Proteins 0.000 description 7
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 7
- FIVPIPIDMRVLAY-UHFFFAOYSA-N aspergillin Natural products C1C2=CC=CC(O)C2N2C1(SS1)C(=O)N(C)C1(CO)C2=O FIVPIPIDMRVLAY-UHFFFAOYSA-N 0.000 description 7
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000000975 dye Substances 0.000 description 7
- FIVPIPIDMRVLAY-RBJBARPLSA-N gliotoxin Chemical compound C1C2=CC=C[C@H](O)[C@H]2N2[C@]1(SS1)C(=O)N(C)[C@@]1(CO)C2=O FIVPIPIDMRVLAY-RBJBARPLSA-N 0.000 description 7
- 229940103893 gliotoxin Drugs 0.000 description 7
- 229930190252 gliotoxin Natural products 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 230000006698 induction Effects 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000013612 plasmid Substances 0.000 description 7
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 7
- 229940045145 uridine Drugs 0.000 description 7
- 238000011725 BALB/c mouse Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 6
- 108010002350 Interleukin-2 Proteins 0.000 description 6
- 102000000588 Interleukin-2 Human genes 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000012190 activator Substances 0.000 description 6
- 208000026935 allergic disease Diseases 0.000 description 6
- 230000007815 allergy Effects 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000007547 defect Effects 0.000 description 6
- 230000000968 intestinal effect Effects 0.000 description 6
- 238000010253 intravenous injection Methods 0.000 description 6
- PGHMRUGBZOYCAA-ADZNBVRBSA-N ionomycin Chemical compound O1[C@H](C[C@H](O)[C@H](C)[C@H](O)[C@H](C)/C=C/C[C@@H](C)C[C@@H](C)C(/O)=C/C(=O)[C@@H](C)C[C@@H](C)C[C@@H](CCC(O)=O)C)CC[C@@]1(C)[C@@H]1O[C@](C)([C@@H](C)O)CC1 PGHMRUGBZOYCAA-ADZNBVRBSA-N 0.000 description 6
- PGHMRUGBZOYCAA-UHFFFAOYSA-N ionomycin Natural products O1C(CC(O)C(C)C(O)C(C)C=CCC(C)CC(C)C(O)=CC(=O)C(C)CC(C)CC(CCC(O)=O)C)CCC1(C)C1OC(C)(C(C)O)CC1 PGHMRUGBZOYCAA-UHFFFAOYSA-N 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 108020004999 messenger RNA Proteins 0.000 description 6
- 230000001717 pathogenic effect Effects 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 239000012266 salt solution Substances 0.000 description 6
- 238000007789 sealing Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 101150013553 CD40 gene Proteins 0.000 description 5
- 102100023715 Poly(A)-specific ribonuclease PARN Human genes 0.000 description 5
- 241000194017 Streptococcus Species 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 102000040945 Transcription factor Human genes 0.000 description 5
- 108091023040 Transcription factor Proteins 0.000 description 5
- 230000003213 activating effect Effects 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- 238000013016 damping Methods 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- 239000012636 effector Substances 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 229940028885 interleukin-4 Drugs 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 235000011007 phosphoric acid Nutrition 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 230000001177 retroviral effect Effects 0.000 description 5
- 210000004989 spleen cell Anatomy 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 5
- 238000013518 transcription Methods 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- 206010002198 Anaphylactic reaction Diseases 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241000711573 Coronaviridae Species 0.000 description 4
- 108010063593 DNA modification methylase SssI Proteins 0.000 description 4
- 108010042407 Endonucleases Proteins 0.000 description 4
- 102000004533 Endonucleases Human genes 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 108060002716 Exonuclease Proteins 0.000 description 4
- 229920001917 Ficoll Polymers 0.000 description 4
- 241000233866 Fungi Species 0.000 description 4
- 108060003951 Immunoglobulin Proteins 0.000 description 4
- 241001529936 Murinae Species 0.000 description 4
- 101000981253 Mus musculus GPI-linked NAD(P)(+)-arginine ADP-ribosyltransferase 1 Proteins 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- VSWDORGPIHIGNW-UHFFFAOYSA-N Pyrrolidine dithiocarbamic acid Chemical compound SC(=S)N1CCCC1 VSWDORGPIHIGNW-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 241000700584 Simplexvirus Species 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 230000036783 anaphylactic response Effects 0.000 description 4
- 208000003455 anaphylaxis Diseases 0.000 description 4
- 230000000890 antigenic effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 239000012228 culture supernatant Substances 0.000 description 4
- 210000004748 cultured cell Anatomy 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 230000005059 dormancy Effects 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 102000013165 exonuclease Human genes 0.000 description 4
- 229940029575 guanosine Drugs 0.000 description 4
- 102000018358 immunoglobulin Human genes 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- 230000002458 infectious effect Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 230000000622 irritating effect Effects 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- FNEZBBILNYNQGC-UHFFFAOYSA-N methyl 2-(3,6-diamino-9h-xanthen-9-yl)benzoate Chemical compound COC(=O)C1=CC=CC=C1C1C2=CC=C(N)C=C2OC2=CC(N)=CC=C21 FNEZBBILNYNQGC-UHFFFAOYSA-N 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 102000040430 polynucleotide Human genes 0.000 description 4
- 108091033319 polynucleotide Proteins 0.000 description 4
- 239000002157 polynucleotide Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 210000002345 respiratory system Anatomy 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- 241000701161 unidentified adenovirus Species 0.000 description 4
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 4
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 3
- 102000006306 Antigen Receptors Human genes 0.000 description 3
- 108010083359 Antigen Receptors Proteins 0.000 description 3
- 108090001008 Avidin Proteins 0.000 description 3
- 244000025254 Cannabis sativa Species 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 3
- 244000301850 Cupressus sempervirens Species 0.000 description 3
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 3
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 3
- 230000004568 DNA-binding Effects 0.000 description 3
- CZGGKXNYNPJFAX-UHFFFAOYSA-N Dimethyldithiophosphate Chemical compound COP(S)(=S)OC CZGGKXNYNPJFAX-UHFFFAOYSA-N 0.000 description 3
- 241000709661 Enterovirus Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 102000003814 Interleukin-10 Human genes 0.000 description 3
- 108090000174 Interleukin-10 Proteins 0.000 description 3
- 108010002616 Interleukin-5 Proteins 0.000 description 3
- 102000000743 Interleukin-5 Human genes 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- 108091027981 Response element Proteins 0.000 description 3
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 3
- 241000242680 Schistosoma mansoni Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000000078 anti-malarial effect Effects 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 238000010241 blood sampling Methods 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 3
- 230000020411 cell activation Effects 0.000 description 3
- 230000022131 cell cycle Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000010367 cloning Methods 0.000 description 3
- 230000000295 complement effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 230000009849 deactivation Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- NAGJZTKCGNOGPW-UHFFFAOYSA-K dioxido-sulfanylidene-sulfido-$l^{5}-phosphane Chemical compound [O-]P([O-])([S-])=S NAGJZTKCGNOGPW-UHFFFAOYSA-K 0.000 description 3
- 238000007599 discharging Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002337 electrophoretic mobility shift assay Methods 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 229960002989 glutamic acid Drugs 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- 231100000283 hepatitis Toxicity 0.000 description 3
- 239000000833 heterodimer Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 230000017306 interleukin-6 production Effects 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 230000001035 methylating effect Effects 0.000 description 3
- 230000031942 natural killer cell mediated cytotoxicity Effects 0.000 description 3
- KDWFDOFTPHDNJL-TUBOTVQJSA-N odn-2006 Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=S)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=S)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(S)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C(N=C(N)C=C2)=O)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)O)N2C3=C(C(NC(N)=N3)=O)N=C2)O)N2C(N=C(N)C=C2)=O)O)N2C3=C(C(NC(N)=N3)=O)N=C2)O)N2C3=C(C(NC(N)=N3)=O)N=C2)O)N2C(N=C(N)C=C2)=O)O)[C@@H](O)C1 KDWFDOFTPHDNJL-TUBOTVQJSA-N 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- 244000052769 pathogen Species 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 150000003230 pyrimidines Chemical class 0.000 description 3
- 230000008521 reorganization Effects 0.000 description 3
- 230000029058 respiratory gaseous exchange Effects 0.000 description 3
- 238000003757 reverse transcription PCR Methods 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- AVWQQPYHYQKEIZ-UHFFFAOYSA-K trisodium;2-dodecylbenzenesulfonate;3-dodecylbenzenesulfonate;4-dodecylbenzenesulfonate Chemical compound [Na+].[Na+].[Na+].CCCCCCCCCCCCC1=CC=C(S([O-])(=O)=O)C=C1.CCCCCCCCCCCCC1=CC=CC(S([O-])(=O)=O)=C1.CCCCCCCCCCCCC1=CC=CC=C1S([O-])(=O)=O AVWQQPYHYQKEIZ-UHFFFAOYSA-K 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000009736 wetting Methods 0.000 description 3
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 2
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- KZELNMSPWPFAEB-UMMCILCDSA-N 2-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-8-sulfanylidene-3,7-dihydropurin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2NC(=S)N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O KZELNMSPWPFAEB-UMMCILCDSA-N 0.000 description 2
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 108700016155 Acyl transferases Proteins 0.000 description 2
- 102000057234 Acyl transferases Human genes 0.000 description 2
- 108020004491 Antisense DNA Proteins 0.000 description 2
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 2
- 240000006891 Artemisia vulgaris Species 0.000 description 2
- 244000075850 Avena orientalis Species 0.000 description 2
- 235000007319 Avena orientalis Nutrition 0.000 description 2
- 230000024704 B cell apoptotic process Effects 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- 241000219495 Betulaceae Species 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 2
- 241001529572 Chaceon affinis Species 0.000 description 2
- 108010055166 Chemokine CCL5 Proteins 0.000 description 2
- 102000001327 Chemokine CCL5 Human genes 0.000 description 2
- 241000606153 Chlamydia trachomatis Species 0.000 description 2
- 241000193403 Clostridium Species 0.000 description 2
- 241000193449 Clostridium tetani Species 0.000 description 2
- 241000186227 Corynebacterium diphtheriae Species 0.000 description 2
- 201000007336 Cryptococcosis Diseases 0.000 description 2
- 241000221204 Cryptococcus neoformans Species 0.000 description 2
- 240000005109 Cryptomeria japonica Species 0.000 description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 240000004585 Dactylis glomerata Species 0.000 description 2
- 108010053770 Deoxyribonucleases Proteins 0.000 description 2
- 102000016911 Deoxyribonucleases Human genes 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 241000606768 Haemophilus influenzae Species 0.000 description 2
- 241000709721 Hepatovirus A Species 0.000 description 2
- 241000228404 Histoplasma capsulatum Species 0.000 description 2
- 240000003857 Holcus lanatus Species 0.000 description 2
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- 241000598436 Human T-cell lymphotropic virus Species 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 102100026720 Interferon beta Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108090000467 Interferon-beta Proteins 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002386 Interleukin-3 Proteins 0.000 description 2
- 102000000646 Interleukin-3 Human genes 0.000 description 2
- 241000588747 Klebsiella pneumoniae Species 0.000 description 2
- AJMOLNFDYWTVQW-QWRGUYRKSA-N L-leucyl-l-leucine methyl ester Chemical compound COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C AJMOLNFDYWTVQW-QWRGUYRKSA-N 0.000 description 2
- 241000589902 Leptospira Species 0.000 description 2
- 241000186779 Listeria monocytogenes Species 0.000 description 2
- 240000000233 Melia azedarach Species 0.000 description 2
- 241000186359 Mycobacterium Species 0.000 description 2
- MQUQNUAYKLCRME-INIZCTEOSA-N N-tosyl-L-phenylalanyl chloromethyl ketone Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H](C(=O)CCl)CC1=CC=CC=C1 MQUQNUAYKLCRME-INIZCTEOSA-N 0.000 description 2
- 108010051791 Nuclear Antigens Proteins 0.000 description 2
- OYCDTPQIKJZGBS-UHFFFAOYSA-N P(O)(O)(O)=O.[O] Chemical compound P(O)(O)(O)=O.[O] OYCDTPQIKJZGBS-UHFFFAOYSA-N 0.000 description 2
- 241000721464 Parietaria officinalis Species 0.000 description 2
- 241000709664 Picornaviridae Species 0.000 description 2
- 241000223960 Plasmodium falciparum Species 0.000 description 2
- 102000052575 Proto-Oncogene Human genes 0.000 description 2
- 108700020978 Proto-Oncogene Proteins 0.000 description 2
- 241000125945 Protoparvovirus Species 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 2
- 241000831652 Salinivibrio sharmensis Species 0.000 description 2
- 244000082988 Secale cereale Species 0.000 description 2
- 235000007238 Secale cereale Nutrition 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 241000194049 Streptococcus equinus Species 0.000 description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 description 2
- 241000193996 Streptococcus pyogenes Species 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 241000223997 Toxoplasma gondii Species 0.000 description 2
- 244000098338 Triticum aestivum Species 0.000 description 2
- 102000000160 Tumor Necrosis Factor Receptor-Associated Peptides and Proteins Human genes 0.000 description 2
- 108010080432 Tumor Necrosis Factor Receptor-Associated Peptides and Proteins Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 208000038016 acute inflammation Diseases 0.000 description 2
- 230000006022 acute inflammation Effects 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 2
- 230000002052 anaphylactic effect Effects 0.000 description 2
- 230000003172 anti-dna Effects 0.000 description 2
- 239000003816 antisense DNA Substances 0.000 description 2
- 239000000074 antisense oligonucleotide Substances 0.000 description 2
- 238000012230 antisense oligonucleotides Methods 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 230000005784 autoimmunity Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 229940038705 chlamydia trachomatis Drugs 0.000 description 2
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 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
- 230000001684 chronic effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 230000012202 endocytosis Effects 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- 210000004475 gamma-delta t lymphocyte Anatomy 0.000 description 2
- 238000001502 gel electrophoresis Methods 0.000 description 2
- 229940047650 haemophilus influenzae Drugs 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- 230000006607 hypermethylation Effects 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000013010 irrigating solution Substances 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 229940115931 listeria monocytogenes Drugs 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 239000003226 mitogen Substances 0.000 description 2
- 230000002073 mitogenetic effect Effects 0.000 description 2
- 230000000394 mitotic effect Effects 0.000 description 2
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229940049547 paraxin Drugs 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 150000003014 phosphoric acid esters Chemical class 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 235000021110 pickles Nutrition 0.000 description 2
- 229940115272 polyinosinic:polycytidylic acid Drugs 0.000 description 2
- 238000003752 polymerase chain reaction Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000004850 protein–protein interaction Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 230000000384 rearing effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Natural products CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 239000000277 virosome Substances 0.000 description 2
- QGVLYPPODPLXMB-UBTYZVCOSA-N (1aR,1bS,4aR,7aS,7bS,8R,9R,9aS)-4a,7b,9,9a-tetrahydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-1,1a,1b,4,4a,7a,7b,8,9,9a-decahydro-5H-cyclopropa[3,4]benzo[1,2-e]azulen-5-one Chemical compound C1=C(CO)C[C@]2(O)C(=O)C(C)=C[C@H]2[C@@]2(O)[C@H](C)[C@@H](O)[C@@]3(O)C(C)(C)[C@H]3[C@@H]21 QGVLYPPODPLXMB-UBTYZVCOSA-N 0.000 description 1
- XDHNQDDQEHDUTM-XJKSCTEHSA-N (3z,5e,7r,8s,9r,11e,13e,15s,16r)-16-[(2s,3r,4s)-4-[(2r,4r,5s,6r)-2,4-dihydroxy-5-methyl-6-propan-2-yloxan-2-yl]-3-hydroxypentan-2-yl]-8-hydroxy-3,15-dimethoxy-5,7,9,11-tetramethyl-1-oxacyclohexadeca-3,5,11,13-tetraen-2-one Chemical compound CO[C@H]1\C=C\C=C(C)\C[C@@H](C)[C@H](O)[C@H](C)\C=C(/C)\C=C(OC)\C(=O)O[C@@H]1[C@@H](C)[C@@H](O)[C@H](C)[C@]1(O)O[C@H](C(C)C)[C@@H](C)[C@H](O)C1 XDHNQDDQEHDUTM-XJKSCTEHSA-N 0.000 description 1
- 101150084750 1 gene Proteins 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- VEKHORVJMXDXNE-UHFFFAOYSA-N 2-cyanoethoxyphosphonamidic acid Chemical compound NP(O)(=O)OCCC#N VEKHORVJMXDXNE-UHFFFAOYSA-N 0.000 description 1
- GHCZTIFQWKKGSB-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;phosphoric acid Chemical class OP(O)(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O GHCZTIFQWKKGSB-UHFFFAOYSA-N 0.000 description 1
- 238000010600 3H thymidine incorporation assay Methods 0.000 description 1
- QRXMUCSWCMTJGU-UHFFFAOYSA-N 5-bromo-4-chloro-3-indolyl phosphate Chemical compound C1=C(Br)C(Cl)=C2C(OP(O)(=O)O)=CNC2=C1 QRXMUCSWCMTJGU-UHFFFAOYSA-N 0.000 description 1
- 102000039549 ATF family Human genes 0.000 description 1
- 108091067350 ATF family Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010013043 Acetylesterase Proteins 0.000 description 1
- 241000186046 Actinomyces Species 0.000 description 1
- 241000186041 Actinomyces israelii Species 0.000 description 1
- 108010044688 Activating Transcription Factor 2 Proteins 0.000 description 1
- 241000701242 Adenoviridae Species 0.000 description 1
- 241000701386 African swine fever virus Species 0.000 description 1
- 241000743339 Agrostis Species 0.000 description 1
- 240000005611 Agrostis gigantea Species 0.000 description 1
- HHGYNJRJIINWAK-FXQIFTODSA-N Ala-Ala-Arg Chemical group C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N HHGYNJRJIINWAK-FXQIFTODSA-N 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- 241000219496 Alnus Species 0.000 description 1
- 241000223602 Alternaria alternata Species 0.000 description 1
- 240000004178 Anthoxanthum odoratum Species 0.000 description 1
- 235000014251 Anthoxanthum odoratum Nutrition 0.000 description 1
- 108020005544 Antisense RNA Proteins 0.000 description 1
- 241000256836 Apis Species 0.000 description 1
- 241000256844 Apis mellifera Species 0.000 description 1
- 241000712892 Arenaviridae Species 0.000 description 1
- 241000508786 Arrhenatherum elatius Species 0.000 description 1
- 235000004355 Artemisia lactiflora Nutrition 0.000 description 1
- 235000003261 Artemisia vulgaris Nutrition 0.000 description 1
- 208000012657 Atopic disease Diseases 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- 101150076489 B gene Proteins 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- 241001148536 Bacteroides sp. Species 0.000 description 1
- 235000017166 Bambusa arundinacea Nutrition 0.000 description 1
- 235000017491 Bambusa tulda Nutrition 0.000 description 1
- 235000018185 Betula X alpestris Nutrition 0.000 description 1
- 235000018212 Betula X uliginosa Nutrition 0.000 description 1
- 235000009109 Betula pendula Nutrition 0.000 description 1
- 241000219430 Betula pendula Species 0.000 description 1
- 241000212384 Bifora Species 0.000 description 1
- 241000702628 Birnaviridae Species 0.000 description 1
- 241000228405 Blastomyces dermatitidis Species 0.000 description 1
- 241000238657 Blattella germanica Species 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000743756 Bromus inermis Species 0.000 description 1
- 241000209202 Bromus secalinus Species 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 102000001764 CREB-Binding Protein Human genes 0.000 description 1
- 108010040163 CREB-Binding Protein Proteins 0.000 description 1
- 101100026251 Caenorhabditis elegans atf-2 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000714198 Caliciviridae Species 0.000 description 1
- 102000007590 Calpain Human genes 0.000 description 1
- 108010032088 Calpain Proteins 0.000 description 1
- 241000589876 Campylobacter Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000723436 Chamaecyparis obtusa Species 0.000 description 1
- 235000000509 Chenopodium ambrosioides Nutrition 0.000 description 1
- 244000098897 Chenopodium botrys Species 0.000 description 1
- 235000005490 Chenopodium botrys Nutrition 0.000 description 1
- 235000007516 Chrysanthemum Nutrition 0.000 description 1
- 244000189548 Chrysanthemum x morifolium Species 0.000 description 1
- 241000223205 Coccidioides immitis Species 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 108010062580 Concanavalin A Proteins 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 241000186216 Corynebacterium Species 0.000 description 1
- 241000186249 Corynebacterium sp. Species 0.000 description 1
- 241000709687 Coxsackievirus Species 0.000 description 1
- 102100023033 Cyclic AMP-dependent transcription factor ATF-2 Human genes 0.000 description 1
- 230000007067 DNA methylation Effects 0.000 description 1
- 230000030933 DNA methylation on cytosine Effects 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 238000011238 DNA vaccination Methods 0.000 description 1
- 241000725619 Dengue virus Species 0.000 description 1
- 241000710829 Dengue virus group Species 0.000 description 1
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 1
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 1
- 241000238713 Dermatophagoides farinae Species 0.000 description 1
- 239000012988 Dithioester Substances 0.000 description 1
- 241001115402 Ebolavirus Species 0.000 description 1
- 240000002943 Elettaria cardamomum Species 0.000 description 1
- 241000508725 Elymus repens Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 241000194031 Enterococcus faecium Species 0.000 description 1
- 241001495410 Enterococcus sp. Species 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 241000186811 Erysipelothrix Species 0.000 description 1
- 241000186810 Erysipelothrix rhusiopathiae Species 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 241000234642 Festuca Species 0.000 description 1
- 241000234645 Festuca pratensis Species 0.000 description 1
- 241000711950 Filoviridae Species 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- 241000605986 Fusobacterium nucleatum Species 0.000 description 1
- 108091092584 GDNA Proteins 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 206010061192 Haemorrhagic fever Diseases 0.000 description 1
- 241000150562 Hantaan orthohantavirus Species 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 241000700739 Hepadnaviridae Species 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 208000005331 Hepatitis D Diseases 0.000 description 1
- 241000700586 Herpesviridae Species 0.000 description 1
- 241000226709 Hesperocyparis arizonica Species 0.000 description 1
- 241001290232 Hesperocyparis macrocarpa Species 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101001076408 Homo sapiens Interleukin-6 Proteins 0.000 description 1
- 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 description 1
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 230000004950 I-kappaB phosphorylation Effects 0.000 description 1
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 1
- 206010061217 Infestation Diseases 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 241000701377 Iridoviridae Species 0.000 description 1
- 241000721662 Juniperus Species 0.000 description 1
- 241000721668 Juniperus ashei Species 0.000 description 1
- 240000005308 Juniperus chinensis Species 0.000 description 1
- 241000592238 Juniperus communis Species 0.000 description 1
- 241000588915 Klebsiella aerogenes Species 0.000 description 1
- 201000008225 Klebsiella pneumonia Diseases 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 241000589248 Legionella Species 0.000 description 1
- 208000007764 Legionnaires' Disease Diseases 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 241000209082 Lolium Species 0.000 description 1
- 244000100545 Lolium multiflorum Species 0.000 description 1
- 240000004296 Lolium perenne Species 0.000 description 1
- 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102000004083 Lymphotoxin-alpha Human genes 0.000 description 1
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 1
- 102000043131 MHC class II family Human genes 0.000 description 1
- 108091054438 MHC class II family Proteins 0.000 description 1
- 241000712079 Measles morbillivirus Species 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 102000003939 Membrane transport proteins Human genes 0.000 description 1
- 108090000301 Membrane transport proteins Proteins 0.000 description 1
- 241000191938 Micrococcus luteus Species 0.000 description 1
- 241000711386 Mumps virus Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000187484 Mycobacterium gordonae Species 0.000 description 1
- 241000186364 Mycobacterium intracellulare Species 0.000 description 1
- 241000186363 Mycobacterium kansasii Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- BKAYIFDRRZZKNF-VIFPVBQESA-N N-acetylcarnosine Chemical compound CC(=O)NCCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 BKAYIFDRRZZKNF-VIFPVBQESA-N 0.000 description 1
- 230000006051 NK cell activation Effects 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- 241000588650 Neisseria meningitidis Species 0.000 description 1
- 241000714209 Norwalk virus Species 0.000 description 1
- 102000019040 Nuclear Antigens Human genes 0.000 description 1
- 108010047956 Nucleosomes Proteins 0.000 description 1
- 241000795633 Olea <sea slug> Species 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 241000702259 Orbivirus Species 0.000 description 1
- 241000712464 Orthomyxoviridae Species 0.000 description 1
- 241000150218 Orthonairovirus Species 0.000 description 1
- 241000702244 Orthoreovirus Species 0.000 description 1
- 235000019082 Osmanthus Nutrition 0.000 description 1
- 241000333181 Osmanthus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 239000012807 PCR reagent Substances 0.000 description 1
- 240000005373 Panax quinquefolius Species 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 241001631646 Papillomaviridae Species 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 241000711504 Paramyxoviridae Species 0.000 description 1
- 208000007542 Paresis Diseases 0.000 description 1
- 241001465379 Parietaria judaica Species 0.000 description 1
- 241000701945 Parvoviridae Species 0.000 description 1
- 241001668545 Pascopyrum Species 0.000 description 1
- 235000002748 Paspalum commersonii Nutrition 0.000 description 1
- 241001330451 Paspalum notatum Species 0.000 description 1
- 240000004928 Paspalum scrobiculatum Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000238675 Periplaneta americana Species 0.000 description 1
- 244000081757 Phalaris arundinacea Species 0.000 description 1
- 241000713137 Phlebovirus Species 0.000 description 1
- 241000746983 Phleum pratense Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- 244000082204 Phyllostachys viridis Species 0.000 description 1
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 1
- 244000239204 Plantago lanceolata Species 0.000 description 1
- 235000010503 Plantago lanceolata Nutrition 0.000 description 1
- 206010035717 Pneumonia klebsiella Diseases 0.000 description 1
- 244000292693 Poa annua Species 0.000 description 1
- 241000136254 Poa compressa Species 0.000 description 1
- 241000209049 Poa pratensis Species 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 101800004937 Protein C Proteins 0.000 description 1
- 102000017975 Protein C Human genes 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 102000055027 Protein Methyltransferases Human genes 0.000 description 1
- 102100027584 Protein c-Fos Human genes 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 1
- 102000007568 Proto-Oncogene Proteins c-fos Human genes 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000219492 Quercus Species 0.000 description 1
- 244000274906 Quercus alba Species 0.000 description 1
- 235000009137 Quercus alba Nutrition 0.000 description 1
- 241000711798 Rabies lyssavirus Species 0.000 description 1
- 101150002130 Rb1 gene Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 241000702247 Reoviridae Species 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- 241000712907 Retroviridae Species 0.000 description 1
- 241000711931 Rhabdoviridae Species 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 description 1
- 244000004774 Sabina virginiana Species 0.000 description 1
- 235000008691 Sabina virginiana Nutrition 0.000 description 1
- 241000235343 Saccharomycetales Species 0.000 description 1
- 101800001700 Saposin-D Proteins 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 241000545593 Scolytinae Species 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000701033 Simian cytomegalovirus Species 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 235000011684 Sorghum saccharatum Nutrition 0.000 description 1
- 244000062793 Sorghum vulgare Species 0.000 description 1
- 244000046109 Sorghum vulgare var. nervosum Species 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 241001478878 Streptobacillus Species 0.000 description 1
- 241001478880 Streptobacillus moniliformis Species 0.000 description 1
- 241000193985 Streptococcus agalactiae Species 0.000 description 1
- 208000037065 Subacute sclerosing leukoencephalitis Diseases 0.000 description 1
- 206010042297 Subacute sclerosing panencephalitis Diseases 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 241000218636 Thuja Species 0.000 description 1
- 108090000941 Transcription factor TFIIB Proteins 0.000 description 1
- 102000004408 Transcription factor TFIIB Human genes 0.000 description 1
- 241000589904 Treponema pallidum subsp. pertenue Species 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 101150117115 V gene Proteins 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 241000700647 Variola virus Species 0.000 description 1
- 241000711975 Vesicular stomatitis virus Species 0.000 description 1
- 229930003756 Vitamin B7 Natural products 0.000 description 1
- 241000710772 Yellow fever virus Species 0.000 description 1
- 241000120645 Yellow fever virus group Species 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229960001570 ademetionine Drugs 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 108700010877 adenoviridae proteins Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000003872 anastomosis Effects 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000005875 antibody response Effects 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 244000309743 astrovirus Species 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 229940065181 bacillus anthracis Drugs 0.000 description 1
- 239000011425 bamboo Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 230000006287 biotinylation Effects 0.000 description 1
- 238000007413 biotinylation Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 235000005300 cardamomo Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 101150093710 clec-87 gene Proteins 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 230000003081 coactivator Effects 0.000 description 1
- 239000003184 complementary RNA Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 230000003229 cytophilic effect Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000013502 data validation Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000004851 dishwashing Methods 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 125000005022 dithioester group Chemical group 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 239000005712 elicitor Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 230000003181 encephalopathic effect Effects 0.000 description 1
- 229940092559 enterobacter aerogenes Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 230000013764 eosinophil chemotaxis Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000002270 exclusion chromatography Methods 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 229940084434 fungoid Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 208000029570 hepatitis D virus infection Diseases 0.000 description 1
- IIRDTKBZINWQAW-UHFFFAOYSA-N hexaethylene glycol Chemical compound OCCOCCOCCOCCOCCOCCO IIRDTKBZINWQAW-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 231100000652 hormesis Toxicity 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229940116886 human interleukin-6 Drugs 0.000 description 1
- 230000004727 humoral immunity Effects 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000001524 infective effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 210000001595 mastoid Anatomy 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- MIKKOBKEXMRYFQ-WZTVWXICSA-N meglumine amidotrizoate Chemical compound C[NH2+]C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I MIKKOBKEXMRYFQ-WZTVWXICSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000009061 membrane transport Effects 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229940052778 neisseria meningitidis Drugs 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 210000001623 nucleosome Anatomy 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- VQWNELVFHZRFIB-UHFFFAOYSA-N odn 1826 Chemical compound O=C1NC(=O)C(C)=CN1C(O1)CC(O)C1COP(O)(=O)OC1CC(N2C(NC(=O)C(C)=C2)=O)OC1COP(O)(=O)OC1CC(N2C3=C(C(NC(N)=N3)=O)N=C2)OC1COP(O)(=O)OC1CC(N2C(N=C(N)C=C2)=O)OC1COP(O)(=O)OC1CC(N2C3=NC=NC(N)=C3N=C2)OC1COP(O)(=O)OC1CC(N2C3=C(C(NC(N)=N3)=O)N=C2)OC1COP(O)(=O)OC1CC(N2C(NC(=O)C(C)=C2)=O)OC1COP(O)(=O)OC1CC(N2C(N=C(N)C=C2)=O)OC1COP(O)(=O)OC1CC(N2C(N=C(N)C=C2)=O)OC1COP(O)(=O)OC1CC(N2C(NC(=O)C(C)=C2)=O)OC1COP(O)(=O)OC(C(O1)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=O)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(O)=O)CC1N1C=C(C)C(=O)NC1=O VQWNELVFHZRFIB-UHFFFAOYSA-N 0.000 description 1
- DHYWDEXXBWTTEH-UHFFFAOYSA-N odn 2007 Chemical compound O=C1NC(=O)C(C)=CN1C1OC(COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(O)=O)C(O)C1 DHYWDEXXBWTTEH-UHFFFAOYSA-N 0.000 description 1
- 229940124276 oligodeoxyribonucleotide Drugs 0.000 description 1
- 239000002751 oligonucleotide probe Substances 0.000 description 1
- 230000005868 ontogenesis Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 238000009304 pastoral farming Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- QGVLYPPODPLXMB-QXYKVGAMSA-N phorbol Natural products C[C@@H]1[C@@H](O)[C@]2(O)[C@H]([C@H]3C=C(CO)C[C@@]4(O)[C@H](C=C(C)C4=O)[C@@]13O)C2(C)C QGVLYPPODPLXMB-QXYKVGAMSA-N 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000008288 physiological mechanism Effects 0.000 description 1
- WIFGCZCFSNIILK-UHFFFAOYSA-N platinum;pyrimidine Chemical class [Pt].C1=CN=CN=C1 WIFGCZCFSNIILK-UHFFFAOYSA-N 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 230000004911 positive regulation of CREB transcription factor activity Effects 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 229960000856 protein c Drugs 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000026267 regulation of growth Effects 0.000 description 1
- 230000005334 regulation of lymphocyte activation Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 238000004153 renaturation Methods 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 108700004030 rev Genes Proteins 0.000 description 1
- 101150098213 rev gene Proteins 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000007727 signaling mechanism Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000003393 splenic effect Effects 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000005987 sulfurization reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 208000006379 syphilis Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- 239000004577 thatch Substances 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229960002203 tilactase Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 229940048102 triphosphoric acid Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 239000011735 vitamin B7 Substances 0.000 description 1
- 235000011912 vitamin B7 Nutrition 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/117—Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
-
- 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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/17—Immunomodulatory nucleic acids
-
- 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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/31—Chemical structure of the backbone
- C12N2310/315—Phosphorothioates
-
- 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
Abstract
本发明涉及含有未甲基化的CpG二核苷酸的核酸序列,其中的CpG二核苷酸调节免疫反应,包括刺激Th1类型的免疫活化、细胞因子的产生、NK溶胞活性、以及B细胞的繁殖。这些序列可以用作合成附剂。
Description
本发明的研究部分地得到了美国国家卫生研究院的第R29-AR42556-01拨款的资助。美国政府有本发明的部分权利。本发明的技术领域
本发明一般地涉及寡核苷酸,具体地讲,涉及那些包括至少一个免疫刺激性的未甲基化CpG二核苷酸的寡核苷酸序列。本发明的背景技术
在二十世纪七十年代,一些研究人员报道了高分子量DNA与细胞膜的结合(Lerner,R.A.et al.,1971.“Membran-associatedDNA in the cytoplasm of diploid human lymphocytes”.Proc.Natl.Acad.Sci.USA68:l12;Agrawal,S.K.,R.W.Wagner,P.K.McAllister,and B.Rosenberg.1975.“Cell-surface-associatednucleic acid in tumorigenic cells made visible with platinum-pyrimidine complexes by electron microscopy”.Proc.Natl.Acad.Sci.USA72:928)。在1985年,Bennett等人首次提出证据证明了DNA与淋巴细胞的结合相似于配体与受体的相互作用,即结合是饱和的、竞争性的、并导致DNA细胞内吞作用和降解为寡核苷酸(Bennett,R.M.,G.T.Gabor,and M.M.Merritt.1985.“DNA binding to human leukocytes.Evidence for receptor-mediated association,internalization,and degradation of DNA”.J.Clin.Invest.76:2182)。类似于DNA,寡脱氧核糖核酸(ODN)也能以饱和、不依赖序列、但依赖温度和能量的形式进入到细胞中(见Jaroszewski,J.W.,and J.S.Cohen.1991.“Cellular uptakeof antisense oligodeoxynucleotides”.Advanced Drug DeliveryReviews6:235;Akhtar,S.,Y.Shoji,and R.L.Juliano.1992.“Pharmaceutical aspects of the biological stability and membranetransport characteristics of antisense oligonucleotides”.In:GeneRegulation:Biology of Antisense RNA and DNA.R.P.Erickson,and J.G.Izant,eds.Raven Press,Ltd.New York,pp.133:and Zhao,Ql,T.Waldschmidt,E.Fisher,C.J.Herrera,and A.M.Krieg.,1994.“Stage specific oligonucleotide uptake in murine bone marrow Bcell precursors”.Blood,84:3660)。但是,还没有克隆化到吸收DNA或ODN的受体,而且,还不清楚ODN结合及细胞吸收是采取与高分子量的DNA相同或不同的机制。
淋巴细胞的ODN吸收已经被证明可由细胞活化来调节。用B细胞分裂素LPS刺激的脾细胞在B细胞群体中显示了ODN吸收的显著提高,而用T细胞分裂素Con A处理的脾细胞显示的ODN吸收的提高是在T细胞中而不是在B细胞中(Krieg,A.M.,F.Gmelig-Meyling,M.F.Gourley,W.J.Kisch,L.A.Chrisey,and A.D.Steinberg.1991.“Uptake of oligodeoxyribonucleotidesby lymphoid cells is heterogeneous and inducible”.AntisenseResearch and Development 1:161)。
已经对一些多聚核苷酸作为反应修饰剂进行了广泛的研究。也许最好的例子是多聚(I,C),这是一种IFN生产的强力诱导子,也是巨嗜细胞活化子和NK活性诱导子(Talmadge,J.E.,J.Adams,H.Phillips,M.Collins,B.Lenz,M.Schneider,E.Schlick,R.Ruffmann,R.H.Wiltrout,and M.A.Chirigos.1985.“Immunomodulatory effects in mice of polyinosinic-polycytidylicacid comlexed with poly-L-lysine and carboxymethylcellulose”.Cancer Res.“Immunomodulation of natural killer activity bypolyribonucleotides”.J.Biol.Resp.Mod.4:512;Krown,S.E.1986.“Interferons and interferon inducers in cancer treatment”.Sem.Oncol.13:207;and Ewel,C.H.,S.J.Urba,W.C.Kopp,J.W.SmithII,R.G.Steis,J.L.Rossio,D.L.Longo,M.J.Jones,W.G.Alvord,C.M.Pinsky,J.M.Beveridge,K.L.McNitt,and S.P.Creekmore.1992.“Polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymethylcellulose in combination with interleukin-2in patients with cancer:clinical and immunological effects”.Canc.Res.52:3005)。看起来,这种鼠NK活化的单一原因是引入了IFN-β分泌(Ishikawa,R.,and C.A.Biron.1993.“IFN inductionand associated changes in splenic leukocyte distribution”.J.Immunol.150:3713)。这种活化是对核糖为特异的,因为对脱氧核糖没有效力。其体外抗肿瘤活性的效力导致多种采用多聚(I,C)复合多聚-L-赖氨酸和羧甲基纤维素(用以减少RNAse降解)的临床研究(Talmadge,J.E.,et al.,1985.出处同上;Wiltrout,R.H.,et al.,1985.出处同上);Krown,S.E.,1986.出处同上);and Ewel.C.H.,et al.,1992.出处同上)。不幸的是,对毒性副作用的研究完全排除了多聚(I,C)成为有用的治疗药剂的可能。
在C8位发生溴或硫醇基取代的鸟嘌呤核糖核苷酸是B细胞的分裂素,并且可以取代“B细胞分化因子”(Feidbush,T.L.,andZ.K.Ballas.1985.“Lymphokine-like activity of8-mercaptoguanosine:induction of T and B cell differentiation”.J.Immunol.134:3204;and Goodman, M.G.1986.“Mechnism ofsnyergy between T cell signals and C8-substituted guaninenucleosides in humoral immunity:B lymphotropic cytokines induceresponsiveness to 8-mercaptoguanosine”.J.Immunol.136:3335 )。8-巯基鸟苷和8-溴鸟苷还可以取代细胞因子来用在MHC限制的CTL的产生(Feldbush,T.L.,1985.出处同上),增大鼠NK活性(Koo,G.C.,M.E.Jewell,C.L.Manyak,N.H.Sigal,and L.S.Wicker.1988.“Activation of murine natural killer cells andmacrophages by8-bromoguanosine”.J.Immunol.140:3249),以及与IL-2一起在诱发鼠LAK产生中的协同效应(Thompson,R.A.,and Z.K.Ballas.1990.“Lymphokine-activated killer(LAK)cells.V.8-Mercaptoguanosine as an IL-2-sparing agent inLAK generation”.J.Immunol.145:3524)。这些C8取代的鸟苷的NK和LAK活性的增大看起来归因于它们对IFN的引入(Thompson,R.A.,et al.,1990.出处同上)。近来,由分枝杆菌产生的5’三磷酸化胸苷被发现是对人γδT细胞亚类为促有丝分裂的(Constant,P.,F.Davodeau,M.A.Peyrat,Y.Poquet,G.Puzo,M.Bonneville,and J.-J.Fournie.1994.“Stimulation of humanγδTcells by nonpeptidic mycobacterial ligands”Science264:267)。该篇报道指明,免疫系统可能产生对微生物核酸的带有倾向性的反应方式。
一些研究已经表明,某些DNA结构可以还带有活化淋巴细胞的潜力。例如,Bell等人曾经报道,在脾细胞上清液中的核小体蛋白质-DNA复合物(不是裸露的DNA)引起了B细胞的繁殖和免疫球蛋白的分泌(Bell,DA.,B.Morrison,and P.VanderBygaart.1990.“Immunogenic DNA-related factors”.J.Clin.Invest.85:1487)。在其它的情况下,裸露的DNA已经被报道具有免疫效应。例如,Messina等人最近曾报道说,多聚(dG)·(dC)和多聚(dG·dC)的260至800bp的片段是对B细胞为促有丝分裂的(Messina,J.P.,G.S.Gilkeson,and D.S.Pisetsky.1993.“Theinfluence of DNA structure on the in vitro stimulation of murinelymphocytes by natural and synthetic polynucleotide antigens”.Cell.Immunol.147:148)。Tokunaga等人已经报道了dG·dC诱导γ-IFN和NK活性(Tokunaga,S.Yamamoto,and K.Namba.1988.“A synthetic single-stranded DNA,poly(dG,dC),inducesinterferon-α/b and-g,augments natural killer activity,andsuppresses tumor growth”Jpn.J.Cancer Res.79:682)。除了这些人造的均聚体序列之外,Pisetsky等人报道了纯净哺乳动物DNA没有可检测性免疫效应,但是,从某些细菌来的DNA则诱导了B细胞的活化和免疫球蛋白的分泌(Messina,J.P.,G.S.Gilkeson,and D.S.Pisetsky.1991.“Stimulation of in vitro murinelymphocyte proliferation by bacterial DNA”.J.Immunol.147:1759)。假设这些数据不是那些特异的污染物的结果,那么,这些研究则建议,细菌DNA的特定结构或它们的特定性质使其能够启动B细胞的活化。对分枝杆菌DNA序列的研究显示,含有某种回文序列的ODN可以活化NK细胞(Yamamoto,S.,T.Yamamoto,T.Kataoka,E.Kuramoto,O.Yano,and T.Tokunaga.1992.“Unique palindromic sequences in syntheticoligonucleotides are required to induce INF and agument INF-meidated natural killer activity”.J.Immunol.148:4072;Kuramoto,E.,O.Yano,Y.Kimura,M.Baba,T.Makino,S.Yamamoto,T.Yamamoto,T.Kataoka,and T.Tokunaga.1991.“Oligonucleotidesequences required fro natural killer cell activation”.Jpn.J.CancerRes.83:1128)。
还报道了其它一些硫代磷酸酯修饰的ODN在体外或体内对B细胞的刺激(Tanaka,T.,C.C.Chu,and W.E.Paul.1992.“Anantisense oligonucleotide complementary to a sequence in Ig2bincreases g2b germline transcripts,stimulates B cell DNA synthesis,and inhibits immunoglobulin secretion”.J.Exp.Med.175:597;Branda,R.F.,A.L.Moore,L.Mathews,J.J.McCormack,and G.Zon.1993.“Immune stimulaiton by an antisense oligomercomplementary to the rev gene of HIV-1”.Biochem.Pharmacol.45:2037;McIntyre,K.W.,K.Lombard-Gillooly,J.R.Perez,C.Kunsch,U.M.Sarmiento,J.D.Larigan,K.T.Landreth,and R.Narayanan.1993.“A sense phosphorothioate oligonucleotidedirected to the initiation codon of transcription factor NF-BT65causes sequence-specific immune stimulation”.Antisense Res.Develop.3:309;and Pisetsky,D.S.,and C.F.Reich.1993.“Stimulation of murine lymphocyte proliferation by aphosphorothioate oligonucleotide with antisense activity for herpessimplex virus”.Life Sciences54:101)。这些报道没有建议出在这些ODN中有可以解释这些效果的共同的结构基元或序列因素。
cAMP效应元件结合蛋白质(CREB)和活化转录因子(ATF)或转录因子的CREB/ATF家族是普遍被表达的一类转录因子,其11个成员已经被克隆化了(reviewed in de Groot,R.P.,and P.Sassone-Corsi:“Hormonal control of gene expression:Multiplicity and versatility of cyclic adenosine 3’,5’-monophosphate-responsive nucler regulators”.Mol.Endocrin.7:145,1993;Lee,K.A.W.,and N.Masson:“Transcriptionalregulation by CREB and its relatives”.Biochim.Biophys.Acta1174:221,1993)。它们都属于蛋白质中碱性区/亮氨酸拉链结构(bZip)类。所有的细胞都显示出对一种或一种以上的CREB/ATF蛋白质的表达,但是,所表达的成员和对mRNA剪接的调节则显示为组织特异性的。对活化区的分化剪接可以确定某一具体的CREB/ATF蛋白质是转录抑制子或活化子。许多的CREB/ATF蛋白质活化病毒性转录,但是,有些缺少活化区的剪接变体则是抑制性的。CREB/ATF蛋白质可以作为均二聚体或异二聚体通过cAMP效应元件来结合DNA,而cAMP效应元件,即CRE,其共有形式是未甲基化序列TGACGTC(如果CpG是甲基化的,则结合就被抑制)(Iguchi-Ariga,S.M.M.,andW.Schaffner:″CpG methylation of the cAMP responsiveenhancer/promoter sequence TGACGTCA abolishes specificefactor binding as well as transcriptional activation″.Genes &Develop.3:612,1989.)。
CRE的转录活性在B细胞活化中被提高(Xie,H.T.C.Chiles,and T.L.Rothstein:″Induction of CREB activity via the surface Igreceptor of B cells″.J.Immunol.151:880,1993)。CREB/ATF蛋白质好象是通过CRE来对多种基因的表达进行调节,包括免疫学上重要的基因,例如,fos、jun B、Rb-1、IL-6、IL-1(Tsukada,J.,K.Saito,W.R.Waterman,A.C.Webb,and P.E.Auron:″Transcription factors NF-IL-6 and CREB recognize a commonessential site in the human prointerleukin 1 gene″.Mol.Cell.Biol.14:7285,1994;Gray,G.D.,O.M.Hernadez,D.Hebel.M.Root,J.M.Pow-Sang,and E.Wickstrom:″antisense DNA inhibition oftumor growth induced by c-Ha-ras oncogene in nude mice″.CancerRes.53:577,1993),IFN-(Du,W.,and T.Maniatis:″AnTF/CREB binding site protein is required for virus induction ofhuman interferon B gene″.Proc.Natl.Acad.Sci.USA 89:2150,1992),TGF-1(Asiedu,C.K.,L.Scott,R.K.Assoian,M.Ehrlich:"Binding of AP-1/CREB proteins and of MDBP to contiguous sitesdownstream of the human TGF-B1 gene″.Biochim.Biophys.Acta1219:55,1994),TGF-2,Ⅱ MHC类(Cox,P.M.,and C.R.Goding:″An ATF/CREB binding motif is required for aberrant constitutiveexpression of the MHC class Ⅱ DRa promoter and activation bySV40T-antigeh″.Nucl.Acids Res.20:4881,1992),E-选择素,GM-CSF,CD-8,种系Ig恒定区基因,TCR V基因,以及繁殖细胞核抗原(Huang,D.,P.M.Shipman-Appasamy,D.J.Orten,S.H.Hinrichs,and M.B.Prystowsky:″Promoter activity of theproliferating-cell nuclear antigen gene is associated with inducibleCRE-binding proteins in interleukin 2-stimulated T lymphocytes:.Mol.Cell.Biol.14:4233,1994)。除了通过cAMP途径的活化,CREB还可以介导对细胞内Ca++浓度变化的转录应答(Sheng,M.,G.McFadden,and M.E.Greenberg:″Membrane depolarizationand calcium induce c-fos transeription via phosphorylation oftranseription fector CREB″.Neuron4:571,1990)。
在CREB/ATF蛋白质的转录活化中,蛋白质-蛋白质之间的相互作用显示为极其重要角色。已经有一些发表的研究报道了在NFKB蛋白质和CREB/ATF蛋白质之间的直接性或间接性相互作用[Whitley,et al.,(1994)Mol.& Cell.Biol.14:6464;Cogswell,et al.,(1994)J.Immun.153:712;Hines,et al.,(1993)Oncogene8:3189;and Du,et al.,(1993)Cell74:887]。通过环AMP途径对CREB的活化需要蛋白质激酶A(PKA),其将CREB341在ser133磷酸化,并允许其与近来克隆化的蛋白质CBP结合(Kwok,R.P.S.,J.R.Lundblad,J.C.Chrivia,J.P.Richards,H.P.Bachinger,R.G.Brennan,S.G.E.Roberts,M.R.Green,and R.H.Goodman:″Nuclear protein CBP is a coactivator for thetranscription factor CREB″.Nature370:223,1994;Arias,J.,A.S.Alberrs,P.Brindle,F.X.Claret,T.Smea,M.Karin,J.Feranmisco,and M.Montminy:″Activation of cAMP and mitogen responsivegenes relies on a common nuclear factor″.Nature370:226,1994.)。CBP随后再与碱性转录因子TFIIB相互作用造成提高了的转录。CREB还被报道与dTAFII110相互作用,该dTAFⅡ110是一种TATA结合蛋白质相关的因子,其结合可以调节转录(Ferreri,K.,G.Gill,and M.Montminy:″The cAMP-regulatedtranscription factor CREB interacts with a component of the TFⅡDcomplex″.Proc.Natl.Acad.Sci.USA91:1210,1994)。除了这些相互作用之外,CREB/ATF蛋白质可以特异性结合多种其它的核因子(Hoeffler,J.P.,J.W.Lustbader,and C.-Y.Chen:″Identification of multiple nuclear factors that interact with cyclicadenosine 3′,5′-monohosphate response element-binding proteinand activating transcription factor-2 by protein-proteininteractions″.Mol.Endocrinol.5:256,1991),但是,这些相互作用中的大多数的生物学重要性还都是未知的。一般都认为CREB与DNA的结合是均二聚体的或与其它的蛋白质的异二聚体。另人惊奇的是,CREB单体对转录的活化是组成性的(Krajewski,Wl,and K.A.W.Lee:″A monomeric derivative of the cellulartranscription factor CREB functions as constitutive activator″.Mol.Cell.Biol.14:7204,1994)。
除了在调节细胞转录中的重要作用之外,最近还证实了CREB/ATF蛋白质被某些感染性病毒和逆病毒所破坏,使其需要病毒复制。例如,在已知的最为强烈的哺乳动物启动子中,即巨细胞病毒立即早期启动子中,含有对启动子功能为必须的CRE的11个拷贝(Chang,Y.-N.,S.Crawfbrd,J.Stall,D.R.Rawlins,K.-T.Jeang,and G.S.Hayward:″The palindromic series Irepeats in the simian cytomegalovirus major immediate-earlypromoter behave as both strong basal enhancers and cyclic AMPresponse elements″.J.Virol.64:264,1990)。诱导众多启动子的腺病毒ElA蛋白质的至少一部分转录活化效应归因于其与CREB/ATF蛋白质的DNA结合区的结合,即与ATF-2的结合,其介导ElA可诱导的转录活化(Liu,F.,and M.R.Green:″Promoter targeting by adenovirus Ela through interaction withdifferent cellular DNA-binding domains″.Nature368:520,1994)。还建议的是,ElA与CREB结合蛋白质CBP相结合(Arany,Z.,W.R.Sellers,D.M.Livingston,and R.Eckner:″ElA-associated p300and CREB-associated CBP belong to a conservedfamily of coactivators″.Cell77:799,1994)。人T嗜淋巴细胞病毒-I(HTLV-1),即造成人T细胞白血病和热带痉挛轻瘫的逆病毒,也需要CREB/ATF蛋白质来复制。在这种情况下,逆病毒产生蛋白质Tax,其与CREB/ATF蛋白质结合,再指引它们从其正常的细胞结合位点改变为存在于HTLV转录增强子中的不同的DNA序列(侧翼序列为G-和C-富集的序列)(Paca-Uccaralertkun,S.,L.-J.Zhao,N.Adya,J.V.Cross,B.R.Cullen,I.M.Boros.and C.-Z.Giam:″In vitro selection of DNA elementshighly responsive to the human T-cell lymphotropic virus type Itranscriptional activator, Tax″. Mol.Cell.Biol.14:456,1994;Adya,N.,L.-J.Zhao,W.Huang,I.Boros,and C.-Z.Giam:″Expansion ofCREB′s DNA recognition specificity by Tax results frominteraction with Ala-Ala-Arg at positions 282-284 near theconserved DNA-binding domain of CREB″.Proc.Natl.Acad.Sci.USA91:5642,1994) 。本发明的概述
本发明的基础是发现了某些含有未甲基化的胞嘧啶-鸟苷(CpG)二核苷酸活化对象中的淋巴细胞并使对象的免疫系统由Th2转变为Th1(例如,诱导单核细胞以及其它细胞产生Th1细胞因子,包括IL-12、IFN-γ、和GM-CSF)。基于这个发现,本发明在一方面涉及新的免疫刺激性核酸组合物。
在一个实施方案中,本发明提供了被分离的免疫刺激性的含有CpG基元的核酸序列,其表达式为:
5′N1X1CGX2N23′其中,至少有一个核苷酸将连续的CpGs间隔开来;X1是腺嘌呤,鸟嘌呤,或胸腺嘧啶;X2是胞嘧啶或胸腺嘧啶;N是任何的核苷酸,且N1+N2是0-26碱基,条件是N1和N2都不含有CCGG四元体或多于一个的CCG或CGG三元体;并且核酸序列的长度为约8-30碱基对。
在另一个实施方案中,本发明提供了被分离的免疫刺激性的含有CpG基元的核酸序列,其表达式为:
5′N1X1X2CGX3X4N23′其中,至少有一个核苷酸将连续的CpGs间隔开来;X1X2是选自GpT、GpG、GpA、ApT和ApA;X3X4是选自TpT或CpT;N是任何的核苷酸,且N1+N2是0-26碱基,条件是N1和N2都不含有CCGG四元体或多于一个的CCG或CGG三元体;并且核酸序列的长度为约8-30碱基对。
在另一个实施方案中,本发明提供了刺激免疫活化的方法,将本发明的核酸序列提供给对象,优选人类。在优选的实施方案中,免疫活化产生主要是Th1形式的免疫活化。
在另一个实施方案中,本发明的核酸序列刺激细胞因子的生产。具体地讲,IL-6、IL-12、IFN-γ、TNF-α和GM-CSF是通过用本文中所述的核酸序列刺激免疫系统来产生的。在另一方面,本发明的核酸序列刺激天然杀死细胞(NK)的溶胞活性和B细胞的繁殖。
在另一个实施方案中,本发明的核酸序列被用作人造附剂来在哺乳动物如小鼠或人中产生抗体。
在另一个实施方案中,通过抑制对象的对CpG介导的淋巴细胞活化的应答来治疗自体免疫紊乱。本发明提供了施加对体内酸化的抑制物如bafilomycina,氯喹,和莫能菌素来缓解自体免疫紊乱。具体地讲,用这种方式治疗了系统性红斑狼苍。
本发明的核酸序列还可以用于治疗、防止或缓解其它的紊乱(例如,肿瘤或癌症,病毒性、真菌性、细菌性或寄生性感染)。此外,本发明的核酸序列可以施加给对象来刺激其对疫苗的应答。进一步,将对象的免疫系统从Th2改变为Th1,本发明的核酸序列可以治疗和防止气喘疾病。此外,本发明的核酸序列可以施加给患有过敏疾病的对象,作为消除敏感的制剂来治疗或防止与气喘相关的过敏反应。
进一步,本发明的核酸序列的诱导白血细胞进入细胞循环的能力支持了其治疗白血病的应用,即提高了在常规的消除化疗之后的白血细胞的敏感性,或者将本发明的核酸序列与其它的免疫治疗物一起使用。
本发明的其它的特点和优点将可以从下面的描述和权利要求书中更为明显地看出。附图的简要说明
图1A-C用制图说明在消除了T细胞的脾细胞培养物中对各种DNA序列的应答的IL-6生产的剂量依赖情况。
图1A是大肠杆菌DNA(1)和小牛胸腺DNA(n)序列和LPS(10倍浓度的大肠杆菌和小牛胸腺DNA)(u)。
图1B是对照的磷酸二脂寡聚脱氧核苷酸(ODN)5′ATGGAAGGTCCAGTGTTCTC3′(SEQ ID No:1)(n)和两个磷酸二脂CpG ODN 5′ATCGACCTACGTGCGTTCTC3′(SEQ IDNo:2)(u)和5′TCCATAACGTTCCTGATGCT3′(SEQ ID No:3)(1)。
图1C是对照的硫代磷酸酯ODN 5′GCTAGATGTTAGCGT3′(SEQ ID No:4)(n)和两个硫代磷酸酯CpG ODN5′GAGAACGTCGACCTTCGAT3′(SEQ ID No:5)(u)和5′GCATGACGTTGAGCT3′(SEQ ID No:6)(1)。数据代表三份的平均值±标准偏差。
图2图示注射后1-8小时所确定的体内CpG DNA诱导的IL-6生产。数据代表从两个小鼠的血清的两次分析的平均值。对BALB/c小鼠(每组两只)静脉内注射100微升的PBS(o)或200微克的CpG硫代磷酸酯0DN5′TCCATGACGTTCCTGATGCT3′(SEQ ID No:7)(n)或非-CpG硫代磷酸酯ODN5′TCCATGAGCTTCCTGAGTCT3′(SEQ ID No:8)(u)。
图3是放射性自显影图,说明IL-6mRNA表达,由反转录聚合酶链反应确定,在肝、脾和胸腺中各个时间的情况,事先对BALB/c小鼠(每组两只)进行体内刺激,静脉内注射100微升的PBS,200微克的CpG硫代磷酸酯ODN5′TCCATGACGTTCCTGATGCT3′(SEQ ID No:7)非-CpG硫代磷酸酯ODN5′TCCATGAGCTTCCTGAGTCT3′(SEQ ID No:8)。
图4A是图示抗IL-6对CpG诱导的IgM生产的剂量依赖性抑制。从DBA/2小鼠来的脾B细胞用CpG ODN5′TCCAAGACGTTCCTGATGCT3′(SEQ ID No:9)刺激,有给出浓度的中性抗-IL-6(u)或等模标本对照Ab(1)的存在,在培养物上清液中的IgM水平有ELISA确定。在没有CpG ODN存在的情况下,抗-IL-6抗体对IgM分泌没有效应(n)。
图4B图示用CpG S-ODN5′TCCATGACGTTCCTGATGCT3′(SEQ ID No:7)和抗-IL-6(u)培养或用抗-IL-6抗体单独培养(n)的脾B细胞CpG-诱导的刺激指数。数据代表三份的平局值±标准偏差。
图5是条块图,说明在wEHI-231细胞中的氯霉素酰基转移酶(CAT)的活性,其中的细胞被不含启动子的CAT结构(pCAT)、阳性对照质粒(RSV)、IL-6启动子-CAT结构自身、以及按照给定浓度的CpG5′TCCATGACGTTCCTGATGCT3′(SEQ ID No:7)或非-CpG5′TCCATGAGCTTCCTGAGTCT3′(SEQ ID No:8)硫代磷酸酯ODN与IL-6启动子-CAT结构所转染。数据代表三份数据的平均值。
图6是含有免疫刺激性的未甲基化CpG的核酸的免疫效果的总体图示,该核酸可以直接活化B细胞和单核细胞(包括巨嗜细胞和树状细胞)。免疫刺激性寡核苷酸不直接活化纯化的NK细胞,但可以使它们适合于应答IL-12并使IFN-γ生产有明显提高。由于使NK细胞被诱导产生IL-12和随后的IFN-γ分泌被提高,免疫刺激性核酸促进了Th1类型的免疫应答。没有发现高纯度的T细胞可以直接活化细胞因子分泌的增加。然而,由免疫刺激性寡核苷酸所诱导的Th1细胞因子分泌促进了细胞毒性淋巴细胞应答的产生。
图7是自显影照相图,显示NFkB mRNA在单核细胞中的诱导结果,这些细胞被大肠杆菌(EC)DNA(含有未甲基化CpG基元)、对照(CT)DNA(不含未甲基化CpG基元)和脂多糖(LPS)等所处理并分别在接触后的第15分钟、30分钟等各时间测量。
图8A显示流式细胞仪的测定结果,使用的是小鼠B细胞,用二倾若丹明123染色来确定反应性氧的种类和水平。在A组中的仅用了染料的情况显示细胞对染料的阳性背景值为28.6%。这个水平的反应性氧种类在用PMA和离子霉素处理20分钟的细胞中被提高到了80%,即阳性对照(B组)。细胞用CpG寡核苷酸(TCCATGACGTTCCTGACGTT,SEQ ID No.10)处理后也显示了反应性氧种类水平的提高,即50%以上的细胞变为阳性(D组)。然而,用同样序列的寡核苷酸处理但CpGs被换为(TCCATGAGCTTCCTGAGTGCT,SEQ ID No.11)则没有显示反应性氧种类水平的提高(E组)。
图8B显示流式细胞仪的结果,使用了小鼠B细胞,有氯喹存在,用二氢若丹明123染色来确定反应性氧种类的水平。氯喹将细胞中背景的反应性氧种类的水平稍微降低了一些,使在A组中的未处理的细胞仅有4.3%为阳性。氯喹完全终止了在用CpG DNA处理的细胞(B组)中对反应性氧种类的诱导,但对用PMA和离子霉素处理的细胞(E组)则没有降低其反应性氧种类水平。
图9说明用肺灌洗细胞计数对时间的作图。该图显示,当小鼠开始被注射了Schistosoma mansoni卵这种诱导Th2应答的“卵”并且随后呼吸Schistosoma mansoni卵抗原“SEA”后(空心环),则在肺部内有众多的发炎的细胞。然而,当小鼠开始接受的是CpG寡核苷酸(SEQ ID No.10)以及卵时,则肺部内的发炎细胞并不随呼吸SEA而提高(空心三角形)。
图10说明肺部灌洗嗜伊红粒细胞计数对时间的作图。该图显示,当小鼠开始注射了卵并随后呼吸SEA(空心环),则在肺部内有众多的嗜伊红粒细胞存在。然而,当小鼠开始接受的是CpG寡核苷酸(SEQ ID No.10)和卵时,则在肺部内的发炎细胞就不随着后来呼吸SEA而增高(空心三角形)。
图11是条块图,说明巨嗜细胞、淋巴细胞、嗜碱性细胞、嗜伊红粒细胞分别暴露于盐水、卵加SEA、卵加SEQ ID No.11及随后的SEA、卵加对照寡核苷酸(SEQ ID No.11)以及随后的SEA后,诱导的细胞百分数的效应。当小鼠在暴露于卵的同时给予对照寡核苷酸,则吸入SEA后对嗜伊红粒细胞在肺部内没有明显效应。因此,当小鼠在第14天或第21天呼吸卵,它们在肺部内产生急性发炎。然而,如果在第0天或第7天开始接触抗原的时候将CpG寡核苷酸同卵一起提供给小鼠,则就完全防止小鼠在随后的第14天呼吸卵抗原所产生的嗜伊红粒细胞增加。
图12是一个条块图,说明注射不同剂量的保护性寡核苷酸SEQ ID No.10所产生的嗜伊红粒细胞计数的情况。
图13是随时间的小鼠产生白细胞介素-4(IL-4)的情况(pg/ml),其所应答的分别是注射卵和随后的SEA(空心菱形);卵加SEQ ID No.10和随后的SEA(空心环);盐水加随后的盐水(空心矩形)。该图的结果显示,所产生的发炎的应答相关于在肺部的Th2细胞因子IL-4的水平。
图14是条块图,说明随时间的小鼠产生白细胞介素-12(IL-12)的情况(pg/ml),其所应答的分别是注射盐水;卵和随后的SEA;卵加SEQ ID No.10和随后的SEA。该图的结果显示,注射含有未甲基化CpG基元的寡核苷酸可以实际上使肺对细胞因子的应答变为产生IL-12,表明是Th1类型的免疫应答。
图15是条块图,说明随时间的小鼠产生伽玛干扰素(IFN-γ)的情况(pg/ml),其所应答的分别是注射盐水;卵和随后的SEA;卵加SEQ ID No.10和随后的SEA。该图的结果显示,注射含有未甲基化CpG基元的寡核苷酸还可以使肺对细胞因子的应答变为产生IFN-γ,表明是Th1类型的免疫应答。本发明的详细描述定义
在本文中,下面各种术语和词组所表达的意思定义如下:
术语“过敏原”指的是可以在易感染的对象中产生过敏反应或气喘反应的物质。过敏原的名单是非常巨大的,可以包括花粉、昆虫毒物、动物皮、真菌孢子和药物(青霉素)等。天然的、动物的和植物的过敏原的实例包括对下面各属为特异性的蛋白质:犬(Canisf familiaris),螨(Dermatophagoides farinae),Felis(Felis domesticus),豚草(Ambrosia artemiisfolia),黑麦草(Lolium perenne或Lolium multiflorum),柳杉(Cryptomeriajaponica),链格孢(Alternaria alternata),小蠹甲(Alder),桤木(Alnus gultinosa),桦木(Betula verrucosa),栎(Quercusalba),木犀榄(Olea europa),蒿(Artemisia vulgaris),车前(Plantago lanceolata),墙草(Parietaria officinalis或Parietariajudaica),小蠊(Blattella germanica),蜂(APis multiflorum),柏木(Cupressus sempervirens,Cupressus arizonica和Cupressusmacrocarpa),刺柏(Juniperus sabinoides,Juniperus virginiana,Juniperus communis和Juniperus ashei),Thuya(Thuyaorientalis),扁柏(Chamaecyparis obtusa),大蠊(Periplanetaamericana),冰草(Agropyron repens),黑麦(Secale cereale),小麦(Triticum aestivum),鸭茅(Dactylis glomerata),羊茅(Festucaelatior),早熟禾(Poapratensis或Poa compressa),燕麦(Avenasativa),绒毛草(Holcus lanatus),黄花茅(Anthoxanthumodoratum),燕麦草(Arrhenatherum elatius),剪股颖(Agrostisalba)梯牧草(Phleum pratense),(Phalaris arundinacea),雀稗(Paspalum notatum),高粱(Sorghum halepensis),以及雀麦(Bromus inermis)。
术语“过敏”指的是对某种物质(过敏原)所获得的过度敏感。过敏包括湿疹、过敏性鼻炎、枯草热、支气管气喘、寻麻疹、食物过敏,以及其它的特异反应性疾病。
术语“气喘”指的是呼吸道的疾病,其特征是发炎,气管狭窄,对吸入的物质的反应增加。气喘虽然不是必然的但也是经常地伴随着特异反应性或过敏性症状。
术语“免疫系统缺陷”指的是这样的一些疾病或紊乱,其中,个体的免疫系统不能正常发挥功能,或将使该个体的免疫应答不能对消除肿瘤或癌症[例如,脑瘤、肺(包括小细胞和非小细胞)癌、卵巢癌、乳腺癌、前列腺癌、直肠癌、以及其它的恶性瘤和肉瘤]或其它的感染而提高其有用性。
感染性的病毒的实例包括:Retroviridae[例如,人免疫缺陷病毒,如HIV-1(也称为HTLV-Ⅲ,LAV或HTLV-Ⅲ/LAV,或HIV-Ⅲ;以及其它的分离物,例如HIV-LP)];小RNA病毒科[Picornaviridae(例如,polio病毒,甲肝病毒,肠道病毒,人柯萨奇病毒,鼻病毒)],嵌杯样病毒[Caliciviridae(例如,造成肠道疾病的品系)],黄色病毒[Flaviridae,例如,登革病毒(dengue viruses),脑病毒(encephalitis viruses),黄热病毒(yellow fever viruses)],冠形病毒[Coronaviridae,例如冠形病毒(coronaviruses)],弹状病毒[Rhabdoviridae,例如,vesicular stomatitis viruses,rabies viruses],Filoviridae(例如,ebola viruses),副粘病毒[Paramyxoviridae,例如,parainfluenzaviruses,mumps virus,measles virus,respiratory syncytialvirus],亚粘病毒[Orthomyxoviridae,例如,influenza viruses],Bungaviridae[例如,Hantaan viruses,bunga viruses,phleboviruses和Nairo viruses],嵌沙样病毒[Arena viridae,例如,hemorrhagic fever viruses],呼吸肠道病毒[Reoviridae,例如,reoviruses,orbiviruses和rotaviruses],Birnaviridae,肝炎病毒[Hepadnaviridae,例如,乙形肝炎病毒(Hepatitis Bvirus)],细小病毒[Parvoviridae(parvoviruses)],乳多孔病毒[Papovaviridae,例如,乳突病毒(papilloma viruses,polyomaviruses)],腺病毒[Adenoviridae(most adenoviruses)],疱疹病毒[Herpesviridae,例如,herpes simplex virus(HSV)1和2,varicella zoster virus,cytomegalovirus(CMV),herpes viruses],痘病毒[variola viruses,vaccinia viruses,pox viruses],和虹色病毒[Iridoviridae,例如,African swine fever virus],以及一些未分类的病毒[例如,海绵脑病的致病剂,δ肝炎致病剂(被认为是乙型肝炎病毒的缺陷型变体),非甲非乙肝炎的致病剂(1类=内部传染,2类=肠胃外传染(如丙型肝炎),Norwalk病毒以及相关的病毒,和星状病毒)]。
感染性细菌的实例包括:Helicobacter pyloris,疏螺旋体(Borelia burgdorferi,Legionella pneumophilia,分杆杆菌[Mycobacteria sps.,例如,结核杆菌(M.Tuberculosis),鸟型结核分支杆菌(M avium),M.intracellulare,M.kansaii,M.gordonae],金黄色葡萄球菌(Staphylococcus aureus),淋病奈瑟氏菌(Neisseria gonorrhoeae),脑膜炎双球菌(Neisseriameningitidis),单核细胞增多性李斯特氏菌(Listeriamonocytogenes),酿脓链球菌[Streptococcus pyogenes(A组Streptococcus)],无孔链球菌[Streptococcus agalactiae(B组Streptococcus)],链球菌属[Streptococcs(viridans组)],粪链球菌(Streptococcus faecalis),牛链球菌(Streptococcus bovis),链球菌属(Streptococcus厌氧菌,anaerobic sps.),肺炎链球菌(Streptococcus pneumoniae),弯曲杆菌(pathogenicCampylobacter sp.,),肠球菌(Enterococcus sp.,),流感嗜血菌(Haemophilus influenzae),炭疽芽孢杆菌(Bacillusantracis),白喉棒杆菌(Corynebacterium diphtheriae),棒杆菌属( Corynebacterium sp.,),红斑丹毒丝菌(Erysipelothrixrhusiopathiae),产气英膜梭菌(Clostridium perfringers),破伤风梭菌(Clostridium tetani),Enterobacter aerogenes,肺炎克雷伯氏菌(Klebsiella pneumoniae),多杀巴斯德氏菌(Pasturella multocida),拟杆菌(Bacteroides sp.,),核粒梭形杆菌(Fusobacterium nucleatum),念球状链杆菌(Streptobacillus moniliformis),梅毒螺旋菌(Treponemapallidium),细弱密螺旋体(Treponema pertenue),钩端螺旋体(Leptospira)和伊氏放线菌(Actinomyces israelli)。
感染性真菌的实例包括:新型隐球菌(Cryptococcusneoformans),英膜组织胞浆菌(Histoplasma capsulatum),粗球孢子菌(Coccidioides immitis),皮炎芽酵母(Blastomycesdermatitidis),沙眼衣原体(Chlamydia trachomatis),白色念球菌(Candida albicans)。其它的感染性有机体(例如,原生动物)包括:恶性疟原虫(Plasmodium falciparum)和鼠弓形虫(Toxoplasma gondii)。
术语“免疫刺激性核酸分子”指的是这样的核酸分子,它们含有未甲基化的胞嘧啶,鸟嘌呤二核苷酸序列(即,“CpGDNA”或含有胞嘧啶并接着鸟苷且由磷酸盐键所连接的DNA)并刺激脊椎动物淋巴细胞(例如,具有促有丝分裂效应,或诱导或提高细胞因子的表达)。免疫刺激性核酸分子可以是双链的或单链的。一般,双链的分子在体内比较稳定,而单链的分子则具有提高了的免疫活性。
在本发明的一个优选的实施方案中,提供了被分离的免疫刺激性核酸序列,其含有的CpG基元由下式表达:
5′N1X1CGX2N23′其中,至少有一个核苷酸将连续的CpGs间隔开来;X1是腺嘌呤,鸟嘌呤,或胸腺嘧啶;X2是胞嘧啶或胸腺嘧啶;N是任何的核苷酸,且N1+N2是0-26碱基,条件是N1和N2都不含有CCGG四元体或多于一个的CCG或CGG三元体;并且核酸序列的长度为约8-30碱基对。
在另一个实施方案中,本发明提供了被分离的免疫刺激性的含有CpG基元的核酸序列,其表达式为:
5′N1X1X2CGX3X4N23′
其中,至少有一个核苷酸将连续的CpGs间隔开来;X1X2是选自GpT、GpG、GpA、ApT和ApA;X3X4是选自TpT或CpT;N是任何的核苷酸,且N1+N2是0-26碱基,条件是N1和N2都不含有CCGG四元体或多于一个的CCG或CGG三元体;并且核酸序列的长度为约8-30碱基对。
优选的是,本发明的免疫刺激性核酸序列包括X1X2,它们选自GpT、GpG、GpA和ApA,且X3X4选自TpT、CpT和GpT(见表5)。为了促进吸收到细胞中,含有免疫刺激性核酸分子的CpG优选为8-30个碱基的长度。然而,如果有足够的免疫刺激性基元的存在,则任何长度的核酸(甚至很多个碱基对长)都可以是免疫刺激性的,因为这样的大型的核酸在细胞内被降解为寡核苷酸。优选的合成性的寡核苷酸不含有CCGG四元体或多于一个的CCG或CGG三元体在其或靠近其5′和/或3′端,和/或其共有的促有丝分裂CpG基元不是回文结构。当寡核苷酸整合有磷酸盐主链的修饰时,用稳定的寡核苷酸可以获得长久的免疫刺激性。例如,当修饰为硫代磷酸酯或硫代磷酸酯类的修饰时既是如此。另外,更具体地讲,磷酸盐主链修饰发生在核酸的5′端,即在核酸5′端的最初两个核苷酸上。进而言之,磷酸盐主链修饰可以发生在核酸的3′端,即在核酸的3′端的最后5个核苷酸上。
优选的免疫刺激性CpG DNA是寡核苷酸时,其长度为8-30个碱基对。另外,CpG二核苷酸可以在质粒中大规模生产,当其被给予个体后,降解为寡核苷酸。优选的免疫刺激性核酸分子[例如,用于提高疫苗的有效性,或在个体内刺激抗体(例如体液的)应答来治疗免疫系统缺陷]具有相对高的对B细胞、单核细胞和/或天然杀死细胞反应的刺激系数(例如,细胞因子、繁殖性、溶胞性或其它的反应)。
本发明的核酸序列刺激对象中的细胞因子的产生。细胞因子包括但不限于IL-6、IL-12、IFN-γ、TNF-α、GM-CSF。这些序列的实例包括:TCCATGTCGCTCCTGATGCT(SEQ ID NO:42),TCCATGTCGTTCCTGATGCT(SEQ ID NO:43),和TCGTCGTTTTGTCGTTTTGTCGTT(SEQ ID NO:56)。
本发明的核酸序列还可以用于刺激天然杀死细胞(NK)在如人的对象中的溶胞活性。具体的但非限制性的实例包括:
TCGTCGTTGTCGTTGTCGTT(SEQ ID NO:57),
TCGTCGTTTTGTCGTTTTGTCGTT(SEQ ID NO:58),
TCGTCGTTGTCGTTTTGTCGTT(SEQ ID NO:59),
GCGTGCGTTGTCGTTGTCGTT(SEQ ID NO:),
TGTCGTTTGTCGTTTGTCGTT(SEQ ID NO:),
TGTCGTTGTCGTTGTCGTT(SEQ ID NO:60)和
TCGTCGTCGTCGTT(SEQ ID NO:61)。
本发明的核酸序列还可以用于在如人的对象中刺激B细胞繁殖。具体的但非限制性的实例包括:
TCCTGTCGTTCCTTGTCGTT(SEQ ID NO:62),
TCCTGTCGTTTTTTGTCGTT(SEQ ID NO:63),
TCGTCGCTGTCTGCCCTTCTT(SEQ ID NO:64),
TCGTCGCTGTTGTCGTTTCTT(SEQ ID NO:65),
TCGTCGTTTTGTCGTTTTGTCGTT(SEQ ID NO:66),
TCGTCGTTGTCGTTTTGTCGTT(SEQ ID NO:67),和
TGTCGTTGTCGTTGTCGTT(SEQ ID NO:68)。
在本发明的另一个方面,本发明的核酸序列可以在哺乳动物中生产抗体时作为附剂使用。具体的但非限制性的实例包括TCCATGACGTTCCTGACGTT(SEQ ID NO:10),GTCG(T/C)T和TGTCG(T/C)T。进而言之,这些核酸序列可以用于治疗和防止气喘疾病的症状,将对象的免疫应答从Th2型改变为Th1型。具体的实例包括TCCATGACGTTCCTGACGTT(SEQ IDNO:10)。
具体的免疫刺激性CpG DNA的刺激指数可以用各种免疫细胞检测来测定。优选地,免疫刺激性CpG DNA的刺激指数对B细胞繁殖为约5,优选至少为至少10,更优选地为至少15,最优选地为至少约20,由3H尿苷在B细胞培养物中测定,其中,在37℃下与20μM的ODN接触20小时,并且用1μCi的3H尿苷冲击,并按照实施例1所述在4小时后收获和计数。对于体内的应用,例如,用于治疗免疫系统缺陷刺激细胞介导的对象中的免疫反应,重要的是,免疫刺激性CpG DNA要能够有效地诱导单核细胞分泌细胞因子和/或天然杀死细胞(NK)的细胞溶胞活性。
优选的免疫刺激性CpG核酸应该可以产生至少约500pg/ml的TNF-α、15pg/ml的IFN-γ、70pg/ml的GM-CSF、275pg/ml的IL-6、200pg/ml的IL-12,具体依据治疗指标而定,可以按照实施例2中的所述的检测来确定。其它优选的免疫刺激性CpGDNAs要能够产生至少约10%,更优选至少约15%,而最优选至少约20%的YAC-1细胞特异性溶胞,或至少约30%,更优选至少约35%,和最优选至少约40%的2C11细胞特异性溶胞,由实施例4中描述的检测来确定。
术语“核酸”或“DNA”指的是多核苷酸{即,含有糖(如核糖或脱氧核糖)且通过磷酸盐基团连接到可交换的有机碱上的分子,其替换嘧啶[例如,胞嘧啶(C)、胸腺嘧啶(T)或尿嘧啶(U)],或替代嘌呤[例如,腺嘌呤(A),鸟嘌呤(G)]}。在本文中,该术语指的是核糖核苷酸以及寡脱氧核糖核苷酸。该术语应该包括多核苷(即,多核苷酸减去一个磷酸)以及其它的含有有机碱的聚合物。核酸分子可以从已经存在的核酸源获得(例如,基因组或cDNA),但是,优选合成性的(例如,由寡核苷酸合成所产生的)。
术语“核酸释放复合物”指的是核酸分子(通过离子键或共价键,或包埋方式)与靶向装置[例如,对靶细胞(如B细胞和天然杀死(NK)细胞)表面有较高亲和结合性和/或提高靶细胞的吸收的分子]结合在一起。核酸释放复合物的实例包括与下列物质结合的核酸:固醇(例如,胆固醇)、脂类(例如,阳离子脂、病毒体、或脂质体)、或靶细胞特异性结合制剂(例如,由靶细胞特异性受体所识别的配体)。优选的复合物必须在体内足够地稳定来防止在被靶细胞内化之前就显著地解脱偶联。然而,这些复合物要能够在细胞内适宜的条件下被剪切,使核酸以功能性的形式被释放。
术语“回文序列”指的是反向的重复(即,如ABCDEE′D′C′B′A′这样的序列,其中A和A′是能够形成常规的watson-Crick碱基对的碱基。在体内,这样的序列可以形成双链结构。
术语“稳定化的核酸分子”指的是在体内对降解(例如,通过外切核酸酶或内切核酸酶的降解)具有相对抵抗性的核酸分子。稳定可以是长度的功能或次级结构的功能。长度为几十个甚至上百个碱基的含有未甲基化CpG的核酸分子对体内降解有相对的抵抗性。对于较短的免疫刺激性核酸分子,次级结构可以稳定和提高其功能。例如,如果核酸分子的3′端具有对上游区的自己互补性,则它就可以回折来形成某种茎-环结构,然后,核酸分子变为稳定的并从而表现更强的活性。
优选的本发明的稳定化核酸分子具有被修饰的主链。用于免疫刺激时,特别优选的核酸分子是硫代磷酸酯(即,核酸分子的至少一个磷酸氧被硫所取代)或硫代磷酸酯修饰的核酸分子。更具体地讲,磷酸主链修饰发生在核酸的5′端,在核酸5′端的最初两个核苷酸上。进而言之,磷酸主链修饰可以发生在核酸的3′端,发生在核酸的3′端的最后5个核苷酸上。除了稳定的核酸分子外,正如本文中进一步描述的那样,硫代磷酸酯-修饰(包括二硫代磷酸酯-修饰)的核酸分子可以提高该核酸分子的免疫刺激程度,它们含有所示的未甲基化CpG二核苷酸。题目为“硫代磷酸酯寡核苷酸类似物的免疫刺激”的国际专利申请公开第WO95/26204号也报道了硫代磷酸酯修饰的寡核苷酸的非序列特异性的免疫刺激效果。如本文所描述的,含有未甲基化CpG的并具有硫代磷酸酯主链的核酸分子已经被发现倾向于活化B细胞活性,而含有未甲基化CpG的并具有磷酸二酯主链的核酸分子已经被发现倾向于活化单核性细胞(巨嗜细胞、树状细胞和单核细胞)和NK细胞。带有优选的人基元的硫代磷酸酯CpG寡核苷酸也是单核性细胞和NK细胞的强活化子。
其它的稳定的核酸分子包括:非离子性DNA类似物,例如烷基或芳基的磷酸酯(其中带电的磷酸氧被烷基或芳基所取代),磷酸二酯和烷基磷酸三酯,其中的带电的氧基团被烷基化。带有二醇例如四甘醇或六甘醇的核酸分子,已经显示在其一个终端或两个终端都是基本抵抗核酸酶的降解的。
术语“对象”指的是人或脊椎动物,包括狗、猫、马、牛、猪、绵羊、山羊、鸡、猴子、大鼠,和小鼠。
在本文中,术语“载体”指的是能够运送与之相连的其它核酸的核酸分子。优选的载体是能够对与之相连的核酸进行自我复制和表达的载体(例如,附加体)。能够对与之可工作地相连的基因的表达进行指导的载体被在本文中成为“表达载体”。总体来说,在重组DNA技术中有用的表达载体经常都是“质粒”形式的,其一般所指的是双链DNA的环形物,其在载体形式时不与染色体相连。在本说明书中,术语“质粒”和“载体”是可以相互替换的,因为质粒是最常用形式的载体。然而,本发明也包括其它形式的载体,即它们的功能等同物,以及随后变为本领域所知的那些载体。某些含有未甲基化CpG并具在在体内和体外的B细胞刺激活性的核酸
在根据随后的实施例1和2的描述所进行的对内源性逆病毒序列具有特异性的两种反义寡核苷酸刺激淋巴细胞效应的研究中,令人惊奇地发现了在24个“对照”(包括在“反义”ODN组中的各种杂乱的、有义的、和错配的对照)中的2个也能够介导B细胞活化和IgM分泌,而其它的“对照”则不具有这样的功能。
这两个研究的结果表明,这种“对照”ODN的B细胞活化机制可能不涉及反义效果,1)通过与基因库(GenBank)所列的脊椎动物DNA序列相比较,没有显示出比那些没有刺激性的ODN更多的同源性,以及2)这两个对照在使用了10μg的脾polyA+RNA的Northen印迹中没有显示出杂交。在不同的合成器上再次合成这些ODN,或用聚丙烯酰胺凝胶电泳或高压液相色谱来充分提纯,都得到相等的刺激,消除了杂质的可能性。采用来自C3H/HeJ小鼠的B细胞也见到了类似的刺激,这消除了脂多糖(LPS)污染会影响结果的可能性。
两个“对照”ODN所造成B细胞活化与两个“反义”ODN的情况相类似的事实提出了这样的可能性,即所有四个ODN对B细胞的刺激通过的是某种非反义机制进行的,所涉及的序列基元在所有的其它的非刺激性对照ODN中都不存在。比较这些序列发现,所有四个刺激性ODN含有的CpG二核苷酸处于与非刺激性对照不同的序列位置。
为了确定存在于刺激性ODN中的CpG基元是否负责所观察到的刺激作用,合成了超过300个的ODN,它们的长度范围是5-42个碱基对,含有甲基化或未甲基化的CpG二核苷酸,或者不含有CpG二核苷酸,并且位置也不同。这些ODN,包括两个原始的“对照”(即ODN1和2)以及两个原始的合成性“反义”物[ODN3D和3M;Krieg,A.M.J.Immunol.143:2448(1989)],然后检查它们的脾细胞体外效果(代表性序列在表1中给出)。含有CpG二核苷酸的几种ODN诱导了B细胞的活化和IgM的分泌;这种刺激的程度一般可以由增加更多的CpG二核苷酸来提高(表1;比较ODN2与2a或3D与3Da和3Db)。看起来刺激不是反义机制或杂质的结果。ODN没有造成可检测的γδ或其它的T细胞种群的繁殖。
如果CpG二核苷酸发生突变,有丝分裂ODN序列都变为非刺激性的(表1;比较ODN1与1a;3D与3Dc;3M与3Ma;以及4与4a),或如果CpG二核苷酸的胞嘧啶被5-甲基胞嘧啶取代(表1;ODN1b,2b,3Dd,和3Mb)。CpG基元的部分甲基化造成刺激效果的部分损失(比较2a与2c,表1)。相对照,对其它的胞嘧啶的甲基化没有减少ODN活性(ODN1c,2d,3De和3Mc)。这些数据确认了CpG基元存在于ODN中活化B细胞的重要元素。
在这些研究的过程中,变的更为清楚的是,在CpG二核苷酸侧翼的碱基在由ODN诱导的小鼠B细胞活化的确定中起着重要的作用。最佳的刺激基元被确定包括有以两个5′嘌呤(优选为GpA二核苷酸)和两个3′嘧啶(优选TpT或TpC二核苷酸)为侧翼的CpG。将CpG基元趋向靠近这种理想形态的ODN突变改善了刺激性(例如,表1,比较ODN2与2e;3M与3Md),而那些打乱该基元的突变则减弱了刺激性(见表1,比较ODN 3D与3Df;4与4b,4c和4d)。另一方面,在CpG以外的突变没有减弱刺激性(例如,表1,比较ODN1与1d;3D与3Dg;3M与3Me)。对于活化人的细胞,最佳的侧翼碱基是稍有不同的(见表5)。
在那些实验过的ODNs中,长度小于8个碱基对的ODN都没有刺激性(例如,表1,ODN4e)。在所测试过的48个长度为8个碱基对的ODN中,确定了具有强刺激性的序列是TCAACGTT(ODN4),其含有自我互补的“回文序列”AACGTT。在对该基元的进一步优化中,发现在两个终端都有G的ODN具有更强的刺激性,特别当ODN被硫代磷酸酯修饰了终端的核苷酸间的连接而具有对核酸酶的抗性后更是如此。ODN1585[5′GGGGTCAACGTTCAGGGGGG3′(SEQ ID NO:12)]中,前两个和最后的5个核苷酸间的连接都被硫代磷酸酯修饰了,使其在小鼠脾细胞的繁殖中平均提高了25.4倍,而相比之下,由ODN1638所造成的繁殖只增加了3.2倍,该ODN1638与ODN1585具有相同的序列,只是在两端的第10位的G被第10位的A所取代。富含G的终端的效果是其为顺式,对ODN加上多G的终端但不将CpG基元与1638一起加入细胞,也不会得到增强的繁殖。对于长度大于8个碱基对的核酸,含有未甲基化CpG的非回文序列基元被发现是更具有刺激性的。
含有6个碱基回文序列以及在5′端有TpC二核苷酸的10元ODN也是活性的(见表1,ODN4b,4c)。在5′端的其它的二核苷酸减弱刺激性(例如,ODN4f,对所有可能的16种二核苷酸都进行了测试)。有3′端二核苷酸存在并不足以补偿对5′端二核苷酸的缺失(见表1,ODN4g)。对回文序列打乱就消除了10元ODN的刺激性(例如,表1,ODN4h),但是,在更长的ODN中,回文序列不是必须的。
表1:寡核苷酸对小鼠B细胞的刺激
刺激性指数′ODN生产 序列(5′至3′) 3H尿嘧啶 IgM | |||
1(SEQ ID NO:13) | GCTAGACGTTAGCGT | 6.1±0.8 | 17.9±3.6 |
1a(SEQ ID No:4) | ■■■■■■T■■■■■■■■ | 1.2±0.2 | 1.7±0.5 |
1b(SEQ ID No:14) | ■■■■■■Z■■■■■■■■ | 1.2±0.1 | 1.8±0.0 |
1c(SEQ ID No:15) | ■■■■■■■■■■■■Z■■ | 10.3±4.4 | 9.5±1.8 |
1d(SEQ ID No:16) | ■■AT■■■■■■GAGC■ | 13.0±2.3 | 18.3±7.5 |
2(SEQ ID No:17) | ATGGAAGGTCCAGCGTTCTC | 2.9±0.2 | 13.6±2.0 |
2a(SEQ ID No:18) | ■■C■■CTC■■G■■■■■■■■■ | 7.7±0.8 | 24.2±3.2 |
2b(SEQ ID No:19) | ■■Z■■CTC■ZG■■Z■■■■■■ | 1.6±0.5 | 2.8±2.2 |
2c(SEQ ID No:20) | ■■Z■■CTC■■G■■■■■■■■■ | 3.1±0.6 | 7.3±1.4 |
2d(SEQ ID No:21) | ■■C■■CTC■■G■■■■■■Z■■ | 7.4±1.4 | 27.7±5.4 |
2e(SEQ ID No:22) | ■■■■■■■■■■■■A■■■■■■ | 5.6±2.0 | ND |
3D(SEQ ID No:23) | GAGAACGCTGGACCTTCCAT | 4.9±0.5 | 19.9±3.6 |
3Da(SEQ ID No:24) | ■■■■■■■■■C■■■■■■■■■■ | 6.6±1.5 | 33.9±6.8 |
3Db(SEQ ID No:25) | ■■■■■■■■■C■■■■■■■G■■ | 10.1±2.8 | 25.4±0.8 |
3Dc(SEQ ID No:26) | ■■■C■A■■■■■■■■■■■■■■ | 1.0±0.1 | 1.2±0.5 |
3Dd(SEQ ID No:27) | ■■■■■Z■■■■■■■■■■■■■■ | 1.2±0.2 | 1.0±0.4 |
3De(SEQ ID No:28) | ■■■■■■■■■■■■■Z■■■■■■ | 4.4±1.2 | 18.8±4.4 |
3Df(SEQ ID No:29) | ■■■■■■■A■■■■■■■■■■■■ | 1.6±0.1 | 7.7±0.4 |
3Dg(SEQ ID No:30) | ■■■■■■■■■CC■G■ACTG■■ | 6.1±1.5 | 18.6±1.5 |
3M(SEQ ID No:31) | TCCATGTCGGTCCTGATGCT | 4.1±0.2 | 23.2±4.9 |
3Ma(SEQ ID No:32) | ■■■■■■CT■■■■■■■■■■■■ | 0.9±0.1 | 1.8±0.5 |
3Mb(SEQ ID No:33 | ■■■■■■■Z■■■■■■■■■■■■ | 1.3±0.3 | 1.5±0.6 |
3Mc(SEQ ID No:34) | ■■■■■■■■■■■Z■■■■■■■■ | 5.4±1.5 | 8.5±2.6 |
3Md(SEQ ID No:35) | ■■■■■■A■■T■■■■■■■■■■ | 17.2±9.4 | ND |
3Me(SEQ ID No:36) | ■■■■■■■■■■■■■■■C■■A■ | 3.6±0.2 | 14.2±5.2 |
4 | TCAACGTT | 6.1±1.4 | 19.2±5.2 |
4a | ■■■■GC■■ | 1.1±0.2 | 1.5±1.1 |
4b | ■■■GCGC■ | 4.5±0.2 | 9.6±3.4 |
4c | ■■■TCGA■ | 2.7±1.0 | ND |
4d | ■■TT■■AA | 1.3±0.2 | ND |
4e | _■■■■■■■ | 1.3±0.2 | 1.1±0.5 |
4f | C■■■■■■■ | 3.9±1.4 | ND |
4g | __■■■■■■CT | 1.4±0.3 | ND |
4h | ■■■■■■■C | 1.2±0.2 | ND |
LPS | 7.8±2.5 | 4.8±1.0 |
′刺激指数是至少三个单独实验的平均值和标准偏差,并且与没有加入ODN的培养物的小孔进行比较。ND=未进行。CpG二核苷酸用下划线标出。黑点表示位置,短线表示缺失。Z代表5甲基胞嘧啶。
表2:确定对小鼠IL-6生产和B细胞活化为最优的CpG基元
IL-6(pg/ml)a | |||||
ODN | 序列(5′-3′) | SIb | IgM(ng/ml)c | CH12.LX | 脾B细胞 |
512(SEQID No:31) | TCCATGTCGGTCCTGATGCT | 1300±106 | 627±43 | 5.8±0.3 | 7315±1324 |
1637(SEQID No:38) | ■■■■■■C■■■■■■■■■■■■■ | 136±27 | 46±6 | 1.7±0.2 | 770±72 |
1615(SEQID No:39) | ■■■■■■G■■■■■■■■■■■■■ | 1201±155 | 850±202 | 3.7±0.3 | 3212±617 |
1614(SEQID No:40) | ■■■■■■A■■■■■■■■■■■■■ | 1533±321 | 1812±103 | 10.8±0.6 | 7558±414 |
1636(SEQID No:41) | ■■■■■■■■■A■■■■■■■■■■ | 1181±76 | 947±132 | 5.4±0.4 | 3983±485 |
1634(SEQID No:42) | ■■■■■■■■■C■■■■■■■■■■ | 1049±223 | 1671±175 | 9.2±0.9 | 6256±261 |
1619(SEQID No:43) | ■■■■■■■■■T■■■■■■■■■■ | 1555±304 | 2908±129 | 12.5±1.0 | 8243±698 |
1618(SEQID No:44) | ■■■■■■A■■T■■■■■■■■■■ | 2109±291 | 2596±166 | 12.9±0.7 | 10425±674 |
1639(SEQID No:45) | ■■■■■AA■■T■■■■■■■■■■ | 1827±83 | 202±132 | 11.5±0.4 | 9489±103 |
1707(SEQID No:46) | ■■■■■■A■■TC■■■■■■■■■ | ND | 1147±175 | 4.0±0.2 | 3534±217 |
1708(SEQID No:47) | ■■■■■CA■■TG■■■■■■■■ | ND | 59±3 | 1.5±0.1 | 466±109 |
黑点代表位置;CpG二核苷酸用下划线标出;ND=未进行a进行的实验为至少三次近似的结果。CH12.LX和脾B细胞的未刺激的对照培养物的IL-6水平≤10pg/ml。未刺激的培养物的IgM水平为547±82ng/ml。CpG二核苷酸用下划线标出,黑点代表位置。b[3H]尿嘧啶吸收用对未刺激的对照(2322.67±213.68cpm)所提高的倍数表示(SI:刺激指数)。细胞用20μM各种CpG O-ODN刺激。数据代表三个数据的平均值±标准偏差。c用ELISA测定。
对淋巴细胞活化的动力学的研究采用了小鼠脾细胞。在加入ODN的同时对细胞进行冲击,4小时后收获,已经有了2倍的3H尿嘧啶的吸收。刺激的峰值在12-48小时,然后降低。24小时后,检测不到完整的ODN,这也许就是当纯化的B细胞随后在有或没有抗-IgM(亚促有丝分裂剂量)条件下与CpG ODN一起培养时发生刺激性下降的原因,在48小时后,两种促有丝分裂还造成繁殖也同时增强约10倍。刺激的力度依赖于浓度,并且在对两种物质为优化的条件下都一致地超过LPS。含有抗核酸酶的硫代磷酸酯主链的寡核苷酸比未修饰的寡核苷酸强大约200倍。
采用细胞生长循环来确定由CpG-ODN活化的B细胞的数量。CpG-ODN诱导了在大于95%的B细胞的循环。用流式细胞仪区分脾B淋巴细胞为CD23-(边缘区)和CD23+(小泡区)亚群,它们对ODN诱导的刺激都有同样的反应,用Percoll梯度区分的B细胞类群也是休眠和活化的种群。这些研究表明,CpG-ODN诱导几乎所有的B细胞进入细胞循环。免疫刺激性核酸分子对小鼠B细胞编程性细胞死亡的封闭
有些B细胞系,例如WEHI-231,被诱导经历生长的休眠和/或编程性细胞死亡,应答于它们的抗原受体与抗-IgM的交联[Jakway,J.P.et al.,″Growth regulation ofthe B lymphoma cell lineWEHI-231 by anti-immunoglobulin,lipopolysaccharide and otherbacterial products″J.Immunol.137:2225(1986);Tsubata,T.,J.Wuand T.Honio:B-cell apoptosis indueced by antigen receptorcorsslinking is blocked by a T-cell signal through CD40.″Nature364:645(1993)]。用某些刺激物如LPS和CD40配体可以将WEHI-231细胞从这种生长休眠状态下恢复出来。含有CpG基元的ODN也被发现可以保护WEHI-231细胞不受抗-IgM诱导的生长休眠的影响,表明这种效果不需要辅助细胞种群。随后的研究工作表明,CpG ODN诱导Bcl-x和myc表达,它们可能对抵抗编程性细胞死亡有作用。再者,CpG核酸被发现可以封闭人细胞的编程性细胞死亡。这种对编程性细胞死亡的抑制具有重要性,因为它将提高和延长CpG DNA的免疫活化。鉴定对诱导小鼠IL-6和IgM分泌以及B细胞繁殖为最优化的CpG基元
为了确定最优化的B细胞刺激性CpG基元是否与对IL-6分泌的最优化CpG基元相同,研究了一组ODN,它们的CpG二核苷酸的侧翼碱基被逐步取代。对该组ODN的研究着重于分析它们对B细胞繁殖、Ig生产、IL-6分泌的效应,使用了脾B细胞和CH12.LX细胞。如表2所示,优化的刺激性基元含有未甲基化的CpG,侧翼为两个5′嘌呤和两个3′嘧啶。一般地说,5′嘌呤向3′嘧啶的突变和3′嘧啶向嘌呤的突变都显著地降低这种效应。从5′嘌呤向C的变化是特别的有破坏性的,但是,从5′嘌呤向T的变化或3′嘧啶向嘌呤的变化所产生的影响就比较小。根据这些分析以及其它的ODN的结果,确定了优化的CpG基元对诱导IL-6分泌为TGACGTT,其相同于优化的促有丝分裂和IgM诱导性CpG基元(表2)。该基元比任何所研究过的含有回文序列的序列都更具有刺激性(1639,1707和1708)。由在细菌DNA中或寡核苷酸中的CpG基元诱导的小鼠细胞因子的分泌
如在实施例9中所描述的那样,以CpG DNA刺激后的脾细胞分泌的IL-6的数量用ELISA测定。采用的不是全脾细胞,而是用去除了T细胞的脾细胞培养物,进行了体外研究,经过最初的研究发现,T细胞对CpG DNA刺激的脾细胞生产IL-6没有任何作用。如表3所示,用大肠杆菌DNA培养的细胞明显地提高了IL-6的生产,而用小牛胸腺DNA培养的细胞则没有提高。为了确认所观察到的用大肠杆菌DNA培养的细胞的IL-6生产的提高不是由于污染物或其它的细菌产物所造成的,在进行分析之前,对DNA用DNA酶进行处理。这种DNA酶的预处理取消了由大肠杆菌DNA诱导的IL-6的生产(表3)。此外,从LPS-非应答C3H/HeJ小鼠来的脾细胞应答了细菌DNA而产生了相似水平的IL-6。为了研究由大肠杆菌DNA诱导的IL-6的分泌是否由细菌DNA中的未甲基化CpG二核苷酸所介导,检验了甲基化的大肠杆菌DNA和一组合成性ODN。如表3所示,CpG ODN显著地诱导了IL-6的分泌(ODN5a,5b,5c),而CpG甲基化大肠杆菌DNA,或含有甲基化CpG的ODN(ODN5f),或不含CpG的ODN(ODN5d)则都没有发生诱导。在CpG二核苷酸(ODN5b)以外位置的改变,以及其它的胞嘧啶的甲基化(ODN5g)都没有减弱CpG ODN的效应。在含有三个CpG的ODN中对一个CpG甲基化的结果是部分地降低了其刺激性(表3,比较ODN5c和5e)。
表3:由在细菌DNA中或寡核苷酸中的CpG基元诱导的小
鼠IL-6的分泌
处理 | IL-6(pg/ml) | |
小牛胸腺DNA | ≤10 | |
小牛胸腺DNA+DNase | ≤10 | |
大肠杆菌DNA | 1169.5±94.1 | |
大肠杆菌DNA+DNase | ≤10 | |
CpG甲基化大肠杆菌DNA | ≤10 | |
LPS | 280.1±17.1 | |
培养基(没有DNA) | ≤10 | |
ODN | ||
5a SEQ ID NO:1 | ATGGACTCTCCAGCGTTCTC | 1096.4±372.0 |
5b SEQ ID NO:2 | ■■■■AGG■■■■■A■■■■■■■■ | 1124.5±126.2 |
5c SEQ ID NO:3 | ■■C■■■■■■■G■■■■■■■ | 1783.0±189.5 |
5d SEQ ID NO:4 | ■■■■AGG■■C■■T■■■■■■■ | ≤10 |
5e SEQ ID NO:5 | ■■C■■■■■■■G■■Z■■■■■■ | 851.1±114.4 |
5f SEQ ID NO:6 | ■■Z■■■■■■ZG■■Z■■■■■■ | ≤10 |
5g SEQ ID NO:7 | ■■C■■■■■■■G■■■■■■Z■■ | 1862.3±87.26 |
去除了T细胞的来自DBA/2小鼠的脾细胞用磷酸二酯修饰的寡核苷酸(O-ODN)(20μM)、小牛胸腺DNA(50μg/ml)、经过或不经过酶处理的大肠杆菌DNA(50μg/ml)、或LPS(10μg/ml)分别刺激24小时。数据代表三个数据的平均值±SD。CpG二核苷酸用下划线标出,黑点代表位置。Z表示5-甲基胞嘧啶。CpG基元可以用作人工附剂
免疫应答的非特异性刺激物是已知的附剂。使用附剂对诱导相对于抗原的强抗体应答是重要的(Harlow and Lane,Antibodies:A Laboratory manual,Cold Spring harbor,N.Y.CurrentEdition;通过在此引述而合并于本文)。附剂总体效应是强烈的,它们的重要性是不会被过分强调的。附剂的作用允许用更小剂量的抗原来产生更为一致的抗体应答。对免疫应答的非特异性活化经常可以分辨出获得免疫应答的成功或失败。应该在第一次注射的时候使用附剂,除非有非常特殊的理由来避免这样做。大多数的附剂含有两个成分。一个成分是用来保护抗原不被快速分解代谢[例如,脂质体或合成的表面活性剂(Hunter et al.,1981)]。脂质体仅仅在免疫原被整合到外脂层时有效,内埋的分子是免疫系统看不见的。其它的成分则是非特异性刺激免疫应答的物质。这些物质的作用是提高淋巴因子的水平。淋巴因子直接刺激抗原处理细胞的活性,并引起注射位置的局部发炎反应。早期的工作完全依赖于热杀死细菌(Dienes1936)或脂多糖(LPS)(Johnsonet al.,1956)。LPS是合理的毒性的,通过对它的结构的分析,其作为附剂的大多数的性质已经被证实为在于称作脂质A的部分。脂质A可以由多种合成的和天然的形式获得,其毒性远远小于LPS,但仍然保存了其前身的LPS分子的大多数良好的附剂性质。脂质A化合物经常用脂质体提供。
近来,寻找强有力的并带有更可接受的副作用的附剂的工作导致了新的合成附剂的产生。在本发明中,我们提供了序列第1826号,即TCCATGACGTTCCTGACGTT(SEQ ID NO:10),它是一种包括了含CpG的核酸的附剂。该序列是强免疫活化序列,并且是非常优秀的附剂,其效率相等于完全Freund′s,甚至超过该附剂,但是,又没有明显的毒性。CpG基元诱导小鼠IL-6生产的效价
细菌DNA和CpG ODN在去除了T细胞的小鼠脾细胞中诱导的IL-6生产是属于剂量依赖型的,但是,脊椎动物DNA和非CpG ODN则不是(图1)。IL-6的生产在大约50μg/ml细菌DNA和40μM的CpG O-ODN水平时是平台式的。由细菌DNA和CpGODN诱导的IL-6的生产的最大值分别在1-1.5ng/ml和2-4ng/ml。这些水平比在LPS(0.35ng/ml)刺激后所见到的要明显地高(图1A)。为了评价带有核酸酶抗性DNA主链的CpG ODN是否也可以诱导IL-6的生产,向去除了T细胞的小鼠脾细胞中加入S-ODN。CpG S-ODN也诱导了剂量依赖型的IL-6生产,并且水平也类似于CpG O-ODN,而非CpG S-ODN则没有诱导IL-6的生产(图1C)。浓度为0.05μM的CpG S-ODN可以在这些细胞中诱导最大的IL-6生产。这个结果表明核酸酶抗性DNA主链修饰保留的CpG DNA对IL-6生产的序列特异性能力,并且CpG S-ODN在该检测系统中比CpG ODN的强度高出80倍以上。CpG DNA在体内对小鼠IL-6分泌的诱导
为了评价细菌DNA和CpG S-ODN体内诱导IL-6分泌的能力,给BALB/c小鼠静脉注射100μg大肠杆菌DNA、小牛胸腺DNA、CpG或非刺激性S-ODN,2小时后采血。在注射了大肠杆菌DNA的组中,血清内IL-6水平为约13ng/ml,而在注射了小牛胸腺DAN的组和注射了PBS的组中,血清内没有检测到IL-6(表4)。在注射了CpG S-ODN的组中,血清内IL-6的水平为约20ng/ml。在注射了非刺激性S-ODN的组中,没有检测到IL-6(表4)。
表4.CpG DAN刺激诱导的小鼠体内IL-6分泌
刺激物 | IL-6(pg/ml) |
PBS | <50 |
大肠杆菌DNA | 13858±3143 |
小牛胸腺DNA | <50 |
CpG S-ODN | 20715±606 |
非-CpG S-ODN | <50 |
小鼠(每组2只)接受静脉注射100μl的PBS、200μg的大肠杆菌DNA或小牛胸腺DNA、或500μg的CpG S-ODN或非-CpG对照S-ODN。注射后2小时采血,按1∶10稀释,每种血清用ELISA测定IL-6。ELISA测定IL-6的敏感限定为5pg/ml。CpG S-ODN的序列是5′GCATGACGTTGAGCT3′(SEQ ID NO:48),非刺激性S-ODN的序列是5′TCTAGATGTTAGCGT3′(SEQID NO:49)。应该注意的是,虽然在序列48中有CpG,但对于刺激效应来讲它太靠近3′端了。数据代表两个结果的平均值±标准偏差。实验进行至少两次且结果类似。用CpG基元刺激后小鼠体内分泌IL-6的动力学
为了评价CpG DNA在体内诱导IL-6分泌的动力学,对BALB/c小鼠静脉注射CpG或对照非-CpG S-ODN。在注射了CpGS-ODN的组中,血清IL-6水平在1小时内就明显提高,并且在2小时达到峰值水平约9ng/ml(图2)。血清中IL-6蛋白质水平在4小时后明显下降,并在12小时后回到基础水平。与CpG DNA刺激的组相反,在注射了非刺激性S-ODN或PBS的组中,血清内IL-6没有明显提高(图2)。CpG基元在体内诱导的IL-6mRNA表达的动力学和组织分布
如图2所示,在CpG DAN刺激后,血清IL-6水平迅速提高。为了调查这种血清IL-6的可能的组织起源以及CpG DNA刺激后体内IL-6基因表达的动力学,在刺激后的不同的时间点对BALB/c小鼠静脉内注射CpG或非CpG S-ODN和RNA,RNA分别取自肝、脾、胸腺、和骨髓。如图3A所示,注射CpG S-ODN后30分钟内,在肝、脾、和胸腺的IL-6mRNA水平已经明显提高。肝内IL-6mRNA在注射后2小时达到峰值,随后迅速下降并在刺激后8小时回到基础水平(图3A)。脾内IL-6mRNA在刺激后2小时达到峰值,然后逐渐降低(图3A)。胸腺内IL-6mRNA在注射后1小时达到峰值,然后逐渐降低(图3A)。在注射CpG S-ODN后1小时内,骨髓内IL-6mRAN明显提高,然后恢复到基础水平。作为对CpG S-ODN的应答,肝、脾、和胸腺的IL-6mRNA表达的提高明显高于骨髓。CpG DNA诱导的小鼠细胞因子表达的形式
在体内或在全脾细胞中,在最初的6个小时内,下列的白细胞介素如,IL-2、IL-3、IL-4、IL-5、和IL-10等都没有检测到其蛋白质水平的显著提高[Ilinman,D.M.et al.,(1996)Proc.Natl.Acad.Sci.USA93:2879-2883]。然而,在注射CpG ODN的小鼠血清中,TNF-α的水平在30分钟内明显提高,IL-6的水平在2小时内显著地升高。在脾细胞中,在首先的2小时内也检测到IL-12和伽玛干扰素(IFN-γ)mRNA的表达的提高。
表5.CpG寡核苷酸诱导人PBMC细胞因子的分泌
ODN | 序列(5′-3′) | IL-61 | TNF-α1 | IFN-γ1 | GM-CSF | IL-12 |
512SEQ ID NO:31 | TCCATGTCGGTCCTGATGCT | 500 | 140 | 15.6 | 70 | 250 |
1637SEQ ID NO:38 | ■■■■■■C■■■■■■■■■■■■■ | 550 | 16 | 7.8 | 15.6 | 16 |
1615SEQ ID NO:39 | ■■■■■■G■■■■■■■■■■■■■ | 600 | 145 | 7.8 | 45 | 145 |
1614SEQ ID NO:40 | ■■■■■■A■■■■■■■■■■■■■ | 550 | 31 | 0 | 50 | 31 |
1636SEQ ID NO:41 | ■■■■■■■■■A■■■■■■■■■■ | 325 | 250 | 35 | 40 | 250 |
1634SEQ ID NO:42 | ■■■■■■■■■C■■■■■■■■■■ | 300 | 400 | 40 | 85 | 400 |
1619SEQ ID NO:43 | ■■■■■■■■■T■■■■■■■■■■ | 275 | 450 | 200 | 80 | 450 |
1618SEQ IDNO:44 | ■■■■■■A■■T■■■■■■■■■■ | 300 | 60 | 15.6 | 15.6 | 62 |
1639SEQ ID NO:45 | ■■■■■AA■■T■■■■■■■■■■ | 625 | 220 | 15.6 | 40 | 220 |
1707SEQ ID NOL:46 | ■■■■■■A■■TC■■■■■■■■■ | 300 | 70 | 17 | 0 | 70 |
1708SEQ ID NO:47 | ■■■■■CA■■TG■■■■■■■■■ | 270 | 10 | 17 | ND | 10 |
黑点代表位置,CpG二核苷酸用下划线标出。
1由ELISA测定,采用了从R&D System的Quantikine试剂盒(pg/ml)。在收集上清液和检测前,细胞培养在10%自身血清并加以给出剂量的寡脱氧核苷酸(12μg/ml),对TNF-α为4小时,对其它的细胞因子为24小时。数据代表相对于没有加入寡脱氧核苷酸的小孔的细胞因子的提高水平。CpG DNA诱导的特异性单核细胞人PBMC的细胞因子的分泌
采用了与研究小鼠细胞因子表达的同一组ODN,来确定人的细胞是否也被CpG基元诱导表达细胞因子(或繁殖),并确定有关的CpG基元。寡核苷酸1619(GTCGTT)是对TNF-α和INF-γ的最好的诱导物,与其几乎相等的在寡核苷酸1634中的基元(GTCGCT)则近随其后(表5)。在寡脱氧核苷酸1637和1614中的基元(GCCGGT和GACGGT)导致强烈的IL-6分泌但对其它的细胞因子则相对没有诱导。因此,这就显示人淋巴细胞同小鼠淋巴细胞一样,应答于CpG二核苷酸而分泌不同的细胞因子,具体由其周围的碱基所决定。然而,对刺激小鼠基元为最好的基元则不同于对人细胞最有效的基元。某些CpG寡脱氧核苷酸对活化人细胞是很差的(寡脱氧核苷酸1707、1708,它们分别含有形成回文的序列GACGTC和CACGTG)。
对DNA应答的细胞表现为单核细胞,因为用L-亮氨酰-亮氨酸甲基酯(L-LME)处理可以消除细胞因子的分泌,该物质对单核细胞为选择性毒性物(但是,也对T淋巴细胞和NK细胞为细胞毒性的),并不影响B细胞的Ig分泌(表6)。经过L-LME处理而存活的细胞用锥虫蓝排斥有>95%的存活率,这表明,这些细胞缺少细胞因子应答并不简单反映非特异性的细胞死亡。应答大肠杆菌DNA的细胞因子分泌需要未甲基化CpG基元,因为甲基化消除了大肠杆菌DNA的作用(表6中倒数第二行)。LPS对DNA的污染并不能解释这些结果,因为在天然的和甲基化的DNA中的污染是相同水平的,而且,加入两倍最高水平的污染物LPS也没有产生效应(未示出)。
表6.CpG DNA诱导入PBMC的细胞因子的分泌
DNA | TNF-α(pg/ml)1 | IL-6(pg/ml) | IFN-γ(pg/ml) | RANTES(pg/ml) |
EC DNA(50μg/ml) | 900 | 12,000 | 700 | 1560 |
EC DNA(5μg/ml) | 850 | 11,000 | 400 | 750 |
EC DNA(0.5μg/ml) | 500 | ND | 200 | 0 |
EC DNA(0.05μg/ml) | 62.5 | 10,000 | 15.6 | 0 |
EC DNA(50μg/ml)+L-LME2 | 0 | ND | ND | ND |
EC DNA(10μg/ml)Methyl3 | 0 | 5 | ND | ND |
CT DNA(50μg/ml) | 0 | 600 | 0 | 0 |
1所有细胞因子的水平的测定都用ELISA进行,采用的是R&D Systems的Quantikine试剂盒,如同前面的表中描述的一样。结果代表从不同的供体来的PBMC的情况。
2对细胞用L-亮氨酰-亮氨酸甲基酯(M-LME)预处理15分钟,来确定在这样的条件下的细胞因子的产生是否是从单核细胞中来的(或来自于其它的对L-LME敏感的细胞)。
3对大肠杆菌DNA用2U/μgDNA的CpG甲基酶(NewEngland Biolabs)甲基化,以HpA-Ⅱ和Msp-Ⅰ酶解来确认甲基化。作为阴性对照,样品内包括的污染物LPS量为在该实验条件下没有诱导可检测细胞因子生产的最高量大肠杆菌DNA中的污染物的两倍。
ND=未进行。
用L-LME处理的PBMC损失了细胞因子生产这个现象建议单核细胞也许对应答CpG DNA的细胞因子生产负责。为了更直接地验证这个假设,测试了CpG DNA对高纯度的人单核细胞和巨嗜细胞的效果。如同所假设的那样,CpG DNA直接活化人巨嗜细胞生产IL-6、GM-CSF、和TNF-α,而非CpG DNA则不能(表7)。
表7.CpG DNA诱导纯化人巨嗜细胞分泌细胞因子
应答CpG基元的诱导的小鼠IgM生产中的IL-6的生物学作用
IL-6(pg/ml) | GM-CSF(pg/ml) | TNF-α(pg/ml) | |
细胞 | 0 | 0 | 0 |
CT DNA(50μg/ml) | 0 | 0 | 0 |
EC DNA(50μg/ml) | 2000 | 15.6 | 1000 |
上述的动力学研究揭示了在CpG刺激后1小时诱导了IL-6的分泌并进而有IgM的分泌。因为对ODN诱导IL-6分泌的优化CpG基元相同于IgM的优化基元(表2),所以检测了CpG基元是否单独诱导IgM和IL-6生产,以及是否IgM的生产依赖于IL-6的产生。加入中性抗-IL-6抗体抑制了体外的由CpG ODN介导的剂量依赖型的IgM生产,但是对照抗体则不能(图4A)。相对照的是,加入IL-6则没有影响CpG诱导的B细胞的繁殖水平和其基础水平(图4B)。应答CpG DNA的IL-6启动子的转录活性的提高
用CpG DNA刺激后的IL-6mRNA和蛋白质水平的提高可以是来源于转录调节或转录后调节的结果。为了确定IL-6启动子的转录活性是否在与CpG ODN一起培养的B细胞中被上调,采用了应答CpG DNA产生IL-6的小鼠B细胞系wEHI-231,对起用IL-6启动子CAT构建物转染[pIL-6/CAT(Pottratz,S.T.et al.,17B-estradiol)Inhibits expression of human interleuking-6-promoter-reporter constructs by a receptor-dependent mechanism.J.Clin.Invest.93:944]。CAT检测在用各种浓度的CpG或非CpGODN刺激后进行。如图5所示,CpG ODN诱导的CAT活性的提高是剂量依赖型的,而非CpG ODN则没有诱导CAT活性。这就肯定了CpG诱导IL-6启动子的转录活性。CpG ODN诱导的B细胞活化对5′和3′硫代磷酸酯核苷酸内连接数目的依赖
为了确定ODN主链上的部分的硫修饰是否足以提高B细胞的活化,选取了一系列具有相同的序列但在5′和3′端的核苷酸内连接的S数目不同的ODN,并测定了它们的效果。根据以前的对核酸酶降解ODN的研究,确定了需要在ODN的5′端有至少两个硫代磷酸酯连接才可以保护ODN不被细胞性外切核酸酶或内切核酸酶所降解。因此,只对含有两个5′硫代磷酸酯修饰的连接的嵌合性ODN以及各种数目的3′修饰的连接进行了检测。
试验了这些ODN对淋巴细胞的刺激效果,使用了三种浓度(3.3,10,和30μM),测定了它们在处理过的脾细胞培养物中的总RNA合成水平(由3H尿苷整合)或DNA合成(有3H胸苷整合)水平(实施例10)。带有CpG基元的O-ODN(0/0硫代磷酸酯修饰)对脾细胞没有刺激,除非在加入的培养基中的浓度为至少10μM(实施例10)。然而,当这个序列发生了在5′端的两个S连接修饰和在3′端的至少3个S连接的修饰时,则在3.3μM的剂量时有显著的刺激表现出来。在这种低剂量的条件下,随着3′端修饰的碱基数目的增加有刺激水平的逐渐增加,当达到或超过6个修饰时,刺激指数开始下降。一般地讲,对脾细胞刺激的优化的3′的S修饰数目为5。在所有测试的3种浓度中,S-ODN都比嵌合性化合物的刺激性小。CpG介导的淋巴细胞活化对主链修饰类型的依赖
硫代磷酸酯修饰的ODN(S-ODN)比磷酸二酯修饰的ODN(O-ODN)具有更强的对核酸酶的抗性。因此,由S-ODN和S-O-ODN(即,嵌合性硫代磷酸酯ODN,其中的中央连接是磷酸二酯,但有2个5′和5个3′的连接是硫代磷酸酯修饰的)所造成的比O-ODN更高的免疫刺激可能是前者的对核酸酶的抗性的结果。为了确定ODN核酸酶抗性在CpG ODN的免疫刺激中的作用,测试了嵌合性ODN的刺激效果,这些ODN中的5′端和3′端都附带有核酸酶抗性,来自于甲基磷酸酯(MP-)、甲基硫代磷酸酯(MPS-)、磷酸二酯(S-)、或二硫代磷酸酯(S2-)的核苷酸内的连接(实施例10)。这些研究显示,无论它们的核酸酶抗性如何,MP-O-ODN实际上都比O-ODN的免疫刺激性低。然而,通过用5′端和3′端的MPS核苷酸内连接来取代非桥连O分子将MP和S的修饰结合起来,就使免疫刺激的水平恢复到稍微高于O-ODN的水平。
S-O-ODN比O-ODN更为具有刺激性,甚至比S-ODN更具有刺激性,至少在高于3.3μM浓度时如此。在低于3μM浓度时,带有3M序列的S-ODN比相应的S-O-ODN更具刺激性,而带有3D序列的S-ODN则比相应的S-O-ODN的刺激性弱(实施例10)。在比较这两个序列的刺激性CpG基元时,注意到了3D序列与侧翼为2个5′端嘌呤和2个3′端嘧啶的CpG这样的基元完全吻合。然而,在ODN3D中紧靠CpG的侧翼碱基不是优化的,其具有5′端嘧啶和3′端嘌呤。根据进一步的试验,发现免疫刺激所需要的序列对S-ODN比对S-O-ODN和O-ODN更为严谨。S-ODN与优化的CpG基元吻合性差就会对淋巴细胞的活化没有刺激或很小(例如,序列3D)。然而,与基元吻合很好的S-ODN,特别是在紧靠CpG的侧翼位置,都比相应的S-O-ODN更具有刺激性(例如,序列3M,序列4和6),虽然在高浓度(大于3μM)时的峰值效应是S-O-ODN的更强(实施例10)。
S2-O-ODN具有显著的刺激性,并且在每个测试浓度都引起比相应的S-ODN或S-O-ODN更为强烈的对淋巴细胞的活化。
在带有S或S2取代的CpG ODN中所见到的对B细胞刺激的升高可能是下述的一个或全部的效应的结果:核酸酶抗性、增强的细胞吸收、增强的蛋白质的结合、和改变了的细胞间的定位。然而,核酸酶抗性不会是唯一的解释,因为MP-O-ODN实际上比带有CpG基元的O-ODN的刺激性低。以前的研究已经显示淋巴细胞对ODN的吸收明显地受到主链的化学结构的影响[Zhao et al.,(1993)Comparison of cellular binding and uptake ofantisense phosphodiester,phosphorothioate,and mixedphosphorethioate and methylphosphonate olignucleotides.(Andisense Research and Development3,53-66;Zhao et al.,(1994)Stage specific oligonucleotide uptake in murine bone marrow B cellprecursors.Blood 84,3660-36666.)]。细胞膜结合和吸收的最高值见于S-ODN,随后是S-O-ODN,O-ODN,和MP-ODN。这种吸收的区分与免疫刺激的程度正好相关。含有未甲基化CpG的寡核苷酸具有时NK细胞的刺激活性
为了确定含有CpG的寡核苷酸除了刺激B细胞外是否还对天然杀死细胞(NK)具有刺激活性,进行了各种实验。如表8所示,用CpG ODN1和3Dd培养的脾细胞中有明显的NK活性的诱导。相比之下,用非CpG对照ODN处理的效应物都相对没有诱导。
表8.CpG寡核苷酸(ODN)诱导的NK活性
由含有CpG基元的DNA而不是非CpG DNA诱导的NK活性
%YAC-1特异性溶胞* | %2C11特异性溶胞 | |||
效应物 | 靶标 | 效应物 | 靶标 | |
ODN | 50∶1 | 100∶1 | 50∶1 | 100∶1 |
无 | -1.1 | -1.4 | 15.3 | 16.6 |
1 | 16.1 | 24.5 | 38.7 | 47.2 |
3Dd | 17.1 | 27.0 | 37.0 | 40.0 |
非-CpG ODN | -1.6 | -1.7 | 14.8 | 15.4 |
在37℃下对细菌DNA培养18小时,然后测定杀死K562(人)或Yac-1(小鼠)靶细胞在去除了B细胞的脾细胞中和在人PBMC细胞中诱导的溶胞活性,但是,脊椎动物的DNA没有这种效果(表9)。为了确定细菌DNA的刺激活性是否归因于其未甲基化CpG二核苷酸水平的提高,对含有未甲基化CpG二核苷酸、甲基化的CpG二核苷酸、或没有CpG二核苷酸的50个以上的合成性ODN进行了测验。结果如表9所示,显示了合成的ODN可以显著地刺激NK活性,只要它们含有至少一个未甲基化CpG二核苷酸即可。在CpG处于回文序列中的ODN(例如ODN1585,其含有回文序列AACGTT)与没有回文序列的ODN(例如ODN1613或1619)之间没有观察到明显的刺激性的区别,要注意的是,优化的刺激一般见于那些CpG侧翼为2个5′端嘌呤或5′端GpT二核苷酸和2个3′端嘧啶的ODN中。动力学实验表明NK活性的峰值出现在加入OND后的约18小时处。数据指出小鼠NK应答依赖于在先的CpG DNA对单核细胞的活化,导致的IL-12、THF-α、和IFN-α/b的生产(实施例11)。表9.含有CpG基元的DNA但不是非CpG DNA诱导的NK活性
LU/106 | ||||
加入的DNA或细胞因子 | 小鼠细胞 | 人细胞 | ||
实验1 | 无 | 0.00 | 0.00 | |
IL-2 | 16.68 | 15.82 | ||
大肠杆菌DNA | 7.23 | 5.05 | ||
小牛胸腺DNA | 0.00 | 0.00 | ||
实验2 | 无 | 0.00 | 3.28 | |
1585ggGGTCAACGTTGACgggg | (SEQ ID NO.12) | 7.38 | 17.98 | |
1629-------------gtc------------- | (SEQ ID NO.50) | 0.00 | 4.4 | |
实验3 | 无 | 0.00 | ||
1613GCTAGACGTTAGTGT | (SEQ ID NO.51) | 5.22 | ||
1769------------Z------------ | (SEQ ID NO.52) | 0.02 | ND | |
1619TCCATGTCGTTCCTGATGCT | (SEQ ID NO.43) | 3.35 | ||
1765-----------Z----------- | (SEQ ID NO.53) | 0.11 |
在ODN中的CpG二核苷酸用下划线标出;Z代表甲基胞嘧啶。小写字母代表核酸酶抗性硫代磷酸酯修饰的核苷酸内连接,其在效价实验中显示了比非修饰的ODN强20倍以上的力度,具体根据侧翼碱基来决定。多G结尾(g)用在了某些ODN中,因为它们显著地提高了ODN吸收水平。
从所有这些研究中,得到了对CpG DNA的免疫效应的更为全面的理解,并将其总结于图6中。
CpG基元的免疫活化可能依赖于CpG侧翼的碱基,在ODN中的CpG的数量和间隔。虽然在理想的碱基成分中的单一CpG可以很强并且是有用的免疫活化子,但在含有几个CpG并带有适宜的侧翼碱基和间隔的ODN中能见到更为优越的效果。对B细胞的活化来讲,优化的CpG基元是TGACGTT。
下面所进行的研究是为了确定对刺激人细胞为优化的ODN序列,检验了变换CpG二核苷酸的数目、间隔和侧翼碱基的效果。确定带有对活化人NK细胞为优化的CpG基元的硫代磷酸酯ODN
要想应用于临床,则ODN必须以不受核酸酶降解的形式提供给对象。用磷酸二酯ODN来达到这个目的的方法是本领域所熟知的,包括将其包被在脂质中或在释放系统中,例如,在纳米颗粒中。这种保护还可以利用对DNA的化学修饰来达到,例如,修饰的DNA主链包括那些核苷酸间连接为抗核酸酶的。有些修饰可以赋予另外的所需性质,例如提高细胞吸收。磷酸二酯连接可以通过用硫替代非桥连氧原子中的一个来进行修饰,从而得到硫代磷酸酯DNA。如果硫代磷酸酯DNA具有CpG基元,则其具有提高了的细胞吸收(Krieg et al.,Antisense Res.Dev.6:133,1996)和改善了的B细胞刺激性。因为NK活化相关于体内的附剂效应,所以确定那些可以活化人NK细胞的硫代磷酸酯ODN是十分重要的。
检验了不同的硫代磷酸酯ODNs-即在各种碱基成分中含有CpG二核苷酸-对人NK细胞活化的效果(表10)。ODN1840含有2份TGTCGTT基元,具有明显的NK溶胞活性(表10)。为了进一步确定其它的对NK活化为优化的ODN,对大约100个含有不同数量和间隔的CpG基元的ODN进行了检测,并以ODN1982作为对照。结果列于表11。
有效的ODNs以TC或TG作为5′端开始,然而,这个要求不是必须的。带有内含CpG基元的ODNs(例如,ODN1840)一般是比GTCGCT基元紧靠5′端的ODN较弱的刺激物(例如,ODN1967和1968)。ODN1968在其3′端的那一半具有第二个GTCGTT基元,其始终比不含第二个基元的ODN1967更具有刺激性。然而,ODN1967比实验1和3中比ODN1968稍强,在实验2中则不是。ODN2005具有第三个GTCGTT基元,其所诱导的NK活性平均比1968稍高。然而,ODN2006中GTCGTT基元之间的间隔由于在每个基元之间都加入了两个T而被增加了,其比ODN2005和ODN2007更为优越,后者只有一个基元添加了间隔性的2个T。在CpG基元之间的最小可接受的间隔是一个核苷酸,只要该ODN在3′端有两个嘧啶(优选T)即可(如ODN2015)。令人惊奇的是,用5′端的T来把两个GTCGTT基元对头连接起来也创造了对NK活性为合理强度的诱导物(例如,ODN2016)。选择胸腺嘧啶(T)来分开相连的CpG二核苷酸不是绝对的,因为ODN2002诱导的相当的NK活化,虽然其中是由腺嘌呤(A)将其CpGs(即CGACGTT)间隔开来。还应该注意的是,不含CpG的ODN(例如ODN1982),含有成串的CpGs的ODN,以及CpGs存在于坏的序列中的ODN(例如,ODN2010)都没有对NK活化的刺激效应。
表10.ODN诱导NK溶胞活性(LU)
ODN | 序列(5′-3′) | LU |
细胞自己 | 0.01 | |
1754 | ACCATGGACGATCTGTTTCCCCTC | 0.02 |
1758 | TCTCCCAGCGTGCGCCAT | 0.05 |
1761 | TACCGCGTGCGACCCTCT | 0.05 |
1776 | ACCATGGACGAACTGTTTCCCCTC | 0.03 |
1777 | ACCATGGACGAGCTGTTTCCCCTC | 0.05 |
1778 | ACCATGGACGACCTGTTTCCCCTC | 0.01 |
1779 | ACCATGGACGTACTGTTTCCCCTC | 0.02 |
1780 | ACCATGGACGGTCTGTTTCCCCTC | 0.29 |
1781 | ACCATGGACGTTCTGTTTCCCCTC | 0.38 |
1823 | GCATGACGTTGAGCT | 0.08 |
1824 | CACGTTGAGGGGCAT | 0.01 |
1825 | CTGCTGAGACTGGAG | 0.01 |
1828 | TCAGCGTGCGCC | 0.01 |
1829 | ATGACGTTCCTGACGTT | 0.42 |
18302 | 随机序列 | 0.25 |
1834 | TCTCCCAGCGGGCGCAT | 0.00 |
1836 | TCTCCCAGCGCGCGCCAT | 0.46 |
1840 | TCCATGTCGTTCCTGTCGTT | 2.70 |
1841 | TCCATAGCGTTCCTAGCGTT | 1.45 |
1842 | TCGTCGCTGTCTCCGCTTCTT | 0.06 |
1851 | TCCTGACGTTCCTGACGTT | 2.32 |
1溶胞单位(LU)按照所述(8)进行。简言之,从正常的供体收集PBMC,用Ficoll离心,然后采用或不采用给定剂量的ODN(加入的剂量为6μg/ml)培养24小时。确定它们的对51Cr-标记的K562细胞的溶胞能力。给出的结果是从几个不同的正常人供体获得的典型的结果。2该寡核苷酸混合物含有的是在每个位置上从4种碱基中随机选择的碱基。
表11.带有良好基元的硫代磷酸酯CpG ODN诱导NK LU
ODN1 | 序列(5′-3′) | 实验1 | 实验2 | 实验3 |
细胞自己 | 0.00 | 1.26 | 0.46 | |
1840 | TCCATGTCGTTCCTGTCGTT | 2.33 | ND | ND |
1960 | TCCTGTCGTTCCTGTCGTT | ND | O.48 | 8.99 |
1961 | TCCATGTCGTTTTTGTCGTT | 4.03 | 1.23 | 5.08 |
1962 | TCCTGTCGTTCCTTGTCGTT | ND | 1.60 | 5.74 |
1963 | TCCTTGTCGTTCCTGTCGTT | 3.42 | ND | ND |
1965 | TCCTGTCGTTTTTTGTCGTT | 0.46 | 0.42 | 3.48 |
1966 | TCGTCGCTGTCTCCGCTTCTT | 2.62 | ND | ND |
1967 | TCGTCGCTGTCTGCCCTTCTT | 5.82 | 1.64 | 8.32 |
1968 | TCGTCGCTGTTGTCGTTTCTT | 3.77 | 5.26 | 6.12 |
19792 | TCCATGTZGTTCCTGTZGTT | 1.32 | ND | ND |
1982 | TCCAGGACTTCTCTCAGGTT | 0.05 | ND | 0.98 |
1990 | TCCATGCGTGCGTGCGTTTT | 2.10 | ND | ND |
1991 | TCCATGCGTTGCGTTGCGTT | 0.89 | ND | ND |
2002 | TCCACGACGTTTTCGACGTT | 4.02 | 1.31 | 9.79 |
2005 | TCGTCGTTGTCGTTGTCGTT | ND | 4.22 | 12.75 |
2006 | TCGTCGTTTTGTCGTTTTGTCGTT | ND | 6.17 | 12.82 |
2007 | TCGTCGTTGTCGTTTTGTCGTT | ND | 2.68 | 9.66 |
2008 | GCGTGCGTTGTCGTTGTCGTT | ND | 1.37 | 8.15 |
2010 | GCGGCGGGCGGCGCGCGCCC | ND | 0.01 | 0.05 |
2012 | TGTCGTTTGTCGTTTGTCGTT | ND | 2.02 | 11.61 |
2013 | TGTCGTTGTCGTTGTCGTTGTCGTT | ND | 0.56 | 5.22 |
2014 | TGTCGTTGTCGTTGTCGTT | ND | 5.74 | 10.89 |
2015 | TCGTCGTCGTCGTT | ND | 4.53 | 10.13 |
2016 | TGTCGTTGTCGTT | ND | 6.54 | 8.06 |
1PBMC基本如本文所述。结果是6个分别的实验的代表;每个实验代表不同的供体。2这是甲基化形式的ODN1840;Z=5-甲基胞嘧啶,LU是溶胞单位,ND=未进行,CpG二核苷酸用下划线标出。确定带有对人B细胞繁殖活化为优化的CpG基元的硫代磷酸酯ODN
CpG ODN诱导B细胞繁殖的能力是其附剂潜力的良好指标。具有强附剂效应的ODN一般都诱导B细胞繁殖。为了确定诱导B细胞繁殖的优化的CpG ODN是否与诱导NK细胞活性的ODN相同,测试了相似的一组ODN(表12)。表现出最为一致的刺激性的ODN是ODN2006(表12)。
表12.硫代磷酸酯CpG ODN对人B细胞繁殖的诱导
DN | 序列(5′-3′) | 刺激指标1 | ||||
实验1 | 实验2 | 实验3 | 实验4 | 实验5 | ||
1840 | TCCATGTCGTTCCTGTCGTT | 4 | ND | ND | ND | N |
1841 | TCCATAGCGTTCCTAGCGTT | 3 | ND | ND | ND | N |
1960 | TCCTGTCGTTCCTGTCGTT | ND | 2.0 | 2.0 | 3.6 | N |
1961 | TCCATGTCGTTTTTGTCGTT | 2 | 3.9 | 1.9 | 3.7 | N |
1962 | TCCTGTCGTTCCTTGTCGTT | ND | 3.8 | 1.9 | 3.9 | 5 |
1963 | TCCTTGTCGTTCCTGTCGTT | 3 | ND | ND | ND | N |
1965 | TCCTGTCGTTTTTTGTCGTT | 4 | 3.7 | 2.4 | 4.7 | 6 |
1967 | TCGTCGCTGTCTGCCCTTCTT | ND | 4.4 | 2.0 | 4.5 | 5 |
1968 | TCGTCGCTGTTGTCGTTTCTT | ND | 4.0 | 2.0 | 4.9 | 8 |
1982 | TCCAGGACTTCTCTCAGGTT | 3 | 1.8 | 1.3 | 3.1 | 3 |
2002 | TCCACGACGTTTTCGACGTT | ND | 2.7 | 1.4 | 4.4 | N |
2005 | TCGTCGTTGTCGTTGTCGTT | 5 | 3.2 | 1.2 | 3.0 | 7 |
2006 | TCGTCGTTTTGTCGTTTTGTCGTT | 4 | 4.5 | 2.2 | 5.8 | 8 |
2007 | TCGTCGTTGTCGTTTTGTCGTT | 3 | 4.0 | 4.2 | 4.1 | N |
2008 | GCGTGCGTTGTCGTTGTCGTT | ND | 3.0 | 2.4 | 1.6 | N |
2010 | GCGGCGGGCGGCGCGCGCCC | ND | 1.6 | 1.9 | 3.2 | N |
2012 | TGTCGTTTGTCGTTTGTCGTT | 2 | 2.8 | 0 | 3.2 | N |
2013 | TGTCGTTGTCGTTGTCGTTGTCGTT | 3 | 2.3 | 3.1 | 2.8 | N |
2014 | TGTCGTTGTCGTTGTCGTT | 3 | 2.5 | 4.0 | 3.2 | 6 |
2015 | TCGTCGTCGTCGTT | 5 | 1.8 | 2.6 | 4.5 | 9 |
2016 | TGTCGTTGTCGTT | ND | 1.1 | 1.7 | 2.7 | 7 |
1细胞=手术中收集的并储存于-70℃的人脾细胞,或从正常供体采集的PBMC细胞并经过Ficoll离心。细胞培养在96孔U底微滴盘逼供内加入或不加入给定剂量的ODN(加入的剂量为6μml)。N=12个实验。细胞培养4-7天,用1μCi的3H胸苷冲击18小时然后收获并闪烁计数。刺激指数=不加入ODN小孔中的cpm与在整个培养过程中用给定ODN刺激的小孔的cpm的比率(一旦建立培养物后就没有再加入进一步的ODN)。ND=未进行。
确定诱导人IL-2分泌的硫代磷酸酯ODN
CpG ODN诱导IL-12分泌的能力是其附剂潜力的良好指标,特别从其诱导Th1免疫应答这种高度依赖IL-12的能力的角度来讲更是如此。因此,检验了某一组硫代磷酸酯ODN诱导人PBMC体外分泌IL-12的能力(表13)。这些实验显示在某些人PBMC细胞中,大多数CpG ODN可以诱导IL-12的分泌(例如,实验1)。然而,其它的供体只应答少数的CpG ODN(例如,实验2)。从大多数对象来的ODN2006则始终诱导IL-2分泌(表13)。
表13.硫代磷酸酯CpG ODN诱导人IL-12分泌
ODN1 | 序列(5′-3′) | IL-12 | (Pg/ml) |
实验1 | 实验2 | ||
细胞自己 | 0 | 0 | |
1962 | TCCTGTCGTTCCTTGTCGTT | 19 | 0 |
1965 | TCCTGTCGTTTTTTGTCGTT | 36 | 0 |
1967 | TCGTCGCTGTCTGCCCTTCTT | 41 | 0 |
1968 | TCGTCGCTGTTGTCGTTTCTT | 24 | 0 |
2005 | TCGTCGTTGTCGTTGTCGTT | 25 | 0 |
2006 | TCGTCGTTTTGTCGTTTTGTCGTT | 29 | 15 |
2014 | TGTCGTTGTCGTTGTCGTT | 28 | 0 |
2015 | TCGTCGTCGTCGTT | 14 | 0 |
2016 | TGTCGTTGTCGTT | 3 | 0 |
1PBMC采集于正常供体并用Ficoll离心,然后以106细胞/孔培养在96孔微滴盘中,加入或不加入给定的ODN,如果加入ODN,其剂量为6μg/ml。24小时后收获上清液,用ELISA方法检测IL-12的水平。对每个实验建立标准曲线,其代表不同的供体。确定对B细胞和单核细胞/NK细胞为特异性的寡核苷酸
如图6所示,CpG DNA可以直接活化高纯度B细胞和单核细胞。CpG DNA活化这些种类细胞的机制中有很多相似之处。例如,都需要NFkB活化,对此在下面给予解释。
在对CpG DNA的不同免疫效应的进一步研究中,发现有多于一种以上的CpG基元。具体地讲,寡核苷酸1668带有最佳的小鼠B细胞基元,它是对B细胞和天然杀死细胞(NK)的活化的强诱导物,而寡核苷酸1758是对B细胞的弱活化物,但仍然诱导很好的NK应答(表14)。
表14.刺激优化小鼠B细胞和NK活化的不同的CpG基元
ODN | 序列 | B细胞活化1 | NK活化2 |
1668 | TCCATGACGTTCCTGATGCT(SEQ ID NO:44) | 42,849 | 2.52 |
1758 | TCTCCCAGCGTGCGCCAT(SEQ ID NO:55) | 1,747 | 6.66 |
无 | 367 | 0.00 |
CpG二核苷酸用下划线标出,寡核苷酸是合成的并有硫代磷酸酯修饰的主链来改善其核酸酶抗性。1按照实施例1所述用200nM的寡脱氧核苷酸培养48小时后的3H胸苷吸收来进行测定。2按照溶胞单位来测定。免疫刺激核酸的目的论基础
脊椎动物DNA是高度甲基化的,并且CpG二核苷酸是不足表达的。然而,刺激性CpG基元是在微生物基因组DNA中常见的,但是在脊椎动物DNA中就很少见。此外,细菌DNA已经被报道可以诱导B细胞繁殖和免疫球蛋白(Ig)的生产,而哺乳动物DNA则不行[Messina,J.P.et al.,J.Immunol.147:1759(1991)]。在实施例3中进一步描述的实验中,用CpG甲基化酶对细菌DNA的甲基化被发现是消除了有丝分裂的,这就证实了CpG状态的差异是细菌DNA引起B细胞刺激的原因。这个数据支持了下面的结论:即存在于细菌DNA中的未甲基化CpG二核苷酸负责了细菌DNA的刺激效应。
就目的论而言,看起来CpG基元造成的淋巴细胞活化代表了免疫防御机制,其可以区分细菌DNA和宿主DNA。宿主DNA一般由于编程性细胞死亡而存在于很多发炎的组织和区域中,但它通常不诱导或很少诱导淋巴细胞活化,因为CpG被抑制和甲基化。然而,含有未甲基化CpG基元的细菌DNA的存在可以准确地在感染的区域引起淋巴细胞活化,这则是有益的。这种新的活化途径提供了T细胞依赖抗原对特异性B细胞活化的快速替代途径。由于CpG途径通过抗原受体协同了B细胞的活化,带有对细菌抗原为特异性抗原受体的B细胞将通过其细胞膜Ig接受一个活化信号以及从细菌DNA来的第二个信号,并从而倾向于有区分地被活化。这个途径与其它的B细胞活化途径的相互作用提供了使用多克隆抗原来诱导抗原特异性应答的生理学机制。
然而,B细胞活化似乎不是完全非特异性的。带有对细菌产物为特异性抗原受体的B细胞可以通过细胞膜Ig接受一个活化信号,以及从细菌DNA来的第二信号,从而更强烈地启动抗原特异性免疫应答。如同其它的免疫防御机制,对细菌DNA的应答可以具有在某些位置的非理想序列。例如,对自身抗原的自身免疫应答将还倾向于由细菌感染来区分性地启动,因为自身抗原还可以由细菌DNA启动来向自身接受性B细胞提供第二活化信号。确实,细菌感染对自身免疫的诱导是临床观察中常见的。例如,自身免疫系统性红斑狼疮,其本身是1)以产生抗-DNA抗体为特征,2)由抑制DNA甲基转移酶的药物所诱导[Comacchia,E.J.et al.,J.Clin.Invest.92:38(1993)],以及3)与被减少的DNA甲基化有关[Richardson,B.,L.et al.,Arth.Rheum 35:647(1992)],所以,它可以部分地由对DNA为特异性的B细胞通过由CpG基元提供的刺激信号的活化来启动,以及由细菌DNA同抗原受体的结合来启动。
此外,脓毒病,其特征是由于大量的对免疫系统的非特异性活化而导致高度发病率和死亡率,在死亡的细菌达到了足以直接活化许多淋巴细胞的浓度而释放出细菌DNA和其它的产物时而活化免疫系统。在脓毒病综合症中CpG DNA作用的进一步证据可见于CoWdery,J.等人的文献[Cowdery,J.,et al.,(1996)TheJournal of Immunolgy 156:4570-4575]。
与抗原通过其表面Ig受体来启动B细胞不同的是,CpG-ODN不诱导任何可检测到的Ca2+流,在蛋白质酪氨酸磷酸化中的改变,或IP3的产生。以带有或不带有CpG基元的ODN与FITC共轭进行的流式细胞仪测定按照Zhao,Q等人所述进行[Amisense Research and Development3:53-66(1993)],并且显示了相等的膜结合,细胞吸收,外流,以及胞内定位。这就建议,也许不存在对CpG ODN为特异性的细胞膜蛋白质。不同于经过细胞膜来起作用,这些数据建议的是含有未甲基化CpG的寡核苷酸需要细胞吸收来发挥活性:与固体Teflon支持物共价连接的ODN是非刺激性的,如同在抗生物素蛋白小珠或抗生物素蛋白涂布的培养皿上固定化的生物素化的ODN一样。与FITC或生物素共轭的CpG ODN保留了全部的有丝分裂性质,表明没有立体性妨碍。
最近的数据表明,转录因子NFkB的介入是CpG效应的直接或间接的介导物。例如,用CpG DNA处理B细胞或单核细胞15分钟后,NFkB结合活性的水平被提高了(图7)。然而,这种提高不是由于那些不含CpG基元的DNA所导致的。此外,还发现的是,NFkB活化的两个不同的抑制物,即PDTC和胶毒素,完全封闭了CpG DNA对淋巴细胞的刺激,由测定B细胞繁殖或单核细胞分泌细胞因子而证实,这就建议两种细胞都需要NFkB活化。
对NFkB的活化可能有几种机制。它们包括通过对各种蛋白质激酶的活化,或通过反应性氧的产生。没有发现在CpG DNA处理B细胞或单核细胞后立即诱导蛋白质激酶活化的任何证据,而且蛋白质激酶A、蛋白质激酶C,以及蛋白质酪氨酸激酶的抑制物都对CpG诱导的活化没有任何影响。然而,CpG DNA在B细胞和单核细胞中都快速诱导反应性氧的生产,用按照Royall,J.A.所述的敏感性荧光染料二氢若丹明123检测所证实[Royall,J.A.,and Ischiropoulos,H.(Archives of Biochemistry andBiophysics 302:348-355(1993))]。然而,对产生这些反应性样的抑制物完全封闭了NFkB的诱导以及随后的CpG DNA对细胞繁殖和细胞因子分泌的诱导。
下一个问题是,CpG DNA如何快速地导致了反应性氧的产生。本发明人的前述研究证实了寡核苷酸和质粒或细菌DNA被细胞内吸到核内体中。这些核内体迅速地在细胞内被酸化。为了确定这个酸化步骤是否在CpG DNA活化反应性氧的机制中是重要的,用核内体酸化的特异性抑制物封闭该酸化步骤,包括氯喹、莫能菌素、和bafilomycin等,它们通过不同的机制工作。图8A显示了流式细胞仪的研究结果,其中采用了小鼠B细胞以及二氢若丹明123染料来确定反应性氧的水平。该图内在A组中仅仅含有染料的样品显示了细胞对染料的阳性背景水平为28.6%。正如所预期的,反应性氧的这个水平在用PMA和离子霉素处理细胞20分钟后被大大地提高到80%,即阳性对照(B组)。用CpG寡核苷酸处理的细胞也显示反应性氧水平的提高,使大于50%的细胞变为阳性(D组)。然而,用除了CpG改变之外序列完全相同的寡核苷酸处理的细胞没有显示这种显著的反应性氧水平的提高(E组)。
在有氯喹存在时,这些结果非常不同(图8B)。氯喹将细胞中反应性氧的背景水平稍微的降低了一些,使在A组中的未处理的细胞只有4.3%为阳性。氯喹完全消除了在用CpG DNA处理的细胞中的反应性氧的诱导(B组),但是对用PMA和离子霉素处理的细胞中的反应性氧的水平没有减弱(E组)。这就证明,与PMA加上离子霉素不同,用CpG DNA处理B细胞后的反应性氧的产生需要DNA在核内体中经历酸化步骤。这是淋巴细胞活化的全新的机制。氯喹、莫能菌素、以及bafilomycin还显示对CpG DNA活化NFkB的封闭,以及对随后的繁殖和细胞因子分泌的诱导的封闭。CpG DNA的慢性免疫活化以及自身免疫疾病
CpG DNA对B细胞的活化协同于通过B细胞受体的信号。这就提出了这样的可能,即DNA特异性B细胞可以通过将细菌DNA与其抗原受体结合以及同时的CpG介导的信号的刺激来活化。此外,CpG DNA诱导B细胞变为抗编程死亡的,这种机制被认为在防止对自身抗原如DNA的免疫应答中是重要的。确实,对bDNA的暴露可以启动抗-DNA的抗体的产生。假定CpGDNA具有促进自身免疫的这种潜在能力,那么值得注意的是,患有自身免疫疾病系统性红斑狼疮的患者都具有持续的升高水平的循环血浆DNA,其在高甲基化CpG中被富集。这个发现建议了在狼疮疾病发病机理中CpG DNA造成的慢性免疫活化所可能扮演的角色。
治疗狼疮疾病的一类有效药剂是抗疟疾药物,例如,氯喹。虽然这些药物的治疗机制还不清楚,但是已知的是它们抑制核内体内的酸化。CpG DNA对淋巴细胞的活化不是通过与细胞表面受体的结合所介导的,而是需要细胞吸收来实现的,这种细胞吸收通过将吸收性内吞到酸化的氯喹敏感的胞内小室而发生。这就建议一种假说,即CpG DAN对淋巴细胞的活化可能在发生时相关于酸化的核内体,并且甚至可能是依赖于pH的。为了检验这个假说,采用了对DNA酸化为特异性的抑制物来确定B细胞或单核细胞是否可能在酸化被抑制的条件下应答于CpG DNA。
被检测到的对CpG DNA应答的最早的淋巴细胞活化现象是反应性氧(ROS)的产生,其在脾细胞以及B细胞和单核细胞中都是在5分钟内被诱导出来的。核内体内部酸化的抑制物包括氯喹、bafilomycin A,以及莫能菌素,它们具有不同的作用机制,对CpG诱导的ROS产生有封闭作用,但是对由PMA、与CD40或IgM配合等所介导的ROS的产生没有影响。这些研究显示ROS的产生是通过多种途径的淋巴细胞活化中一种所共有的现象。这种ROS的产生一般独立于核内体中的酸化,而酸化是应答CpGDAN的ROS中所需要的。应答CpG的ROS的生产并不被NFkB抑制物如胶霉毒素所抑制,确认其不是NFkB活化的次级现象。
为了确定CpG DAN在核内体中的酸化是否对其所起到的其它免疫刺激效果是必须的,进行了各种实验。LPS和CpG DNA都诱导相似快速的NFkB活化,提高了原癌基因mRNA水平,以及细胞因子分泌。DNA对NFkB的活化依赖于CpG基元,因为其不被用CpG甲基酶处理的bDAN诱导,也不被因为碱基变换而打乱了CpG的ODN所诱导。采用特异性抗体的超迁移实验指出,被活化的NFkB复合物包括p50和p60组分。并非出人意料的是,在LPS或CpG处理的细胞中的NFkB活化伴随有IkBα和IkBβ的降解。然而,核内体酸化的抑制物选择性地封闭了所有的CpG诱导的活化,但没有对任何LPS诱导的胞内活化现象进行了封闭。值得注意的是,已经确定的是很低浓度的氯喹(<10μM)抑制了CpG介导的淋巴细胞的活化,因为该剂量远远低于治疗疟疾和记性其它的被报道的免疫效应所需要的剂量(例如,100-1000μM)。这些实验支持了在CpG DNA刺激效果的介导中依赖于pH的信号机制的角色。
表15.核内体酸化或NFkB活化的抑制物时CpG诱导的
TNF-α和IL-12表达的特异性封闭
抑制物 | ||||||||||||
活化物 | 培养基 | Bafilomycin(250nM) | 氯喹(2.5μg/ml) | 莫能菌素(10nM) | NAC50mM | TPCK50μM | 胶霉毒素0.1μg/ml | 双胶霉毒素0.1μg/ml | ||||
TNF-α | IL-12 | TNF-α | IL-12 | TNF-α | IL-12 | TNF-α | IL-12 | TNF-α | TNF-α | TNF-α | TNF-α | |
培养基 | 37 | 147 | 46 | 102 | 27 | 20 | 22 | 73 | 10 | 24 | 17 | 41 |
CpGODN | 455 | 17,114 | 71 | 116 | 28 | 6 | 49 | 777 | 54 | 23 | 31 | 441 |
LPS | 901 | 22,458 | 1370 | 4051 | 1025 | 12418 | 491 | 4796 | 417 | 46 | 178 | 1120 |
表15给出了IL-2和TNF-α的检测:小鼠单核细胞系J774(对IL-12为1×105细胞/毫升,对TNF-α为1×106细胞/毫升),在有给出的浓度的抑制物或没有抑制物的条件下培养2小时,然后用CpG寡核苷酸(ODN)1826(TCCATGACGTTCCTGACGTTSEQ ID NO:10)刺激,剂量为2μM,对LPS为(10μg/ml),对TNF-α为4小时,对IL-12为24小时,收集上清液。对上清液用ELISA检测IL-12或TNF-α(pg/ml),操作参见以前的文献[A.K.Krieg,A.-K.Yi,S.Matson,T.J.Waldschmidt,G.A.Bishop,R.Teasdale,G.Koretzky and D.Klinman,Nature374,546(1995);Yi,A.-K.,D.M.Klinman,T.L.Martin,S.Matson and A.M.Krieg,J.Immunol,157:5394-5402(1996);Krieg,A.M.,J.Lab.Clin.Med.,128,128-133(1996)]。用不含有CpG基元的ODN培养细胞没有诱导细胞因子的分泌。在IL-6的检测中也见到了相似的CpG应答的特异性抑制,也见于采用原脾细胞或B细胞系CH12.LX和wEHI-231的实验中。2.5μg/ml氯喹相当于<5μM。NFkB活化的其它抑制物包括PDTC和钙蛋白酶抑制物Ⅰ和Ⅱ,都给出了相似的抑制效果。给出的数据代表在10个不同的实验中所得到的结果。
过量的CpG基元的免疫活化可能对自身免疫疾病系统性红斑狼疮的发病有作用,其伴随着升高水平的循环高甲基化CpGDNA。氯喹和有关的抗疟疾化合物是对系统性红斑狼疮和其它的一些自身免疫疾病的有效的治疗药物,虽然它们的作用机制尚不明了。我们对极低浓度氯喹可以特异性抑制CpG介导的淋巴细胞活化的能力的确定,建议出了一种新的有效的机制。值得注意的是,狼疮的经常复发被认为是微生物感染启动的。在感染的组织中存在的bDNA水平可以是足以诱导局部发炎应答的。与在脓毒综合症和其它的疾病中CpG DNA起者介导物的作用相结合,我们的研究建议了抗疟疾药物作为核内体酸化的抑制物的新的医药用途。
CpG诱导的ROS生产可能是细胞活化的偶然结果,或者是介导这种活化的信号。ROS的清除物N-乙酰基-L-半胱氨酸(NAC)封闭CpG诱导的NFkB活化,细胞因子的产生,以及B细胞的繁殖,这就建议了在这些途径中ROS生产的起因角色。这些数据与前面的支持ROS在活化NFkB中的角色的证据相吻合。WEHI-231B细胞(5×105细胞/毫升)在有或没有氯喹[5μg/ml(<10μM)]或胶霉毒素(0.2μg/ml)条件下预培养30分钟。然后对细胞等份试样按照上述在RPMI培养基中10分钟,添加或不添加CpG ODN(1826)或非CpN ODN(1911)1μM,或佛波醇豆蔻乙酸酯(PMA)加离子霉素(iono)。然后对细胞用二氢若丹明123染色并用流式细胞仪分析胞内ROS的产生,具体操作按照以前所述的进行[A.K.Krieg,A.-K.Yi,S.Matson,T.J.Waldschmidt,G.A.Bishop,R.Teasdale,G.Koretzky and D.Klinman,Nature374,546(1995);Yi,A.-K.,D.M.Klinman,T.L.Martin,S.Matson and A.M.Krieg,J.Immunol,157:5394-5402(1996);Krieg,A.M.,J.Lab.Clin.Med.,128,128-133(1996)]。J774细胞,一种单核细胞系,显示了相似的依赖pH的CpG诱导的ORS应答。与之相对照,CpG DNA没有诱导胞间ROS的产生,也没有任何可检测的嗜中性白细胞ROS。这些氯喹的浓度(以及那些与其它的核内体酸化抑制物一起使用的浓度)防止了内化的CpG DNA的酸化,用荧光偶联ODN如Tonkinson等人所述的进行了证实[Tonkinson et al.,Nucl.Acids Res.22,4268(1994);A.M.Krieg,In:Delivery Strategies for Antisense OligonucleotideTherapeutics.Editor,S.Akhtar,CRC Press,Inc.,pp.177(1995)]。用高于抑制核内体酸化所需浓度,观察到了非特异性的抑制效果。每个实验都进行至少三次并得到相似结果。
虽然已知NFkB对基因表达是重要的调节物,但其在对CpGDNA的应答中的角色却始终不清楚。为了确定这个NFkB活化对CpG介导的基因表达是必须的,对细胞在有或没有二硫代氨基甲酸吡咯烷(PDTC)这种IkB磷酸化抑制物存在的条件下用CpG DNA活化。这些NFkB活化的抑制物完全封闭了CpG诱导的原癌基因和细胞因子mRNA和蛋白质的表达,显示NFkB在这些现象中作为介导物的基本作用。在这些研究所用的条件中,没有任何一个抑制物减弱了细胞的生存力。J774,一种小鼠单核细胞系,以5μg/ml的水平在有小牛胸腺(CT)、大肠杆菌(EC)、或甲基化大肠杆菌(mEC)DNA(用CpG甲基化酶进行甲基化4)存在的条件下培养,或与0.75μM的CpG寡核苷酸(ODN1826,表15)或非CpG ODN(TCCATGAGCTTCCTGAGTCT;ODN1745)培养1小时,然后,对细胞进行溶胞,制备核酸提取物。含有共同NFkB位点的双链ODN被5′端放射性标记,用作EMSA的探针,具体操作按照以前所述进行[J.D.Dignam,R.M.Lebovitz and R.G.Roeder,Nucliec Acids Res.11,1475(1983);M.Briskin,M.Damore,R.Law,G.Lee,P.W.Kincade,C.H.Sibley,M.Kuehl and R.Wall,Mol.Cell.Biol.10,422(1990)]。p50/p65异源双体的位置用对p65和p50的特异性抗体以超迁移方法确定[Santa Cruz Biotechnology,Santa Cruz,CA]。用J774细胞建立氯喹对CpG诱导的但不是LPS诱导的NFkB活化的抑制。将细胞在有或没有氯喹(20μg/ml)存在的条件下预培养2小时,然后按照上述用EC DNA、CpG ODN、非CpG ODN或LPS(1μg/ml)刺激1小时。在B细胞系、WEHI-231和原脾细胞中见到了相似的氯喹敏感性CpG诱导的对NFkB的活化。这些实验都进行三次,氯喹的浓度范围是2.5至20μg/ml,得到了相似的结果。
还明白了的是,CpG刺激的mRNA表达需要核内体酸化以及在B细胞和单核细胞中的NFkB活化。J774细胞(2×106细胞/毫升)在有或没有氯喹[2.5μg/ml(<5μM)],或N-甲苯磺酰基-L-苯并氨酸氯甲酮(TPCK,50μM),这是一种丝氨酸/苏氨酸蛋白酶抑制物,其防止IkB蛋白水解并因此而封闭NFkB活化。然后对细胞进行刺激,使用的是大肠杆菌DNA(EC,50μg/ml)、小牛胸腺DNA(CT,50μg/ml)、LPS(10μg/ml)、CpG ODN(1826,1μM)、或对照的非CpG ODN(1911,1μM),进行3小时。wEHI-231B细胞(5×105细胞/毫升)在有或没有胶霉毒素(0.1μM)或双胶霉毒素(0.1μg/ml)存在的条件下培养2小时,然后进行刺激,使用的是CpG ODN(1826),或对照的非CpG ODN(1911,TCCAGGACTTTCCTCAGGTT),用量为0.5μM,时间为8小时。在这两种情况下,细胞被收集后,用RNAzol按照厂商的说明书来制备RNA。进行多探针Rnase保护检测,操作按照以前所述的进行[A.-K.Yi,P.Hornbeck,D.E.Lafrenz and A.M.Krieg,J.Immunol.,157,4918-4925(1996)]。将可比数量的RNA装入每条道内,用核糖体μRNA作为加载对照(L32)。对这些实验重复三次,得到相似的结果。
这些结果表明淋巴细胞对CpG DNA的应答是通过新的途径完成的,涉及了依赖pH的胞内ROS的产生。依赖pH的步骤可能是CpG DNA的运转或加工步骤,ROS的产生,或某些其它的现象。ROS被广泛地认为是在多种类型细胞中的信号途径的第二信使,但是在此之前还没有被证明是可以在B细胞中介导刺激信号的。
假设在核内体之中或其附近有一种蛋白质,它特异性识别含有CpG基元的DNA,并导致反应性氧的产生。为了探测细胞的胞质中能够特异性结合CpG DNA的蛋白质,进行了电泳迁移率变动分析(EMSA),其中使用的是以5′放射性标记的带有或不带有CpG基元的寡核苷酸。发现有一条带似乎代表与具有CpG基元的单链寡核苷酸特异性结合的蛋白质,但其不与缺少CpG基元的寡核苷酸结合,也不与含有被甲基化了的CpG基元的寡核苷酸结合。这个结合活性在加入了过量的含有NFkB结合位点的寡核苷酸时被封闭。这就建议NFkB或相关的蛋白质是与刺激性CpG寡核苷酸结合的蛋白质或蛋白质复合体的组成部分。
在NFkB被强烈活化的时间点上没有发现CREB/ATF蛋白质被活化。因而,这些数据没有提供NFkB蛋白质实际上结合CpG核酸的证据,而是说明了CpG活性在某种方式上需要该蛋白质。可能的是,CREB/ATF或相关的蛋白质与NFkB蛋白质或其它的蛋白质以某种方式相互作用,这样可以解释CREB蛋白质的结合基元与优化的CpG基元的显著的相似性。还可能的是寡核苷酸结合CREB/ATF或相关的蛋白质,并导致NFkB的活化。
另外,很可能的是,CpG核酸可以与TRAF蛋白质中的一种相结合,该蛋白质与CD40的胞质区结合,并在CD40被交联时调节NFkB活性。这样的TRAF蛋白质的例子包括TRAF-2和TRAF-5。制备免疫刺激性核酸的方法
在本发明中,核酸可以使用本领域熟知的任何数目的方法全程合成。例如,可以采用b-氰乙基氨基磷酸酯法[S.L.Beaucageand M.H.Caruthers,(1986)Tet.Let.22:1859],核苷H-磷酸酯法[Caregg et al.,(1986)Tet.Let.27:4051-4054;Froehler et al.,(1986)Nucl.Acid.Res.14:5399-5407;Caregg et al.,(1986)Tet.Let.27:4055-4058,Gaffney et al.,(1988)Tet.Let.29:2619-2622]。这些化学合成可以用市售的各种自动化寡核苷酸合成仪还完成。另外,也可以用已知的方法从已经存在的核酸序列(例如,基因组DNA或cDNA)中制备出来,例如,那些利用限制性酶,核酸外切酶和核酸内切酶的技术。
为了用于体内,核酸优选具有相当的抗降解性(例如,对核酸外切酶或核酸内切酶的降解有抗性的)核酸。次级结构,例如茎-环结构,可以稳定核酸来抵抗降解。另外,核酸的稳定化可以通过磷酸酯主链修饰来实现。优选的稳定核酸具有至少部分的硫代磷酸酯修饰的主链。硫代磷酸酯可以用自动化技术由氨基磷酸酯或H-磷酸酯来化学合成。芳基的和酰基的磷酸酯可以通过如美国专利第4,469,863号所描述的方法来制备,并且,芳基磷酸三酯(其中的带电的氧基团被美国专利第5,023,243号和欧洲专利第092,574号所述的方法所烷基化)可以用市售的制剂以自动化固相合成法来制备。进行其它的DNA主链修饰和替换的方法已经被描述了[Uhlmann,E.and Peyman,A.(1990)Chem.Rev.90:544;Goodchild,J.(1990)Bioconjugate Chem.1:165]。带有CpG基元的2′-O-甲基核酸还引起免疫活化,环氧修饰的CpG核酸也如此。事实上,还没有发现任何主链的修饰可以完全消除CpG效应,虽然用5-甲基的C取代C可以极大地消弱之。
为了体内给药,核酸可以结合有能与靶细胞[例如,B细胞,单核细胞和天然杀死细胞(NK)]表面更高度亲和的分子和/或提高靶细胞的细胞吸收而形成“核酸释放复合体”的分子。核酸可以是离子性地或共价地与适宜的分子通过本领域所熟知的技术连接起来。可以使用的有各种的偶联和交联制剂,例如,蛋白质A,碳二亚胺,N-琥珀酰基-3-(2-吡啶二硫基)丙酸盐(SPDP)。核酸还可以用熟知的技术包埋在脂质体或病毒体中。免疫刺激性核酸分子的医疗应用
根据免疫刺激性核酸分子的性质,可以将含有至少一个未甲基化CpG二核苷酸的核酸分子给对象体内给药来治疗“免疫系统缺陷”疾病。另外,含有至少一个未甲基化CpG二核苷酸的核酸分子可以同来自免疫系统缺陷疾病的患者的淋巴细胞(例如,B细胞,单核细胞或NK细胞)在体外接触来活化这些淋巴细胞,然后再将这些淋巴细胞送回到对象体内。
正如本文所描述的,作为对含有未甲基化CpG的核酸分子的应答,有更多数量的脾细胞分泌了IL-6、IL-12、IFN-γ、IFN-α、IFN-β、IL-1、IL-3、IL-10、TNF-α、TNF-β、GM-CSF、RANTES、甚至还有其它的物质。在B细胞、CD4+T细胞和单核细胞中发现了IL-6表达的提高。
免疫刺激性核酸分子还可以同疫苗一起提供给对象来促进其免疫系统并从而产生对疫苗的更好的应答。优选的是,将免疫刺激性核酸分子与疫苗一起或稍微提前一点提供给对象。常规的附剂可以同疫苗一起使用,其一般包括抗原,常规的附剂可以通过提高抗原的吸收来进一步改善免疫疫苗的效果。
如果疫苗是DNA疫苗,则至少有两个成分决定其效率。首先,由疫苗编码的抗原决定免疫应答的特异性。其次,如果质粒的主链含有CpG基元,其就作为疫苗的附剂起作用。因此,CpGDNA起着有效的“危险信号”的作用,并引起免疫系统对该区域内的新抗原产生强烈的反应。这种作用方式似乎是CpG DNA对树枝状细胞和其它的“专业”抗原提呈细胞的局部刺激性效应以及对B细胞的共同刺激效应的结果。
免疫刺激性寡核苷酸和含有未甲基化CpG的疫苗直接活化淋巴细胞并共同刺激抗原特异性应答,这是与常规的附剂(例如,铝沉淀物)完全不同的,常规附剂在单独注射时被认为是通过吸附抗原来起作用并从而使其对免疫细胞更为有效。进而言之,常规附剂只对某些抗原有效,仅仅诱导抗体(体液)免疫应答(Th2),并且在诱导细胞免疫应答(Th1)方面很差。对于许多的致病物,体液应答对防御仅有很小的作用,有时甚至是有害的。
此外,免疫刺激性寡核苷酸可以在化疗或免疫治疗之前、之中或之后给药,来提高肿瘤细胞对以后的化疗或免疫治疗的应答,或通过诱导恢复性细胞因子如GM-CSF来加速骨髓的恢复。CpG核酸还提高天然杀死细胞的溶胞活性和依赖抗体的细胞毒性(ADCC)。对NK活性和ADCC的诱导可以独自或与其它的治疗一起在癌症的免疫治疗中带来有益效果。
所述的免疫刺激性核酸分子的另外的一种应用是对过敏的去敏感化治疗,过敏一般由对无害的过敏原产生IgE抗体所导致的。由未甲基化CpG核酸诱导的细胞因子主要是属于“Th1”类型的,其最主要的特点是细胞免疫应答并与IL-12和IFN-γ有关。其它的主要类型的免疫应答被称为“Th2”免疫应答,其更多地相关于抗体免疫应答并产生IL-4、IL-5和IL-10。一般来讲,所有的过敏疾病都表现为Th2类型免疫应答介导的和Th1免疫应答介导的自身免疫疾病。根据免疫刺激性核酸分子将对象的免疫应答从Th2(其与IgE抗体的产生和过敏有关)转换为Th1应答(其对抵抗过敏反应)的能力,可以单独向对象提供有效剂量的免疫刺激性核酸或与免疫原一起提供来治疗或防止过敏。
含有未甲基化CpG基元的核酸还具有在治疗气喘中的重要的应用。Th2细胞因子,特别是IL-4和IL-5,都是在气喘病人的呼吸道中呈增高量的。这些细胞因子促进了气喘发炎反应的重要的方面,包括IgE同种型之间的变换,嗜伊红粒细胞趋化性和活化,以及掩饰细胞的生长等。Th1细胞因子,特别是IFN-γ和IL-12,可以对Th2克隆的形成和Th2细胞因子的生产进行抑制。
如同在下面的实施例12中所具体描述的那样,含有未甲基化CpG基元的寡核苷酸(即,TCCATGACGTTCCTGACGTT,SEQ ID NO:11),但不是对照寡核苷酸(TCCATGAGCTTCCTGAGTCT SEQ ID NO:11,),可以在小鼠气喘模型中防止发炎细胞浸入和嗜伊红粒细胞化。进而言之,对嗜伊红粒细胞性发炎的抑制是相关于对Th2应答的抑制和对Th1应答的诱导的。
在治疗应用中,有效剂量的适宜的免疫刺激性核酸分子自己或是其与释放复合体的制剂可以用任何能够让寡核苷酸被适宜的靶细胞(例如,B细胞和单核细胞)吸收的方式向对象给药。其它的给药的途径包括注射(皮下、静脉内、肠胃外、腹膜内、胸内,等)。注射可以一次给足,也可以连续渗透。
核酸自己或其与释放复合体一起,都可以与药理学可接受的载体一同给药。在本文中,术语“药理学可接受的载体”指的是那些能够同核酸或核酸释放复合体一起给药并使核酸可以发挥其有关功能的物质。这样的载体的例子包括溶液、溶剂、分散介质、延缓制剂、乳液,等等。根据药理学活性物质来选用这样的介质是本领域熟知的。其它的适合用于核酸的常规载体也都在本发明所包括的范围之内。
术语核酸分子的“有效剂量”指的是对实现所需要的生物学效果为必须的或充足的剂量。例如,对含有至少一个未甲基化CpG的核酸用于治疗免疫系统缺陷来讲,该剂量是对消除肿瘤、癌症、或细菌的、病毒的、或真菌感染为必须的剂量。对于用作疫苗附剂来讲,有效剂量是可以促进对象对疫苗的免疫应答的剂量。对于治疗气喘的“有效剂量”则是讲与气喘相关的Th2类型的免疫应答转变为Th1类型的应答所需要的剂量。对于任何具体的应用的有效剂量,可以根据诸多因素来决定,例如,需要治疗的疾病或状态,具体使用的核酸(例如,含有的未甲基化CpG基元的数目或它们在核酸中的位置),治疗对象的身高和体重,以及疾病的程度等。本领域的技术人员不需要进行非必须的实验就可以确定具体的寡核苷酸的实际用量。
本发明将由下面的实施例中给予更为细致的描述,这些实施例不从任何角度限制本发明。在本申请全文中所提到的文献(包括文献材料,授权的专利,公开的专利申请,和共悬未决的专利申请)都通过在此引述而合并于本文。实施例
实施例1:ODN对B细胞总RNA合成以及细胞循环的效应
从不带有特异性病原体的6-12周龄的DBA/2或BXSB小鼠(饲养在Iowa大学动物实验中心,没有发现明显的品系差异)的脾中获得B细胞,用抗-Thy-1.2消除T细胞,对淋巴细胞M离心(Cedarlane Laboratories,Hornby,Ontario,Canada)(此后称为“B细胞”)。B细胞中含有少于1%的CD4+或CD8+细胞。8×104个B细胞分三份加入96孔微滴盘中,每孔中含有100μl的RPMI,其中含有10%的FBS(在65℃下热灭活30分钟),50μM的2-巯基乙醇,100U/ml的青霉素,100μg/ml链霉素,以及2mM的L-谷氨酸。在进行37℃下的20小时培养的开始时刻,加入20μM的ODN,给细胞加以1μCi的3H尿苷,4小时后收获细胞。将全脾细胞用20μM的ODN培养48小时后,对分泌Ig的B细胞用ELISA点检测法计数。表1给出了有关的结果,数据代表与未用ODN培养的细胞比较得到的刺激指数。3H胸苷吸收检测显示了相似的结果,但是有从降解的ODN释放的胸苷造成的非特异性抑制[Matson.S and A.M.Krieg(1992)Nonspecificsuppression of 3H-thymidine incorporation by controloligonucleotides.Antisense Research and Development 2:325]。
实施例2:ODN对B细胞生产IgM的效应
从新杀死的小鼠获得的脾制备单个细胞的悬浮液,用抗-Thyl,抗-CD4,和抗-CD8和补体处理,具体方法见Leibson等人的文献[Leibson et al.,J.Exp.Med.154:1681(1981)]。按照DeFranco等人的程序[DeFranco et al.,J.Exp.Med.155:1523(1982)]从不连续Percoll梯度的63-70%的带中分离休眠的B细胞(T细胞污染<0.2%)。这些都按照上述用30μM的ODN或20μg/ml的LPS培养48小时。正在分泌IgM的B细胞数在此时为最大,有ELISA点检测法确定[Klinman,D.M.et al.,J.Immunol.144:506(1990)]。在这个检测中,B细胞在抗-Ig涂布的微滴盘上培养6小时。它们所产生的Ig(>99%的IgM)用磷酸酶-标记的抗-Ig检测[Southern Biotechnology Associated,Birmingham,AL]。每个B细胞产生的抗体用加入BCIP(Sigma Chemical Co.,St.Louis MO)来观察,在有磷酸酶存在时,形成不溶性兰色沉淀。对细胞进行稀释后,产生了20-40点孔的结果,用其来确定样品中分泌抗体的B细胞的总数。所有的检测都进行三次(数据给出在表1)。在有些实验中,培养物上清液被用ELISA来检测IgM,显示了应答CpG-ODN的相似结果。
实施例3:细菌DNA对B细胞的刺激
对DBA/2B细胞进行培养,不加入DNA,或加入50μg/ml的a)Micrococcus lysodeikticus;b)NZB/N小鼠脾;c)NFS/N小鼠脾基因组DNA,培养48小时后,加入3H胸苷,4小时后收获细胞。对双份的DNA样品用DNASE I在37℃下酶解30分钟,然后加入细胞培养物。用ELISA-点检测法确定了在48小时的时候,大肠杆菌DNA诱导分泌IgM的B细胞数目提高了8.8倍。
对DBA/2的B细胞进行培养,不加入任何物质,或加入50μg/ml的LPS,或20μM的ODN1、1a、4、或4a。培养细胞并在第4、8、24和48小时收集细胞。对BXSB细胞按照实施例1所述进行培养,分别加入5、10、20、40、80μM的ODN 1、1a、4、4a或LPS。在这个实验中,没加入ODN的小孔中为3833cpm。每个实验都进行至少三次,得到了相似的结果。重复的三个小孔的标准偏差小于5%。
实施例4:ODN对天然杀死细胞(NK)活性的效应
10×106个C57BL/6脾细胞培养在2ml的RPMI中(按照实施例1进行补充),加入或不加入40μM的CpG或非-CpG ODN,培养48小时。洗过细胞后,用于在短期51Cr释放检测中作为效应细胞,检测中使用了YAC-1和2C11这两种NK敏感靶细胞系[Balias,Z.K.et al.(1993)J.Immunol.150:17]。加入的效应细胞浓度不同,直至在V底微滴盘中达到每0.2ml含有104个51Cr标记的靶细胞,在37℃温度于5%的CO2下培养4小时。然后离心,对上清液的等份试样计数放射活性。特异性溶胞的百分数的计算是,在有效应细胞存在时的51Cr释放减去靶细胞自己培养时的51Cr释放,与用2%乙酸溶胞后的总释放量减去细胞单独培养时的51Cr cpm释放相比。
实施例5:对CpG硫代磷酸酯ODN的体外研究
对小鼠称重,腹腔内注射0.25ml的无菌PBS或给定剂量的硫代磷酸酯ODN溶于PBS。24小时后,收获脾细胞,洗过之后染色,进行流式细胞仪测定,使用藻红蛋白偶连6B2,来控制B细胞,以及生物素偶连的抗Ly-6A/E或抗-Iad(Pharmingen,SanDiego,CA)或抗-Bla-1[Hardy,R.R.et al.,J.Exp.Med.159:1169(1984)]。每种条件都实验了两只小鼠,每只小鼠单独进行分析。
实施例6:硫代磷酸酯ODN对B细胞刺激的效价
用硫代磷酸酯ODN培养B细胞,ODN带有对照ODN1a的序列,或CpG ODN1d的序列,或是带有3Dd的序列,20小时后,加入3H尿苷,或44小时后加入3H胸苷,然后收获细胞并确定cpm。
实施例7:挽救B细胞干编程性死亡
WEHI-231细胞(5×104个/孔)于37℃下培养1小时,存在或不存在LPS、对照ODN1a、CpG ODN1d、3Dd,然后加入抗-IgM(1μ/ml)。细胞继续培养20小时,加入2μCi/孔的3H胸苷4小时。在这个实验中,没有ODN的细胞或有抗-IgM的细胞得到了90.4×103cpm的3H胸苷吸收。表1中给出的磷酸二酯ODN也给予了相似的保护,虽然由于ODN的降解有一些非特异性抑制。每个实验都进行至少3次,得到相似结果。
实施例8:体内诱导小鼠IL-6
DBA/2雌性小鼠(2月龄)腹膜内注射500g CpG或对照硫代磷酸酯ODN。在注射后的不同时间点对小鼠采血。每个时间点研究2只小鼠。用Elisa测定IL-6,IL-6的浓度用与标准曲线比较来计算,标准曲线用重组的IL-6获得。该检测的敏感度为10pg/ml。 8小时后无法检测。
实施例9:系统性诱导小鼠IL-6转录
小鼠和细胞系.DBA/2,BALB/c,和C3H/HeJ小鼠,5-10周龄,用作淋巴细胞来源。所有的小鼠都来自于The JacksonLaboratory(Bar Harbor,ME),并在Iowa大学的动物饲养中心的无特异性病原体条件下培育和饲养。小鼠B细胞系CH12.LX由Bishop博士(Iowa大学)慷慨提供。
制备细胞。对小鼠折颈处死。从小鼠的脾无菌制备单个细胞的悬浮液。使用抗-Thy-1.2和补体制备消除了T细胞的小鼠脾细胞,并对淋巴细胞M(Cedarlane Laboratories,Hornby,Ontairo,Canada)离心,具体如前人所述[Krieg,A.M.et al.,(1989)A rolefor endogenous retroviral sequences in the regulation of lymphocyteactivation.J.Immunol.143:2448]。
ODN和DNA.磷酸二酯寡核苷酸(O-ODN)和主链修饰的硫代磷酸酯ODN(S-ODN)得自于Iowa大学DNA中心机构或Operon Technologies(Alameda,CA)。大肠杆菌DNA(菌系B)和小牛胸腺DNA购自于Sigma公司(St.Louis,MO)。所有的DNA和ODN都被纯化,使用的是酚∶氯仿∶异戊醇(25∶24∶1)和/或乙醇沉淀。在使用前,对大肠杆菌DNA和小牛胸腺DNA煮沸10分钟,冰冷却5分钟,使它们成为单链。对于某些实验,大肠杆菌DNA和小牛胸腺DNA都用DNaseⅠ(2U/μg DNA)酶解,37℃下2小时,在1X SSC中,有5mM MgCl2存在。为了对大肠杆菌DNA中的CpG二核苷酸内的胞嘧啶甲基化,将大肠杆菌DNA用C:G甲基酶(M.SssⅠ;2U/μg的DNA)于NE缓冲液内处理,补充以160μM的S-腺苷甲硫氨酸,37℃下过夜培养。对甲基化的DNA的纯化按照上述进行。甲基化的效率有HpaⅡ酶解,凝胶电泳分析来确定。所有的酶都购自于New EnglandBiolabs(Beverly,MA)。在ODN中的LPS水平低于12.5ng/ml,大肠杆菌DNA和小牛胸腺DNA中含有少于2.5ng的LPS/mg的DNA,由鲎检测确定。
细胞培养物。所有的细胞都在润湿箱中的5%的CO2内以37℃培养,加入RPMI-1640并补充以10%(v/v)的热灭活小牛血清(FCS),1.5mM L-谷氨酸(50μg/ml),CpG或非CpG磷酸二酯ODN(O-ODN)(20μM),硫代磷酸酯ODN(S-ODN)(0.5μM),或大肠杆菌DNA(50μg/ml)或小牛胸腺DNA(50μg/ml),37℃下24小时(对IL-6生产),或5天(对IgM生产)。刺激物浓度的选择按照以前的研究和滴定来决定。在某些情况下,细胞用CpG O-ODN处理,加入不同浓度(1-10μg/ml)的中性的大鼠IgGl抗小鼠IL-6抗体(杂交瘤MP5-20F3)或对照大鼠IgGl单克隆抗大肠杆菌b-半乳糖苷酶(杂交瘤GL113;ATCC,Rockville,MD)(20),5天。在培养结束时,对培养物上清液用ELISA按照下述进行分析。
体内诱导IL-6和IgM.BALB/c小鼠静脉注射PBS,小牛胸腺DNA(200μg/100μl PBS/小鼠),大肠杆菌DNA(200μg/100μl PBS/小鼠),或CpG或非CpG S-ODN(200μg/100μl PBS/小鼠)。小鼠(2只/每组)在不同的时间点后眶采血并折颈处死。取出肝,脾,胸腺,骨髓,从这些器官中用RANzol根据厂商的说明(Tel-Test,Friendswood,TX)制备RNA。
ELISA.平底Immun 1盘(Dynatech Laboratories,Inc.,Chantilly,VA)被涂布,使用的是100μl/孔抗-小鼠IL-6单克隆抗体(MP5-20F3)(2μg/ml),或抗小鼠IgMμ-链特异性(5μg/ml;Sigma,St.Louis,MO)在碳酸酯-碳酸氢酯,pH9.6缓冲液(15nMNa2CO3,35mM NaHCO3),4℃过夜。然后,用TPBS(0.5mMMgCl2O6H2O,2.68mM KCl,1.47mM KH2PO4,0.14M NaCl,6.6mM K2HPO4,0.5%Tween20)洗该盘,用10%FCS在TPBS中室温下封闭该盘2小时,然后再次洗该盘。培养物上清、小鼠血清、重组的小鼠IL-6(Pharmingen,San Diego,CA)或纯化的小鼠IgM(Calbiochem,San Diego,CA)都用10%FCS进行适宜的稀释,加入到小孔中,三份重复,室温下培育6小时。洗该盘,生物素化大鼠抗-小鼠IL-6单克隆抗体(MP5-32C11,Pharmingen,SanDiego,CA)(1μg/ml在10%FCS中)或生物素化的抗-小鼠Ig(Sigma,St.Louis,MO)以100μl/孔的剂量加入到各个小孔中,室温下培育45分钟,然后用TPBS洗。辣根过氧化物酶(HRP)共轭的抗生物素蛋白(Bio-rad Laboratories,Hercules,CA)以1∶4000的比例在10%FCS(100μl/孔)中稀释,加入到小孔中,室温下培育30分钟。洗盘后,加入苯基二胺二盐酸化物(OPD,Sigma,St.Louis MO),0.05M磷酸盐-柠檬酸盐缓冲液,pH5.0,30分钟。加入0.67N的H2SP4终止反应,用微滴盘读数仪(Cambridge Technology,Inc.,Watertown,MA)在490-600nm处读盘。结果在图1和2中给出。
RT-PCR.有义引物、反义引物、以及IL-6的内部寡核苷酸探针都用公开的序列来合成[Montgomery,RA.and M.S.Dallman(1991),Analysis of cytokine gene expression during fetalthymic ontogeny using the polymerase chain reaction(J.Immunol.)147:554]。cDNA合成以及IL-6的PCR都基本按照Montgomery和Dallman所述的方法进行[Montgomery,R.A.and M.S.Dallman(1991),Analysis of cytokine gene expression during fetal thymicontogeny using the polymerase chain reaction(J.Immunol.)147:554],采用了RT-PCR试剂,该试剂来自Perkin-Elmer公司(Hayward,CA)。扩增30个循环后分析样品,采用了凝胶电泳和非印迹(unblot)分析方法[Stoye,J.P.et al.,(1991)DNAhybridization in dried gels with fragmented probes:animprovement over blotting techniques,Techniques3:123]。简言之,凝胶在变性缓冲液(0.05M NaOH,1.5M NaCl)中于室温下杂化30分钟,然后在复性缓冲液(1.5M NaCl,1M Tris,pH8)中培育30分钟,再用双蒸水洗。干燥凝胶后,在47℃预杂化2小时,杂化缓冲液(5X SSPE,0.1%SDS)含有10μg/ml的变性大麻哈鱼精子DNA。对凝胶用2×106cpm/ml的IL-6[(5′CATTTCCACGATTTCCCA3′)SEQ ID NO:56]的g-[32P]ATP终端标记的内部寡核苷酸在47℃过夜杂交,室温下洗4次(2XSSC,0.2%SDS),然后放射性自显影。结果在图3中给出。
细胞繁殖检测。DBA/2小鼠脾B细胞(5×104个细胞/100μl/孔)在37℃下用培养基、CpG或非CpG S-ODN(0.5μM)或O-ODN(20μM)处理24小时。最后4小时,加入[3H]胸苷或[3H]尿苷(1μCi/孔)。吸收的[3H]数量用液相闪烁分析仪(PackardInstrument Co.,Downers Grove,IL)测定。
转染和CAT检测。WEHI-231细胞(107细胞)用电穿孔加入20μg对照的或人IL-6启动子-CAT构建物(由阿肯色大学的S.Manolagas慷慨提供)[Pottratz,S.T.et al.,(1994)17B-estradiolinhibits expression of human interleukin-6 promoter-reporterconstructs by a receptor-dependent mechanism.J.Clin.Invest.93:944],250mV和960μF。电穿孔后,对细胞用各种浓度的CpG或非-CpG ODN刺激。转染16小时后,用溶液检测法来测定氯霉素酰基转移酶(CAT)的活性[Seed,B.and J.Y.Sheen(1988)Asingle phase-extraction assay for chloramphenical acetyl transferaseactivity.Gene76:271]。结果在图5中给出。
实施例10:决定CpG基元对B细胞刺激程度的
寡脱氧核苷酸修饰
采用标准程序在Applied Biosystem公司(Applied BiosystemsInc.,Foster City,CA)的型号为380A、380B、或394的DNA合成仪对ODN进行了合成[Beacage and Caruthers(1981)Deoxynucleoside phosphoramidites--A new class of keyintermediates for deoxypolynucleotide syntheses.TetrahedronLetters22,1859-1862]。对磷酸二酯ODN用标准的β-氰乙基氨基磷酸酯化学方法合成。硫代磷酸酯连接用元素硫氧化亚磷酸连接来加入,而不是采用常规的碘氧化法。四种常见的核苷酸氨基磷酸酯购自于Applied Bisystem公司。所有含OND的磷酸二酯和硫代磷酸酯都用浓氨水在55℃处理12小时来去保护。对ODN用凝胶排阻层析提纯并在使用前冷冻干燥二硫代磷酸酯连接用脱氧核苷酸S-(b-苯甲酰基巯基乙基)吡咯烷硫代氨基磷酸硫酯来加入[Wiesler,W.T.et al.,(1993)In Methods in MolecularBiology:Protocols for Oligonucleotides and Analogs-Synthesis andProperties,Agrawal,S.(ed),Humana Press,191-206.]。含有ODN的二硫酯用浓氨水在55℃处理12小时去保护,然后用反向HPLC提纯。
为了合成在所需要的核苷酸间的连接位置含有甲基硫代磷酸酯或甲基磷酸酯以及磷酸二酯的ODN,采用了两种不同的合成途径。这两种途径的主要区别是对二烷基氨基甲基核苷酸磷化氢采用了偶连试剂,而对甲基硫代磷酸酯采用了氧化试剂。为了合成它们的衍生物,对二烷基氨基甲基核苷酸磷化氢延长了其缩化时间,因为偶连动力学比较缓慢[Jager and Engels,(1984)Synthesis of deoxynucleoside methylphophonates via aphosphonamidite approach.Tetrahedron Letters27,1437-1440]。在偶连步骤完成后,对甲基磷酸二酯用硫化试剂处理[5%元素硫,100mM的N,N-二甲基氨基吡咯烷,存在于二硫化碳/吡啶/三乙胺中],四个连续的450秒处理,每次都产生了甲基硫代磷酸酯。为了产生硫代磷酸酯连接,对甲基磷酸二酯用标准的氧化试剂处理(0.1M碘,在四氢呋喃/2,6-二甲基吡啶/水中)。
对硅胶结合的寡聚物用蒸馏吡啶/浓氨水为1∶1(v/v)在4℃下处理4天。上清液真空干燥后,溶解于水中,在G50/50的Sephadex柱上色谱。
在本文中,O-ODN指的是磷酸二酯ODN;S-ODN指的是完全硫代磷酸酯修饰的ODN;S-O-ODN指的是嵌合性ODN,其中的中央连接是磷酸二酯,但是5′和3′端的两个连接是硫代磷酸酯修饰的;S2-O-ODN指的是嵌合性ODN,其中的中央连接是磷酸二酯,但5′和3′端的两个连接是二硫代磷酸酯修饰的;MP-O-ODN是嵌合性ODN,其中的中央连接是磷酸二酯,但5′和3′端的两个连接是甲基磷酸酯修饰的。所研究的ODN序列(对CpG二核苷酸用下划线标出)包括:
3D(5″GAGAACGCTGGACCTTAT),(SEQ ID NO.14);
3M(5′TCCATGTCGGTCCTGATGCT),(SEQ ID NO.31);
5(5′GGCGTTATTCCTGACTCGCC),(SEQ ID NO.57);
6(5′CCTACGTTGTATGCGCCCAGCT),(SEQ ID NO.58)。这些序列基本上代表了在这些研究过程上所测验过的百种CpG和非-CpG的ODN。
小鼠。DBA/2或BXSB来自于The Jackson Laboratory(BarHarbor,ME),饲养在没有特异性病原体的条件下,用5-10周龄的小鼠作淋巴细胞来源,得到类似的结果。
细胞繁殖检测。对于细胞繁殖检测,将小鼠脾细胞(5×104个细胞/100μl/孔)于37℃的5%CO2润湿箱中培养于RPMI-1640中,补充以10%(v/v)热灭活小牛血清(对O-ODN实验加热到65℃,对仅仅使用修饰的ODN的实验加热到56℃),1.5μM L-谷氨酸,50μM的2-巯基乙醇,100U/ml青霉素和100μg/ml链霉素,按照给出的要求培养24小时或48小时。每个小孔中加入1μCi的3H尿苷或胸苷(按给出的要求进行),继续培养4小时后,收获细胞。对过滤物用闪烁仪计数。三份重复的小孔的标准偏差小于5%。结果在图6-8中给出。
实施例11:NK活性的诱导
磷酸二酯ODN购自于Operon Technologies公司(OperonTechnologies,Alameda,CA)。硫代磷酸酯ODN购自于Iowa大学的DNA中心机构,或购自于Midland Cerrified ReagentCompany(Midland,TX)。大肠杆菌(菌系B)DNA和小牛胸腺DNA购自于Sigma公司(Sigma,St.Louis,MO)。所有的DNA和ODN都用酚∶氯仿∶异戊醇(25∶24∶1)萃取和/或乙醇沉淀来纯化。在ODN中的LPS水平低于12.5ng/ml,所含有的大肠杆菌DNA和小牛胸腺DNA低于2.5ngLPS/mg DNA,由鲎检测方法确定。
不含有病毒的4-6周龄的DBA/2小鼠、C57BL/6(B6)小鼠,以及先天无胸腺的BALB/C小鼠都根据合同通过VeteransAffairs来自于National Cancer Institute(Bethesda,MD)。C57BL/6SCID小鼠饲养在Iowa大学动物饲养站的SPF封闭饲养设施中。
人外周血单核淋巴细胞(PBMC)按照前述获得[Ballas,Z.K.et al.,(1990)J.Allergy Clin.Immunol.85:453;Ballas,Z.K.and W.Rasmussen(1990)J.Immunol.145:1039;Ballas,Z.K.and W.Rasmussen(1993)J.Immunol.150:17]。人或小鼠的细胞按5×106个细胞/孔的数量放在24孔微滴盘中的小孔内,培养于37℃的5%CO2的润湿箱中[Ballas,Z.K.et al.,(1990)J.Allergy Clin.Immunol.85:453;Ballas,Z.K.and W.Rasmussen(1990)J.Immunol 145:1039;and Ballas,Z.K.and W.Rasmussen(1993)J.Immunol.150:17],仅加入培养基,或加入CpG或非CpG ODN,剂量按给出的数据办理,或加入大肠杆菌DNA或小牛胸腺DNA(50μg/ml)并在37℃培养24小时。所有的培养物在18小时后收获,将这些细胞作为效应细胞,按照以前的描述用在标准的4小时51Cr-释放检测中来针对K562(人)或YAC-1(小鼠)靶细胞。在计算溶胞单位(LU)时,1LU定义为30%特异性溶胞所需要的细胞数。如同所给出的那样,在开始培养的时候,加入中性的抗IFN-β抗体(Lee Biomolecular,San Diego,CA),或IL-12(C15.1,C15.6,C17.8,和C17.15;来自于Giorgio Trinchieri博士,The Wistar Institute,Philadelphia,PA),或加入它们的同型物对照,直至浓度为10μg/ml。在加入抗-IL-12时,同时加入4中单克隆抗体(MAB)(或它们的同型物对照)各10μg。重组的人IL-2的使用浓度为100U/ml。
实施例12:在小鼠气喘模型中防止发炎细胞的侵入
和嗜伊红粒细胞化的发生
6-8周龄的C56BL/6小鼠(来自The Jackson Laboratory,BarHarbor,ME)在第0天和第7天腹膜内注射5000血吸虫卵(Schistosoma mansoni eggs)进行免疫。这些血吸虫卵含有抗原[血吸虫卵抗原(SEA)],其诱导Th2免疫应答(例如,IgE抗体的生产)。IgE抗体的产生是已知的气喘的重要诱因。
然后,对免疫的小鼠用寡核苷酸(30μg在200μl盐水中,注射)处理,这些寡核苷酸中要么含有未甲基化CpG基元(即,TCCATGACGTTCCTGACGTT;SEQ ID NO.10),或不含这种基元(即,对照物,TCCATGAGCTTCCTGAGTCT;SEQ ID NO.11)。溶解性SEA(10μg在25μl盐水中)在笫14天和第21天鼻内滴入给药。盐水用作对照。
经过呼吸道的攻击后,在不同的时间点处死小鼠。进行全肺灌洗,收集呼吸道和肺泡的发炎细胞。用ELISA测定灌洗液的细胞因子水平。从全肺洗液中分离RNA,进行Northern分析和RT-PCR研究,使用了CsCl梯度。对肺部组织充气并灌注4%仲甲醛来进行组织学检查。
图9显示的是,小鼠开始被腹膜内注射了血吸虫卵,然后吸入血吸虫卵抗原(空心环),则在肺部有很多的发炎细胞。然而,当小鼠在开始的时候,与血吸虫卵一起接受了含有未甲基化CpG基元的核酸,则在随后吸入血吸虫卵抗原(空心三角形)后,肺部没有发炎细胞的增多。
图10显示的是,测定肺部灌洗液中嗜伊红粒细胞所获得的相似的结果。嗜伊红粒细胞是与气喘非常相关的发炎细胞。
图11显示,当小鼠在开始的时候用对照寡核苷酸与血吸虫卵一起处理,在吸入了SEA后,对随后的嗜伊红粒细胞侵入肺部没有效应。因此,当小鼠在第14天和第21天吸入血吸虫卵后,它们发生了肺部的急性发炎反应。然而,在第0天和第7天开始接触抗原的时候将CpG寡核苷酸与血吸虫卵一起提供给小鼠的话,则几乎彻底消除了在第14天吸入血吸虫卵抗原所造成的嗜伊红粒细胞的增高。
图12显示,很低剂量的寡核苷酸(<10μg)就可以提供这样的保护。
图13显示,所发生的发炎应答相关于肺部Th2细胞因子IL-4的水平。
图14显示,提供含有未甲基化CpG基元的寡核苷酸可以实际上将肺部的细胞因子应答改变为IL-12的生产,标明Th1类型的免疫应答。
图15显示,提供含有未甲基化CpG基元的寡核苷酸还可以将肺部的细胞因子应答改变为IFN-γ的生产,标明Th1类型的免疫应答。
实施例13:CpG寡核苷酸诱导人PRMC分泌细胞因子
对Ficoll的Hypaque用常规离心从全血中制备人PBMC。细胞(5×105/ml)在96孔微滴盘内,与10%自身血清,CpG或对照寡核苷酸(对磷酸二酯寡核苷酸为24μg/ml,对核酸酶抗性硫代磷酸酯寡核苷酸为6μg/ml)一起培养,在TNF-α时为4小时,在其它的细胞因子时为24小时,然后收获上清并用ELISA检测,使用Quantikine试剂盒,或使用来自R&D Systems(pg/ml)的试剂,或使用来自Biosource的细胞因子ELISA试剂盒(对IL-12检测)。各检测都按照厂商的说明书进行。表6提供了这些实验的数据,以比没有加入寡脱氧核苷酸的小孔高出的细胞因子水平来表达。
本领域的技术人员将能够采用不超过常规的实验来认识或确定那些本发明描述的具体实施方案的众多等同物。这些等同物都是包括在本发明的权利要求书中的。
Claims (41)
1.一种被分离的核酸序列,其含有至少一个未甲基化CpG二核苷酸,其通式如下:
5′N1X1CGX2N23′
其中至少一个核苷酸将连续的CpGs分开;X1是腺嘌呤,鸟嘌呤,或胸腺嘧啶;X2是胞嘧啶或胸腺嘧啶;N是核苷酸,并且N1+N2是约0-26个碱基,条件是N1和N2不含有CCGG四元体或多于一个的CCG或CGG三元体;并且核酸序列的长度为约8-30个碱基。
2.根据权利要求1所述的核酸序列,其中的X1是胸腺嘧啶。
3.根据权利要求1所述的核酸序列,其中所述的X2是胸腺嘧啶。
4.根据权利要求1所述的核酸序列,其是GTCG(T/C)T或是TGACGTT。
5.根据权利要求1所述的核酸序列,其中的所述的序列是TGTCG(T/C)T。
6.根据权利要求1所述的核酸序列,其中所述的序列是TCCATGTCGTTCCTGTCGTT。
7.根据权利要求1所述的核酸序列,其中所述的序列是TCCTGACGTTCCTGACGTT。
8.根据权利要求1所述的核酸序列,其中所述的序列是TCGTCGTTTTGTCGTTTTGTCGTT。
9.一种被分离的核酸序列,其含有至少一个未甲基化CpG二核酸,其通式如下:
5′NX1X2CGX3X4N3′
其中至少一个核苷酸将连续的CpGs分开;X1X2选自GpT、GpG、GpA、ApT和ApA;X3X4选自TpT或CpT;N是核苷酸,并且N1+N2是约0-26个碱基,条件是N1和N2不含有CCGG四元体或多于一个的CCG或CGG三元体;并且核酸序列的长度为约8-30个碱基。
10.根据权利要求9所述的核酸序列,其中所述的分离至少两个连续的CpGs的核苷酸是胸腺嘧啶。
11.根据权利要求9所述的核酸序列,其中所述的X3和X4是胸腺嘧啶。
12.根据权利要求1或9中的任何一个所述的核酸序列,其中至少一个核苷酸具有磷酸主链修饰。
13.根据权利要求12所述的核酸序列,其中所述的磷酸主链修饰是硫代磷酸酯修饰或磷酸二酯修饰。
14.根据权利要求13所述的核酸序列,其中所述的磷酸主链修饰发生在核酸的5′端。
15.根据权利要求14所述的核酸序列,其中所述的磷酸主链修饰发生在核酸的5′端的前两个核苷酸间的连接。
16.根据权利要求13所述的核酸序列,其中所述的磷酸主链修饰发生在核酸的3′端。
17.根据权利要求16所述的核酸序列,其中所述的磷酸主链修饰发生在核酸的3′端的最后5个核苷酸间的连接。
18.一种刺激对象的免疫活化的方法,其中所述的刺激主要是Th1类型的免疫活化,该方法包括向对象提供具有权利要求1或9所述的核酸序列。
19.根据权利要求18所述的方法,其中所述的对象是人。
20.一种刺激对象的细胞因子生产的方法,该方法包括给对象提供权利要求1或9所述的核酸序列。
21.根据权利要求20所述的方法,其中所述的细胞因子选自包括IL-6、IL-12、IFN-γ、TNF-α和GM-CSF的一组。
22.根据权利要求20所述的方法,其中所述的对象是人。
23.根据权利要求20所述的方法,其中所述的核酸序列选自包括下述序列的一组:
TCCATGTCGCTCCTGATGCT,
TCCATAACGTTCCTGATGCT,
TCCATGACGATCCTGATGCT
TCCATGGCGGTCCTGATGCT
TCCATGTCGGTCCTGATGCT
TCCATAACGTCCCTGATGCT
TCCATGTCGTTCCTGATGCT,以及
TCGTCGTTTTGTCGTTTTGTCGTT。
24.一种刺激对象的NK溶胞活性的方法,该方法包括向对象提供具有权利要求1或9的通式的核酸序列。
25.根据权利要求24所述的方法,其中所述的对象是人。
26.根据权利要求24所述的方法,其中所述的核酸序列选自包括下述序列的一组:
TCGTCGTTGTCGTTGTCGTT,
TCCATGACGGTCCTGATGCT,
TCCATGACGATCCTGATGCT,
TCCATGACGCTCCTGATGCT,
TCCATGACGTTCCTGATGCT,
TCCATAACGTTCCTGATGCT,
TCCATCACGTGCCTGATGCT,
GGGGTCAACGTTGAGGGGGG,
TCGTCGTTTTGTCGTTTTGTCGTT,
TCGTCGTTGTCGTTTTGTCGTT,
GCGTGCGTTGTCGTTGTCGTT,
TGTCGTTTGTCGTTTGTCGTT,
TGTCGTTGTCGTTGTCGTT,以及
TCGTCGTCGTCGTT。
27.一种刺激对象的B细胞繁殖的方法,该方法包括向对象提供具有权利要求1或9的通式的核酸序列。
28.根据权利要求27所述的方法,其中所述的对象是人。
29.根据权利要求27所述的方法,其中所述的核酸序列选自包括下述序列的一组:
TCCTGTCGTTCCTTGTCGTT,
TCCTGTCGTTTTTTGTCGTT,
TCGTCGCTGTCTGCCCTTCTT,
TCGTCGCTGTTGTCGTTTCTT,
TCGTCGTTTTGTCGTTTTGTCGTT,
TCGTCGTTGTCGTTTTGTCGTT,以及
TGTCGTTGTCGTTGTCGTT。
30.一种刺激对象的免疫活化的方法,该方法包括向对象提供具有权利要求1或9的通式的核酸序列,其中所述的核酸序列起附剂的作用。
31.根据权利要求30所述的方法,其中所述的对象是哺乳动物。
32.根据权利要求30所述的方法,其中所述的核酸序列选自包括下述序列的一组:
TCCATGACGTTCCTGACGTT,
GTCG(T/C)T,以及
TGTCG(T/C)T。
33.一种治疗患有气喘疾病的对象的方法,该方法包括向该对象提供处于药理学可接受的载体中的具有权利要求1或9的通式的核酸序列。
34.根据权利要求33所述的方法,其中所述的对象是人。
35.根据权利要求33所述的方法,其中所述的核酸序列是TCCATGACGTTCCTGACGTT。
36.一种通过对CpG介导的淋巴细胞活化的抑制来治疗患有自身免疫疾病或其它的与CpG相关的疾病的对象的方法,该方法包括向该对象提供处于药理学可接受的载体中的核内体酸化抑制物。
37.根据权利要求36所述的方法,其中所述的对象是人。
38.根据权利要求36所述的方法,其中所述的抑制物选自包括bafilomycin、氯喹、和莫能菌素的一组。
39.根据权利要求38所述的方法,其中所述的抑制物的提供剂量小于约10μM。
40.根据权利要求36所述的方法,其中的疾病选自包括系统性红斑狼疮、脓毒症、肠炎、牛皮癣、龈炎、关节炎、克罗恩氏病(Crohn′s disease)、格雷夫斯氏病(Grave′s disease)、和气喘的一组。
41.根据权利要求40所述的方法,其中所述的疾病是系统性红斑狼疮。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/738,652 | 1996-10-30 | ||
US08/738,652 US6207646B1 (en) | 1994-07-15 | 1996-10-30 | Immunostimulatory nucleic acid molecules |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2007101300520A Division CN101265285A (zh) | 1996-10-30 | 1997-10-30 | 免疫刺激性核酸分子 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1235609A true CN1235609A (zh) | 1999-11-17 |
CN100338086C CN100338086C (zh) | 2007-09-19 |
Family
ID=24968901
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2007101300520A Pending CN101265285A (zh) | 1996-10-30 | 1997-10-30 | 免疫刺激性核酸分子 |
CNB971993521A Expired - Lifetime CN100338086C (zh) | 1996-10-30 | 1997-10-30 | 免疫刺激性核酸分子 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2007101300520A Pending CN101265285A (zh) | 1996-10-30 | 1997-10-30 | 免疫刺激性核酸分子 |
Country Status (14)
Country | Link |
---|---|
US (32) | US6207646B1 (zh) |
EP (5) | EP1714969A3 (zh) |
JP (5) | JP2001503267A (zh) |
KR (1) | KR100689942B1 (zh) |
CN (2) | CN101265285A (zh) |
AT (1) | ATE332966T1 (zh) |
AU (3) | AU5242498A (zh) |
CA (1) | CA2270345C (zh) |
DE (1) | DE69736331T2 (zh) |
DK (1) | DK0948510T3 (zh) |
ES (2) | ES2268736T3 (zh) |
NZ (1) | NZ335397A (zh) |
PT (1) | PT948510E (zh) |
WO (1) | WO1998018810A1 (zh) |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1296378C (zh) * | 2004-05-17 | 2007-01-24 | 中国人民解放军第三军医大学 | 高免疫活性 CpG-S ODN 和拮抗 CpG-S ODN 作用的 CpG-N ODN 的基因序列及其应用 |
WO2007012285A1 (fr) * | 2005-07-28 | 2007-02-01 | Changchun Huapu Biotechnology Co., Ltd. | Desoxynucleosides monocatenaires resistant aux infections virales |
CN1307196C (zh) * | 2004-01-08 | 2007-03-28 | 延世大学校 | 具有改善的免疫调节功能的经修饰的CpG寡聚脱氧核苷酸 |
CN100439386C (zh) * | 2003-03-05 | 2008-12-03 | 长春华普生物技术有限公司 | 增强蛋白类疫苗免疫效果的含CpG单链脱氧寡核苷酸 |
CN100438908C (zh) * | 2001-10-06 | 2008-12-03 | 梅瑞尔有限公司 | CpG制剂及相关方法 |
CN100546657C (zh) * | 2002-11-21 | 2009-10-07 | 贝希尔治疗学股份有限公司 | 预防和治疗疾病的方法及免疫调节核酸组合物 |
CN101932707B (zh) * | 2008-01-31 | 2013-08-21 | 库瑞瓦格有限责任公司 | 作为免疫刺激剂/佐剂的式(I)(NuGlXmGnNv)a的核酸及其衍生物 |
CN103550783A (zh) * | 2013-04-27 | 2014-02-05 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 一种核酸类药物靶向递送系统及其制备方法 |
CN102864152B (zh) * | 2005-11-07 | 2015-11-18 | 艾德拉药物股份有限公司 | 包含经修饰的免疫刺激性二核苷酸的基于寡核苷酸的化合物之免疫刺激特性 |
CN105530957A (zh) * | 2013-07-19 | 2016-04-27 | 财团法人国家卫生研究院 | CpG寡脱氧核苷酸、包含其的免疫组合物及制备组合物并通过其刺激免疫反应的方法 |
CN110004150A (zh) * | 2018-08-01 | 2019-07-12 | 中国农业科学院兰州兽医研究所 | 一种具有免疫增强活性的CpG寡聚核苷酸序列及其应用 |
CN110646557A (zh) * | 2019-10-12 | 2020-01-03 | 北京航空航天大学 | 携带idh基因突变的胶质母细胞瘤患者的尿液代谢标志物及其用途 |
CN112107693A (zh) * | 2013-12-03 | 2020-12-22 | 西北大学 | 脂质体颗粒、制备所述脂质体颗粒的方法以及其用途 |
Families Citing this family (821)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL105325A (en) * | 1992-04-16 | 1996-11-14 | Minnesota Mining & Mfg | Immunogen/vaccine adjuvant composition |
US6498147B2 (en) * | 1992-05-22 | 2002-12-24 | The Scripps Research Institute | Suppression of nuclear factor-κb dependent processes using oligonucleotides |
CA2110946A1 (en) * | 1992-12-09 | 1994-06-10 | Elazar Rabbani | Induction of immunocompatibility by nucleic acid |
US20030109469A1 (en) * | 1993-08-26 | 2003-06-12 | Carson Dennis A. | Recombinant gene expression vectors and methods for use of same to enhance the immune response of a host to an antigen |
US5849719A (en) | 1993-08-26 | 1998-12-15 | The Regents Of The University Of California | Method for treating allergic lung disease |
US6727230B1 (en) | 1994-03-25 | 2004-04-27 | Coley Pharmaceutical Group, Inc. | Immune stimulation by phosphorothioate oligonucleotide analogs |
US20030026782A1 (en) * | 1995-02-07 | 2003-02-06 | Arthur M. Krieg | Immunomodulatory oligonucleotides |
US6239116B1 (en) * | 1994-07-15 | 2001-05-29 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US6207646B1 (en) * | 1994-07-15 | 2001-03-27 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US6429199B1 (en) | 1994-07-15 | 2002-08-06 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules for activating dendritic cells |
US7935675B1 (en) * | 1994-07-15 | 2011-05-03 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US7034007B1 (en) * | 1995-06-07 | 2006-04-25 | East Carolina University | Low adenosine anti-sense oligonucleotide, compositions, kit & method for treatment of airway disorders associated with bronchoconstriction, lung inflammation, allergy(ies) & surfactant depletion |
US5981501A (en) * | 1995-06-07 | 1999-11-09 | Inex Pharmaceuticals Corp. | Methods for encapsulating plasmids in lipid bilayers |
US7422902B1 (en) * | 1995-06-07 | 2008-09-09 | The University Of British Columbia | Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer |
US6825174B2 (en) * | 1995-06-07 | 2004-11-30 | East Carolina University | Composition, formulations & method for prevention & treatment of diseases and conditions associated with bronchoconstriction, allergy(ies) & inflammation |
EP0909323B1 (en) | 1996-01-04 | 2007-02-28 | Novartis Vaccines and Diagnostics, Inc. | Helicobacter pylori bacterioferritin |
JP4359654B2 (ja) * | 1996-01-30 | 2009-11-04 | ザ リージェンツ オブ ザ ユニバーシティー オブ カリフォルニア | 抗原特異的免疫応答を生起させる遺伝子発現ベクターおよびその使用方法 |
US20030078223A1 (en) * | 1996-01-30 | 2003-04-24 | Eyal Raz | Compositions and methods for modulating an immune response |
US7812149B2 (en) | 1996-06-06 | 2010-10-12 | Isis Pharmaceuticals, Inc. | 2′-Fluoro substituted oligomeric compounds and compositions for use in gene modulations |
US9096636B2 (en) | 1996-06-06 | 2015-08-04 | Isis Pharmaceuticals, Inc. | Chimeric oligomeric compounds and their use in gene modulation |
US20040147022A1 (en) * | 1996-06-06 | 2004-07-29 | Baker Brenda F. | 2'-methoxy substituted oligomeric compounds and compositions for use in gene modulations |
US20050119470A1 (en) * | 1996-06-06 | 2005-06-02 | Muthiah Manoharan | Conjugated oligomeric compounds and their use in gene modulation |
US20040171031A1 (en) * | 1996-06-06 | 2004-09-02 | Baker Brenda F. | Sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation |
US5898031A (en) * | 1996-06-06 | 1999-04-27 | Isis Pharmaceuticals, Inc. | Oligoribonucleotides for cleaving RNA |
US6610661B1 (en) | 1996-10-11 | 2003-08-26 | The Regents Of The University Of California | Immunostimulatory polynucleotide/immunomodulatory molecule conjugates |
CA2268957C (en) | 1996-10-25 | 2008-04-29 | Minnesota Mining And Manufacturing Company | Immune response modifier compounds for treatment of th2 mediated and related diseases |
EP0855184A1 (en) * | 1997-01-23 | 1998-07-29 | Grayson B. Dr. Lipford | Pharmaceutical composition comprising a polynucleotide and an antigen especially for vaccination |
NZ337054A (en) * | 1997-01-30 | 2001-03-30 | Chiron Corp | Microparticles PLA and PLG with adsorbed viral antigen to stimulate immune responses particularly for intracellular viruses such as HSV-1 or HSV-2, varicella zoster virus. epstein-barr virus or cytomegalovirus (CMV) |
US6884435B1 (en) * | 1997-01-30 | 2005-04-26 | Chiron Corporation | Microparticles with adsorbent surfaces, methods of making same, and uses thereof |
AU738513B2 (en) * | 1997-02-28 | 2001-09-20 | University Of Iowa Research Foundation, The | Use of nucleic acids containing unmethylated CpG dinucleotide in the treatment of LPS-associated disorders |
US6406705B1 (en) * | 1997-03-10 | 2002-06-18 | University Of Iowa Research Foundation | Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant |
EP1005368B1 (en) * | 1997-03-10 | 2009-09-02 | Ottawa Hospital Research Institute | Use of nucleic acids containing unmethylated CpG dinucleotide in combination with alum as adjuvants |
US6426334B1 (en) * | 1997-04-30 | 2002-07-30 | Hybridon, Inc. | Oligonucleotide mediated specific cytokine induction and reduction of tumor growth in a mammal |
US20030104044A1 (en) * | 1997-05-14 | 2003-06-05 | Semple Sean C. | Compositions for stimulating cytokine secretion and inducing an immune response |
US6287591B1 (en) | 1997-05-14 | 2001-09-11 | Inex Pharmaceuticals Corp. | Charged therapeutic agents encapsulated in lipid particles containing four lipid components |
EP1003531B1 (en) | 1997-05-20 | 2007-08-22 | Ottawa Health Research Institute | Processes for preparing nucleic acid constructs |
EP1374894A3 (en) * | 1997-06-06 | 2004-09-22 | Dynavax Technologies Corporation | Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof |
ATE432348T1 (de) | 1997-06-06 | 2009-06-15 | Univ California | Inhibitoren von immunstimulatorischen dna sequenz aktivität |
US20040006034A1 (en) * | 1998-06-05 | 2004-01-08 | Eyal Raz | Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof |
US6589940B1 (en) | 1997-06-06 | 2003-07-08 | Dynavax Technologies Corporation | Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof |
US6221882B1 (en) * | 1997-07-03 | 2001-04-24 | University Of Iowa Research Foundation | Methods for inhibiting immunostimulatory DNA associated responses |
AU2003203948B2 (en) * | 1997-09-05 | 2005-12-22 | The Regents Of The University Of California | Use of immunostimulatory oligonucleotides for preventing or reducing antigen-stimulated, granulocyte-mediated inflammation |
JP4663113B2 (ja) * | 1997-09-05 | 2011-03-30 | 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 | 抗原刺激顆粒球媒介炎症を予防または軽減するための免疫刺激オリゴヌクレオチドの使用 |
WO1999051259A2 (en) * | 1998-04-03 | 1999-10-14 | University Of Iowa Research Foundation | Methods and products for stimulating the immune system using immunotherapeutic oligonucleotides and cytokines |
AU3884199A (en) * | 1998-05-06 | 1999-11-23 | Ottawa Health Research Institute | Methods for the prevention and treatment of parasitic infections and related diseases using cpg oligonucleotides |
NZ508650A (en) * | 1998-05-14 | 2003-05-30 | Coley Pharm Gmbh | Regulating hematopoiesis using unmethylated C and G CpG-oligonucleotides with a phosphorothioate modification |
DK1079824T3 (da) | 1998-05-19 | 2011-11-21 | Res Dev Foundation | Triterpen-sammensætninger og fremgangsmåder til anvendelse deraf |
DE69932717T2 (de) * | 1998-05-22 | 2007-08-09 | Ottawa Health Research Institute, Ottawa | Methoden und produkte zur induzierung mukosaler immunität |
KR19990086271A (ko) * | 1998-05-27 | 1999-12-15 | 손경식 | 면역세포의 신규한 엔도뉴클레아제 및 이를 사용한 면역보조제 |
US6562798B1 (en) * | 1998-06-05 | 2003-05-13 | Dynavax Technologies Corp. | Immunostimulatory oligonucleotides with modified bases and methods of use thereof |
US6693086B1 (en) * | 1998-06-25 | 2004-02-17 | National Jewish Medical And Research Center | Systemic immune activation method using nucleic acid-lipid complexes |
US20030022854A1 (en) * | 1998-06-25 | 2003-01-30 | Dow Steven W. | Vaccines using nucleic acid-lipid complexes |
US20040247662A1 (en) * | 1998-06-25 | 2004-12-09 | Dow Steven W. | Systemic immune activation method using nucleic acid-lipid complexes |
EP1100807A1 (en) * | 1998-07-27 | 2001-05-23 | University Of Iowa Research Foundation | STEREOISOMERS OF CpG OLIGONUCLEOTIDES AND RELATED METHODS |
US7049302B1 (en) | 1998-08-10 | 2006-05-23 | Antigenics Inc. | Compositions of CPG and saponin adjuvants and uses thereof |
CA2343052A1 (en) * | 1998-09-18 | 2000-03-30 | Dynavax Technologies Corporation | Methods of treating ige-associated disorders and compositions for use therein |
AU6425999A (en) * | 1998-10-09 | 2000-05-01 | Dynavax Technologies Corporation | Anti hiv compositions comprising immunostimulatory polynucleotides and hiv antigens |
US6423493B1 (en) * | 1998-10-26 | 2002-07-23 | Board Of Regents The University Of Texas System | Combinatorial selection of oligonucleotide aptamers |
WO2000037067A2 (en) * | 1998-12-22 | 2000-06-29 | Panacea Pharmaceuticals, Llc | Sensitizing agents for the treatment of skin lesions |
US6558951B1 (en) * | 1999-02-11 | 2003-05-06 | 3M Innovative Properties Company | Maturation of dendritic cells with immune response modifying compounds |
ATE464907T1 (de) * | 1999-02-17 | 2010-05-15 | Csl Ltd | Immunogene komplexe und methoden in bezug auf diese |
WO2000050006A2 (en) | 1999-02-26 | 2000-08-31 | Chiron Corporation | Microemulsions with adsorbed macromoelecules and microparticles |
PT1154790E (pt) * | 1999-02-26 | 2005-03-31 | Chiron Srl | Reforco da actividade bactericida de antigenios contra a neisseria com oligonucleotidos contendo motivos cg |
GB2348132B (en) * | 1999-03-02 | 2004-08-04 | Nedaa Abdul-Ghani Nasif | Asthma/allergy therapy that targets t-lymphocytes and/or eosinophils |
FR2790955B1 (fr) * | 1999-03-19 | 2003-01-17 | Assist Publ Hopitaux De Paris | Utilisation d'oligonucleotides stabilises comme principe actif antitumoral |
EP1176966B1 (en) | 1999-04-12 | 2013-04-03 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Oligodeoxynucleotide and its use to induce an immune response |
US6977245B2 (en) | 1999-04-12 | 2005-12-20 | The United States Of America As Represented By The Department Of Health And Human Services | Oligodeoxynucleotide and its use to induce an immune response |
US6562801B1 (en) | 1999-04-15 | 2003-05-13 | Board Of Regents, The University Of Texas System | PpGpp and pppGpp as immunomodulatory agents |
GB9908885D0 (en) * | 1999-04-19 | 1999-06-16 | Smithkline Beecham Biolog | Vccine |
US6558670B1 (en) | 1999-04-19 | 2003-05-06 | Smithkline Beechman Biologicals S.A. | Vaccine adjuvants |
PL203951B1 (pl) * | 1999-04-19 | 2009-11-30 | Smithkline Beecham Biolog | Kompozycja adiuwantowa, kompozycja szczepionki oraz sposób jej wytwarzania, szczepionka oraz zastosowanie |
CA2370708A1 (en) * | 1999-04-20 | 2000-10-26 | Smithkline Beecham Biologicals S.A. | Vaccine comprising rsv antigen and cpg oligonucleotide |
ATE306938T1 (de) * | 1999-06-29 | 2005-11-15 | Glaxosmithkline Biolog Sa | Verwendung von cpg als adjuvans für hivimpstoff |
US20050002958A1 (en) * | 1999-06-29 | 2005-01-06 | Smithkline Beecham Biologicals Sa | Vaccines |
US6514948B1 (en) | 1999-07-02 | 2003-02-04 | The Regents Of The University Of California | Method for enhancing an immune response |
FR2795963A1 (fr) * | 1999-07-08 | 2001-01-12 | Pasteur Merieux Serums Vacc | Polynucleotide immunostimulant |
DE19935756A1 (de) * | 1999-07-27 | 2001-02-08 | Mologen Forschungs Entwicklung | Kovalent geschlossenes Nukleinsäuremolekül zur Immunstimulation |
US20050226890A1 (en) * | 1999-08-12 | 2005-10-13 | Cohen David I | Tat-based vaccine compositions and methods of making and using same |
WO2001012804A2 (en) * | 1999-08-13 | 2001-02-22 | Hybridon, Inc. | MODULATION OF OLIGONUCLEOTIDE CpG-MEDIATED IMMUNE STIMULATION BY POSITIONAL MODIFICATION OF NUCLEOSIDES |
EP1204425B1 (en) | 1999-08-19 | 2009-01-07 | Dynavax Technologies Corporation | Methods of modulating an immune response using immunostimulatory sequences and compositions for use therein |
AU780535B2 (en) * | 1999-08-27 | 2005-03-24 | Inex Pharmaceuticals Corp. | Compositions for stimulating cytokine secretion and inducing an immune response |
US20050249794A1 (en) * | 1999-08-27 | 2005-11-10 | Semple Sean C | Compositions for stimulating cytokine secretion and inducing an immune response |
AP2006003503A0 (en) * | 1999-09-25 | 2006-02-28 | Univ Iowa Res Found | Immunostimulatory nucleic acids. |
EP1688147A1 (en) * | 1999-09-27 | 2006-08-09 | Coley Pharmaceutical Group, Inc. | Methods Related to Immunostimulatory Nucleic Acid-Induced Interferon |
EP1220684B2 (en) * | 1999-09-27 | 2010-07-14 | Coley Pharmaceutical Group, Inc. | Methods related to immunostimulatory nucleic acid-induced interferon |
US6949520B1 (en) * | 1999-09-27 | 2005-09-27 | Coley Pharmaceutical Group, Inc. | Methods related to immunostimulatory nucleic acid-induced interferon |
ES2541830T3 (es) | 1999-10-29 | 2015-07-27 | Novartis Vaccines And Diagnositics S.R.L. | Péptidos antigénicos de Neisseria |
US7223398B1 (en) | 1999-11-15 | 2007-05-29 | Dynavax Technologies Corporation | Immunomodulatory compositions containing an immunostimulatory sequence linked to antigen and methods of use thereof |
EP1322655B1 (en) * | 2000-01-14 | 2007-11-14 | The Government of the United States of America, as represented by the Secretary of the Department of Health and Human Services | Oligodeoxynucleotide and its use to induce an immune response |
AU3108001A (en) * | 2000-01-20 | 2001-12-24 | Coley Pharmaceutical Group, Inc. | Immunostimulatory nucleic acids for inducing a th2 immune response |
US6552006B2 (en) | 2000-01-31 | 2003-04-22 | The Regents Of The University Of California | Immunomodulatory polynucleotides in treatment of an infection by an intracellular pathogen |
US7585847B2 (en) | 2000-02-03 | 2009-09-08 | Coley Pharmaceutical Group, Inc. | Immunostimulatory nucleic acids for the treatment of asthma and allergy |
US20030130217A1 (en) * | 2000-02-23 | 2003-07-10 | Eyal Raz | Method for treating inflammatory bowel disease and other forms of gastrointestinal inflammation |
US6613751B2 (en) | 2000-02-23 | 2003-09-02 | The Regents Of The University Of California | Method for treating inflammatory bowel disease and other forms of gastrointestinal inflammation |
WO2001062092A1 (en) * | 2000-02-25 | 2001-08-30 | Thomas Jefferson University | Formulations and methods for using the same to elicit an immune response |
US20040131628A1 (en) * | 2000-03-08 | 2004-07-08 | Bratzler Robert L. | Nucleic acids for the treatment of disorders associated with microorganisms |
US20010046967A1 (en) | 2000-03-10 | 2001-11-29 | Gary Van Nest | Methods of preventing and treating respiratory viral infection using immunomodulatory polynucleotide |
US20020098199A1 (en) | 2000-03-10 | 2002-07-25 | Gary Van Nest | Methods of suppressing hepatitis virus infection using immunomodulatory polynucleotide sequences |
US7157437B2 (en) | 2000-03-10 | 2007-01-02 | Dynavax Technologies Corporation | Methods of ameliorating symptoms of herpes infection using immunomodulatory polynucleotide sequences |
US20030129251A1 (en) | 2000-03-10 | 2003-07-10 | Gary Van Nest | Biodegradable immunomodulatory formulations and methods for use thereof |
US7129222B2 (en) * | 2000-03-10 | 2006-10-31 | Dynavax Technologies Corporation | Immunomodulatory formulations and methods for use thereof |
AU2001251407A1 (en) * | 2000-04-07 | 2001-10-23 | The Regents Of The University Of California | Synergistic improvements to polynucleotide vaccines |
ES2238044T3 (es) * | 2000-05-01 | 2005-08-16 | Hybridon, Inc. | Modulacion de la estimulacion inmunologica mediada por el oligonucleotido cpg mediante modificacion posicional de nucleosidos. |
US6696064B2 (en) * | 2000-06-20 | 2004-02-24 | The United States Of America As Represented By The Department Of Health And Human Services | Methods of protecting vasculature from damage by diphtheria toxin-and pseudomonas toxin-based immunotoxins during therapy |
US7767197B2 (en) | 2000-06-22 | 2010-08-03 | Endo Pharmaceuticals Colorado LLC | Delivery vehicle composition and methods for delivering antigens and other drugs |
AU7013401A (en) | 2000-06-22 | 2002-01-02 | Univ Iowa Res Found | Methods for enhancing antibody-induced cell lysis and treating cancer |
CA2410297C (en) * | 2000-06-23 | 2011-03-15 | American Cyanamid Company | Assembly of wild-type and chimeric influenza virus-like particles (vlps) |
WO2002002172A1 (en) * | 2000-06-30 | 2002-01-10 | Univ Jefferson | Dna palindrome - oligoguanylic acid compositions and uses thereof |
KR100917101B1 (ko) * | 2000-08-04 | 2009-09-15 | 도요 보세키 가부시키가이샤 | 플렉시블 금속적층체 및 그 제조방법 |
US20080044435A1 (en) * | 2004-03-16 | 2008-02-21 | Cohen David I | Tat-Based Tolerogen Compositions and Methods of Making and Using Same |
JP2005503320A (ja) * | 2000-08-25 | 2005-02-03 | イエダ・リサーチ・アンド・デベロツプメント・カンパニー・リミテツド | CpG−含有ポリヌクレオチドで自己免疫疾患を処置または防止する方法 |
WO2002022809A2 (en) * | 2000-09-15 | 2002-03-21 | Coley Pharmaceutical Gmbh | PROCESS FOR HIGH THROUGHPUT SCREENING OF CpG-BASED IMMUNO-AGONIST/ANTAGONIST |
CA2423487C (en) * | 2000-09-26 | 2015-12-15 | Hybridon, Inc. | Modulation of immunostimulatory activity of immunostimulatory oligonucleotide analogs by positional chemical changes |
CA2425303A1 (en) | 2000-10-27 | 2002-05-02 | John Telford | Nucleic acids and proteins from streptococcus groups a & b |
JP2008531580A (ja) * | 2000-12-08 | 2008-08-14 | スリーエム イノベイティブ プロパティズ カンパニー | 免疫応答修飾因子の標的化送達のための組成物および方法 |
ES2307568T3 (es) * | 2000-12-08 | 2008-12-01 | Coley Pharmaceutical Gmbh | Acidos nucleicos de tipo cpg y metodos de uso de los mismos. |
US6677347B2 (en) * | 2000-12-08 | 2004-01-13 | 3M Innovative Properties Company | Sulfonamido ether substituted imidazoquinolines |
DE60142410D1 (de) * | 2000-12-27 | 2010-07-29 | Dynavax Tech Corp | Immunomodulatorische polynukleotide und verfahren zur deren verwendung |
KR20030070101A (ko) * | 2001-01-12 | 2003-08-27 | 아마토 세이야쿠 가부시키가이샤 | 미생물 감염 방지제 |
US7264810B2 (en) * | 2001-01-19 | 2007-09-04 | Cytos Biotechnology Ag | Molecular antigen array |
EP1355661A2 (de) * | 2001-01-31 | 2003-10-29 | Mologen Forschungs-, Entwicklungs- und Vertriebs GmbH | Tumorvakzine |
US20030050268A1 (en) * | 2001-03-29 | 2003-03-13 | Krieg Arthur M. | Immunostimulatory nucleic acid for treatment of non-allergic inflammatory diseases |
CA2443493A1 (en) * | 2001-04-13 | 2002-10-24 | Wyeth | Surface proteins of streptococcus pyogenes |
US20070128229A1 (en) * | 2002-04-12 | 2007-06-07 | Wyeth | Surface proteins of Streptococcus pyogenes |
EP1572868A4 (en) | 2001-04-16 | 2007-04-04 | Wyeth Corp | NOVEL OPEN READING FRAMES OF STREPTOCOCCUS PNEUMONIAE ENCODING POLYPEPTIDE ANTIGENS AND USES THEREOF |
US7034140B2 (en) * | 2001-04-24 | 2006-04-25 | E.I. Du Pont De Nemours And Company | Genes involved in isoprenoid compound production |
CA2448031A1 (en) | 2001-05-21 | 2002-11-28 | Intercell Ag | Method for stabilising of nucleic acids |
US6818787B2 (en) * | 2001-06-11 | 2004-11-16 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
GB0115176D0 (en) | 2001-06-20 | 2001-08-15 | Chiron Spa | Capular polysaccharide solubilisation and combination vaccines |
US7785610B2 (en) * | 2001-06-21 | 2010-08-31 | Dynavax Technologies Corporation | Chimeric immunomodulatory compounds and methods of using the same—III |
CN100334228C (zh) | 2001-06-21 | 2007-08-29 | 戴纳瓦克斯技术公司 | 嵌合免疫调制化合物及其使用方法 |
CN1931365A (zh) * | 2001-06-29 | 2007-03-21 | 希龙公司 | Hcv e1e2疫苗组合物 |
GB0118249D0 (en) | 2001-07-26 | 2001-09-19 | Chiron Spa | Histidine vaccines |
GB0121591D0 (en) | 2001-09-06 | 2001-10-24 | Chiron Spa | Hybrid and tandem expression of neisserial proteins |
US7666674B2 (en) | 2001-07-27 | 2010-02-23 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Use of sterically stabilized cationic liposomes to efficiently deliver CPG oligonucleotides in vivo |
WO2003012061A2 (en) * | 2001-08-01 | 2003-02-13 | Coley Pharmaceutical Gmbh | Methods and compositions relating to plasmacytoid dendritic cells |
JP2005518343A (ja) * | 2001-08-03 | 2005-06-23 | メダレックス, インク. | 新規なpgc−1イソフォームおよびその使用媒介型免疫治療を向上させるためのその使用 |
WO2003014316A2 (en) | 2001-08-07 | 2003-02-20 | Dynavax Technologies Corporation | Immunomodulatory compositions, formulations, and methods for use thereof |
US7354909B2 (en) * | 2001-08-14 | 2008-04-08 | The United States Of America As Represented By Secretary Of The Department Of Health And Human Services | Method for rapid generation of mature dendritic cells |
SI1446162T1 (sl) * | 2001-08-17 | 2009-04-30 | Coley Pharm Gmbh | Kombinacija zaporedja imunostimulatornih oligonukleotidov z izboljšano aktivnostjo |
CN100488981C (zh) | 2001-08-24 | 2009-05-20 | 维多利亚大学创新和发展公司 | 含有蛋白酶激活序列的气单胞菌溶素原及其应用 |
US20030133913A1 (en) * | 2001-08-30 | 2003-07-17 | 3M Innovative Properties Company | Methods of maturing plasmacytoid dendritic cells using immune response modifier molecules |
BR0212366A (pt) * | 2001-09-07 | 2004-07-27 | Univ Boston | Método e composição para tratar distúrbios associados com o complexo imune |
EP2196217A1 (en) | 2001-09-14 | 2010-06-16 | Cytos Biotechnology AG | Packaging of immunostimulatory substances into virus-like particles: method of preparation and use |
JP4360906B2 (ja) * | 2001-09-14 | 2009-11-11 | サイトス バイオテクノロジー アーゲー | ウィルス様粒子によって誘導される免疫応答を高めるための、抗原提示細胞のインビボでの活性化 |
WO2003027313A2 (en) | 2001-09-24 | 2003-04-03 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | SUPPRESSORS OF CpG OLIGONUCLEOTIDES AND METHODS OF USE |
US7514415B2 (en) | 2002-08-01 | 2009-04-07 | The United States Of America As Represented By The Department Of Health And Human Services | Method of treating inflammatory arthropathies with suppressors of CpG oligonucleotides |
US20030119774A1 (en) * | 2001-09-25 | 2003-06-26 | Marianna Foldvari | Compositions and methods for stimulating an immune response |
AR045702A1 (es) | 2001-10-03 | 2005-11-09 | Chiron Corp | Composiciones de adyuvantes. |
CA2461315A1 (en) * | 2001-10-05 | 2003-04-17 | Coley Pharmaceutical Gmbh | Toll-like receptor 3 signaling agonists and antagonists |
DK1455593T3 (da) | 2001-10-06 | 2013-08-26 | Merial Ltd | Fremgangsmåder og sammensætninger til fremme af vækst og medfødt immunitet hos unge dyr |
MX339524B (es) | 2001-10-11 | 2016-05-30 | Wyeth Corp | Composiciones inmunogenicas novedosas para la prevencion y tratamiento de enfermedad meningococica. |
AU2002360278A1 (en) * | 2001-10-12 | 2003-11-11 | Coley Pharmaceutical Gmbh | Methods and products for enhancing immune responses using imidazoquinoline compounds |
US7276489B2 (en) * | 2002-10-24 | 2007-10-02 | Idera Pharmaceuticals, Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5′ ends |
US20030125292A1 (en) * | 2001-11-07 | 2003-07-03 | Sean Semple | Mucoscal vaccine and methods for using the same |
EP1441758A2 (de) * | 2001-11-09 | 2004-08-04 | MediGene Aktiengesellschaft | Allogene vakzine enthaltend eine ein costimulatorisches polypeptid exprimierende tumorzelle |
US7179798B2 (en) * | 2001-11-16 | 2007-02-20 | Russell R. Roby | Methods and compositions for the treatment of pain and other hormone-allergy-related symptoms using dilute hormone solutions |
DK1719511T3 (da) * | 2001-11-16 | 2009-04-14 | Coley Pharm Group Inc | N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methansulfonamid, en farmaceutisk sammensætning omfattende samme, og anvendelse deraf |
JP2005519035A (ja) * | 2001-12-07 | 2005-06-30 | インターツェル・アクチェンゲゼルシャフト | 免疫促進性オリゴデオキシヌクレオチド |
US8466116B2 (en) | 2001-12-20 | 2013-06-18 | The Unites States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Use of CpG oligodeoxynucleotides to induce epithelial cell growth |
CA2365732A1 (en) * | 2001-12-20 | 2003-06-20 | Ibm Canada Limited-Ibm Canada Limitee | Testing measurements |
AU2002366710A1 (en) * | 2001-12-20 | 2003-07-09 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of | USE OF CpG OLIGODEOXYNUCLEOTIDES TO INDUCE ANGIOGENESIS |
WO2003055514A1 (en) * | 2001-12-21 | 2003-07-10 | Antigenics Inc. | Compositions comprising immunoreactive reagents and saponins, and methods of use thereof |
CA2474709A1 (en) * | 2002-02-04 | 2003-08-14 | Biomira, Inc. | Immunostimulatory, covalently lipidated oligonucleotides |
US8088388B2 (en) * | 2002-02-14 | 2012-01-03 | United Biomedical, Inc. | Stabilized synthetic immunogen delivery system |
EP2572707A3 (en) | 2002-02-20 | 2013-11-06 | Novartis Vaccines and Diagnostics, Inc. | Microparticles with adsorbed polypeptide-containing molecules |
JP2005518433A (ja) * | 2002-02-22 | 2005-06-23 | スリーエム イノベイティブ プロパティズ カンパニー | Uvb−誘導免疫抑制を軽減し治療する方法 |
US6923958B2 (en) * | 2002-03-02 | 2005-08-02 | The Scripps Research Institute | DNA vaccines encoding CEA and a CD40 ligand and methods of use thereof |
EP2258712A3 (en) * | 2002-03-15 | 2011-05-04 | Multicell Immunotherapeutics, Inc. | Compositions and Methods to Initiate or Enhance Antibody and Major-histocompatibility Class I or Class II-restricted T Cell Responses by Using Immunomodulatory, Non-coding RNA Motifs |
KR100981471B1 (ko) * | 2002-03-15 | 2010-09-10 | 더 큐레이터스 오브 더 유니버시티 오브 미주리 | 효소 활성이 감소된 형별불능 헤모필러스 인플루엔자의p4 변형 단백질 |
JP2005526778A (ja) * | 2002-03-15 | 2005-09-08 | アストラル,インコーポレイテッド | 免疫調節性非コードrnaモチーフを用いて抗体及び主要組織適合性クラスi拘束性又はクラスii拘束性t細胞の応答を開始或いは増強させるための組成物及び方法 |
US8153141B2 (en) | 2002-04-04 | 2012-04-10 | Coley Pharmaceutical Gmbh | Immunostimulatory G, U-containing oligoribonucleotides |
US20030224013A1 (en) * | 2002-04-19 | 2003-12-04 | Cole Garry T. | Methods for protection against Coccidioides spp. infection using Coccidioides spp. urea amidohydrolase (Ure) protein |
US20040009943A1 (en) * | 2002-05-10 | 2004-01-15 | Inex Pharmaceuticals Corporation | Pathogen vaccines and methods for using the same |
US20040009944A1 (en) * | 2002-05-10 | 2004-01-15 | Inex Pharmaceuticals Corporation | Methylated immunostimulatory oligonucleotides and methods of using the same |
US20040013649A1 (en) * | 2002-05-10 | 2004-01-22 | Inex Pharmaceuticals Corporation | Cancer vaccines and methods of using the same |
US9045727B2 (en) | 2002-05-17 | 2015-06-02 | Emory University | Virus-like particles, methods of preparation, and immunogenic compositions |
US20060088909A1 (en) * | 2002-05-17 | 2006-04-27 | Compans Richard W | Virus-like particles, methods of preparation, and immunogenic compositions |
KR100456681B1 (ko) * | 2002-05-22 | 2004-11-10 | 주식회사 대웅 | 박테리아의 염색체 dna 파쇄물과 비독성리포폴리사카라이드를 포함하는 면역강화 및 조절 조성물 |
CA2388049A1 (en) | 2002-05-30 | 2003-11-30 | Immunotech S.A. | Immunostimulatory oligonucleotides and uses thereof |
US20040009949A1 (en) * | 2002-06-05 | 2004-01-15 | Coley Pharmaceutical Group, Inc. | Method for treating autoimmune or inflammatory diseases with combinations of inhibitory oligonucleotides and small molecule antagonists of immunostimulatory CpG nucleic acids |
DE60335186D1 (de) * | 2002-06-20 | 2011-01-13 | Cytos Biotechnology Ag | Verpackte virusartige partikel in kombination mit cpg zur verwendung als adjuvantien mit allergenen. herstellungsverfahren und verwendung |
US7807803B2 (en) * | 2002-07-03 | 2010-10-05 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US7605138B2 (en) * | 2002-07-03 | 2009-10-20 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US20040053880A1 (en) * | 2002-07-03 | 2004-03-18 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
AU2003247880B2 (en) * | 2002-07-03 | 2010-09-02 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US7569553B2 (en) * | 2002-07-03 | 2009-08-04 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US7576066B2 (en) * | 2002-07-03 | 2009-08-18 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
AU2003255969A1 (en) * | 2002-07-17 | 2004-02-02 | Coley Pharmaceutical Gmbh | Use of cpg nucleic acids in prion-disease |
US20060270620A1 (en) * | 2002-07-23 | 2006-11-30 | University Of South Florida | Method of Enhancing Therapeutic Effect of Nucleic Acids |
CN1650012A (zh) | 2002-07-24 | 2005-08-03 | 英特塞尔股份公司 | 来自致病病毒的备选阅读框所编码的抗原 |
AU2003299863B2 (en) | 2002-08-15 | 2009-09-24 | 3M Innovative Properties Company | Immunostimulatory compositions and methods of stimulating an immune response |
AR040996A1 (es) * | 2002-08-19 | 2005-04-27 | Coley Pharm Group Inc | Acidos nucleicos inmunoestimuladores |
GB0220194D0 (en) | 2002-08-30 | 2002-10-09 | Chiron Spa | Improved vesicles |
US7785608B2 (en) * | 2002-08-30 | 2010-08-31 | Wyeth Holdings Corporation | Immunogenic compositions for the prevention and treatment of meningococcal disease |
US7595303B1 (en) * | 2002-09-05 | 2009-09-29 | University Of South Florida | Genetic adjuvants for immunotherapy |
US20050196382A1 (en) * | 2002-09-13 | 2005-09-08 | Replicor, Inc. | Antiviral oligonucleotides targeting viral families |
CA2484339A1 (en) | 2002-09-13 | 2004-03-25 | Intercell Ag | Method for isolating hepatitis c virus peptides |
CN1694959B (zh) * | 2002-09-13 | 2013-09-18 | 雷普利瑟公司 | 非序列互补的抗病毒寡核苷酸 |
US8263091B2 (en) * | 2002-09-18 | 2012-09-11 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Method of treating and preventing infections in immunocompromised subjects with immunostimulatory CpG oligonucleotides |
US7301554B2 (en) * | 2002-09-20 | 2007-11-27 | Ricoh Company, Ltd. | Light scanning device, scanning line adjusting method, scanning line adjusting control method, image forming apparatus, and image forming method |
WO2004031382A1 (ja) * | 2002-10-02 | 2004-04-15 | Mochida Pharmaceutical Co., Ltd. | 新規なモノクローナル抗体の作製方法 |
US8043622B2 (en) | 2002-10-08 | 2011-10-25 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Method of treating inflammatory lung disease with suppressors of CpG oligonucleotides |
DK2351579T3 (en) | 2002-10-11 | 2017-01-09 | Novartis Vaccines And Diagnostics S R L | Polypeptide vaccines for broad protection against hypervirulent meningococcal lineages. |
CA2503457A1 (en) * | 2002-10-25 | 2004-05-06 | University Of Connecticut Health Center | Apparatus and method for immunotherapy of a cancer through controlled cell lysis |
MXPA05004588A (es) | 2002-10-29 | 2005-12-14 | Coley Pharmaceutical Group Ltd | Metodos y productos relacionados con el tratamiento y prevencion de infeccion de virus de hepatitis c. |
JP4976653B2 (ja) * | 2002-11-01 | 2012-07-18 | ザ ガバメント オブ ザ ユナイテッド ステイツ オブ アメリカ アズ リプレゼンティッド バイ ザ セクレタリー オブ ザ デパートメント オブ ヘルス アンド ヒューマン サービシス | 免疫刺激性CpGオリゴヌクレオチドを用いてバイオテロ病原体による感染症を予防する方法 |
CA2504929C (en) * | 2002-11-05 | 2014-07-22 | Charles Allerson | Compositions comprising alternating 2'-modified nucleosides for use in gene modulation |
EP2279746B1 (en) | 2002-11-15 | 2013-10-02 | Novartis Vaccines and Diagnostics S.r.l. | Surface proteins in neisseria meningitidis |
US8039443B2 (en) * | 2002-11-21 | 2011-10-18 | Archemix Corporation | Stabilized aptamers to platelet derived growth factor and their use as oncology therapeutics |
US8853376B2 (en) | 2002-11-21 | 2014-10-07 | Archemix Llc | Stabilized aptamers to platelet derived growth factor and their use as oncology therapeutics |
US10100316B2 (en) * | 2002-11-21 | 2018-10-16 | Archemix Llc | Aptamers comprising CPG motifs |
US20050124565A1 (en) * | 2002-11-21 | 2005-06-09 | Diener John L. | Stabilized aptamers to platelet derived growth factor and their use as oncology therapeutics |
GB0227346D0 (en) | 2002-11-22 | 2002-12-31 | Chiron Spa | 741 |
AU2003287324A1 (en) * | 2002-12-11 | 2004-06-30 | 3M Innovative Properties Company | Gene expression systems and recombinant cell lines |
AU2003287316A1 (en) * | 2002-12-11 | 2004-06-30 | 3M Innovative Properties Company | Assays relating to toll-like receptor activity |
AU2003300919A1 (en) * | 2002-12-11 | 2004-06-30 | Coley Pharmaceutical Gmbh | 5' cpg nucleic acids and methods of use |
US20040213808A1 (en) * | 2002-12-11 | 2004-10-28 | Michael Lieberman | Recombinant vaccine against flavivirus infection |
CN100546998C (zh) | 2002-12-23 | 2009-10-07 | 戴纳伐克斯技术股份有限公司 | 免疫刺激序列寡核苷酸和使用方法 |
US8158768B2 (en) | 2002-12-23 | 2012-04-17 | Dynavax Technologies Corporation | Immunostimulatory sequence oligonucleotides and methods of using the same |
JP2006516099A (ja) * | 2002-12-23 | 2006-06-22 | ダイナバックス テクノロジーズ コーポレイション | 分枝状の免疫調節化合物及び該化合物の使用方法 |
WO2004060396A2 (en) | 2002-12-27 | 2004-07-22 | Chiron Corporation | Immunogenic compositions containing phospholpid |
US7387271B2 (en) | 2002-12-30 | 2008-06-17 | 3M Innovative Properties Company | Immunostimulatory combinations |
EP2289546A3 (en) | 2003-01-30 | 2011-03-30 | Novartis Vaccines and Diagnostics S.r.l. | Injectable vaccines against multiple meningococcal serogroups |
US7354907B2 (en) * | 2003-02-07 | 2008-04-08 | Idera Pharmaceuticals, Inc. | Short immunomodulatory oligonucleotides |
WO2004071459A2 (en) * | 2003-02-13 | 2004-08-26 | 3M Innovative Properties Company | Methods and compositions related to irm compounds and toll-like receptor 8 |
ES2385933T3 (es) | 2003-02-20 | 2012-08-03 | University Of Connecticut Health Center | Métodos para la producción de complejos de moléculas antígenas de alfa (2) macroglobulina. |
GB2398783A (en) | 2003-02-26 | 2004-09-01 | Antonio Lanzavecchia | A method for producing immortalised human B memory lymphocytes |
US7485432B2 (en) * | 2003-02-27 | 2009-02-03 | 3M Innovative Properties Company | Selective modulation of TLR-mediated biological activity |
AU2004218349A1 (en) | 2003-03-04 | 2004-09-16 | 3M Innovative Properties Company | Prophylactic treatment of UV-induced epidermal neoplasia |
MXPA05009694A (es) * | 2003-03-13 | 2005-10-20 | 3M Innovative Properties Co | Metodos para mejorar la calidad de la piel. |
CA2518445A1 (en) | 2003-03-13 | 2004-09-23 | 3M Innovative Properties Company | Method of tattoo removal |
US7704514B2 (en) | 2003-03-24 | 2010-04-27 | Intercell Ag | Vaccines |
US20040192585A1 (en) * | 2003-03-25 | 2004-09-30 | 3M Innovative Properties Company | Treatment for basal cell carcinoma |
US7537767B2 (en) | 2003-03-26 | 2009-05-26 | Cytis Biotechnology Ag | Melan-A- carrier conjugates |
CN1795274A (zh) * | 2003-03-26 | 2006-06-28 | 多单元免疫治疗公司 | 诱导细胞死亡和/或凋亡的选定的rna基序 |
CA2517839A1 (en) | 2003-03-26 | 2004-10-07 | Martin F. Bachmann | Melan-a peptide analogue-virus-like-particle conjugates |
US20060210588A1 (en) * | 2003-03-26 | 2006-09-21 | Cytos Biotechnology Ag | Hiv-peptide-carrier-conjugates |
US20040235770A1 (en) * | 2003-04-02 | 2004-11-25 | Coley Pharmaceutical Group, Ltd. | Immunostimulatory nucleic acid oil-in-water formulations and related methods of use |
ES2529736T3 (es) | 2003-04-10 | 2015-02-25 | Novartis Vaccines And Diagnostics, Inc. | Composición inmunogénica que comprende una proteína espicular del coronavirus del SARS |
US20040265351A1 (en) * | 2003-04-10 | 2004-12-30 | Miller Richard L. | Methods and compositions for enhancing immune response |
AU2004244962A1 (en) * | 2003-04-10 | 2004-12-16 | 3M Innovative Properties Company | Delivery of immune response modifier compounds using metal-containing particulate support materials |
JP2007525177A (ja) | 2003-04-21 | 2007-09-06 | アーケミックス コーポレイション | 血小板由来増殖因子に対する安定化アプタマーおよび腫瘍治療剤としてのそれらの使用 |
JP4673217B2 (ja) * | 2003-04-23 | 2011-04-20 | 由紀夫 佐藤 | メチル化CpGポリヌクレオチド |
US20050250106A1 (en) * | 2003-04-24 | 2005-11-10 | David Epstein | Gene knock-down by intracellular expression of aptamers |
RU2364419C2 (ru) * | 2003-04-25 | 2009-08-20 | Новартис Вэксинес Энд Дайэгностикс, Инк. | Композиции, содержащие катионные микрочастицы и днк hcv е1е2, и способы их применения |
EP1617845A4 (en) * | 2003-04-28 | 2006-09-20 | 3M Innovative Properties Co | COMPOSITIONS AND METHODS FOR INDUCING OPOID RECEPTORS |
WO2004100965A1 (ja) * | 2003-05-15 | 2004-11-25 | Japan Science And Technology Agency | 免疫刺激剤 |
US8080642B2 (en) * | 2003-05-16 | 2011-12-20 | Vical Incorporated | Severe acute respiratory syndrome DNA compositions and methods of use |
WO2005020964A1 (en) | 2003-06-02 | 2005-03-10 | Chiron Corporation | Immunogenic compositions based on microparticles comprising adsorbed toxoid and a polysaccharide-containing antigen |
WO2005000884A1 (en) | 2003-06-05 | 2005-01-06 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Poly-gamma-glutamic conjugates for eliciting immune responses directed against bacilli |
EP2371834B1 (en) * | 2003-06-11 | 2016-02-17 | Idera Pharmaceuticals, Inc. | Stabilized immunomodulatory oligonucleotides |
JP2007524615A (ja) * | 2003-06-20 | 2007-08-30 | コーリー ファーマシューティカル ゲーエムベーハー | 低分子トール様レセプター(tlr)アンタゴニスト |
KR20060031607A (ko) * | 2003-07-10 | 2006-04-12 | 사이토스 바이오테크놀로지 아게 | 패킹된 바이러스-양 입자 |
US20050013812A1 (en) * | 2003-07-14 | 2005-01-20 | Dow Steven W. | Vaccines using pattern recognition receptor-ligand:lipid complexes |
RU2006102188A (ru) * | 2003-07-31 | 2006-07-10 | ЗМ Инновейтив Пропертиз Компани (US) | Биоактивные композиции, включающие триазины |
WO2005016273A2 (en) * | 2003-08-05 | 2005-02-24 | 3M Innovative Properties Company | Infection prophylaxis using immune response modifier compounds |
JP2007502288A (ja) * | 2003-08-12 | 2007-02-08 | スリーエム イノベイティブ プロパティズ カンパニー | オキシム置換イミダゾ含有化合物 |
US20060035242A1 (en) | 2004-08-13 | 2006-02-16 | Michelitsch Melissa D | Prion-specific peptide reagents |
US20050065136A1 (en) * | 2003-08-13 | 2005-03-24 | Roby Russell R. | Methods and compositions for the treatment of infertility using dilute hormone solutions |
US8071652B2 (en) * | 2003-08-21 | 2011-12-06 | The Board Of Regents Of The University Of Texas System | Method of treating irritable bowel syndrome |
EP1660122A4 (en) * | 2003-08-25 | 2007-10-24 | 3M Innovative Properties Co | IMMUNOSTIMULATORY COMBINATIONS AND TREATMENTS |
AU2004268616B2 (en) * | 2003-08-25 | 2010-10-07 | 3M Innovative Properties Company | Delivery of immune response modifier compounds |
EP1658076B1 (en) * | 2003-08-27 | 2013-03-06 | 3M Innovative Properties Company | Aryloxy and arylalkyleneoxy substituted imidazoquinolines |
JP2007504172A (ja) * | 2003-09-02 | 2007-03-01 | スリーエム イノベイティブ プロパティズ カンパニー | 粘膜に関連した症状の処置に関する方法 |
AU2004270201A1 (en) * | 2003-09-05 | 2005-03-17 | 3M Innovative Properties Company | Treatment for CD5+ B cell lymphoma |
EP1670507A4 (en) | 2003-09-12 | 2007-10-17 | Antigenics Inc | VACCINE FOR THE TREATMENT AND PREVENTION OF INFECTION CAUSED BY HERPES SIMPLEX VIRUS |
CA2536139A1 (en) * | 2003-09-25 | 2005-04-07 | Coley Pharmaceutical Group, Inc. | Nucleic acid-lipophilic conjugates |
EP1670506B1 (en) | 2003-10-02 | 2012-11-21 | Novartis AG | Liquid vaccines for multiple meningococcal serogroups |
GB0323103D0 (en) | 2003-10-02 | 2003-11-05 | Chiron Srl | De-acetylated saccharides |
BRPI0414856A (pt) * | 2003-10-03 | 2006-11-21 | 3M Innovative Properties Co | imidazoquinolinas alcóxi-substituìdas |
US20090075980A1 (en) * | 2003-10-03 | 2009-03-19 | Coley Pharmaceutical Group, Inc. | Pyrazolopyridines and Analogs Thereof |
US7544697B2 (en) * | 2003-10-03 | 2009-06-09 | Coley Pharmaceutical Group, Inc. | Pyrazolopyridines and analogs thereof |
WO2005034979A2 (en) * | 2003-10-11 | 2005-04-21 | Inex Pharmaceuticals Corporation | Methods and compositions for enhancing innate immunity and antibody dependent cellular cytotoxicity |
GB0323965D0 (en) * | 2003-10-13 | 2003-11-19 | Glaxosmithkline Biolog Sa | Immunogenic compositions |
CA2540949A1 (en) * | 2003-10-30 | 2005-05-12 | Coley Pharmaceutical Gmbh | C-class oligonucleotide analogs with enhanced immunostimulatory potency |
US20050239733A1 (en) * | 2003-10-31 | 2005-10-27 | Coley Pharmaceutical Gmbh | Sequence requirements for inhibitory oligonucleotides |
WO2005041891A2 (en) * | 2003-10-31 | 2005-05-12 | 3M Innovative Properties Company | Neutrophil activation by immune response modifier compounds |
US20050100983A1 (en) * | 2003-11-06 | 2005-05-12 | Coley Pharmaceutical Gmbh | Cell-free methods for identifying compounds that affect toll-like receptor 9 (TLR9) signaling |
CA2545774A1 (en) | 2003-11-14 | 2005-06-02 | 3M Innovative Properties Company | Oxime substituted imidazo ring compounds |
WO2005048945A2 (en) * | 2003-11-14 | 2005-06-02 | 3M Innovative Properties Company | Hydroxylamine substituted imidazo ring compounds |
US8691837B2 (en) * | 2003-11-25 | 2014-04-08 | 3M Innovative Properties Company | Substituted imidazo ring systems and methods |
US20050287118A1 (en) * | 2003-11-26 | 2005-12-29 | Epitomics, Inc. | Bacterial plasmid with immunological adjuvant function and uses thereof |
US20050277127A1 (en) * | 2003-11-26 | 2005-12-15 | Epitomics, Inc. | High-throughput method of DNA immunogen preparation and immunization |
US8940755B2 (en) * | 2003-12-02 | 2015-01-27 | 3M Innovative Properties Company | Therapeutic combinations and methods including IRM compounds |
US20050226878A1 (en) * | 2003-12-02 | 2005-10-13 | 3M Innovative Properties Company | Therapeutic combinations and methods including IRM compounds |
US9090673B2 (en) | 2003-12-12 | 2015-07-28 | City Of Hope | Synthetic conjugate of CpG DNA and T-help/CTL peptide |
PL2336147T3 (pl) | 2003-12-17 | 2015-01-30 | Janssen Alzheimer Immunotherap | Immunogenne koniugaty A beta z nośnikiem peptydowym i sposoby ich otrzymywania |
AU2004299501B2 (en) | 2003-12-17 | 2010-12-23 | Wyeth Llc | Immunogenic peptide carrier conjugates and methods of producing same |
JP4817599B2 (ja) * | 2003-12-25 | 2011-11-16 | 独立行政法人科学技術振興機構 | 免疫活性増強剤とこれを用いた免疫活性の増強方法 |
WO2005066170A1 (en) * | 2003-12-29 | 2005-07-21 | 3M Innovative Properties Company | Arylalkenyl and arylalkynyl substituted imidazoquinolines |
EP1699398A4 (en) * | 2003-12-30 | 2007-10-17 | 3M Innovative Properties Co | IMPROVING THE IMMUNE RESPONSE |
US8735421B2 (en) * | 2003-12-30 | 2014-05-27 | 3M Innovative Properties Company | Imidazoquinolinyl sulfonamides |
WO2005072290A2 (en) * | 2004-01-23 | 2005-08-11 | Joslin Diabetes Center | Methods of treating, reducing, or preventing autoimmune conditions |
US20050181035A1 (en) * | 2004-02-17 | 2005-08-18 | Dow Steven W. | Systemic immune activation method using non CpG nucleic acids |
EP1720568A2 (en) | 2004-02-19 | 2006-11-15 | Coley Pharmaceutical Group, Inc. | Immunostimulatory viral rna oligonucleotides |
CN1918293A (zh) * | 2004-02-20 | 2007-02-21 | 莫洛根股份公司 | 用于对人及高等动物进行治疗性和预防性免疫刺激的取代的非编码核酸分子 |
US20060193821A1 (en) * | 2004-03-05 | 2006-08-31 | Diener John L | Aptamers to the human IL-12 cytokine family and their use as autoimmune disease therapeutics |
US20080254065A1 (en) | 2004-03-09 | 2008-10-16 | Chiron Corporation | Influenza Virus Vaccines |
US8569474B2 (en) | 2004-03-09 | 2013-10-29 | Isis Pharmaceuticals, Inc. | Double stranded constructs comprising one or more short strands hybridized to a longer strand |
WO2005090968A1 (en) * | 2004-03-16 | 2005-09-29 | Inist Inc. | Tat-based immunomodulatory compositions and methods of their discovery and use |
EP2545931A1 (en) | 2004-03-19 | 2013-01-16 | Herbs Spring, LLC | Herbal therapy for the treatment of food allergy |
WO2005094531A2 (en) * | 2004-03-24 | 2005-10-13 | 3M Innovative Properties Company | Amide substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines |
TWI235440B (en) * | 2004-03-31 | 2005-07-01 | Advanced Semiconductor Eng | Method for making leadless semiconductor package |
EP1730281A2 (en) * | 2004-04-02 | 2006-12-13 | Coley Pharmaceutical Group, Inc. | Immunostimulatory nucleic acids for inducing il-10 responses |
US20050260755A1 (en) * | 2004-04-06 | 2005-11-24 | Isis Pharmaceuticals, Inc. | Sequential delivery of oligomeric compounds |
WO2005105106A2 (en) * | 2004-04-21 | 2005-11-10 | Roby Russell R | Hormone treatment of macular degeneration |
WO2005105107A2 (en) * | 2004-04-21 | 2005-11-10 | Roby Russell R | Hormone treatment of multiple sclerosis |
US7579450B2 (en) * | 2004-04-26 | 2009-08-25 | Archemix Corp. | Nucleic acid ligands specific to immunoglobulin E and their use as atopic disease therapeutics |
JP2008505857A (ja) * | 2004-04-28 | 2008-02-28 | スリーエム イノベイティブ プロパティズ カンパニー | 粘膜ワクチン接種のための組成物および方法 |
GB0409745D0 (en) | 2004-04-30 | 2004-06-09 | Chiron Srl | Compositions including unconjugated carrier proteins |
BRPI0510315A (pt) | 2004-04-30 | 2007-10-16 | Chiron Srl | integração de vacinação com conjugado meningocócico |
GB0500787D0 (en) | 2005-01-14 | 2005-02-23 | Chiron Srl | Integration of meningococcal conjugate vaccination |
CN1989439B (zh) * | 2004-05-06 | 2010-12-29 | 美国政府健康及人类服务部 | 治疗葡萄膜炎的方法以及组合物 |
GB0410220D0 (en) | 2004-05-07 | 2004-06-09 | Kirkham Lea Ann | Mutant pneumolysin proteins |
GB0410866D0 (en) | 2004-05-14 | 2004-06-16 | Chiron Srl | Haemophilius influenzae |
EP1766094A4 (en) | 2004-05-18 | 2009-11-25 | Vical Inc | INFLUENZA VIRUS VACCINE COMPOSITION AND METHODS OF USE |
US20090104226A1 (en) | 2004-05-21 | 2009-04-23 | Novartis Vaccines And Diagnostics Inc. | Alphavirus Vectors for Respiratory Pathogen Vaccines |
WO2005116064A2 (en) | 2004-05-21 | 2005-12-08 | Wyeth | Altered fibronectin-binding protein of staphylococcus aureus |
HUE026644T2 (en) | 2004-05-28 | 2016-07-28 | Oryxe | Mixture for transdermal administration of low and high molecular weight compounds |
US20050267145A1 (en) * | 2004-05-28 | 2005-12-01 | Merrill Bryon A | Treatment for lung cancer |
CA2569419A1 (en) * | 2004-06-03 | 2005-12-22 | Isis Pharmaceuticals, Inc. | Double strand compositions comprising differentially modified strands for use in gene modulation |
US8394947B2 (en) | 2004-06-03 | 2013-03-12 | Isis Pharmaceuticals, Inc. | Positionally modified siRNA constructs |
AU2005326144A1 (en) * | 2004-06-08 | 2006-08-03 | Coley Pharmaceutical Gmbh | Abasic oligonucleotide as carrier platform for antigen and immunostimulatory agonist and antagonist |
WO2005123080A2 (en) * | 2004-06-15 | 2005-12-29 | 3M Innovative Properties Company | Nitrogen-containing heterocyclyl substituted imidazoquinolines and imidazonaphthyridines |
TW200613554A (en) | 2004-06-17 | 2006-05-01 | Wyeth Corp | Plasmid having three complete transcriptional units and immunogenic compositions for inducing an immune response to HIV |
WO2006009826A1 (en) * | 2004-06-18 | 2006-01-26 | 3M Innovative Properties Company | Aryloxy and arylalkyleneoxy substituted thiazoloquinolines and thiazolonaphthyridines |
US20070259881A1 (en) * | 2004-06-18 | 2007-11-08 | Dellaria Joseph F Jr | Substituted Imidazo Ring Systems and Methods |
WO2006038923A2 (en) * | 2004-06-18 | 2006-04-13 | 3M Innovative Properties Company | Aryl substituted imidazonaphthyridines |
WO2006065280A2 (en) * | 2004-06-18 | 2006-06-22 | 3M Innovative Properties Company | Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and methods |
US7482158B2 (en) * | 2004-07-01 | 2009-01-27 | Mathison Brian H | Composite polynucleic acid therapeutics |
EP1781325A2 (en) | 2004-07-18 | 2007-05-09 | CSL Limited | Immuno stimulating complex and oligonucleotide formulations for inducing enhanced interferon-gamma responses |
US20060025390A1 (en) * | 2004-07-28 | 2006-02-02 | Roby Russell R | Treatment of hormone allergy and related symptoms and disorders |
US20060165716A1 (en) | 2004-07-29 | 2006-07-27 | Telford John L | Immunogenic compositions for gram positive bacteria such as streptococcus agalactiae |
ATE548389T1 (de) | 2004-08-03 | 2012-03-15 | Innate Pharma | Therapeutische und diagnostische verfahren und zusammensetzungen zum targeting von 4ig-b7-h3 und dem entsprechenden nk-zellen-rezeptor |
EP1786450A4 (en) * | 2004-08-27 | 2009-11-11 | 3M Innovative Properties Co | HIV IMMUNOSTIMATORY COMPOSITIONS |
US20090270443A1 (en) * | 2004-09-02 | 2009-10-29 | Doris Stoermer | 1-amino imidazo-containing compounds and methods |
US7884086B2 (en) * | 2004-09-08 | 2011-02-08 | Isis Pharmaceuticals, Inc. | Conjugates for use in hepatocyte free uptake assays |
WO2006032697A2 (en) | 2004-09-24 | 2006-03-30 | Intercell Ag | MODIFIED VPl-CAPSID PROTEIN OF PARVOVIRUS B19 |
JP2008000001A (ja) * | 2004-09-30 | 2008-01-10 | Osaka Univ | 免疫刺激オリゴヌクレオチドおよびその医薬用途 |
EP2769735B1 (en) | 2004-10-06 | 2017-04-19 | MedImmune, LLC | Refrigerator-temperature stable influenza vaccine compositions |
EP1797173B1 (en) | 2004-10-08 | 2014-05-14 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA as represented by THE SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES | Modulation of replicative fitness by using less frequently used synonymous codons |
WO2006042254A2 (en) * | 2004-10-08 | 2006-04-20 | 3M Innovative Properties Company | Adjuvant for dna vaccines |
MY159370A (en) * | 2004-10-20 | 2016-12-30 | Coley Pharm Group Inc | Semi-soft-class immunostimulatory oligonucleotides |
CN101175508A (zh) | 2004-10-21 | 2008-05-07 | 惠氏公司 | 表皮葡萄球菌多肽抗原的免疫原性组合物 |
GB0424092D0 (en) | 2004-10-29 | 2004-12-01 | Chiron Srl | Immunogenic bacterial vesicles with outer membrane proteins |
EP3034089A1 (en) | 2004-11-02 | 2016-06-22 | Archemix LLC | Stabilized aptamers to platelet derived growth factor and their use as oncology therapeutics |
US7332324B2 (en) | 2004-12-03 | 2008-02-19 | University Of Toledo | Attenuated vaccine useful for immunizations against Coccidioides spp. infections |
WO2006063072A2 (en) * | 2004-12-08 | 2006-06-15 | 3M Innovative Properties Company | Immunomodulatory compositions, combinations and methods |
WO2006065751A2 (en) * | 2004-12-13 | 2006-06-22 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Cpg oligonucleotide prodrugs, compositions thereof and associated therapeutic methods |
WO2006073760A2 (en) | 2004-12-17 | 2006-07-13 | Dana-Farber Cancer Institute, Inc. | Regulation of mink in thymocytes and t lymphocytes |
CA2592922A1 (en) * | 2004-12-29 | 2006-07-06 | Mannkind Corporation | Methods to trigger, maintain and manipulate immune responses by targeted administration of biological response modifiers into lymphoid organs |
CA2594674C (en) | 2004-12-30 | 2016-05-17 | 3M Innovative Properties Company | Substituted chiral fused [1,2]imidazo[4,5-c] ring compounds |
ES2538498T3 (es) | 2004-12-30 | 2015-06-22 | Meda Ab | Utilización de Imiquimod para el tratamiento de metástasis cutáneas provenientes de un tumor de cáncer de mama |
WO2006074003A2 (en) * | 2004-12-30 | 2006-07-13 | 3M Innovative Properties Company | CHIRAL FUSED [1,2]IMIDAZO[4,5-c] RING COMPOUNDS |
EP2433647A3 (en) | 2005-01-27 | 2012-06-06 | Children's Hospital & Research Center at Oakland | GNA1870-based vesicle vaccines for broad spectrum protection against diseases caused by Neisseria meningitidis |
CA2549423C (en) * | 2005-01-28 | 2012-10-02 | Hyung-Joo Kwon | Oligonucleotides derived from mycobacterium for stimulating immune function, treating immune-related diseases, atopic dermatitis and/or protecting normal immune cell |
GB0502095D0 (en) | 2005-02-01 | 2005-03-09 | Chiron Srl | Conjugation of streptococcal capsular saccharides |
US9248127B2 (en) * | 2005-02-04 | 2016-02-02 | 3M Innovative Properties Company | Aqueous gel formulations containing immune response modifiers |
US7968563B2 (en) | 2005-02-11 | 2011-06-28 | 3M Innovative Properties Company | Oxime and hydroxylamine substituted imidazo[4,5-c] ring compounds and methods |
JP2008530245A (ja) | 2005-02-18 | 2008-08-07 | ノバルティス ヴァクシンズ アンド ダイアグノスティクス, インコーポレイテッド | 尿路病原性菌株由来の抗原 |
WO2006089264A2 (en) | 2005-02-18 | 2006-08-24 | Novartis Vaccines And Diagnostics Inc. | Proteins and nucleic acids from meningitis/sepsis-associated escherichia coli |
CN101160401A (zh) * | 2005-02-24 | 2008-04-09 | 科勒制药集团公司 | 免疫刺激寡核苷酸 |
NZ561144A (en) * | 2005-03-04 | 2009-09-25 | Dynavax Tech Corp | Vaccines comprising oligonucleotides having immunostimulatory sequences (ISS) wherein the ISS are conjugated to antigens and stabilized by buffer conditions and further excipients |
US8101345B1 (en) | 2005-03-25 | 2012-01-24 | Isis Pharmaceuticals, Inc. | Proinflammatory nucleic acids |
EP1869043A2 (en) | 2005-04-01 | 2007-12-26 | Coley Pharmaceutical Group, Inc. | Pyrazolopyridine-1,4-diamines and analogs thereof |
AU2006232375A1 (en) | 2005-04-01 | 2006-10-12 | Coley Pharmaceutical Group, Inc. | 1-substituted pyrazolo (3,4-c) ring compounds as modulators of cytokine biosynthesis for the treatment of viral infections and neoplastic diseases |
CA2878579C (en) | 2005-04-08 | 2018-01-23 | Wyeth | Multivalent pneumococcal polysaccharide-protein conjugate composition |
EP1874325A2 (en) * | 2005-04-08 | 2008-01-09 | Coley Pharmaceutical Group, Inc. | Methods for treating infectious disease exacerbated asthma |
US7709001B2 (en) | 2005-04-08 | 2010-05-04 | Wyeth Llc | Multivalent pneumococcal polysaccharide-protein conjugate composition |
WO2006110655A2 (en) | 2005-04-08 | 2006-10-19 | Chimerix, Inc. | Compounds, compositions and methods for the treatment of poxvirus infections |
US20070003608A1 (en) * | 2005-04-08 | 2007-01-04 | Almond Merrick R | Compounds, compositions and methods for the treatment of viral infections and other medical disorders |
CA2604683C (en) | 2005-04-12 | 2019-04-30 | Duke University | Method of inducing neutralizing antibodies to human immunodeficiency virus |
US8119146B2 (en) | 2005-04-18 | 2012-02-21 | Angelica Medina-Selby | Expressing hepatitis B virus surface antigen for vaccine preparation |
JP2008539252A (ja) * | 2005-04-25 | 2008-11-13 | スリーエム イノベイティブ プロパティズ カンパニー | 免疫活性化組成物 |
US20060241076A1 (en) * | 2005-04-26 | 2006-10-26 | Coley Pharmaceutical Gmbh | Modified oligoribonucleotide analogs with enhanced immunostimulatory activity |
US20090075342A1 (en) * | 2005-04-26 | 2009-03-19 | Sharon Cload | Metabolic profile directed aptamer medicinal chemistry |
WO2006133553A1 (en) | 2005-06-14 | 2006-12-21 | Protox Therapeutics Incorporated | Method of treating or preventing benign prostatic hyperplasia using modified pore-forming proteins |
US8101385B2 (en) | 2005-06-30 | 2012-01-24 | Archemix Corp. | Materials and methods for the generation of transcripts comprising modified nucleotides |
MX2007016561A (es) | 2005-06-30 | 2008-03-10 | Archemix Corp | Materiales y metodos para la generacion de transcriptos de acido nucleico completamente modificados en la posicion 2. |
ATE476193T1 (de) | 2005-07-01 | 2010-08-15 | Index Pharmaceuticals Ab | Immunstimulatorisches verfahren |
DK2179737T3 (da) | 2005-07-01 | 2013-11-11 | Index Pharmaceuticals Ab | Modulering af respons på steroider |
NZ565311A (en) * | 2005-07-07 | 2009-10-30 | Pfizer | Anti-ctla-4 antibody and cpg-motif-containing synthetic oligodeoxynucleotide combination therapy for cancer treatment |
WO2007008904A2 (en) * | 2005-07-08 | 2007-01-18 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Targeting poly-gamma-glutamic acid to treat staphylococcus epidermidis and related infections |
CA2615626A1 (en) | 2005-07-18 | 2007-01-25 | Novartis Ag | Small animal model for hcv replication |
WO2007088423A2 (en) * | 2005-09-16 | 2007-08-09 | Coley Pharmaceutical Gmbh | Immunostimulatory single-stranded ribonucleic acid with phosphodiester backbone |
EA013375B1 (ru) * | 2005-09-16 | 2010-04-30 | Коли Фармасьютикал Гмбх | МОДУЛЯЦИЯ ИММУНОСТИМУЛИРУЮЩИХ СВОЙСТВ КОРОТКОЙ ИНТЕРФЕРИРУЮЩЕЙ РИБОНУКЛЕИНОВОЙ КИСЛОТЫ (siРНК) С ПОМОЩЬЮ МОДИФИКАЦИИ НУКЛЕОТИДОВ |
US20070081972A1 (en) * | 2005-09-30 | 2007-04-12 | The University Of Iowa Research Foundation | Polymer-based delivery system for immunotherapy of cancer |
EP1945247A1 (en) | 2005-10-18 | 2008-07-23 | Novartis Vaccines and Diagnostics, Inc. | Mucosal and systemic immunizations with alphavirus replicon particles |
AU2006306805A1 (en) | 2005-10-28 | 2007-05-03 | Index Pharmaceuticals Ab | Composition and method for the prevention, treatment and/or alleviation of an inflammatory disease |
US20090304742A1 (en) | 2005-11-04 | 2009-12-10 | Novartis Vaccines And Diagnostics Srl | Influenza vaccines with reduced amount of emulsion adjuvant |
CA2628328A1 (en) | 2005-11-04 | 2007-05-10 | Novartis Vaccines And Diagnostics S.R.L. | Influenza vaccines including combinations of particulate adjuvants and immunopotentiators |
CA2628424A1 (en) | 2005-11-04 | 2007-05-10 | Novartis Vaccines And Diagnostics S.R.L. | Adjuvanted influenza vaccines including cytokine-inducing agents |
HUE051122T2 (hu) | 2005-11-04 | 2021-03-01 | Seqirus Uk Ltd | Sejttenyészetben növesztett influenzavírusból elõállított nemvirion anti-géneket tartalmazó adjuvált vakcinák |
ES2514316T3 (es) | 2005-11-22 | 2014-10-28 | Novartis Vaccines And Diagnostics, Inc. | Partículas similares a virus (VLPs) de Norovirus y Sapovirus |
DK1957647T3 (en) | 2005-11-25 | 2015-04-07 | Zoetis Belgium S A | Immunostimulatory oligoribonucleotides |
GB0524066D0 (en) | 2005-11-25 | 2006-01-04 | Chiron Srl | 741 ii |
AU2006325225B2 (en) | 2005-12-14 | 2013-07-04 | Cytos Biotechnology Ag | Immunostimulatory nucleic acid packaged particles for the treatment of hypersensitivity |
PT2478916T (pt) | 2006-01-27 | 2020-07-03 | Seqirus Uk Ltd | Vacinas de influenza que contêm hemaglutinina e proteínas da matriz |
EP2405002B1 (en) * | 2006-02-15 | 2014-09-24 | AdiuTide Pharmaceuticals GmbH | Compositions and methods for oligonucleotide formulations |
EP3085373A1 (en) | 2006-02-22 | 2016-10-26 | 3M Innovative Properties Company | Immune response modifier conjugates |
EP2253957B1 (en) | 2006-03-14 | 2013-05-15 | Oregon Health and Science University | Methods for producing an immune response to tuberculosis. |
CA2646891A1 (en) * | 2006-03-23 | 2007-09-27 | Novartis Ag | Immunopotentiating compounds |
WO2007109813A1 (en) | 2006-03-23 | 2007-09-27 | Novartis Ag | Imidazoquinoxaline compounds as immunomodulators |
EP2382987A1 (en) | 2006-03-24 | 2011-11-02 | Novartis Vaccines and Diagnostics GmbH | Storage of influenza vaccines without refrigeration |
CA2647942A1 (en) | 2006-03-31 | 2007-11-08 | Novartis Ag | Combined mucosal and parenteral immunization against hiv |
WO2007119815A1 (ja) | 2006-04-14 | 2007-10-25 | Kyowa Hakko Kirin Co., Ltd. | Toll様受容体9作動薬 |
TW200806315A (en) | 2006-04-26 | 2008-02-01 | Wyeth Corp | Novel formulations which stabilize and inhibit precipitation of immunogenic compositions |
CA2653939C (en) | 2006-05-31 | 2013-01-22 | Toray Industries, Inc. | Immunostimulatory oligonucleotides and use thereof in pharmaceuticals |
US20080026986A1 (en) * | 2006-06-05 | 2008-01-31 | Rong-Fu Wang | Reversal of the suppressive function of specific t cells via toll-like receptor 8 signaling |
US20100015168A1 (en) | 2006-06-09 | 2010-01-21 | Novartis Ag | Immunogenic compositions for streptococcus agalactiae |
CA2655108C (en) | 2006-06-12 | 2019-05-07 | Cytos Biotechnology Ag | Processes for packaging oligonucleotides into virus-like particles of rna bacteriophages |
CN101472610A (zh) | 2006-06-20 | 2009-07-01 | 特朗斯吉有限公司 | 重组病毒疫苗 |
WO2008094183A2 (en) * | 2006-07-11 | 2008-08-07 | University Of Connecticut | Use of conditional plasmodium strains lacking nutrient transporters in malaria vaccination |
US8153116B2 (en) | 2006-07-11 | 2012-04-10 | University Of Connecticut | Use of conditional plasmodium strains lacking an essential gene in malaria vaccination |
US7906506B2 (en) * | 2006-07-12 | 2011-03-15 | 3M Innovative Properties Company | Substituted chiral fused [1,2] imidazo [4,5-c] ring compounds and methods |
GB0614460D0 (en) | 2006-07-20 | 2006-08-30 | Novartis Ag | Vaccines |
US20100166788A1 (en) | 2006-08-16 | 2010-07-01 | Novartis Vaccines And Diagnostics | Immunogens from uropathogenic escherichia coli |
ES2536401T3 (es) | 2006-09-11 | 2015-05-25 | Novartis Ag | Fabricación de vacunas contra virus de la gripe sin usar huevos |
MX2009003398A (es) | 2006-09-27 | 2009-08-12 | Coley Pharm Gmbh | Analogos de oligonucleotidos cpg que contienen analogos t hidrofobos con actividad inmunoestimuladora mejorada. |
DE102006050655A1 (de) * | 2006-10-24 | 2008-04-30 | Halmon Beheer B.V. | Pharmazeutische Zusammensetzung zur Behandlung allergischer Erkrankungen |
RU2009115687A (ru) * | 2006-10-26 | 2010-11-10 | Коли Фармасьютикал Гмбх (De) | Олигорибонуклеотиды и их применения |
EP2078197B1 (en) | 2006-11-01 | 2016-03-23 | Ventana Medical Systems, Inc. | Haptens, hapten conjugates, compositions thereof and method for their preparation and use |
US20090142362A1 (en) * | 2006-11-06 | 2009-06-04 | Avant Immunotherapeutics, Inc. | Peptide-based vaccine compositions to endogenous cholesteryl ester transfer protein (CETP) |
CA2669137A1 (en) | 2006-11-09 | 2008-06-19 | Dynavax Technologies Corporation | Long term disease modification using immunostimulatory oligonucleotides |
ES2528166T3 (es) * | 2006-11-15 | 2015-02-04 | Eli Lilly And Company | Métodos y composiciones para tratar la gripe |
US20110045022A1 (en) | 2006-12-06 | 2011-02-24 | Theodore Tsai | Vaccines including antigen from four strains of influenza virus |
AR064642A1 (es) | 2006-12-22 | 2009-04-15 | Wyeth Corp | Polinucleotido vector que lo comprende celula recombinante que comprende el vector polipeptido , anticuerpo , composicion que comprende el polinucleotido , vector , celula recombinante polipeptido o anticuerpo , uso de la composicion y metodo para preparar la composicion misma y preparar una composi |
US20080149123A1 (en) * | 2006-12-22 | 2008-06-26 | Mckay William D | Particulate material dispensing hairbrush with combination bristles |
GB0700562D0 (en) | 2007-01-11 | 2007-02-21 | Novartis Vaccines & Diagnostic | Modified Saccharides |
CA2678404C (en) | 2007-02-28 | 2019-03-19 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Brachyury polypeptides and methods for use |
JP2010523676A (ja) * | 2007-04-13 | 2010-07-15 | デューク ユニバーシティ | ヒト免疫不全ウイルスに対する中和抗体を誘導する方法 |
US8518903B2 (en) | 2007-04-19 | 2013-08-27 | University of Pittsburgh—of the Commonwealth System of Higher Education | Use of toll-like receptor-9 agonists |
EP2377952A1 (en) | 2007-04-26 | 2011-10-19 | Ludwig Institute For Cancer Research | Methods for diagnosing and treating astrocytomas |
US20100285041A1 (en) | 2007-05-17 | 2010-11-11 | Eugen Uhlmann | Class A Oligonucleotides with Immunostimulatory Potency |
CA2687535C (en) * | 2007-05-18 | 2017-08-22 | Coley Pharmaceutical Gmbh | Phosphate-modified oligonucleotide analogs with enhanced immunostimulatory activity |
EP3561513A1 (en) * | 2007-05-23 | 2019-10-30 | Ventana Medical Systems, Inc. | Polymeric carriers for immunohistochemistry and in situ hybridization |
BRPI0811228A2 (pt) * | 2007-05-24 | 2014-10-21 | Glaxonsmithkline Biolog S A | Composição liofilizada, e, métodos para produzir uma composição liofilizada e para produzir uma composição imunológica. |
PT2185191E (pt) | 2007-06-27 | 2012-11-27 | Novartis Ag | Vacinas contra a gripe com baixo teor de aditivos |
GB0713880D0 (en) | 2007-07-17 | 2007-08-29 | Novartis Ag | Conjugate purification |
GB0714963D0 (en) | 2007-08-01 | 2007-09-12 | Novartis Ag | Compositions comprising antigens |
US7879812B2 (en) | 2007-08-06 | 2011-02-01 | University Of Iowa Research Foundation | Immunomodulatory oligonucleotides and methods of use therefor |
KR20100075843A (ko) * | 2007-08-21 | 2010-07-05 | 다이나박스 테크놀로지 코퍼레이션 | 인플루엔자 단백질 조성물 및 그 제조 및 사용 방법 |
US8287885B2 (en) | 2007-09-12 | 2012-10-16 | Novartis Ag | GAS57 mutant antigens and GAS57 antibodies |
KR20100068422A (ko) * | 2007-10-09 | 2010-06-23 | 콜리 파마슈티칼 게엠베하 | 변경된 당 잔기를 함유하는 면역자극성 올리고뉴클레오티드 유사체 |
US20110014231A1 (en) * | 2007-11-05 | 2011-01-20 | Mor Research Applications Ltd | Anti-measles cancer immunotherapy |
WO2009062112A2 (en) | 2007-11-09 | 2009-05-14 | The Salk Institute For Biological Studies | Use of tam receptor inhibitors as antimicrobials |
GB0810305D0 (en) | 2008-06-05 | 2008-07-09 | Novartis Ag | Influenza vaccination |
JP2011506334A (ja) | 2007-12-07 | 2011-03-03 | ノバルティス アーゲー | 免疫応答を誘導するための組成物 |
GB0818453D0 (en) | 2008-10-08 | 2008-11-12 | Novartis Ag | Fermentation processes for cultivating streptococci and purification processes for obtaining cps therefrom |
NZ586430A (en) | 2007-12-21 | 2012-09-28 | Novartis Ag | Mutant forms of streptolysin o (slo) |
CA2710350A1 (en) * | 2007-12-21 | 2009-07-02 | Wyeth Llc | Genetically modified attenuated vesicular stomatitis virus, compositions and methods of use thereof |
CN101977610B (zh) * | 2008-01-25 | 2012-05-16 | 奇默里克斯公司 | 治疗病毒感染的方法 |
CA2716212A1 (en) | 2008-02-21 | 2009-08-27 | Novartis Ag | Meningococcal fhbp polypeptides |
EP2265640B1 (en) | 2008-03-10 | 2015-11-04 | Children's Hospital & Research Center at Oakland | Chimeric factor h binding proteins (fhbp) containing a heterologous b domain and methods of use |
EP2268309B1 (en) | 2008-03-18 | 2015-01-21 | Novartis AG | Improvements in preparation of influenza virus vaccine antigens |
AU2009246169B2 (en) | 2008-05-15 | 2015-01-22 | Dynavax Technologies Corporation | Long term disease modification using immunostimulatory oligonucleotides |
WO2009143292A2 (en) | 2008-05-21 | 2009-11-26 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Method of treating pneumoconiosis with oligodeoxynucleotides |
ES2557594T3 (es) | 2008-06-05 | 2016-01-27 | Ventana Medical Systems, Inc. | Método para el procesamiento histoquímico y el uso de una composición para el procesamiento histoquímico |
EP2303318A2 (en) | 2008-06-20 | 2011-04-06 | Wyeth LLC | Compositions and methods of use of orf1358 from beta-hemolytic streptococcal strains |
JP5659332B2 (ja) | 2008-06-27 | 2015-01-28 | ゾエティス・エルエルシー | 新規なアジュバント組成物 |
TWI351288B (en) * | 2008-07-04 | 2011-11-01 | Univ Nat Pingtung Sci & Tech | Cpg dna adjuvant in avian vaccines |
US20110136897A1 (en) * | 2008-08-14 | 2011-06-09 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Toll-like receptor 9 agonists for the treatment of anxiety-related disorders and inflammatory disorders |
WO2010027818A2 (en) | 2008-08-25 | 2010-03-11 | Dana-Farber Cancer Institute, Inc. | Conserved hemagglutinin epitope, antibodies to the epitope, and methods of use |
CA2737455A1 (en) | 2008-09-18 | 2010-03-25 | Novartis Ag | Vaccine adjuvant combinations |
EP2385371B1 (en) | 2008-09-22 | 2014-10-22 | Oregon Health and Science University | Methods for detecting a mycobacterium tuberculosis infection |
DK2344522T3 (en) * | 2008-10-16 | 2016-04-18 | Univ Saskatchewan | Combinatorial Adjuvant formulation |
US8691502B2 (en) | 2008-10-31 | 2014-04-08 | Tremrx, Inc. | T-cell vaccination with viral vectors via mechanical epidermal disruption |
NZ592368A (en) | 2008-11-05 | 2013-11-29 | Wyeth Llc | Multicomponent immunogenic composition for the prevention of beta-hemolytic streptococcal (bhs) disease |
US8329188B2 (en) * | 2008-11-12 | 2012-12-11 | Theraclone Sciences, Inc. | Human M2e peptide immunogens |
SG171914A1 (en) | 2008-12-02 | 2011-07-28 | Chiralgen Ltd | Method for the synthesis of phosphorus atom modified nucleic acids |
US8552165B2 (en) * | 2008-12-09 | 2013-10-08 | Heather Davis | Immunostimulatory oligonucleotides |
EP2376108B1 (en) * | 2008-12-09 | 2017-02-22 | Pfizer Vaccines LLC | IgE CH3 PEPTIDE VACCINE |
PT2376107E (pt) | 2008-12-09 | 2014-07-25 | Coley Pharm Group Inc | Oligonucleotídeos imunoestimulantes |
US8585505B2 (en) | 2008-12-15 | 2013-11-19 | Tetris Online, Inc. | Inter-game interactive hybrid asynchronous computer game infrastructure |
CN102307477B (zh) | 2009-01-05 | 2015-07-29 | 埃皮托吉尼西斯股份有限公司 | 佐剂组合物及使用方法 |
US20100233270A1 (en) | 2009-01-08 | 2010-09-16 | Northwestern University | Delivery of Oligonucleotide-Functionalized Nanoparticles |
MX2011007456A (es) | 2009-01-12 | 2011-08-03 | Novartis Ag | Antigenos del dominio de proteina de superficie de union a colageno tipo b (can_b) en vacunas contra bacteria gram positiva. |
US8664183B2 (en) | 2009-02-27 | 2014-03-04 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | SPANX-B polypeptides and their use |
AU2010220103A1 (en) | 2009-03-06 | 2011-09-22 | Novartis Ag | Chlamydia antigens |
DK2411043T3 (da) | 2009-03-23 | 2013-10-21 | Pin Pharma Inc | Behandling af cancer med immunostimulatorisk hiv tat derivat-polypeptider |
US20120070458A1 (en) | 2009-03-24 | 2012-03-22 | Novartis Ag | Adjuvanting meningococcal factor h binding protein |
AU2010229835B2 (en) | 2009-03-25 | 2015-01-15 | The Board Of Regents Of The University Of Texas System | Compositions for stimulation of mammalian innate immune resistance to pathogens |
WO2010114628A2 (en) * | 2009-04-03 | 2010-10-07 | Duke University | Formulation for inducing broadly reactive neutralizing anti-hiv antibodies |
EP2413953B1 (en) | 2009-04-03 | 2017-11-08 | Agenus Inc. | Methods for preparing and using multichaperone-antigen complexes |
SG175092A1 (en) | 2009-04-14 | 2011-11-28 | Novartis Ag | Compositions for immunising against staphylococcus aerus |
KR20120022984A (ko) * | 2009-04-21 | 2012-03-12 | 셀렉타 바이오사이언시즈, 인크. | Th1 편향 반응을 제공하는 면역나노치료법 |
ES2552153T3 (es) | 2009-04-30 | 2015-11-26 | Coley Pharmaceutical Group, Inc. | Vacuna neumocócica y usos de la misma |
AU2010254549B2 (en) | 2009-05-27 | 2016-10-20 | Selecta Biosciences, Inc. | Nanocarriers possessing components with different rates of release |
EP2442826B1 (en) | 2009-06-15 | 2015-07-08 | National University of Singapore | Influenza vaccine, composition, and methods of use |
SG10201406432RA (en) | 2009-06-22 | 2014-11-27 | Wyeth Llc | Compositions and methods for preparing staphylococcus aureus serotype 5 and 8 capsular polysaccharide conjugate immunogenic compositions |
AR078601A1 (es) | 2009-06-22 | 2011-11-23 | Wyeth Llc | Composiciones inmunogenicas de antigenos de staphylococcus aureus |
KR101885383B1 (ko) | 2009-07-06 | 2018-08-03 | 웨이브 라이프 사이언시스 리미티드 | 신규한 핵산 프로드러그 및 그의 사용 방법 |
SG178026A1 (en) | 2009-07-15 | 2012-03-29 | Novartis Ag | Rsv f protein compositions and methods for making same |
ES2526996T3 (es) | 2009-07-16 | 2015-01-19 | Novartis Ag | Inmunógenos desintoxicados de Escherichia coli |
KR101346197B1 (ko) | 2009-07-17 | 2014-02-06 | 한림대학교 산학협력단 | 리포좀에 포집된 올리고뉴클레오타이드 및 에피토프를 포함하는 면역증강용 조성물 |
US8614200B2 (en) | 2009-07-21 | 2013-12-24 | Chimerix, Inc. | Compounds, compositions and methods for treating ocular conditions |
PE20120817A1 (es) | 2009-07-30 | 2012-07-07 | Pfizer Vaccines Llc | Peptidos tau antigenicos y usos de los mismos |
US20110033515A1 (en) * | 2009-08-04 | 2011-02-10 | Rst Implanted Cell Technology | Tissue contacting material |
AU2010284329B2 (en) * | 2009-08-18 | 2015-04-16 | Takeda Pharmaceutical Company Limited | Aptamers to tissue factor pathway inhibitor and their use as bleeding disorder therapeutics |
US8598327B2 (en) | 2009-08-18 | 2013-12-03 | Baxter International Inc. | Aptamers to tissue factor pathway inhibitor and their use as bleeding disorder therapeutics |
KR101873179B1 (ko) | 2009-08-26 | 2018-06-29 | 셀렉타 바이오사이언시즈, 인크. | T-세포 도움을 유도하는 조성물 |
NZ598458A (en) | 2009-08-27 | 2014-03-28 | Novartis Ag | Hybrid polypeptides including meningococcal fhbp sequences |
CN102740882A (zh) | 2009-08-27 | 2012-10-17 | 诺华有限公司 | 含有铝、寡核苷酸和聚阳离子的佐剂 |
WO2011026111A1 (en) | 2009-08-31 | 2011-03-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Oral delivery of a vaccine to the large intestine to induce mucosal immunity |
CA2846746A1 (en) | 2009-09-03 | 2011-03-10 | Pfizer Vaccines Llc | Pcsk9 vaccine |
CN102695523A (zh) | 2009-09-10 | 2012-09-26 | 诺华有限公司 | 针对呼吸道疾病的组合疫苗 |
GB0917002D0 (en) | 2009-09-28 | 2009-11-11 | Novartis Vaccines Inst For Global Health Srl | Improved shigella blebs |
GB0917003D0 (en) | 2009-09-28 | 2009-11-11 | Novartis Vaccines Inst For Global Health Srl | Purification of bacterial vesicles |
CN102724988B (zh) | 2009-09-30 | 2014-09-10 | 诺华股份有限公司 | 脑膜炎球菌fHBP多肽的表达 |
US8974799B2 (en) | 2009-09-30 | 2015-03-10 | Novartis Ag | Conjugation of Staphylococcus aureus type 5 and type 8 capsular polysaccharides |
ES2594485T3 (es) | 2009-10-07 | 2016-12-20 | Uvic Industry Partnerships Inc. | Vacunas que comprenden transgenes sensibles al calor |
WO2011047340A1 (en) | 2009-10-16 | 2011-04-21 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Insertion of foreign genes in rubella virus and their stable expression in a live, attenuated viral vaccine |
GB0918392D0 (en) | 2009-10-20 | 2009-12-02 | Novartis Ag | Diagnostic and therapeutic methods |
JP5960055B2 (ja) | 2009-10-27 | 2016-08-02 | ノバルティス アーゲー | 改変髄膜炎菌fHBPポリペプチド |
GB0919690D0 (en) | 2009-11-10 | 2009-12-23 | Guy S And St Thomas S Nhs Foun | compositions for immunising against staphylococcus aureus |
EP2502076B1 (en) | 2009-11-20 | 2018-04-18 | Oregon Health and Science University | Methods for detecting a mycobacterium tuberculosis infection |
KR20120120185A (ko) | 2009-12-22 | 2012-11-01 | 셀덱스 쎄라퓨틱스, 인크. | 백신 조성물 |
PT2534150T (pt) | 2010-02-12 | 2017-05-02 | Chimerix Inc | Métodos para tratar uma infecção viral |
GB201003333D0 (en) | 2010-02-26 | 2010-04-14 | Novartis Ag | Immunogenic proteins and compositions |
US8685416B2 (en) | 2010-03-02 | 2014-04-01 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Compositions and methods for the treatment of cancer |
JP2013521002A (ja) | 2010-03-05 | 2013-06-10 | プレジデント アンド フェロウズ オブ ハーバード カレッジ | 誘導樹状細胞組成物及びその使用 |
WO2011112599A2 (en) | 2010-03-12 | 2011-09-15 | The United States Of America, As Represented By The Secretary. Department Of Health & Human Services | Immunogenic pote peptides and methods of use |
WO2012020326A1 (en) | 2010-03-18 | 2012-02-16 | Novartis Ag | Adjuvanted vaccines for serogroup b meningococcus |
EP2552942B1 (en) | 2010-03-30 | 2017-12-27 | Children's Hospital & Research Center at Oakland | Factor h binding proteins (fhbp) with altered properties and methods of use thereof |
GB201005625D0 (en) | 2010-04-01 | 2010-05-19 | Novartis Ag | Immunogenic proteins and compositions |
EP2556151A1 (en) | 2010-04-07 | 2013-02-13 | Novartis AG | Method for generating a parvovirus b19 virus-like particle |
WO2011130379A1 (en) | 2010-04-13 | 2011-10-20 | Novartis Ag | Benzonapthyridine compositions and uses thereof |
WO2011139709A2 (en) | 2010-04-26 | 2011-11-10 | Chimerix, Inc. | Methods of treating retroviral infections and related dosage regimes |
NO2569436T3 (zh) | 2010-05-14 | 2018-04-28 | ||
MX2012013713A (es) | 2010-05-26 | 2013-01-28 | Selecta Biosciences Inc | Composiciones de nanovehiculos con adyuvante no acoplado. |
US10456463B2 (en) | 2010-05-28 | 2019-10-29 | Zoetis Belgium S.A | Vaccines comprising cholesterol and CpG as sole adjuvant-carrier molecules |
CA2800913C (en) | 2010-06-03 | 2019-07-23 | Pharmacyclics, Inc. | The use of inhibitors of bruton's tyrosine kinase (btk) |
DK2575870T3 (en) | 2010-06-04 | 2017-02-13 | Wyeth Llc | vaccine Formulations |
WO2011154878A1 (en) | 2010-06-07 | 2011-12-15 | Pfizer Vaccines Llc | Ige ch3 peptide vaccine |
GB201009861D0 (en) | 2010-06-11 | 2010-07-21 | Novartis Ag | OMV vaccines |
EP2585106A1 (en) | 2010-06-25 | 2013-05-01 | Novartis AG | Combinations of meningococcal factor h binding proteins |
EP3153578A1 (en) | 2010-07-06 | 2017-04-12 | Novartis Ag | Norovirus derived immunogenic compositions and methods |
US9192661B2 (en) | 2010-07-06 | 2015-11-24 | Novartis Ag | Delivery of self-replicating RNA using biodegradable polymer particles |
ES2850973T3 (es) | 2010-08-23 | 2021-09-01 | Wyeth Llc | Formulaciones estables de antígenos rLP2086 de Neisseria meningitidis |
ES2585328T5 (es) | 2010-09-10 | 2022-12-14 | Wyeth Llc | Variantes no lipidadas de antígenos ORF2086 de Neisseria meningitidis |
EP2616545B1 (en) | 2010-09-14 | 2018-08-29 | University of Pittsburgh - Of the Commonwealth System of Higher Education | Computationally optimized broadly reactive antigens for influenza |
GB201101665D0 (en) | 2011-01-31 | 2011-03-16 | Novartis Ag | Immunogenic compositions |
US9072760B2 (en) | 2010-09-24 | 2015-07-07 | University of Pittsburgh—of the Commonwealth System of Higher Education | TLR4 inhibitors for the treatment of human infectious and inflammatory disorders |
US10668092B2 (en) | 2010-09-24 | 2020-06-02 | The John Hopkins University | Compositions and methods for treatment of inflammatory disorders |
JP5868324B2 (ja) | 2010-09-24 | 2016-02-24 | 株式会社Wave Life Sciences Japan | 不斉補助基 |
GB201017519D0 (en) | 2010-10-15 | 2010-12-01 | Novartis Vaccines Inst For Global Health S R L | Vaccines |
US9994443B2 (en) | 2010-11-05 | 2018-06-12 | Selecta Biosciences, Inc. | Modified nicotinic compounds and related methods |
WO2012072769A1 (en) | 2010-12-01 | 2012-06-07 | Novartis Ag | Pneumococcal rrgb epitopes and clade combinations |
EP2468866A1 (en) * | 2010-12-21 | 2012-06-27 | Index Pharmaceuticals AB | Biologically active oligonucleotides capable of modulating the immune system |
HUE033072T2 (hu) | 2010-12-22 | 2017-11-28 | Wyeth Llc | Staphylococcus aureus antigének immunogén készítményei |
NZ612285A (en) | 2010-12-22 | 2015-09-25 | Bayer Ip Gmbh | Enhanced immune response in bovine species |
WO2012088425A2 (en) | 2010-12-22 | 2012-06-28 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Gap junction-enhancing agents for treatment of necrotizing enterocolitis and inflammatory bowel disease |
GB201021867D0 (en) | 2010-12-23 | 2011-02-02 | Mologen Ag | Non-coding immunomodulatory DNA construct |
WO2012085668A2 (en) | 2010-12-24 | 2012-06-28 | Novartis Ag | Compounds |
EP2471926A3 (en) * | 2010-12-30 | 2012-07-11 | Intervet International BV | Immunostimulatory oligodeoxynucleotides |
AU2012211278B2 (en) | 2011-01-26 | 2016-11-10 | Glaxosmithkline Biologicals Sa | RSV immunization regimen |
JP6002691B2 (ja) | 2011-02-11 | 2016-10-05 | バクスアルタ ゲーエムベーハー | 組織因子経路阻害剤に対するアプタマーおよび出血障害治療薬としてのそれらの使用 |
US20140004142A1 (en) | 2011-03-02 | 2014-01-02 | Pfizer Inc. | Pcsk9 vaccine |
JP6054942B2 (ja) | 2011-04-08 | 2016-12-27 | イミューン デザイン コーポレイション | 免疫原性組成物、ならびに体液性および細胞性免疫応答を誘発するための該組成物の使用方法 |
US9452212B2 (en) | 2011-04-14 | 2016-09-27 | Dynavax Technologies Corporation | Methods and compositions for eliciting an immune response against hepatitis B virus |
WO2012149307A2 (en) | 2011-04-27 | 2012-11-01 | Immune Design Corp. | Synthetic long peptide (slp)-based vaccines |
LT2707385T (lt) | 2011-05-13 | 2017-12-11 | Glaxosmithkline Biologicals Sa | Iš anksto sulieti rsv f antigenai |
FR2975600B1 (fr) | 2011-05-24 | 2013-07-05 | Assist Publ Hopitaux De Paris | Agents pour le traitement de tumeurs |
WO2012160184A1 (en) * | 2011-05-26 | 2012-11-29 | Intervet International B.V. | Immunostimulatory oligodeoxynucleotides |
CA2837227C (en) | 2011-06-01 | 2022-05-10 | Janus Biotherapeutics, Inc. | Novel immune system modulators |
US9353115B2 (en) | 2011-06-01 | 2016-05-31 | Janus Biotherapeutics, Inc. | Immune system modulators |
JP6460789B2 (ja) | 2011-06-03 | 2019-01-30 | スリーエム イノベイティブ プロパティズ カンパニー | ポリエチレングリコールセグメントを有するヘテロ2官能性リンカー及び該リンカーから調製された免疫反応調節複合体 |
CA2838023C (en) | 2011-06-03 | 2019-08-13 | 3M Innovative Properties Company | Hydrazino 1h-imidazoquinolin-4-amines and conjugates made therefrom |
WO2012174455A2 (en) | 2011-06-17 | 2012-12-20 | University Of Tennessee Research Foundation | Group a streptococcus multivalent vaccine |
US9580475B2 (en) | 2011-06-20 | 2017-02-28 | University of Pittsburgh—of the Commonwealth System of Higher Education | Computationally optimized broadly reactive antigens for H1N1 influenza |
ITMI20111182A1 (it) | 2011-06-28 | 2012-12-29 | Canio Buonavoglia | Vaccino per coronavirus canino |
EP3508219A1 (en) | 2011-07-06 | 2019-07-10 | GlaxoSmithKline Biologicals S.A. | Self-replicating rna prime - protein boost vaccines |
EP3332802A1 (en) | 2011-07-06 | 2018-06-13 | GlaxoSmithKline Biologicals SA | Immunogenic combination compositions and uses thereof |
CN103764171B (zh) | 2011-07-08 | 2016-08-17 | 诺华股份有限公司 | 酪氨酸连接方法 |
WO2013007703A1 (en) * | 2011-07-08 | 2013-01-17 | Universität Zürich | CLASS A CpG OLIGONUCLEOTIDES FOR PREVENTION OF VIRAL INFECTION IN CATS |
DK2734208T3 (en) | 2011-07-19 | 2017-06-19 | Wave Life Sciences Ltd | PROCEDURES FOR SYNTHESIS OF FUNCTIONALIZED NUCLEIC ACIDS |
US20130023736A1 (en) | 2011-07-21 | 2013-01-24 | Stanley Dale Harpstead | Systems for drug delivery and monitoring |
ES2687129T3 (es) | 2011-07-25 | 2018-10-23 | Glaxosmithkline Biologicals Sa | Composiciones y métodos para evaluar la inmunogenicidad funcional de vacunas contra parvovirus |
EA201490381A1 (ru) | 2011-07-29 | 2014-06-30 | Селекта Байосайенсиз, Инк. | Синтетические наноносители, которые стимулируют формирование гуморального иммунного ответа и иммунного ответа, опосредованного цитотоксическими т-лимфоцитами (ctl) |
GB201114923D0 (en) | 2011-08-30 | 2011-10-12 | Novartis Ag | Immunogenic proteins and compositions |
WO2013039792A1 (en) | 2011-09-12 | 2013-03-21 | The United States Of America As Represented By The Secretary, Department Of Health And Human Services | Immunogens based on an hiv-1 gp120 v1v2 epitope |
US9511130B2 (en) | 2011-09-14 | 2016-12-06 | Glaxosmithkline Biologicals Sa | Escherichia coli vaccine combination |
CN103917245B (zh) | 2011-09-14 | 2017-06-06 | 葛兰素史密丝克莱恩生物有限公司 | 用于制备糖‑蛋白质糖缀合物的方法 |
US20140234360A1 (en) | 2011-09-30 | 2014-08-21 | The United States of America, as represented by the Secretary, Dept.of Health and Human Services | Influenza vaccine |
AU2012318694B2 (en) | 2011-10-04 | 2016-12-22 | Janus Biotherapeutics, Inc. | Novel imidazole quinoline-based immune system modulators |
EP2768847A4 (en) | 2011-10-20 | 2015-11-11 | Us Gov Health & Human Serv | DENGUE VIRUS E-GLYCOPROTEIN POLYPEPTIDES WITH MUTATIONS FOR ELIMINATING IMMUNOMINANT CROSS-REACTIVE EPITOPES |
US9493517B2 (en) | 2011-11-07 | 2016-11-15 | Glaxosmithkline Biologicals Sa | Conjugates comprising an antigen and a carrier molecule |
US9694063B2 (en) | 2011-12-08 | 2017-07-04 | Glaxosmithkline Biologicals Sa | Clostridium difficile toxin-based vaccine |
EA201491081A1 (ru) | 2012-01-16 | 2016-11-30 | Элизабет Маккенна | Композиции и способы для лечения заболеваний и расстройств печени |
WO2013108272A2 (en) | 2012-01-20 | 2013-07-25 | International Centre For Genetic Engineering And Biotechnology | Blood stage malaria vaccine |
AU2013217166B2 (en) | 2012-02-07 | 2017-04-06 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Computationally optimized broadly reactive antigens for H3N2, H2N2, and B influenza viruses |
WO2013122827A1 (en) | 2012-02-13 | 2013-08-22 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Computationally optimized broadly reactive antigens for human and avian h5n1 influenza |
US20150273042A1 (en) | 2012-02-24 | 2015-10-01 | Novartis Ag | Pilus proteins and compositions |
SA115360586B1 (ar) | 2012-03-09 | 2017-04-12 | فايزر انك | تركيبات لعلاج الالتهاب السحائي البكتيري وطرق لتحضيرها |
MX2018011291A (es) | 2012-03-09 | 2023-01-31 | Pfizer | Composiciones de neisseria meningitidis y metodos de las mismas. |
CA2866185C (en) | 2012-03-23 | 2021-04-06 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Pathogenic phlebovirus isolates and compositions and methods of use |
EP2841098A4 (en) | 2012-04-23 | 2016-03-02 | Allertein Therapeutics Llc | NANOPARTICLES FOR THE TREATMENT OF ALLERGIES |
ES2837825T3 (es) | 2012-04-26 | 2021-07-01 | Glaxosmithkline Biologicals Sa | Antígenos y combinaciones de antígenos |
US10279026B2 (en) | 2012-04-26 | 2019-05-07 | Glaxosmithkline Biologicals Sa | Antigens and antigen combinations |
US10076535B2 (en) | 2012-04-27 | 2018-09-18 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Use of CPG oligonucleotides co-formulated with an antibiotic to accelerate wound healing |
PE20142406A1 (es) | 2012-05-04 | 2015-01-23 | Pfizer | Antigenos asociados a prostata y regimenes de inmunoterapia basados en vacuna |
CN104736180A (zh) | 2012-05-22 | 2015-06-24 | 诺华股份有限公司 | 脑膜炎球菌血清组x偶联物 |
WO2013177291A1 (en) | 2012-05-23 | 2013-11-28 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Salmonella typhi ty21a expressing yersinia pestis f1-v fusion protein and uses thereof |
US9427476B2 (en) | 2012-05-24 | 2016-08-30 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Multivalent meningococcal conjugates and methods for preparing conjugates |
US9687542B2 (en) | 2012-06-19 | 2017-06-27 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Rift valley fever virus replicon particles and use thereof |
JP6157607B2 (ja) | 2012-06-19 | 2017-07-05 | ボルボ ラストバグナー アーベー | ガス流を制御するための装置、排気後処理システム、及び車両を推進するシステム |
KR102057217B1 (ko) | 2012-06-20 | 2020-01-22 | 에스케이바이오사이언스 주식회사 | 다가 폐렴구균 다당류-단백질 접합체 조성물 |
CN104853770A (zh) | 2012-07-06 | 2015-08-19 | 诺华股份有限公司 | 免疫原性组合物及其应用 |
CN104684923B (zh) * | 2012-07-13 | 2018-09-28 | 株式会社新日本科学 | 手性核酸佐剂 |
KR101850319B1 (ko) | 2012-07-13 | 2018-04-20 | 웨이브 라이프 사이언시스 리미티드 | 비대칭 보조 그룹 |
CN104661664B (zh) | 2012-07-13 | 2020-07-03 | 波涛生命科学有限公司 | 手性控制 |
CA2879443A1 (en) | 2012-07-19 | 2014-01-23 | Zoetis Llc | Bovine influenza virus compositions |
EP2877598A1 (en) | 2012-07-24 | 2015-06-03 | Pharmacyclics, Inc. | Mutations associated with resistance to inhibitors of bruton's tyrosine kinase (btk) |
AU2013295770A1 (en) | 2012-07-27 | 2015-01-29 | Zoetis Services Llc | Tick toxin compositions |
DK2885007T3 (en) | 2012-08-16 | 2018-12-03 | Pfizer | Methods for glycoconjugation and compositions |
EP3639851A1 (en) | 2012-09-04 | 2020-04-22 | Bavarian Nordic A/S | Methods and compositions for enhancing vaccine immune responses |
WO2014043535A1 (en) | 2012-09-14 | 2014-03-20 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Compositions for the treatment of cancer |
ES2752190T3 (es) | 2012-09-14 | 2020-04-03 | Us Health | Proteína Brachyury, vectores adenovirales que codifican proteína Brachyury y su uso |
RU2662970C2 (ru) | 2012-09-18 | 2018-07-31 | Новартис Аг | Везикулы наружной мембраны |
WO2014047588A1 (en) | 2012-09-21 | 2014-03-27 | Elizabeth Mckenna | Naturally occurring cpg oligonucleotide compositions and therapeutic applications thereof |
US9562066B2 (en) * | 2012-09-25 | 2017-02-07 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Oral therapy of necrotizing enterocolitis |
AU2013326503B2 (en) | 2012-10-03 | 2018-04-19 | Glaxosmithkline Biologicals Sa | Immunogenic composition |
KR20150080592A (ko) | 2012-11-02 | 2015-07-09 | 파마시클릭스, 인코포레이티드 | Tec 패밀리 키나제 억제제 애쥬번트 요법 |
WO2014074785A1 (en) | 2012-11-08 | 2014-05-15 | Ludwig Institute For Cancer Research Ltd. | Methods of predicting outcome and treating breast cancer |
KR20140075196A (ko) | 2012-12-11 | 2014-06-19 | 에스케이케미칼주식회사 | 다가 폐렴구균 다당류-단백질 접합체 조성물 |
KR20140075201A (ko) | 2012-12-11 | 2014-06-19 | 에스케이케미칼주식회사 | 다가 폐렴구균 다당류-단백질 접합체 조성물 |
TWI465241B (zh) | 2012-12-19 | 2014-12-21 | Ind Tech Res Inst | 圓柏(Juniperus chinensis)萃取物或木酚素(lignan)用於製造抑制血管新生之藥物的用途 |
CN106177933B (zh) | 2012-12-20 | 2020-09-29 | 辉瑞公司 | 免疫原性组合物 |
EP2948469A4 (en) | 2013-01-23 | 2016-11-02 | Univ Leland Stanford Junior | STABILIZED HEPATITIS B CORE POLYPEPTIDE |
EP2953638B1 (en) | 2013-02-07 | 2023-07-05 | Children's Medical Center Corporation | Protein antigens that provide protection against pneumococcal colonization and/or disease |
EP2964665B1 (en) | 2013-03-08 | 2018-08-01 | Pfizer Inc | Immunogenic fusion polypeptides |
CA2902560A1 (en) | 2013-03-14 | 2014-09-25 | President And Fellows Of Harvard College | Nanoparticle-based compositions |
DE102013004595A1 (de) | 2013-03-15 | 2014-09-18 | Emergent Product Development Germany Gmbh | RSV-Impfstoffe |
CA2907098A1 (en) | 2013-03-15 | 2014-09-25 | Zoetis Services Llc | Cross-protection of bovines against b. trehalosi infection by a multi-valent vaccine |
EP3760223A1 (en) | 2013-04-03 | 2021-01-06 | N-Fold Llc | Nanoparticle composition for desensitizing a subject to peanut allergens |
CA2909721A1 (en) | 2013-04-19 | 2014-10-23 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Lone star virus |
AR095882A1 (es) | 2013-04-22 | 2015-11-18 | Hoffmann La Roche | Terapia de combinación de anticuerpos contra csf-1r humano con un agonista de tlr9 |
WO2015132619A1 (en) | 2013-05-15 | 2015-09-11 | The Governors Of The University Of Alberta | E1e2 hcv vaccines and methods of use |
WO2014201245A1 (en) | 2013-06-12 | 2014-12-18 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Tlr-9 agonist with tlr-7 and/or tlr-8 agonist for treating tumors |
CN105579582A (zh) | 2013-07-25 | 2016-05-11 | 埃克西奎雷股份有限公司 | 用于预防和治疗用途的作为免疫刺激剂的基于球形核酸的构建体 |
EP3632458A1 (en) | 2013-07-26 | 2020-04-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of bacterial infections |
KR101905278B1 (ko) | 2013-09-08 | 2018-10-08 | 화이자 인코포레이티드 | 나이세리아 메닌지티디스 조성물 및 그의 방법 |
AR097584A1 (es) | 2013-09-12 | 2016-03-23 | Hoffmann La Roche | Terapia de combinación de anticuerpos contra el csf-1r humano y anticuerpos contra el pd-l1 humano |
KR102257743B1 (ko) | 2013-09-19 | 2021-05-28 | 조에티스 서비시즈 엘엘씨 | 유성 아쥬반트 |
WO2015048635A1 (en) | 2013-09-27 | 2015-04-02 | Duke University | Mper-liposome conjugates and uses thereof |
EP3052517B1 (en) | 2013-09-30 | 2023-07-19 | Triad National Security, LLC | Mosaic conserved region hiv immunogenic polypeptides |
US9663556B2 (en) | 2013-10-04 | 2017-05-30 | Pin Pharma, Inc. | Treatment of cancers with immunostimulatory HIV tat derivative polypeptides |
ES2715890T3 (es) | 2013-11-01 | 2019-06-06 | Pfizer | Vectores de expresión de antígenos asociados a la próstata |
EP2870974A1 (en) | 2013-11-08 | 2015-05-13 | Novartis AG | Salmonella conjugate vaccines |
NZ719934A (en) | 2013-11-28 | 2022-10-28 | Bavarian Nordic As | Compositions and methods vectors for inducing an enhanced immune response using poxvirus vectors |
EP3079716B1 (en) | 2013-12-13 | 2019-05-08 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Multi-epitope tarp peptide vaccine and uses thereof |
WO2015095868A1 (en) | 2013-12-20 | 2015-06-25 | Wake Forest University Health Sciences | Methods and compositions for increasing protective antibody levels induced by pneumococcal polysaccharide vaccines |
EP3095460A4 (en) * | 2014-01-15 | 2017-08-23 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant having anti-allergic activity, and anti-allergic agent |
JPWO2015108047A1 (ja) * | 2014-01-15 | 2017-03-23 | 株式会社新日本科学 | 免疫誘導活性を有するキラル核酸アジュバンド及び免疫誘導活性剤 |
JPWO2015108048A1 (ja) * | 2014-01-15 | 2017-03-23 | 株式会社新日本科学 | 抗腫瘍作用を有するキラル核酸アジュバンド及び抗腫瘍剤 |
SG10201912897UA (en) | 2014-01-16 | 2020-02-27 | Wave Life Sciences Ltd | Chiral design |
RU2743793C1 (ru) | 2014-01-21 | 2021-02-26 | Пфайзер Инк. | Капсульные полисахариды Streptococcus pneumoniae и их конъюгаты |
US11160855B2 (en) | 2014-01-21 | 2021-11-02 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof |
AU2015208820B2 (en) | 2014-01-21 | 2020-05-14 | Pfizer Inc. | Streptococcus pneumoniae capsular polysaccharides and conjugates thereof |
AU2015208821B2 (en) | 2014-01-21 | 2017-11-02 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof |
AU2015209575A1 (en) | 2014-01-21 | 2016-07-21 | Immune Design Corp. | Compositions for use in the treatment of allergic conditions |
WO2016130569A1 (en) | 2015-02-09 | 2016-08-18 | Mj Biologics, Inc. | A composition comprising pedv antigens and methods for making and using the composition |
EP3104877B1 (en) | 2014-02-11 | 2020-01-22 | The USA, as represented by The Secretary, Department of Health and Human Services | Pcsk9 vaccine and methods of using the same |
EP3443983B1 (en) | 2014-02-14 | 2022-07-20 | Pfizer Inc. | Immunogenic glycoprotein conjugates |
GB2523187A (en) | 2014-02-18 | 2015-08-19 | Mologen Ag | Covalently closed non-coding immunomodulatory DNA construct |
EP3110401A4 (en) | 2014-02-25 | 2017-10-25 | Merck Sharp & Dohme Corp. | Lipid nanoparticle vaccine adjuvants and antigen delivery systems |
WO2015128461A1 (en) * | 2014-02-28 | 2015-09-03 | Bayer Animal Health Gmbh | Immunostimulatory plasmids |
US10034934B2 (en) | 2014-03-11 | 2018-07-31 | Regents Of The University Of Minnesota | Porcine epidemic diarrhea virus vaccines and methods of use thereof |
WO2015143400A1 (en) | 2014-03-20 | 2015-09-24 | Pharmacyclics, Inc. | Phospholipase c gamma 2 and resistance associated mutations |
KR102297357B1 (ko) | 2014-03-26 | 2021-09-02 | 글락소스미스클라인 바이오로지칼즈 에스.에이. | 돌연변이 스태필로코쿠스 항원 |
US9549914B2 (en) | 2014-04-03 | 2017-01-24 | The Johns Hopkins University | Treatment of human cytomegalovirus by modulating Wnt |
US10111948B2 (en) | 2014-04-25 | 2018-10-30 | Tria Bioscience Corp. | Synthetic hapten carrier compositions and methods |
AU2015263888A1 (en) * | 2014-05-23 | 2017-01-19 | Gregory CAUCHON | Coating method and materials |
EP3149479A2 (en) | 2014-05-30 | 2017-04-05 | Sanofi Pasteur Inc. | Expression and conformational analysis of engineered influenza hemagglutinin |
CA2953216C (en) | 2014-06-04 | 2020-12-22 | Exicure, Inc. | Multivalent delivery of immune modulators by liposomal spherical nucleic acids for prophylactic or therapeutic applications |
US20150374815A1 (en) | 2014-06-25 | 2015-12-31 | Selecta Biosciences, Inc. | Methods and compositions for treatment with synthetic nanocarriers and immune checkpoint inhibitors |
WO2016011083A1 (en) | 2014-07-15 | 2016-01-21 | Immune Design Corp. | Prime-boost regimens with a tlr4 agonist adjuvant and a lentiviral vector |
EP3398948A3 (en) | 2014-08-22 | 2018-12-05 | Janus Biotherapeutics, Inc. | 2,4,6,7-tetrasubstituted pteridine compounds and methods of synthesis and use thereof |
US10286065B2 (en) | 2014-09-19 | 2019-05-14 | Board Of Regents, The University Of Texas System | Compositions and methods for treating viral infections through stimulated innate immunity in combination with antiviral compounds |
SG11201702656WA (en) | 2014-10-06 | 2017-04-27 | Exicure Inc | Anti-tnf compounds |
US20160129097A1 (en) * | 2014-11-06 | 2016-05-12 | Jeremy Delk | Method of processing a veterinary tumor vaccine and a veterinary tumor vaccine processing kit |
CA2968531A1 (en) | 2014-11-21 | 2016-05-26 | Northwestern University | The sequence-specific cellular uptake of spherical nucleic acid nanoparticle conjugates |
WO2016103531A1 (ja) * | 2014-12-26 | 2016-06-30 | 国立研究開発法人医薬基盤・健康・栄養研究所 | 免疫賦活活性を有する核酸多糖複合体の抗腫瘍薬としての応用 |
WO2016109310A1 (en) | 2014-12-31 | 2016-07-07 | Checkmate Pharmaceuticals, Llc | Combination tumor immunotherapy |
DK3244917T3 (da) | 2015-01-15 | 2023-05-22 | Pfizer | Immunogene sammensætninger til anvendelse i pneumokokvacciner |
PL3244920T3 (pl) | 2015-01-16 | 2023-09-25 | Zoetis Services Llc | Szczepionka przeciw pryszczycy |
WO2016131048A1 (en) | 2015-02-13 | 2016-08-18 | Icahn School Of Medicine At Mount Sinai | Rna containing compositions and methods of their use |
AU2016221318B2 (en) | 2015-02-19 | 2020-06-25 | Pfizer Inc. | Neisseria meningitidis compositions and methods thereof |
AU2016228514B2 (en) | 2015-03-12 | 2021-06-17 | Zoetis Services Llc | Pyolysin methods and compositions |
PE20180172A1 (es) | 2015-05-04 | 2018-01-22 | Pfizer | Conjugados proteina-polisacarido de estreptococo grupo b, metodos para producir conjugados, composiciones inmunogenas que comprenden conjugados y sus usos |
WO2016180852A1 (en) | 2015-05-12 | 2016-11-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for preparing antigen-specific t cells from an umbilical cord blood sample |
SG10201912485PA (en) | 2015-05-13 | 2020-02-27 | Agenus Inc | Vaccines for treatment and prevention of cancer |
WO2016183371A1 (en) | 2015-05-13 | 2016-11-17 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Methods for the treatment or prevention of ischemic tissue damage |
US10584148B2 (en) | 2015-06-02 | 2020-03-10 | Sanofi Pasteur Inc. | Engineered influenza antigenic polypeptides and immunogenic compositions thereof |
WO2016200787A2 (en) | 2015-06-09 | 2016-12-15 | The Board Of Regents Of The University Of Oklahoma | Compositions and treatments for haemophilus influenzae |
US10954492B2 (en) | 2015-06-10 | 2021-03-23 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Processes for production and purification of nucleic acid-containing compositions |
AU2016281904B2 (en) | 2015-06-26 | 2022-08-11 | Seqirus UK Limited | Antigenically matched influenza vaccines |
US10449212B2 (en) | 2015-07-09 | 2019-10-22 | National Institute For Materials Science | Immunostimulating oligonucleotide complex |
NZ739007A (en) | 2015-07-21 | 2022-08-26 | Pfizer | Immunogenic compositions comprising conjugated capsular saccharide antigens, kits comprising the same and uses thereof |
EP3328424A1 (en) | 2015-07-31 | 2018-06-06 | Bayer Animal Health GmbH | Enhanced immune response in porcine species |
BR112018002919B1 (pt) | 2015-08-14 | 2024-02-27 | Zoetis Services Llc | Composição imunogênica eficaz compreendendo uma cepa de mycoplasma bovis e usos da mesma para prevenção de doenças causadas por mycoplasma bovis |
US10709758B2 (en) | 2015-09-03 | 2020-07-14 | The Board Of Regents Of The University Of Oklahoma | Peptide inhibitors of clostridium difficile toxin B (TcdB) toxin |
LU92821B1 (en) | 2015-09-09 | 2017-03-20 | Mologen Ag | Combination comprising immunostimulatory oligonucleotides |
EP3349717A4 (en) | 2015-09-17 | 2019-04-17 | JRX Biotechnology, Inc. | APPROACHES TO IMPROVE HYDRATION OR HUMIDIFICATION OF THE SKIN |
GB2542425A (en) | 2015-09-21 | 2017-03-22 | Mologen Ag | Means for the treatment of HIV |
US10526309B2 (en) | 2015-10-02 | 2020-01-07 | The University Of North Carolina At Chapel Hill | Pan-TAM inhibitors and Mer/Axl dual inhibitors |
WO2017062246A1 (en) | 2015-10-05 | 2017-04-13 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Human rota virus g9p[6] strain and use as a vaccine |
AU2016343845B2 (en) | 2015-10-30 | 2023-04-13 | Baylor College Of Medicine | Compositions and methods for the treatment of HER2-expressing solid tumors |
EP3377098A1 (en) | 2015-11-20 | 2018-09-26 | Pfizer Inc | Immunogenic compositions for use in pneumococcal vaccines |
US10596248B2 (en) | 2015-12-09 | 2020-03-24 | Jingang Medicine (Australia) Pty Ltd | Immunomodulating composition for treatment |
WO2017123201A1 (en) | 2016-01-11 | 2017-07-20 | Zoetis Services Llc | Novel cross protective vaccine compositions for porcine epidemic diarrhea virus |
PL3407910T3 (pl) | 2016-01-29 | 2022-08-16 | Bavarian Nordic A/S | Rekombinowana zmodyfikowana szczepionka przeciwko wirusowi krowianki ankara (mva) przeciwko wirusowi zapalenia mózgu koni |
WO2017189448A1 (en) | 2016-04-25 | 2017-11-02 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Bivalent immunogenic conjugate for malaria and typhoid |
US20190298824A1 (en) | 2016-05-04 | 2019-10-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Serv | Albumin-binding immunomodulatory compositions and methods of use thereof |
WO2017201390A1 (en) | 2016-05-19 | 2017-11-23 | The Regents Of The University Of Michigan | Novel adjuvant compositions |
US11033615B2 (en) | 2016-05-31 | 2021-06-15 | The Government of the United States, As Represented by the Secretary of the Army Fort Detrick, Maryland | Zika virus vaccine and methods of production |
EP3464328A1 (en) | 2016-06-02 | 2019-04-10 | Sanofi Pasteur Inc. | Engineered influenza antigenic polypeptides and immunogenic compositions thereof |
US11116832B2 (en) | 2016-06-03 | 2021-09-14 | Sanofi Pasteur Inc. | Modification of engineered influenza hemagglutinin polypeptides |
EP3468590A1 (en) | 2016-06-13 | 2019-04-17 | The United States of America, as represented by the Secretary, Department of Health and Human Services | Nucleic acids encoding zika virus-like particles and their use in zika virus vaccines and diagnostic assays |
EP3474890A1 (en) | 2016-06-22 | 2019-05-01 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften E. V. | Pneumococcal polysaccharide-protein conjugate composition |
EP3269385A1 (en) | 2016-07-12 | 2018-01-17 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Pneumococcal polysaccharide-protein conjugate composition |
EP3481849A1 (en) | 2016-07-08 | 2019-05-15 | The U.S.A. as represented by the Secretary, Department of Health and Human Services | Chimeric dengue/zika viruses live-attenuated zika virus vaccines |
US10632185B2 (en) | 2016-07-08 | 2020-04-28 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Chimeric west nile/zika viruses and methods of use |
MX2019001341A (es) | 2016-08-05 | 2019-07-04 | Sanofi Pasteur Inc | Composicion de conjugado de polisacarido neumococico multivalente-proteina. |
JP7001687B2 (ja) | 2016-08-05 | 2022-02-04 | サノフィ パスツール インコーポレイティッド | 多価肺炎球菌多糖体-タンパク質コンジュゲート組成物 |
US10182146B2 (en) * | 2016-08-22 | 2019-01-15 | Nice Ltd. | System and method for dynamic redundant call recording |
CN109790220A (zh) | 2016-08-25 | 2019-05-21 | 豪夫迈·罗氏有限公司 | 与巨噬细胞激活剂组合的抗csf-1r抗体的间歇给药 |
WO2018039629A2 (en) | 2016-08-25 | 2018-03-01 | Northwestern University | Micellar spherical nucleic acids from thermoresponsive, traceless templates |
US10172933B2 (en) | 2016-10-31 | 2019-01-08 | The United States Of America, As Represented By The Secretary Of Agriculture | Mosaic vaccines for serotype a foot-and-mouth disease virus |
US10751402B2 (en) | 2016-11-09 | 2020-08-25 | Pfizer Inc. | Immunogenic compositions and uses thereof |
JP7304287B2 (ja) | 2016-12-22 | 2023-07-06 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | 抗pd-l1/pd1治療の不成功後の、抗pd-l1抗体との組み合わせでの抗csf-1r抗体を用いた腫瘍の治療 |
ES2911490T3 (es) | 2017-01-20 | 2022-05-19 | Pfizer | Composiciones inmunogénicas para su uso en vacunas antineumocócicas |
KR102567845B1 (ko) | 2017-01-31 | 2023-08-17 | 화이자 인코포레이티드 | 네이세리아 메닌기티디스 조성물 및 그의 방법 |
US20200222550A1 (en) | 2017-01-31 | 2020-07-16 | Merck Sharp & Dohme Corp. | Methods for production of capsular polysaccharide protein conjugates from streptococcus pneumoniae serotype 19f |
WO2018141029A1 (en) | 2017-02-06 | 2018-08-09 | Meat & Livestock Australia Limited | Immunostimulating compositions and uses therefore |
GB201703529D0 (en) | 2017-03-06 | 2017-04-19 | Cambridge Entpr Ltd | Vaccine composition |
US10525119B2 (en) | 2017-03-31 | 2020-01-07 | Boston Medical Center Corporation | Methods and compositions using highly conserved pneumococcal surface proteins |
WO2018201090A1 (en) | 2017-04-28 | 2018-11-01 | Exicure, Inc. | Synthesis of spherical nucleic acids using lipophilic moieties |
CA3066915A1 (en) | 2017-06-11 | 2018-12-20 | Molecular Express, Inc. | Methods and compositions for substance use disorder vaccine formulations and uses thereof |
BR112019027387A8 (pt) | 2017-06-23 | 2022-12-06 | Univ Maryland | Composições imunogênicas |
US11464845B2 (en) | 2017-07-21 | 2022-10-11 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Neisseria meningitidis immunogenic compositions |
CA3074708A1 (en) | 2017-09-07 | 2019-03-14 | Merck Sharp & Dohme Corp. | Pneumococcal polysaccharides and their use in immunogenic polysaccharide-carrier protein conjugates |
WO2019048631A1 (en) | 2017-09-08 | 2019-03-14 | Mina Therapeutics Limited | SMALL HNF4A ACTIVATOR RNA COMPOSITIONS AND METHODS OF USE |
US11806364B2 (en) | 2017-09-28 | 2023-11-07 | Industry-Academic Cooperation Foundation, Yonsei University | Method for producing myeloid-derived suppressor cells, myeloid-derived suppressor cells produced thereby, and methods thereof |
EP3703745B1 (en) | 2017-11-04 | 2024-04-10 | Nevada Research & Innovation Corporation | Immunogenic conjugates and methods of use thereof |
PE20201338A1 (es) | 2017-12-06 | 2020-11-25 | Merck Sharp & Dohme | Composiciones que comprenden conjugados de polisacarido de streptococcus pneumoniae con proteina y metodos de uso de estos |
WO2019126197A1 (en) | 2017-12-18 | 2019-06-27 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Bacterial polysaccharide-conjugated carrier proteins and use thereof |
CA3086205A1 (en) | 2017-12-19 | 2019-06-27 | Massachusetts Institute Of Technology | Antigen-adjuvant coupling reagents and methods of use |
EP3743107A1 (en) | 2018-01-22 | 2020-12-02 | The United States of America, as represented by the Secretary, Department of Health and Human Services | Broadly protective inactivated influenza virus vaccine |
KR20200128116A (ko) | 2018-02-28 | 2020-11-11 | 화이자 인코포레이티드 | Il-15 변이체 및 이의 용도 |
MX2020009149A (es) * | 2018-03-02 | 2021-01-15 | Elicio Therapeutics Inc | Compuestos que incluyen una secuencia de kras mutante y un lipido y usos de los mismos. |
US11633471B2 (en) | 2018-03-06 | 2023-04-25 | Unm Rainforest Innovations | Compositions and methods for reducing serum triglycerides |
EP3774884B1 (en) | 2018-03-28 | 2023-12-06 | Sanofi Pasteur Inc. | Methods of generating broadly protective vaccine compositions comprising hemagglutinin |
WO2019195314A2 (en) | 2018-04-03 | 2019-10-10 | Sanofi | Antigenic epstein barr virus polypeptides |
BR112020019938A2 (pt) | 2018-04-03 | 2021-01-26 | Sanofi | polipeptídeos antigênicos de vírus sincicial respiratório |
JP2021519600A (ja) | 2018-04-03 | 2021-08-12 | サノフイSanofi | 抗原性インフルエンザ−フェリチンポリペプチド |
JP2021519599A (ja) | 2018-04-03 | 2021-08-12 | サノフイSanofi | 抗原性ospaポリペプチド |
EP3773698A1 (en) | 2018-04-03 | 2021-02-17 | Sanofi | Ferritin proteins |
EP3797121A1 (en) | 2018-05-23 | 2021-03-31 | Pfizer Inc | Antibodies specific for cd3 and uses thereof |
CA3100829A1 (en) | 2018-05-23 | 2019-11-28 | Pfizer Inc. | Antibodies specific for gucy2c and uses thereof |
EP3574915A1 (en) | 2018-05-29 | 2019-12-04 | Neovacs | Immunogenic product comprising il-4 and/or il-13 for treating disorders associated with aberrant il-4 and/or il 13 expression or activity |
US11260119B2 (en) | 2018-08-24 | 2022-03-01 | Pfizer Inc. | Escherichia coli compositions and methods thereof |
US20220031830A1 (en) | 2018-12-04 | 2022-02-03 | The Rockefeller University | Hiv vaccine immunogens |
EP3893926A1 (en) | 2018-12-12 | 2021-10-20 | Pfizer Inc. | Immunogenic multiple hetero-antigen polysaccharide-protein conjugates and uses thereof |
US20220023413A1 (en) | 2018-12-12 | 2022-01-27 | The U.S.A., As Represented By The Secretary, Department Of Health And Human Services | Recombinant mumps virus vaccine expressing genotype g fusion and hemagglutinin-neuraminidase proteins |
WO2020123989A1 (en) | 2018-12-14 | 2020-06-18 | University Of Georgia Research Foundation, Inc. | Crimean-congo hemorrhagic fever virus replicon particles and use thereof |
AU2019401535B2 (en) | 2018-12-19 | 2023-12-14 | Merck Sharp & Dohme Llc | Compositions comprising Streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof |
US20220370606A1 (en) | 2018-12-21 | 2022-11-24 | Pfizer Inc. | Combination Treatments Of Cancer Comprising A TLR Agonist |
CN114269373A (zh) | 2019-04-02 | 2022-04-01 | 赛诺菲 | 抗原性多聚呼吸道合胞病毒多肽 |
CA3136278A1 (en) | 2019-04-10 | 2020-10-15 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens, kits comprising the same and uses thereof |
EP3966331A4 (en) * | 2019-05-10 | 2023-07-05 | Microbio (Shanghai) Co., Ltd. | DIMER CPG OLIGONUCLEOTIDES FOR USE IN MODULATION OF IMMUNE RESPONSE |
US20210008110A1 (en) * | 2019-06-14 | 2021-01-14 | Serhat Gumrukcu | Activated lymphocytic cells and methods of using the same to treat cancer and infectious conditions |
US20220280636A1 (en) | 2019-07-19 | 2022-09-08 | Merck Sharp & Dohme Corp. | Antigenic glycoprotein e polypeptides, compositions, and methods of use thereof |
MX2022001190A (es) | 2019-07-30 | 2022-02-22 | Phibro Animal Health Corporation | Una composicion para administracion en la mucosa para aves. |
CN114728050A (zh) | 2019-07-31 | 2022-07-08 | 圣诺菲·帕斯图尔公司 | 多价肺炎球菌多糖-蛋白质缀合物组合物及其使用方法 |
JP2022545181A (ja) | 2019-08-30 | 2022-10-26 | ユニバーシティ オブ ロチェスター | がん治療のためのセプチン阻害剤 |
WO2021084429A1 (en) | 2019-11-01 | 2021-05-06 | Pfizer Inc. | Escherichia coli compositions and methods thereof |
MX2022006578A (es) | 2019-12-17 | 2022-07-04 | Pfizer | Anticuerpos especificos para cd47, pd-l1 y sus usos. |
US20230039456A1 (en) | 2019-12-17 | 2023-02-09 | The U.S.A., As Represented By The Secretary, Department Of Health And Human Services | Live attenuated leishmania parasite vaccines with enhanced safety characteristics |
US20230241196A1 (en) | 2020-01-27 | 2023-08-03 | Oregon State University | Gonorrhea subunit vaccine |
BR112022015994A2 (pt) | 2020-02-13 | 2022-10-11 | Univ Illinois | Composição imunogênica multivalente, vetor recombinante, célula hospedeira recombinante, e, métodos para induzir uma resposta imune protetora e para imunizar um animal contra dirofilariose |
PE20230170A1 (es) | 2020-02-23 | 2023-02-01 | Pfizer | Composiciones de escherichia coli y sus metodos |
JP2023515829A (ja) | 2020-02-28 | 2023-04-14 | サノフィ パスツール インコーポレイテッド | 小児対象のための高用量インフルエンザワクチン |
US11213482B1 (en) | 2020-03-05 | 2022-01-04 | University of Pittsburgh—Of the Commonwealth System of Higher Educat | SARS-CoV-2 subunit vaccine and microneedle array delivery system |
US20230146256A1 (en) | 2020-04-17 | 2023-05-11 | Regents Of The University Of Minnesota | SARS-CoV-2 SPIKE RECEPTOR BINDING DOMAIN AND COMPOSITIONS AND METHODS THEREOF |
EP3900739A1 (en) | 2020-04-21 | 2021-10-27 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Synthetic streptococcus pneumoniae saccharide conjugates to conserved membrane protein |
EP4149440A1 (en) | 2020-05-11 | 2023-03-22 | Erytech Pharma | Red cell extracellular vesicles (rcevs) containing cargoes and methods of use and production thereof |
JP2023533793A (ja) | 2020-07-17 | 2023-08-04 | ファイザー・インク | 治療用抗体およびそれらの使用 |
AU2021332183A1 (en) | 2020-08-26 | 2023-03-02 | Pfizer Inc. | Group B streptococcus polysaccharide-protein conjugates, methods for producing conjugates, immunogenic compositions comprising conjugates, and uses thereof |
EP4213874A1 (en) | 2020-09-17 | 2023-07-26 | Neovacs | Immunogenic product comprising an ige fragment for treating ige-mediated inflammatory disorders |
JP2023542528A (ja) | 2020-09-24 | 2023-10-10 | フレッド ハッチンソン キャンサー センター | Sox2抗原を標的とする免疫療法 |
WO2022066973A1 (en) | 2020-09-24 | 2022-03-31 | Fred Hutchinson Cancer Research Center | Immunotherapy targeting pbk or oip5 antigens |
PE20231934A1 (es) | 2020-10-27 | 2023-12-01 | Pfizer | Composiciones de escherichia coli y metodos de las mismas |
JP2022075575A (ja) | 2020-11-04 | 2022-05-18 | ファイザー・インク | 肺炎球菌ワクチンにおける使用のための免疫原性組成物 |
CA3200968A1 (en) | 2020-11-10 | 2022-05-19 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof |
US20220202923A1 (en) | 2020-12-23 | 2022-06-30 | Pfizer Inc. | E. coli fimh mutants and uses thereof |
WO2022147373A1 (en) | 2020-12-31 | 2022-07-07 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Antibody-guided pcsk9-mimicking immunogens lacking 9-residue sequence overlap with human proteins |
EP4288087A1 (en) | 2021-02-03 | 2023-12-13 | The Board of Trustees of the University of Illinois | Vaccine and methods for preventing filariasis and dirofilariasis |
US20220387576A1 (en) | 2021-05-28 | 2022-12-08 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof |
BR112023023671A2 (pt) | 2021-05-28 | 2024-02-06 | Pfizer | Composições imunogênicas compreendendo antígenos de sacarídeo capsular conjugados e usos dos mesmos |
WO2022261251A1 (en) | 2021-06-08 | 2022-12-15 | Glyde Bio Inc. | Immunogenic compositions comprising tumour-associated antigen |
EP4104830A1 (en) | 2021-06-16 | 2022-12-21 | Burghardt Wittig | Sequential innate and adaptive immune modulation for cancer treatment |
WO2023288263A1 (en) | 2021-07-16 | 2023-01-19 | The Board Of Trustees Of The University Of Illinois | Universal vaccine for influenza virus based on tetrameric m2 protein incorporated into nanodiscs |
WO2023018817A1 (en) | 2021-08-11 | 2023-02-16 | Sanofi Pasteur Inc. | Truncated influenza neuraminidase and methods of using the same |
WO2023059857A1 (en) | 2021-10-08 | 2023-04-13 | Sanofi Pasteur Inc. | Multivalent influenza vaccines |
WO2023079113A1 (en) | 2021-11-05 | 2023-05-11 | Sanofi | Hybrid multivalent influenza vaccines comprising hemagglutinin and neuraminidase and methods of using the same |
AR127585A1 (es) | 2021-11-05 | 2024-02-07 | Sanofi Sa | Vacuna de arn de virus sincicial respiratorio |
WO2023081798A1 (en) | 2021-11-05 | 2023-05-11 | Sanofi Pasteur Inc. | Multivalent influenza vaccines comprising recombinant hemagglutinin and neuraminidase and methods of using the same |
WO2023102388A1 (en) | 2021-11-30 | 2023-06-08 | Sanofi Pasteur Inc. | Human metapneumovirus viral vector-based vaccines |
US20230310571A1 (en) | 2021-11-30 | 2023-10-05 | Sanofi Pasteur Inc. | Human metapneumovirus vaccines |
WO2023111262A1 (en) | 2021-12-17 | 2023-06-22 | Sanofi | Lyme disease rna vaccine |
WO2023135515A1 (en) | 2022-01-13 | 2023-07-20 | Pfizer Inc. | Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof |
WO2023144206A1 (en) | 2022-01-27 | 2023-08-03 | Sanofi Pasteur | Modified vero cells and methods of using the same for virus production |
WO2023161817A1 (en) | 2022-02-25 | 2023-08-31 | Pfizer Inc. | Methods for incorporating azido groups in bacterial capsular polysaccharides |
WO2023177579A1 (en) | 2022-03-14 | 2023-09-21 | Sanofi Pasteur Inc. | Machine-learning techniques in protein design for vaccine generation |
WO2023201109A1 (en) | 2022-04-15 | 2023-10-19 | Yale University | Exatecan formulation |
WO2023214082A2 (en) | 2022-05-06 | 2023-11-09 | Sanofi | Signal sequences for nucleic acid vaccines |
WO2023218322A1 (en) | 2022-05-11 | 2023-11-16 | Pfizer Inc. | Process for producing of vaccine formulations with preservatives |
WO2024003239A1 (en) | 2022-06-29 | 2024-01-04 | Bavarian Nordic A/S | RECOMBINANT MODIFIED saRNA (VRP) AND VACCINIA VIRUS ANKARA (MVA) PRIME-BOOST REGIMEN |
WO2024069420A2 (en) | 2022-09-29 | 2024-04-04 | Pfizer Inc. | Immunogenic compositions comprising an rsv f protein trimer |
Family Cites Families (524)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2002A (en) * | 1841-03-12 | Tor and planter for plowing | ||
US2004A (en) * | 1841-03-12 | Improvement in the manner of constructing and propelling steam-vessels | ||
US2005A (en) * | 1841-03-16 | Improvement in the manner of constructing molds for casting butt-hinges | ||
US2010A (en) * | 1841-03-18 | Machine foe | ||
US2003A (en) * | 1841-03-12 | Improvement in horizontal windivhlls | ||
US3521637A (en) * | 1967-11-28 | 1970-07-28 | Nelson J Waterbury | Tampon or similar sanitary napkin containing vitamin a |
US3627874A (en) | 1969-07-16 | 1971-12-14 | Merck & Co Inc | Vaccine preparation |
US3761585A (en) | 1971-04-05 | 1973-09-25 | Beecham Group Ltd | Vaccines containing modified allergenic material |
US3906092A (en) | 1971-11-26 | 1975-09-16 | Merck & Co Inc | Stimulation of antibody response |
DE2643213C2 (de) | 1976-09-25 | 1985-02-21 | Bayer Ag, 5090 Leverkusen | Verfahren zum Abschwächen oder Inaktivieren von Mikroorganismen |
US4469863A (en) | 1980-11-12 | 1984-09-04 | Ts O Paul O P | Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof |
US5023243A (en) * | 1981-10-23 | 1991-06-11 | Molecular Biosystems, Inc. | Oligonucleotide therapeutic agent and method of making same |
JP2547714B2 (ja) | 1981-10-23 | 1996-10-23 | モルキユラ− バイオシステムズ インコ−ポレテツド | オリゴヌクレオチド治療剤及びその製法 |
ES507187A0 (es) | 1981-11-16 | 1983-01-01 | Union Ind Y Agro Ganader S A U | Procedimiento de obtencion de una leche humanizada adiciona-da de nucleotidos con destino a la alimentacion infantil. |
US5766920A (en) * | 1982-08-11 | 1998-06-16 | Cellcor, Inc. | Ex vivo activation of immune cells |
SE8205892D0 (sv) | 1982-10-18 | 1982-10-18 | Bror Morein | Immunogent membranproteinkomplex, sett for framstellning och anvendning derav som immunstimulerande medel och sasom vaccin |
US4452775A (en) * | 1982-12-03 | 1984-06-05 | Syntex (U.S.A.) Inc. | Cholesterol matrix delivery system for sustained release of macromolecules |
SE8405493D0 (sv) | 1984-11-01 | 1984-11-01 | Bror Morein | Immunogent komplex samt sett for framstellning derav och anvendning derav som immunstimulerande medel |
US5308626A (en) * | 1985-06-28 | 1994-05-03 | Toni N. Mariani | Lymphokine activated effector cells for antibody-dependent cellular cytotoxicity (ADCC) treatment of cancer and other diseases |
EP0231039B1 (en) | 1986-01-14 | 1992-01-08 | De Staat Der Nederlanden Vertegenwoordigd Door De Minister Van Welzijn, Volksgezondheid En Cultuur | Process for preparing immunological complexes and pharmaceutical composition containing these complexes |
US4806463A (en) | 1986-05-23 | 1989-02-21 | Worcester Foundation For Experimental Biology | Inhibition of HTLV-III by exogenous oligonucleotides |
US5194428A (en) | 1986-05-23 | 1993-03-16 | Worcester Foundation For Experimental Biology | Inhibition of influenza virus replication by oligonucleotide phosphorothioates |
US5059519A (en) | 1986-07-01 | 1991-10-22 | University Of Massachusetts Medical School | Oligonucleotide probes for the determination of the proclivity for development of autoimmune diseases |
US5075109A (en) * | 1986-10-24 | 1991-12-24 | Southern Research Institute | Method of potentiating an immune response |
US5264423A (en) | 1987-03-25 | 1993-11-23 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibitors for replication of retroviruses and for the expression of oncogene products |
US5276019A (en) | 1987-03-25 | 1994-01-04 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibitors for replication of retroviruses and for the expression of oncogene products |
ES2007350A6 (es) | 1987-05-29 | 1989-06-16 | Ganadera Union Ind Agro | Productos alimenticios enriquecidos con nucleosidos yno nucleotidos para la nutricion infantil y de adultos, y procedimiento para su preparacion. |
CA1339596C (en) | 1987-08-07 | 1997-12-23 | New England Medical Center Hospitals, Inc. | Viral expression inhibitors |
US5004810A (en) | 1988-09-30 | 1991-04-02 | Schering Corporation | Antiviral oligomers |
NZ230747A (en) | 1988-09-30 | 1992-05-26 | Bror Morein | Immunomodulating matrix comprising a complex of at least one lipid and at least one saponin; certain glycosylated triterpenoid saponins derived from quillaja saponaria molina |
US5087617A (en) * | 1989-02-15 | 1992-02-11 | Board Of Regents, The University Of Texas System | Methods and compositions for treatment of cancer using oligonucleotides |
US5112605A (en) * | 1989-03-17 | 1992-05-12 | Genentech, Inc. | Temporal gamma-interferon administration for allergies |
US5703055A (en) | 1989-03-21 | 1997-12-30 | Wisconsin Alumni Research Foundation | Generation of antibodies through lipid mediated DNA delivery |
US5693622A (en) | 1989-03-21 | 1997-12-02 | Vical Incorporated | Expression of exogenous polynucleotide sequences cardiac muscle of a mammal |
US5629158A (en) * | 1989-03-22 | 1997-05-13 | Cemu Bitecknik Ab | Solid phase diagnosis of medical conditions |
US4958013A (en) | 1989-06-06 | 1990-09-18 | Northwestern University | Cholesteryl modified oligonucleotides |
US5399346A (en) * | 1989-06-14 | 1995-03-21 | The United States Of America As Represented By The Department Of Health And Human Services | Gene therapy |
US4981684A (en) * | 1989-10-24 | 1991-01-01 | Coopers Animal Health Limited | Formation of adjuvant complexes |
US5178860A (en) | 1989-09-01 | 1993-01-12 | Coopers Animal Health Limited | Adjuvant complexes and vaccine made therefrom |
US5399676A (en) * | 1989-10-23 | 1995-03-21 | Gilead Sciences | Oligonucleotides with inverted polarity |
US5676954A (en) | 1989-11-03 | 1997-10-14 | Vanderbilt University | Method of in vivo delivery of functioning foreign genes |
US5786189A (en) | 1989-11-29 | 1998-07-28 | Smithkline Beecham Biologicals (S.A.) | Vaccine |
US5457189A (en) | 1989-12-04 | 1995-10-10 | Isis Pharmaceuticals | Antisense oligonucleotide inhibition of papillomavirus |
US5514788A (en) * | 1993-05-17 | 1996-05-07 | Isis Pharmaceuticals, Inc. | Oligonucleotide modulation of cell adhesion |
US5587361A (en) | 1991-10-15 | 1996-12-24 | Isis Pharmaceuticals, Inc. | Oligonucleotides having phosphorothioate linkages of high chiral purity |
US5514577A (en) * | 1990-02-26 | 1996-05-07 | Isis Pharmaceuticals, Inc. | Oligonucleotide therapies for modulating the effects of herpes viruses |
US5248670A (en) | 1990-02-26 | 1993-09-28 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotides for inhibiting herpesviruses |
US5166195A (en) | 1990-05-11 | 1992-11-24 | Isis Pharmaceuticals, Inc. | Antisense inhibitors of the human immunodeficiency virus phosphorothioate oligonucleotides |
WO1991019813A1 (en) | 1990-06-11 | 1991-12-26 | The University Of Colorado Foundation, Inc. | Nucleic acid ligands |
EP0468520A3 (en) | 1990-07-27 | 1992-07-01 | Mitsui Toatsu Chemicals, Inc. | Immunostimulatory remedies containing palindromic dna sequences |
US5245022A (en) * | 1990-08-03 | 1993-09-14 | Sterling Drug, Inc. | Exonuclease resistant terminally substituted oligonucleotides |
US5591720A (en) | 1990-08-16 | 1997-01-07 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating the effects of cytomegalovirus infections |
US6042838A (en) | 1991-02-15 | 2000-03-28 | Uab Research Foundation | immunogenic compositions for mucosal administration of pneumococcal surface protein A (PspA) |
WO1992016192A1 (en) * | 1991-03-15 | 1992-10-01 | Amgen Inc. | Pulmonary administration of granulocyte colony stimulating factor |
US5683985A (en) | 1991-04-18 | 1997-11-04 | The Salk Institute For Biological Studies | Oligonucleotide decoys and methods relating thereto |
US5498410A (en) * | 1991-04-22 | 1996-03-12 | Gleich; Gerald J. | Method for the treatment of eosinophil-associated conditions with anionic polymers |
US5681555A (en) | 1991-04-22 | 1997-10-28 | Gleich; Gerald J. | Method for the treatment of bronchial asthma by parenteral administration of anionic polymers |
WO1994008003A1 (en) | 1991-06-14 | 1994-04-14 | Isis Pharmaceuticals, Inc. | ANTISENSE OLIGONUCLEOTIDE INHIBITION OF THE ras GENE |
EP0587749A4 (en) | 1991-05-31 | 1995-08-30 | Genta Inc | Compositions and delivery systems for transdermal administration of neutral oligomers |
US5582986A (en) | 1991-06-14 | 1996-12-10 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide inhibition of the ras gene |
US6030954A (en) * | 1991-09-05 | 2000-02-29 | University Of Connecticut | Targeted delivery of poly- or oligonucleotides to cells |
US5576302A (en) | 1991-10-15 | 1996-11-19 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating hepatitis C virus having phosphorothioate linkages of high chiral purity |
WO1993009789A1 (en) | 1991-11-15 | 1993-05-27 | Temple University - Of The Commonwealth System Of Higher Education | Treatment of melanoma with antisense oligonucleotides to c-myb proto-oncogene |
JPH07501694A (ja) | 1991-11-18 | 1995-02-23 | タノックス バイオシステムズ インコーポレイテッド | 免疫グロブリン生産のアイソタイプ特異的抑制のためのアンチセンスオリゴヌクレオチド |
US5858784A (en) * | 1991-12-17 | 1999-01-12 | The Regents Of The University Of California | Expression of cloned genes in the lung by aerosol- and liposome-based delivery |
JPH07503615A (ja) | 1992-02-04 | 1995-04-20 | カイロン コーポレイション | 肝炎療剤 |
US5643578A (en) * | 1992-03-23 | 1997-07-01 | University Of Massachusetts Medical Center | Immunization by inoculation of DNA transcription unit |
US6498147B2 (en) | 1992-05-22 | 2002-12-24 | The Scripps Research Institute | Suppression of nuclear factor-κb dependent processes using oligonucleotides |
CA2134773A1 (en) | 1992-06-04 | 1993-12-09 | Robert J. Debs | Methods and compositions for in vivo gene therapy |
US5726518A (en) * | 1992-07-22 | 1998-03-10 | Nikon Corporation | Supporting device of relative moving element of vibration actuator or vibration motor |
US5585479A (en) | 1992-07-24 | 1996-12-17 | The United States Of America As Represented By The Secretary Of The Navy | Antisense oligonucleotides directed against human ELAM-I RNA |
AU678769B2 (en) | 1992-07-27 | 1997-06-12 | Hybridon, Inc. | Oligonucleotide alkylphosphonothioates |
US6107062A (en) * | 1992-07-30 | 2000-08-22 | Inpax, Inc. | Antisense viruses and antisense-ribozyme viruses |
WO1994004196A1 (en) | 1992-08-14 | 1994-03-03 | Imperial Cancer Research Technology Limited | Tumour therapy |
US5429199A (en) * | 1992-08-26 | 1995-07-04 | Kennametal Inc. | Cutting bit and cutting insert |
AU678415B2 (en) | 1992-10-05 | 1997-05-29 | Hybridon, Inc. | Therapeutic anti-HIV oligonucleotide and pharmaceutical |
US5593972A (en) * | 1993-01-26 | 1997-01-14 | The Wistar Institute | Genetic immunization |
EP0692972B2 (en) * | 1993-04-02 | 2012-03-21 | AntiCancer, Inc. | Method for delivering beneficial compositions to hair follicles |
US5567604A (en) | 1993-04-23 | 1996-10-22 | Aronex Pharmaceuticals, Inc. | Anti-viral guanosine-rich oligonucleotides |
SG54115A1 (en) * | 1993-04-27 | 1998-11-16 | Gerber Scient Products Inc | Thermal printing apparatus with improved power supply |
US5840497A (en) | 1993-06-11 | 1998-11-24 | The Commonwealth Of Australia Commonwealth Scientific And Industrial Research Organization | Method for specific silencing of genes by DNA methylation |
KR960703170A (ko) * | 1993-06-23 | 1996-06-19 | 알버트 디. 프리센. | 안티센스 올리고뉴클레오티드 및 인간면역결핍바이러스감염에서 그것의 치료적이용(antisense oligonucleotides and therapeutic use thereof in human immunodeficiency virus infection) |
WO1995003407A2 (en) | 1993-07-19 | 1995-02-02 | Gen-Probe Incorporated | Oligonucleotides with activity against human immunodeficiency virus |
US6004534A (en) | 1993-07-23 | 1999-12-21 | Massachusetts Institute Of Technology | Targeted polymerized liposomes for improved drug delivery |
US6605708B1 (en) | 1993-07-28 | 2003-08-12 | Hybridon, Inc. | Building blocks with carbamate internucleoside linkages and oligonucleotides derived therefrom |
AU705889B2 (en) | 1993-08-26 | 1999-06-03 | Regents Of The University Of California, The | Method, compositions and devices for administration of naked polynucleotides which encode antigens and immunostimulatory peptides |
US5679647A (en) | 1993-08-26 | 1997-10-21 | The Regents Of The University Of California | Methods and devices for immunizing a host against tumor-associated antigens through administration of naked polynucleotides which encode tumor-associated antigenic peptides |
US5985847A (en) | 1993-08-26 | 1999-11-16 | The Regents Of The University Of California | Devices for administration of naked polynucleotides which encode biologically active peptides |
US5849719A (en) * | 1993-08-26 | 1998-12-15 | The Regents Of The University Of California | Method for treating allergic lung disease |
US20030109469A1 (en) | 1993-08-26 | 2003-06-12 | Carson Dennis A. | Recombinant gene expression vectors and methods for use of same to enhance the immune response of a host to an antigen |
US5830877A (en) | 1993-08-26 | 1998-11-03 | The Regents Of The University Of California | Method, compositions and devices for administration of naked polynucleotides which encode antigens and immunostimulatory |
US5804566A (en) | 1993-08-26 | 1998-09-08 | The Regents Of The University Of California | Methods and devices for immunizing a host through administration of naked polynucleotides with encode allergenic peptides |
FR2711670B1 (fr) * | 1993-10-22 | 1996-01-12 | Pasteur Institut | Vecteur nucléotidique, composition le contenant et vaccin pour l'immunisation à l'encontre d'une hépatite. |
DE4338704A1 (de) * | 1993-11-12 | 1995-05-18 | Hoechst Ag | Stabilisierte Oligonucleotide und deren Verwendung |
US5595756A (en) * | 1993-12-22 | 1997-01-21 | Inex Pharmaceuticals Corporation | Liposomal compositions for enhanced retention of bioactive agents |
DE69432315T2 (de) | 1993-12-23 | 2004-02-12 | Biognostik Gesellschaft für Biomolekulare Diagnostik mbH | ANTISENSE NUKLEINSÄUREN ZUR VORBEUGUNG UND BEHANDLUNG VON BESCHWERDEN IN WELCHEN DIE EXPRIMIERUNG VON C-erbB-2 EINE ROLLE SPIELT |
US5712384A (en) | 1994-01-05 | 1998-01-27 | Gene Shears Pty Ltd. | Ribozymes targeting retroviral packaging sequence expression constructs and recombinant retroviruses containing such constructs |
US5728518A (en) * | 1994-01-12 | 1998-03-17 | The Immune Response Corporation | Antiviral poly-and oligonucleotides |
US5646126A (en) | 1994-02-28 | 1997-07-08 | Epoch Pharmaceuticals | Sterol modified oligonucleotide duplexes having anticancer activity |
EP0804249A2 (en) | 1994-03-15 | 1997-11-05 | Brown University Research Foundation | Polymeric gene delivery system |
US5596091A (en) * | 1994-03-18 | 1997-01-21 | The Regents Of The University Of California | Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides |
WO1995026204A1 (en) | 1994-03-25 | 1995-10-05 | Isis Pharmaceuticals, Inc. | Immune stimulation by phosphorothioate oligonucleotide analogs |
US6727230B1 (en) * | 1994-03-25 | 2004-04-27 | Coley Pharmaceutical Group, Inc. | Immune stimulation by phosphorothioate oligonucleotide analogs |
US5451569A (en) | 1994-04-19 | 1995-09-19 | Hong Kong University Of Science And Technology R & D Corporation Limited | Pulmonary drug delivery system |
US5696248A (en) | 1994-06-15 | 1997-12-09 | Hoechst Aktiengesellschaft | 3'-modified oligonucleotide derivatives |
US5543152A (en) | 1994-06-20 | 1996-08-06 | Inex Pharmaceuticals Corporation | Sphingosomes for enhanced drug delivery |
US5741516A (en) | 1994-06-20 | 1998-04-21 | Inex Pharmaceuticals Corporation | Sphingosomes for enhanced drug delivery |
US6429199B1 (en) * | 1994-07-15 | 2002-08-06 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules for activating dendritic cells |
US6207646B1 (en) * | 1994-07-15 | 2001-03-27 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
ES2267100T5 (es) | 1994-07-15 | 2011-04-08 | The University Of Iowa Research Foundation | Oligonucleótidos inmunomoduladores. |
US6239116B1 (en) * | 1994-07-15 | 2001-05-29 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US20030050263A1 (en) * | 1994-07-15 | 2003-03-13 | The University Of Iowa Research Foundation | Methods and products for treating HIV infection |
US7935675B1 (en) * | 1994-07-15 | 2011-05-03 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US20030026782A1 (en) * | 1995-02-07 | 2003-02-06 | Arthur M. Krieg | Immunomodulatory oligonucleotides |
JPH10502820A (ja) | 1994-07-18 | 1998-03-17 | ユニバーシティ・オブ・ノース・カロライナ・アット・チャペル・ヒル | 腫瘍増殖、浸潤および転移を阻害するためのオリゴヌクレオシド化合物および方法 |
US5646262A (en) * | 1994-07-28 | 1997-07-08 | Georgetown University | Antisense oligonucleotides against hepatitis B viral replication |
US5785992A (en) * | 1994-09-30 | 1998-07-28 | Inex Pharmaceuticals Corp. | Compositions for the introduction of polyanionic materials into cells |
US5753613A (en) * | 1994-09-30 | 1998-05-19 | Inex Pharmaceuticals Corporation | Compositions for the introduction of polyanionic materials into cells |
AU3559695A (en) * | 1994-09-30 | 1996-04-26 | Inex Pharmaceuticals Corp. | Glycosylated protein-liposome conjugates and methods for their preparation |
WO1996012008A1 (en) | 1994-10-13 | 1996-04-25 | Merck & Co., Inc. | Synthesis of methylase-resistant genes |
US6630455B1 (en) | 1995-01-13 | 2003-10-07 | Vanderbilt University | Methods for inducing mucosal immune responses |
US6008202A (en) * | 1995-01-23 | 1999-12-28 | University Of Pittsburgh | Stable lipid-comprising drug delivery complexes and methods for their production |
US5795587A (en) * | 1995-01-23 | 1998-08-18 | University Of Pittsburgh | Stable lipid-comprising drug delivery complexes and methods for their production |
DE19502912A1 (de) | 1995-01-31 | 1996-08-01 | Hoechst Ag | G-Cap Stabilisierte Oligonucleotide |
US5674483A (en) * | 1995-01-31 | 1997-10-07 | National Jewish Medical And Research Center | Treatment for diseases involving inflammation |
PL321711A1 (en) | 1995-02-09 | 1997-12-22 | Icn Pharmaceuticals | Methods of and compositions for controlling the cd28 expression |
US5932556A (en) | 1995-09-17 | 1999-08-03 | Tam; Robert C | Methods and compositions for regulation of CD28 expression |
GB9505438D0 (en) | 1995-03-17 | 1995-05-03 | Sod Conseils Rech Applic | Antisense oligonucleotides |
US5703057A (en) | 1995-04-07 | 1997-12-30 | Board Of Regents The University Of Texas System | Expression library immunization |
AU716486B2 (en) | 1995-04-13 | 2000-02-24 | Milkhaus Laboratory, Inc. | Methods for treating respiratory disease |
US6096721A (en) * | 1995-04-13 | 2000-08-01 | Milkhaus Laboratory, Inc. | Method for treating mucositis by sublingual administration of DNA |
UA56132C2 (uk) | 1995-04-25 | 2003-05-15 | Смітклайн Бічем Байолоджікалс С.А. | Композиція вакцини (варіанти), спосіб стабілізації qs21 відносно гідролізу (варіанти), спосіб приготування композиції вакцини |
US5858987A (en) * | 1995-05-05 | 1999-01-12 | Mitotix, Inc. | E6AP antisense constructs and methods of use |
RU2205874C2 (ru) | 1995-05-11 | 2003-06-10 | Апплайд Резеч Системз Арс Холдинг Н.В. | Нуклеотидная последовательность, способная ингибировать активность il-6, плазмидный вектор для трансфекции в клетки млекопитающих, нуклеотидная последовательность, используемая при терапии, фармацевтическая композиция (варианты) |
US5955059A (en) * | 1995-06-06 | 1999-09-21 | Trustees Of Boston University | Use of locally applied DNA fragments |
US6040296A (en) * | 1995-06-07 | 2000-03-21 | East Carolina University | Specific antisense oligonucleotide composition & method for treatment of disorders associated with bronchoconstriction and lung inflammation |
US5705385A (en) * | 1995-06-07 | 1998-01-06 | Inex Pharmaceuticals Corporation | Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer |
US6025339A (en) * | 1995-06-07 | 2000-02-15 | East Carolina University | Composition, kit and method for treatment of disorders associated with bronchoconstriction and lung inflammation |
US5994315A (en) | 1995-06-07 | 1999-11-30 | East Carolina University | Low adenosine agent, composition, kit and method for treatment of airway disease |
US5981501A (en) | 1995-06-07 | 1999-11-09 | Inex Pharmaceuticals Corp. | Methods for encapsulating plasmids in lipid bilayers |
US7034007B1 (en) * | 1995-06-07 | 2006-04-25 | East Carolina University | Low adenosine anti-sense oligonucleotide, compositions, kit & method for treatment of airway disorders associated with bronchoconstriction, lung inflammation, allergy(ies) & surfactant depletion |
AU723163B2 (en) | 1995-06-07 | 2000-08-17 | Tekmira Pharmaceuticals Corporation | Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer |
US5830878A (en) | 1995-06-07 | 1998-11-03 | Megabios Corporation | Cationic lipid: DNA complexes for gene targeting |
JPH11509088A (ja) | 1995-06-23 | 1999-08-17 | プレジデント アンド フェローズ オブ ハーバード カレッジ | 血管内皮増殖因子受容体をコードする遺伝子の転写調節 |
US5985662A (en) | 1995-07-13 | 1999-11-16 | Isis Pharmaceuticals Inc. | Antisense inhibition of hepatitis B virus replication |
JPH11510142A (ja) | 1995-07-21 | 1999-09-07 | ブラウン・ユニバーシティ・リサーチ・ファンデーション | 核酸負荷ポリマー微粒子を使用した遺伝子治療法 |
US6248720B1 (en) * | 1996-07-03 | 2001-06-19 | Brown University Research Foundation | Method for gene therapy using nucleic acid loaded polymeric microparticles |
US5968909A (en) | 1995-08-04 | 1999-10-19 | Hybridon, Inc. | Method of modulating gene expression with reduced immunostimulatory response |
US6667293B1 (en) * | 1995-09-12 | 2003-12-23 | Hybridon, Inc. | Use of cyclodextrins to modulate gene expression with reduced immunostimulatory response |
WO1997012633A1 (en) | 1995-10-04 | 1997-04-10 | Immunex Corporation | Dendritic cell stimulatory factor |
US5736152A (en) * | 1995-10-27 | 1998-04-07 | Atrix Laboratories, Inc. | Non-polymeric sustained release delivery system |
US5780448A (en) * | 1995-11-07 | 1998-07-14 | Ottawa Civic Hospital Loeb Research | DNA-based vaccination of fish |
JP4359654B2 (ja) | 1996-01-30 | 2009-11-04 | ザ リージェンツ オブ ザ ユニバーシティー オブ カリフォルニア | 抗原特異的免疫応答を生起させる遺伝子発現ベクターおよびその使用方法 |
US20030078223A1 (en) * | 1996-01-30 | 2003-04-24 | Eyal Raz | Compositions and methods for modulating an immune response |
SE9600648D0 (sv) * | 1996-02-21 | 1996-02-21 | Bror Morein | Receptorbimdande enhet |
US5994316A (en) | 1996-02-21 | 1999-11-30 | The Immune Response Corporation | Method of preparing polynucleotide-carrier complexes for delivery to cells |
SE9600647D0 (sv) | 1996-02-21 | 1996-02-21 | Bror Morein | Ny användning |
US5843770A (en) | 1996-03-11 | 1998-12-01 | The Immune Response Corporation | Antisense constructs directed against viral post-transcriptional regulatory sequences |
US6620805B1 (en) | 1996-03-14 | 2003-09-16 | Yale University | Delivery of nucleic acids by porphyrins |
US6030955A (en) * | 1996-03-21 | 2000-02-29 | The Trustees Of Columbia University In The City Of New York And Imclone Systems, Inc. | Methods of affecting intracellular phosphorylation of tyrosine using phosphorothioate oligonucleotides, and antiangiogenic and antiproliferative uses thereof |
US6121247A (en) | 1996-03-29 | 2000-09-19 | The Johns Hopkins University | Therapy for allergic diseases |
US6184037B1 (en) | 1996-05-17 | 2001-02-06 | Genemedicine, Inc. | Chitosan related compositions and methods for delivery of nucleic acids and oligonucleotides into a cell |
AU705647B2 (en) | 1996-07-10 | 1999-05-27 | Immunex Corporation | Method of activating dendritic cells |
EP1342477A1 (en) | 1996-07-16 | 2003-09-10 | Archibald James Mixson, M.D. | Cationic vehicle: dna complexes and their use in gene therapy |
US5854418A (en) | 1996-07-25 | 1998-12-29 | The Trustees Of Columbia University In The City Of New York | Kaposi's sarcoma-associated herpesvirus (KSHV) viral macrophage inflammatory protein-1α II (vMIP-1α II) and uses thereof |
US5856462A (en) * | 1996-09-10 | 1999-01-05 | Hybridon Incorporated | Oligonucleotides having modified CpG dinucleosides |
DE19637223A1 (de) * | 1996-09-13 | 1998-04-09 | Beiersdorf Ag | Wiederlösbare, selbstklebende Vorrichtung |
US6610661B1 (en) | 1996-10-11 | 2003-08-26 | The Regents Of The University Of California | Immunostimulatory polynucleotide/immunomodulatory molecule conjugates |
US6562345B1 (en) * | 1996-11-12 | 2003-05-13 | City Of Hope | Immuno-reactive peptide CTL epitopes of human cytomegalovirus |
US20060002959A1 (en) * | 1996-11-14 | 2006-01-05 | Government Of The United States | Skin-sctive adjuvants for transcutaneous immuization |
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 |
US20060002949A1 (en) * | 1996-11-14 | 2006-01-05 | Army Govt. Of The Usa, As Rep. By Secretary Of The Office Of The Command Judge Advocate, Hq Usamrmc. | Transcutaneous immunization without heterologous adjuvant |
SE9604296D0 (sv) | 1996-11-22 | 1996-11-22 | Astra Ab | New pharmaceutical formulation of polypeptides |
FR2757876B1 (fr) | 1996-12-27 | 1999-04-09 | Biovector Therapeutics Sa | Conjuges d'un vecteur particulaire et d'oligonucleotides, leur procede de preparation et les compositions pharmaceutiques les contenant |
IL130192A0 (en) | 1996-12-27 | 2000-06-01 | Icn Pharmaceuticals | G-rich oligo aptamers and method of modulating an immune response |
EP0855184A1 (en) | 1997-01-23 | 1998-07-29 | Grayson B. Dr. Lipford | Pharmaceutical composition comprising a polynucleotide and an antigen especially for vaccination |
US20030064945A1 (en) * | 1997-01-31 | 2003-04-03 | Saghir Akhtar | Enzymatic nucleic acid treatment of diseases or conditions related to levels of epidermal growth factor receptors |
GB9702021D0 (en) | 1997-01-31 | 1997-03-19 | Imperial College | Medicaments |
US7517952B1 (en) * | 1997-02-25 | 2009-04-14 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of prostate cancer |
AU738513B2 (en) * | 1997-02-28 | 2001-09-20 | University Of Iowa Research Foundation, The | Use of nucleic acids containing unmethylated CpG dinucleotide in the treatment of LPS-associated disorders |
US6406705B1 (en) * | 1997-03-10 | 2002-06-18 | University Of Iowa Research Foundation | Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant |
EP1005368B1 (en) * | 1997-03-10 | 2009-09-02 | Ottawa Hospital Research Institute | Use of nucleic acids containing unmethylated CpG dinucleotide in combination with alum as adjuvants |
US5965542A (en) | 1997-03-18 | 1999-10-12 | Inex Pharmaceuticals Corp. | Use of temperature to control the size of cationic liposome/plasmid DNA complexes |
US6426334B1 (en) | 1997-04-30 | 2002-07-30 | Hybridon, Inc. | Oligonucleotide mediated specific cytokine induction and reduction of tumor growth in a mammal |
US6835395B1 (en) | 1997-05-14 | 2004-12-28 | The University Of British Columbia | Composition containing small multilamellar oligodeoxynucleotide-containing lipid vesicles |
US20030104044A1 (en) * | 1997-05-14 | 2003-06-05 | Semple Sean C. | Compositions for stimulating cytokine secretion and inducing an immune response |
US6287591B1 (en) | 1997-05-14 | 2001-09-11 | Inex Pharmaceuticals Corp. | Charged therapeutic agents encapsulated in lipid particles containing four lipid components |
EP0983289A4 (en) | 1997-05-19 | 2001-04-25 | Merck & Co Inc | OLIGONUCLEOTIDE ADJUVANT |
EP1003531B1 (en) * | 1997-05-20 | 2007-08-22 | Ottawa Health Research Institute | Processes for preparing nucleic acid constructs |
US20040006034A1 (en) * | 1998-06-05 | 2004-01-08 | Eyal Raz | Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof |
ATE432348T1 (de) * | 1997-06-06 | 2009-06-15 | Univ California | Inhibitoren von immunstimulatorischen dna sequenz aktivität |
US6589940B1 (en) | 1997-06-06 | 2003-07-08 | Dynavax Technologies Corporation | Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof |
US6221882B1 (en) * | 1997-07-03 | 2001-04-24 | University Of Iowa Research Foundation | Methods for inhibiting immunostimulatory DNA associated responses |
AU8428998A (en) | 1997-07-24 | 1999-02-16 | Inex Pharmaceuticals Corporation | Preparation of lipid-nucleic acid particles using a solvent extraction and direct hydration method |
US5877309A (en) * | 1997-08-13 | 1999-03-02 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotides against JNK |
EP1007657B1 (en) | 1997-08-19 | 2006-02-08 | Idera Pharmaceuticals, Inc. | Hiv-specific oligonucleotides and methods of their use |
JP4663113B2 (ja) * | 1997-09-05 | 2011-03-30 | 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 | 抗原刺激顆粒球媒介炎症を予防または軽減するための免疫刺激オリゴヌクレオチドの使用 |
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 |
CA2312900A1 (en) * | 1997-12-02 | 1999-06-10 | Powderject Vaccines, Inc. | Transdermal delivery of particulate vaccine compositions |
AU1656799A (en) | 1997-12-12 | 1999-07-05 | Inex Pharmaceuticals Corp. | Cationic drugs encapsulated in anionic liposomes |
US7393630B2 (en) * | 1997-12-16 | 2008-07-01 | Novartis Vaccines And Diagnostics, Inc. | Use of microparticles combined with submicron oil-in-water emulsions |
WO1999033493A1 (en) | 1997-12-23 | 1999-07-08 | Inex Pharmaceuticals Corporation | Polyamide oligomers |
GB9727262D0 (en) | 1997-12-24 | 1998-02-25 | Smithkline Beecham Biolog | Vaccine |
US20050031638A1 (en) * | 1997-12-24 | 2005-02-10 | Smithkline Beecham Biologicals S.A. | Vaccine |
JPH11209289A (ja) * | 1998-01-22 | 1999-08-03 | Taisho Pharmaceut Co Ltd | 粘膜免疫誘起剤 |
ES2289200T3 (es) | 1998-02-25 | 2008-02-01 | The Government Of The United States, As Represented By The Secretary Of The Army | Uso de mejoradores para penetracion de la piel y agentes de alteracion de barrera para mejorar la respuesta inmune transcutanea. |
US6646068B2 (en) * | 1998-03-12 | 2003-11-11 | Lucite International Uk Limited | Polymer composition |
WO1999051259A2 (en) * | 1998-04-03 | 1999-10-14 | University Of Iowa Research Foundation | Methods and products for stimulating the immune system using immunotherapeutic oligonucleotides and cytokines |
HUP0101619A3 (en) | 1998-04-09 | 2003-11-28 | Smithkline Beecham Biolog | Adjuvant compositions |
ATE331739T1 (de) | 1998-04-28 | 2006-07-15 | Inex Pharmaceuticals Corp | Polyanionische polymere mit verbesserter fusogenfähigkeit |
AU3884199A (en) | 1998-05-06 | 1999-11-23 | Ottawa Health Research Institute | Methods for the prevention and treatment of parasitic infections and related diseases using cpg oligonucleotides |
NZ508650A (en) * | 1998-05-14 | 2003-05-30 | Coley Pharm Gmbh | Regulating hematopoiesis using unmethylated C and G CpG-oligonucleotides with a phosphorothioate modification |
DE69932717T2 (de) | 1998-05-22 | 2007-08-09 | Ottawa Health Research Institute, Ottawa | Methoden und produkte zur induzierung mukosaler immunität |
US6881561B1 (en) | 1998-05-27 | 2005-04-19 | Cheil Jedang Corporation | Endonuclease of immune cell, process for producing the same and immune adjuvant using the same |
US6248329B1 (en) * | 1998-06-01 | 2001-06-19 | Ramaswamy Chandrashekar | Parasitic helminth cuticlin nucleic acid molecules and uses thereof |
US6562798B1 (en) * | 1998-06-05 | 2003-05-13 | Dynavax Technologies Corp. | Immunostimulatory oligonucleotides with modified bases and methods of use thereof |
EP1089764B1 (en) | 1998-06-10 | 2004-09-01 | Biognostik Gesellschaft für biomolekulare Diagnostik mbH | Stimulating the immune system |
WO1999066947A1 (en) * | 1998-06-23 | 1999-12-29 | The Board Of Trustees Of The Leland Stanford Junior University | Adjuvant therapy |
US20030022854A1 (en) * | 1998-06-25 | 2003-01-30 | Dow Steven W. | Vaccines using nucleic acid-lipid complexes |
US20040247662A1 (en) | 1998-06-25 | 2004-12-09 | Dow Steven W. | Systemic immune activation method using nucleic acid-lipid complexes |
US6693086B1 (en) * | 1998-06-25 | 2004-02-17 | National Jewish Medical And Research Center | Systemic immune activation method using nucleic acid-lipid complexes |
CA2335393C (en) | 1998-07-20 | 2008-09-23 | Inex Pharmaceuticals Corporation | Liposomal encapsulated nucleic acid-complexes |
EP1100807A1 (en) | 1998-07-27 | 2001-05-23 | University Of Iowa Research Foundation | STEREOISOMERS OF CpG OLIGONUCLEOTIDES AND RELATED METHODS |
GB9817052D0 (en) | 1998-08-05 | 1998-09-30 | Smithkline Beecham Biolog | Vaccine |
EP0979869A1 (en) | 1998-08-07 | 2000-02-16 | Hoechst Marion Roussel Deutschland GmbH | Short oligonucleotides for the inhibition of VEGF expression |
US7049302B1 (en) * | 1998-08-10 | 2006-05-23 | Antigenics Inc. | Compositions of CPG and saponin adjuvants and uses thereof |
US20010034330A1 (en) | 1998-08-10 | 2001-10-25 | Charlotte Kensil | Innate immunity-stimulating compositions of CpG and saponin and methods thereof |
DE69943392D1 (de) * | 1998-08-20 | 2011-06-09 | Du Pont | Gene für fettsäuremodfizierende enzyme von planzen und damit verbundene bildung von konjugierten doppelbindungen |
EP1108017A2 (en) | 1998-09-03 | 2001-06-20 | Coley Pharmaceutical GmbH | G-motif oligonucleotides and uses thereof |
US20020065236A1 (en) | 1998-09-09 | 2002-05-30 | Yew Nelson S. | CpG reduced plasmids and viral vectors |
FR2783170B1 (fr) | 1998-09-11 | 2004-07-16 | Pasteur Merieux Serums Vacc | Emulsion immunostimulante |
EP1671646A3 (en) | 1998-09-18 | 2007-08-29 | Dynavax Technologies Corporation | Methods of treating IgE-associated disorders and compositions for use therein |
CA2343052A1 (en) | 1998-09-18 | 2000-03-30 | Dynavax Technologies Corporation | Methods of treating ige-associated disorders and compositions for use therein |
WO2000020039A1 (en) | 1998-10-05 | 2000-04-13 | The Regents Of The University Of California | Methods and adjuvants for stimulating mucosal immunity |
AU6425999A (en) | 1998-10-09 | 2000-05-01 | Dynavax Technologies Corporation | Anti hiv compositions comprising immunostimulatory polynucleotides and hiv antigens |
PL201482B1 (pl) | 1998-10-16 | 2009-04-30 | Smithkline Beecham Biolog | Sposoby wytwarzania kompozycji szczepionki oraz kompozycja szczepionki |
AUPP807399A0 (en) | 1999-01-08 | 1999-02-04 | Csl Limited | Improved immunogenic lhrh composition and methods relating thereto |
EP1165773A4 (en) | 1999-02-02 | 2005-01-05 | Biocache Pharmaceuticals Inc | IMPROVED PLATFORM FOR PRESENTING ANTIGENS |
US6887464B1 (en) * | 1999-02-02 | 2005-05-03 | Biocache Pharmaceuticals, Inc. | Advanced antigen presentation platform |
JP2002536344A (ja) | 1999-02-05 | 2002-10-29 | ジエンザイム コーポレイション | 抗腫瘍免疫を発生させるためのカチオン性脂質の使用 |
US6207819B1 (en) | 1999-02-12 | 2001-03-27 | Isis Pharmaceuticals, Inc. | Compounds, processes and intermediates for synthesis of mixed backbone oligomeric compounds |
WO2000054803A2 (en) * | 1999-03-16 | 2000-09-21 | Panacea Pharmaceuticals, Llc | Immunostimulatory nucleic acids and antigens |
SI1163000T1 (sl) | 1999-03-19 | 2008-06-30 | Glaxosmithkline Biolog Sa | Vakcina proti antigenom iz bakterij |
FR2790955B1 (fr) | 1999-03-19 | 2003-01-17 | Assist Publ Hopitaux De Paris | Utilisation d'oligonucleotides stabilises comme principe actif antitumoral |
US6625426B2 (en) * | 1999-03-22 | 2003-09-23 | Ronald Baratono | Combined rear view mirror and telephone |
EP1176966B1 (en) | 1999-04-12 | 2013-04-03 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Oligodeoxynucleotide and its use to induce an immune response |
US6977245B2 (en) * | 1999-04-12 | 2005-12-20 | The United States Of America As Represented By The Department Of Health And Human Services | Oligodeoxynucleotide and its use to induce an immune response |
AU4642600A (en) | 1999-04-15 | 2000-11-02 | Regents Of The University Of California, The | Methods and compositions for use in potentiating antigen presentation by antigenpresenting cells |
PL203951B1 (pl) | 1999-04-19 | 2009-11-30 | Smithkline Beecham Biolog | Kompozycja adiuwantowa, kompozycja szczepionki oraz sposób jej wytwarzania, szczepionka oraz zastosowanie |
US6558670B1 (en) * | 1999-04-19 | 2003-05-06 | Smithkline Beechman Biologicals S.A. | Vaccine adjuvants |
AU4978100A (en) | 1999-04-29 | 2000-11-17 | Coley Pharmaceutical Gmbh | Screening for immunostimulatory dna functional modifyers |
AP1891A (en) | 1999-05-06 | 2008-09-23 | The Immune Response Corp | HIV immunogenic compositions and methods. |
US6737066B1 (en) * | 1999-05-06 | 2004-05-18 | The Immune Response Corporation | HIV immunogenic compositions and methods |
AU776268B2 (en) | 1999-06-08 | 2004-09-02 | Aventis Pasteur | Immunostimulant oligonucleotide |
US6479504B1 (en) | 1999-06-16 | 2002-11-12 | The University Of Iowa Research Foundation | Antagonism of immunostimulatory CpG-oligonucleotides by 4-aminoquinolines and other weak bases |
ATE306938T1 (de) | 1999-06-29 | 2005-11-15 | Glaxosmithkline Biolog Sa | Verwendung von cpg als adjuvans für hivimpstoff |
US20050002958A1 (en) * | 1999-06-29 | 2005-01-06 | Smithkline Beecham Biologicals Sa | Vaccines |
GB9915204D0 (en) | 1999-06-29 | 1999-09-01 | Smithkline Beecham Biolog | Vaccine |
US6514948B1 (en) * | 1999-07-02 | 2003-02-04 | The Regents Of The University Of California | Method for enhancing an immune response |
FR2795963A1 (fr) * | 1999-07-08 | 2001-01-12 | Pasteur Merieux Serums Vacc | Polynucleotide immunostimulant |
DE19935756A1 (de) * | 1999-07-27 | 2001-02-08 | Mologen Forschungs Entwicklung | Kovalent geschlossenes Nukleinsäuremolekül zur Immunstimulation |
WO2001012804A2 (en) | 1999-08-13 | 2001-02-22 | Hybridon, Inc. | MODULATION OF OLIGONUCLEOTIDE CpG-MEDIATED IMMUNE STIMULATION BY POSITIONAL MODIFICATION OF NUCLEOSIDES |
EP1204425B1 (en) | 1999-08-19 | 2009-01-07 | Dynavax Technologies Corporation | Methods of modulating an immune response using immunostimulatory sequences and compositions for use therein |
US20050249794A1 (en) | 1999-08-27 | 2005-11-10 | Semple Sean C | Compositions for stimulating cytokine secretion and inducing an immune response |
US6395678B1 (en) * | 1999-09-01 | 2002-05-28 | Aero-Terra-Aqua Technologies Corporation | Bead and process for removing dissolved metal contaminants |
GB9921146D0 (en) | 1999-09-07 | 1999-11-10 | Smithkline Beecham Biolog | Novel composition |
GB9921147D0 (en) | 1999-09-07 | 1999-11-10 | Smithkline Beecham Biolog | Novel composition |
AP2006003503A0 (en) * | 1999-09-25 | 2006-02-28 | Univ Iowa Res Found | Immunostimulatory nucleic acids. |
US6949520B1 (en) | 1999-09-27 | 2005-09-27 | Coley Pharmaceutical Group, Inc. | Methods related to immunostimulatory nucleic acid-induced interferon |
EP1220684B2 (en) * | 1999-09-27 | 2010-07-14 | Coley Pharmaceutical Group, Inc. | Methods related to immunostimulatory nucleic acid-induced interferon |
US20070031446A1 (en) | 2003-07-11 | 2007-02-08 | Intercell Ag | Hcv vaccines |
JP2003512826A (ja) * | 1999-10-27 | 2003-04-08 | カイロン コーポレイション | Hcv特異的t細胞の活性化 |
US7223398B1 (en) | 1999-11-15 | 2007-05-29 | Dynavax Technologies Corporation | Immunomodulatory compositions containing an immunostimulatory sequence linked to antigen and methods of use thereof |
NZ518999A (en) | 1999-11-19 | 2002-12-20 | Csl Ltd | Vaccine compositions |
US20010031262A1 (en) * | 1999-12-06 | 2001-10-18 | Michael Caplan | Controlled delivery of antigens |
AU2593701A (en) | 1999-12-21 | 2001-07-03 | Regents Of The University Of California, The | Method for preventing an anaphylactic reaction |
AU781812B2 (en) | 2000-01-13 | 2005-06-16 | Antigenics, Inc. | Innate immunity-stimulating compositions of CPG and saponin and methods thereof |
EP1322655B1 (en) * | 2000-01-14 | 2007-11-14 | The Government of the United States of America, as represented by the Secretary of the Department of Health and Human Services | Oligodeoxynucleotide and its use to induce an immune response |
AU3108001A (en) * | 2000-01-20 | 2001-12-24 | Coley Pharmaceutical Group, Inc. | Immunostimulatory nucleic acids for inducing a th2 immune response |
US6852705B2 (en) | 2000-01-21 | 2005-02-08 | Merial | DNA vaccines for farm animals, in particular bovines and porcines |
US6815429B2 (en) | 2000-01-26 | 2004-11-09 | Hybridon, Inc. | Modulation of oligonucleotide CpG-mediated immune stimulation by positional modification of nucleosides |
AT409085B (de) | 2000-01-28 | 2002-05-27 | Cistem Biotechnologies Gmbh | Pharmazeutische zusammensetzung zur immunmodulation und herstellung von vakzinen |
MXPA02007413A (es) | 2000-01-31 | 2004-07-30 | Smithkline Beecham Biolog | Vacuna para la inmunizacion profilactica o terapeutica contra el vih. |
US6552006B2 (en) * | 2000-01-31 | 2003-04-22 | The Regents Of The University Of California | Immunomodulatory polynucleotides in treatment of an infection by an intracellular pathogen |
US7585847B2 (en) * | 2000-02-03 | 2009-09-08 | Coley Pharmaceutical Group, Inc. | Immunostimulatory nucleic acids for the treatment of asthma and allergy |
FR2805265B1 (fr) | 2000-02-18 | 2002-04-12 | Aventis Pasteur | Oligonucleotides immunostimulants |
US20030130217A1 (en) * | 2000-02-23 | 2003-07-10 | Eyal Raz | Method for treating inflammatory bowel disease and other forms of gastrointestinal inflammation |
US6613751B2 (en) * | 2000-02-23 | 2003-09-02 | The Regents Of The University Of California | Method for treating inflammatory bowel disease and other forms of gastrointestinal inflammation |
US6423539B2 (en) | 2000-02-24 | 2002-07-23 | The Board Of Trustees Of The Leland Stanford Junior University | Adjuvant treatment by in vivo activation of dendritic cells |
US20020156033A1 (en) | 2000-03-03 | 2002-10-24 | Bratzler Robert L. | Immunostimulatory nucleic acids and cancer medicament combination therapy for the treatment of cancer |
US20040131628A1 (en) * | 2000-03-08 | 2004-07-08 | Bratzler Robert L. | Nucleic acids for the treatment of disorders associated with microorganisms |
US20020107212A1 (en) | 2000-03-10 | 2002-08-08 | Nest Gary Van | Methods of reducing papillomavirus infection using immunomodulatory polynucleotide sequences |
US20030129251A1 (en) * | 2000-03-10 | 2003-07-10 | Gary Van Nest | Biodegradable immunomodulatory formulations and methods for use thereof |
US20020098199A1 (en) | 2000-03-10 | 2002-07-25 | Gary Van Nest | Methods of suppressing hepatitis virus infection using immunomodulatory polynucleotide sequences |
US6851845B2 (en) * | 2000-03-10 | 2005-02-08 | The Maitland Company, Inc. | Method and apparatus for processing waste material |
US20020028784A1 (en) * | 2000-03-10 | 2002-03-07 | Nest Gary Van | Methods of preventing and treating viral infections using immunomodulatory polynucleotide sequences |
US20010046967A1 (en) | 2000-03-10 | 2001-11-29 | Gary Van Nest | Methods of preventing and treating respiratory viral infection using immunomodulatory polynucleotide |
US7157437B2 (en) * | 2000-03-10 | 2007-01-02 | Dynavax Technologies Corporation | Methods of ameliorating symptoms of herpes infection using immunomodulatory polynucleotide sequences |
US7129222B2 (en) | 2000-03-10 | 2006-10-31 | Dynavax Technologies Corporation | Immunomodulatory formulations and methods for use thereof |
AU2001249609A1 (en) | 2000-03-28 | 2001-10-08 | Department Of Veterans Affairs | Methods for increasing a cytotoxic T lymphocyte response in vivo |
US8246945B2 (en) * | 2000-04-06 | 2012-08-21 | University Of Arkansas | Methods and reagents for decreasing clinical reaction to allergy |
AU2001251407A1 (en) | 2000-04-07 | 2001-10-23 | The Regents Of The University Of California | Synergistic improvements to polynucleotide vaccines |
US7524826B2 (en) | 2000-04-14 | 2009-04-28 | Mcmaster University And Hamilton Health Sciences Corporation | Method of inhibiting the generation of active thrombin on the surface of a cell within an atherosclerotic plaque |
US6321873B1 (en) * | 2000-04-21 | 2001-11-27 | Tra-Lor-Mate, Inc. | Ladder mounting system |
ES2238044T3 (es) | 2000-05-01 | 2005-08-16 | Hybridon, Inc. | Modulacion de la estimulacion inmunologica mediada por el oligonucleotido cpg mediante modificacion posicional de nucleosidos. |
WO2001085910A2 (en) * | 2000-05-05 | 2001-11-15 | The Regents Of The University Of California | Agents that modulate dna-pk activity and methods of use thereof |
US20020013287A1 (en) | 2000-05-09 | 2002-01-31 | Reliable Biopharmaceuticals, Inc. St Louis Missouri | Polymeric compounds useful as prodrugs |
ATE299696T1 (de) | 2000-05-12 | 2005-08-15 | Pharmacia & Upjohn Co Llc | Impfstoffzusammensetzung und verfahren zur herstellung derselben sowie verfahren zur impfung von wirbeltieren |
US6339630B1 (en) * | 2000-05-18 | 2002-01-15 | The United States Of America As Represented By The United States Department Of Energy | Sealed drive screw operator |
GB0011903D0 (en) * | 2000-05-18 | 2000-07-05 | Astrazeneca Ab | Combination chemotherapy |
AU2001275294A1 (en) * | 2000-06-07 | 2001-12-17 | Biosynexus Incorporated. | Immunostimulatory RNA/DNA hybrid molecules |
AU7013401A (en) * | 2000-06-22 | 2002-01-02 | Univ Iowa Res Found | Methods for enhancing antibody-induced cell lysis and treating cancer |
US20020165178A1 (en) * | 2000-06-28 | 2002-11-07 | Christian Schetter | Immunostimulatory nucleic acids for the treatment of anemia, thrombocytopenia, and neutropenia |
BRPI0112928B1 (pt) | 2000-07-27 | 2017-08-29 | Children's Hospital & Research Center At Oakland | A composition comprising preparations comprising outer membrane vesicles (OMV), microvesicles (MV) or both MVO and MV |
WO2002009748A1 (en) | 2000-07-31 | 2002-02-07 | Yale University | Innate immune system-directed vaccines |
US20020198165A1 (en) * | 2000-08-01 | 2002-12-26 | Bratzler Robert L. | Nucleic acids for the prevention and treatment of gastric ulcers |
CA2420840A1 (en) | 2000-09-01 | 2003-02-27 | Epigenomics Ag | Method for determining the degree of methylation of defined cytosines in genomic dna in the sequence context 5'-cpg-3' |
WO2002018631A2 (de) * | 2000-09-01 | 2002-03-07 | Epigenomics Ag | Diagnose von bestehenden erkrankungen oder der prädisposition für bestimmte erkrankungen |
US20020091097A1 (en) * | 2000-09-07 | 2002-07-11 | Bratzler Robert L. | Nucleic acids for the prevention and treatment of sexually transmitted diseases |
WO2002022809A2 (en) * | 2000-09-15 | 2002-03-21 | Coley Pharmaceutical Gmbh | PROCESS FOR HIGH THROUGHPUT SCREENING OF CpG-BASED IMMUNO-AGONIST/ANTAGONIST |
GB0023008D0 (en) | 2000-09-20 | 2000-11-01 | Glaxo Group Ltd | Improvements in vaccination |
US6787524B2 (en) * | 2000-09-22 | 2004-09-07 | Tanox, Inc. | CpG oligonucleotides and related compounds for enhancing ADCC induced by anti-IgE antibodies |
CA2423487C (en) | 2000-09-26 | 2015-12-15 | Hybridon, Inc. | Modulation of immunostimulatory activity of immunostimulatory oligonucleotide analogs by positional chemical changes |
SE0003538D0 (sv) * | 2000-09-29 | 2000-09-29 | Isconova Ab | New immunogenic complex |
US7537772B1 (en) * | 2000-10-02 | 2009-05-26 | Emergent Product Development Gaithersburg Inc. | Chlamydia protein, gene sequence and the uses thereof |
FR2814958B1 (fr) | 2000-10-06 | 2003-03-07 | Aventis Pasteur | Composition vaccinale |
GB0025577D0 (en) * | 2000-10-18 | 2000-12-06 | Smithkline Beecham Biolog | Vaccine |
KR100831139B1 (ko) * | 2000-10-18 | 2008-05-20 | 글락소스미스클라인 바이오로지칼즈 에스.에이. | 백신 |
EP1330520A2 (en) | 2000-11-02 | 2003-07-30 | Inex Pharmaceuticals Corp. | Therapeutic oligonucleotides of reduced toxicity |
EP1360486A2 (en) * | 2000-12-08 | 2003-11-12 | 3M Innovative Properties Company | Screening method for identifying compounds that selectively induce interferon alpha |
ES2307568T3 (es) * | 2000-12-08 | 2008-12-01 | Coley Pharmaceutical Gmbh | Acidos nucleicos de tipo cpg y metodos de uso de los mismos. |
US20030055014A1 (en) * | 2000-12-14 | 2003-03-20 | Bratzler Robert L. | Inhibition of angiogenesis by nucleic acids |
DE60142410D1 (de) * | 2000-12-27 | 2010-07-29 | Dynavax Tech Corp | Immunomodulatorische polynukleotide und verfahren zur deren verwendung |
US7337306B2 (en) * | 2000-12-29 | 2008-02-26 | Stmicroelectronics, Inc. | Executing conditional branch instructions in a data processor having a clustered architecture |
US20030050268A1 (en) * | 2001-03-29 | 2003-03-13 | Krieg Arthur M. | Immunostimulatory nucleic acid for treatment of non-allergic inflammatory diseases |
US7713942B2 (en) | 2001-04-04 | 2010-05-11 | Nordic Vaccine Technology A/S | Cage-like microparticle complexes comprising sterols and saponins for delivery of polynucleotides |
US7105495B2 (en) | 2001-04-30 | 2006-09-12 | Idera Pharmaceuticals, Inc. | Modulation of oligonucleotide CpG-mediated immune stimulation by positional modification of nucleosides |
US7176296B2 (en) | 2001-04-30 | 2007-02-13 | Idera Pharmaceuticals, Inc. | Modulation of oligonucleotide CpG-mediated immune stimulation by positional modification of nucleosides |
US20030129605A1 (en) | 2001-05-04 | 2003-07-10 | Dong Yu | Immunostimulatory activity of CpG oligonucleotides containing non-ionic methylphosophonate linkages |
EP1528937B1 (en) * | 2001-06-05 | 2016-08-10 | The Regents Of The University Of Michigan | Nanoemulsion vaccines |
EP1395262A4 (en) | 2001-06-15 | 2006-04-12 | Ribapharm Corp | NUCLEOSIDE-VACCINE-ADJUVANTS |
US7785610B2 (en) | 2001-06-21 | 2010-08-31 | Dynavax Technologies Corporation | Chimeric immunomodulatory compounds and methods of using the same—III |
US20040132677A1 (en) | 2001-06-21 | 2004-07-08 | Fearon Karen L. | Chimeric immunomodulatory compounds and methods of using the same-IV |
CN100334228C (zh) | 2001-06-21 | 2007-08-29 | 戴纳瓦克斯技术公司 | 嵌合免疫调制化合物及其使用方法 |
WO2003000232A2 (en) | 2001-06-25 | 2003-01-03 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Method for preparation of vesicles loaded with immunostimulator y oligodeoxynucleotides |
US20030003970A1 (en) | 2001-06-28 | 2003-01-02 | Alan Johnson | Portable communications device |
CN1931365A (zh) | 2001-06-29 | 2007-03-21 | 希龙公司 | Hcv e1e2疫苗组合物 |
US6982033B2 (en) * | 2001-07-13 | 2006-01-03 | Donald Hubbard H | Aerobic treatment plant with filter pipe |
US7666674B2 (en) | 2001-07-27 | 2010-02-23 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Use of sterically stabilized cationic liposomes to efficiently deliver CPG oligonucleotides in vivo |
WO2003040308A2 (en) | 2001-07-27 | 2003-05-15 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Use of sterically stabilized cationic liposomes to efficiently deliver cpg oligonucleotides in vivo |
WO2003012061A2 (en) * | 2001-08-01 | 2003-02-13 | Coley Pharmaceutical Gmbh | Methods and compositions relating to plasmacytoid dendritic cells |
WO2003014316A2 (en) * | 2001-08-07 | 2003-02-20 | Dynavax Technologies Corporation | Immunomodulatory compositions, formulations, and methods for use thereof |
JP2005510462A (ja) | 2001-08-10 | 2005-04-21 | ダイナバックス テクノロジーズ コーポレイション | 免疫調節オリゴヌクレオチドの生成及びその使用方法 |
US7354909B2 (en) * | 2001-08-14 | 2008-04-08 | The United States Of America As Represented By Secretary Of The Department Of Health And Human Services | Method for rapid generation of mature dendritic cells |
SI1446162T1 (sl) * | 2001-08-17 | 2009-04-30 | Coley Pharm Gmbh | Kombinacija zaporedja imunostimulatornih oligonukleotidov z izboljšano aktivnostjo |
US20030133913A1 (en) | 2001-08-30 | 2003-07-17 | 3M Innovative Properties Company | Methods of maturing plasmacytoid dendritic cells using immune response modifier molecules |
WO2003027313A2 (en) * | 2001-09-24 | 2003-04-03 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | SUPPRESSORS OF CpG OLIGONUCLEOTIDES AND METHODS OF USE |
US7514415B2 (en) * | 2002-08-01 | 2009-04-07 | The United States Of America As Represented By The Department Of Health And Human Services | Method of treating inflammatory arthropathies with suppressors of CpG oligonucleotides |
US20030119774A1 (en) | 2001-09-25 | 2003-06-26 | Marianna Foldvari | Compositions and methods for stimulating an immune response |
DE60234782D1 (de) | 2001-09-28 | 2010-01-28 | Purdue Research Foundation | Behandlungsverfahren mit liganden-immunogenkonjugaten |
CA2461315A1 (en) * | 2001-10-05 | 2003-04-17 | Coley Pharmaceutical Gmbh | Toll-like receptor 3 signaling agonists and antagonists |
CN100438908C (zh) | 2001-10-06 | 2008-12-03 | 梅瑞尔有限公司 | CpG制剂及相关方法 |
DK1455593T3 (da) | 2001-10-06 | 2013-08-26 | Merial Ltd | Fremgangsmåder og sammensætninger til fremme af vækst og medfødt immunitet hos unge dyr |
AU2002360278A1 (en) * | 2001-10-12 | 2003-11-11 | Coley Pharmaceutical Gmbh | Methods and products for enhancing immune responses using imidazoquinoline compounds |
WO2003035836A2 (en) | 2001-10-24 | 2003-05-01 | Hybridon Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5' ends |
US7276489B2 (en) * | 2002-10-24 | 2007-10-02 | Idera Pharmaceuticals, Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5′ ends |
US20030125292A1 (en) | 2001-11-07 | 2003-07-03 | Sean Semple | Mucoscal vaccine and methods for using the same |
DK1719511T3 (da) | 2001-11-16 | 2009-04-14 | Coley Pharm Group Inc | N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methansulfonamid, en farmaceutisk sammensætning omfattende samme, og anvendelse deraf |
TW200303759A (en) * | 2001-11-27 | 2003-09-16 | Schering Corp | Methods for treating cancer |
CA2469082A1 (en) * | 2001-12-04 | 2003-06-12 | Raj K. Puri | Chimeric molecule for the treatment of th2-like cytokine mediated disorders |
DE10161755B4 (de) * | 2001-12-15 | 2005-12-15 | Infineon Technologies Ag | Kontaktstift zum Testen mikroelektronischer Bauteile mit kugelförmigen Kontakten |
AU2002366710A1 (en) * | 2001-12-20 | 2003-07-09 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of | USE OF CpG OLIGODEOXYNUCLEOTIDES TO INDUCE ANGIOGENESIS |
US8466116B2 (en) * | 2001-12-20 | 2013-06-18 | The Unites States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Use of CpG oligodeoxynucleotides to induce epithelial cell growth |
WO2003055514A1 (en) | 2001-12-21 | 2003-07-10 | Antigenics Inc. | Compositions comprising immunoreactive reagents and saponins, and methods of use thereof |
CA2474709A1 (en) | 2002-02-04 | 2003-08-14 | Biomira, Inc. | Immunostimulatory, covalently lipidated oligonucleotides |
US8088388B2 (en) | 2002-02-14 | 2012-01-03 | United Biomedical, Inc. | Stabilized synthetic immunogen delivery system |
US20030232443A1 (en) | 2002-06-18 | 2003-12-18 | Isis Pharmaceuticals Inc. | Antisense modulation of centromere protein B expression |
US8153141B2 (en) * | 2002-04-04 | 2012-04-10 | Coley Pharmaceutical Gmbh | Immunostimulatory G, U-containing oligoribonucleotides |
WO2003087308A2 (en) * | 2002-04-11 | 2003-10-23 | Zymogenetics, Inc. | Use of interleukin-24 to treat ovarian cancer |
CA2483012C (en) * | 2002-04-22 | 2011-05-24 | Bioniche Life Sciences Inc. | Oligonucleotide compositions and their use for the modulation of immune responses |
US6948271B2 (en) * | 2002-05-06 | 2005-09-27 | Innovative Supply, Inc. | Identification and tracking system for deceased bodies |
BR0309814A (pt) * | 2002-05-08 | 2005-03-01 | Dana Corp | Métodos de formação de plasma |
JP2005532315A (ja) | 2002-05-10 | 2005-10-27 | イネックス ファーマシューティカルズ コーポレイション | メチル化免疫刺激性オリゴヌクレオチド及びその使用方法 |
EP1505942B1 (en) | 2002-05-10 | 2008-08-13 | Tekmira Pharmaceuticals Corporation | Pathogen vaccines and methods for using the same |
US20040009944A1 (en) | 2002-05-10 | 2004-01-15 | Inex Pharmaceuticals Corporation | Methylated immunostimulatory oligonucleotides and methods of using the same |
CA2487452A1 (en) | 2002-05-28 | 2003-12-04 | Robinson Ramirez-Pineda | A method for generating antigen-presenting cells |
CA2388049A1 (en) | 2002-05-30 | 2003-11-30 | Immunotech S.A. | Immunostimulatory oligonucleotides and uses thereof |
US20040009949A1 (en) * | 2002-06-05 | 2004-01-15 | Coley Pharmaceutical Group, Inc. | Method for treating autoimmune or inflammatory diseases with combinations of inhibitory oligonucleotides and small molecule antagonists of immunostimulatory CpG nucleic acids |
US20040013688A1 (en) * | 2002-07-03 | 2004-01-22 | Cambridge Scientific, Inc. | Vaccines to induce mucosal immunity |
US7576066B2 (en) * | 2002-07-03 | 2009-08-18 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US20040053880A1 (en) * | 2002-07-03 | 2004-03-18 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US7569553B2 (en) * | 2002-07-03 | 2009-08-04 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US7605138B2 (en) | 2002-07-03 | 2009-10-20 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
US7807803B2 (en) * | 2002-07-03 | 2010-10-05 | Coley Pharmaceutical Group, Inc. | Nucleic acid compositions for stimulating immune responses |
AU2003255969A1 (en) | 2002-07-17 | 2004-02-02 | Coley Pharmaceutical Gmbh | Use of cpg nucleic acids in prion-disease |
CN1468957A (zh) | 2002-07-19 | 2004-01-21 | 中国人民解放军第二军医大学 | 一种用作人用治疗性疫苗佐剂的质粒 |
US20050209183A1 (en) | 2002-07-25 | 2005-09-22 | Phenion Gmbh & Co. Kg | Cosmetic or pharmaceutical preparations comprising nucleic acids based on non-methylated CPG motifs |
EP1393745A1 (en) | 2002-07-29 | 2004-03-03 | Hybridon, Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5'ends |
NZ538628A (en) * | 2002-08-12 | 2008-06-30 | Dynavax Tech Corp | Immunomodulatory compositions, methods of making, and methods of use thereof |
AR040996A1 (es) * | 2002-08-19 | 2005-04-27 | Coley Pharm Group Inc | Acidos nucleicos inmunoestimuladores |
US6928476B2 (en) * | 2002-08-23 | 2005-08-09 | Mirra, Inc. | Peer to peer remote data storage and collaboration |
US6744084B2 (en) * | 2002-08-29 | 2004-06-01 | Micro Technology, Inc. | Two-transistor pixel with buried reset channel and method of formation |
US7186700B2 (en) * | 2002-09-13 | 2007-03-06 | Idenix Pharmaceuticals, Inc. | β-L-2′-deoxynucleosides for the treatment of resistant HBV strains and combination therapies |
US8263091B2 (en) * | 2002-09-18 | 2012-09-11 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Method of treating and preventing infections in immunocompromised subjects with immunostimulatory CpG oligonucleotides |
US6994870B2 (en) * | 2002-09-18 | 2006-02-07 | Jaw-Ji Tsai | Local nasal immunotherapy with allergen strip for allergic rhinitis |
AU2003278845A1 (en) | 2002-09-19 | 2004-04-08 | Coley Pharmaceutical Gmbh | Toll-like receptor 9 (tlr9) from various mammalian species |
US6988995B2 (en) * | 2002-09-30 | 2006-01-24 | Carl Zeiss Meditec, Inc. | Method and system for detecting the effects of Alzheimer's disease in the human retina |
US8043622B2 (en) * | 2002-10-08 | 2011-10-25 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Method of treating inflammatory lung disease with suppressors of CpG oligonucleotides |
MXPA05004588A (es) | 2002-10-29 | 2005-12-14 | Coley Pharmaceutical Group Ltd | Metodos y productos relacionados con el tratamiento y prevencion de infeccion de virus de hepatitis c. |
JP4976653B2 (ja) * | 2002-11-01 | 2012-07-18 | ザ ガバメント オブ ザ ユナイテッド ステイツ オブ アメリカ アズ リプレゼンティッド バイ ザ セクレタリー オブ ザ デパートメント オブ ヘルス アンド ヒューマン サービシス | 免疫刺激性CpGオリゴヌクレオチドを用いてバイオテロ病原体による感染症を予防する方法 |
WO2004041183A2 (en) | 2002-11-01 | 2004-05-21 | The Regents Of The University Of California | Methods of treating pulmonary fibrotic disorders |
AU2003300919A1 (en) * | 2002-12-11 | 2004-06-30 | Coley Pharmaceutical Gmbh | 5' cpg nucleic acids and methods of use |
KR100525321B1 (ko) | 2002-12-13 | 2005-11-02 | 안웅식 | 파필로마바이러스 항원 단백질 및CpG-올리고데옥시뉴클레오타이드를 포함하는파필로마바이러스 유발 질환의 예방 또는 치료용 약제학적조성물 |
CN100546998C (zh) | 2002-12-23 | 2009-10-07 | 戴纳伐克斯技术股份有限公司 | 免疫刺激序列寡核苷酸和使用方法 |
JP2006516099A (ja) | 2002-12-23 | 2006-06-22 | ダイナバックス テクノロジーズ コーポレイション | 分枝状の免疫調節化合物及び該化合物の使用方法 |
US7851453B2 (en) | 2003-01-16 | 2010-12-14 | Idera Pharmaceuticals, Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by utilizing modified immunostimulatory dinucleotides |
US7189781B2 (en) * | 2003-03-13 | 2007-03-13 | H.B. Fuller Licensing & Finance Inc. | Moisture curable, radiation curable sealant composition |
CN100355453C (zh) | 2003-03-24 | 2007-12-19 | 英特塞尔股份公司 | 改进的疫苗 |
CA2517839A1 (en) | 2003-03-26 | 2004-10-07 | Martin F. Bachmann | Melan-a peptide analogue-virus-like-particle conjugates |
US20040235770A1 (en) | 2003-04-02 | 2004-11-25 | Coley Pharmaceutical Group, Ltd. | Immunostimulatory nucleic acid oil-in-water formulations and related methods of use |
US20050004144A1 (en) * | 2003-04-14 | 2005-01-06 | Regents Of The University Of California | Combined use of IMPDH inhibitors with toll-like receptor agonists |
EP1631687A2 (en) | 2003-04-22 | 2006-03-08 | Coley Pharmaceutical GmbH | Methods and products for identification and assessment of tlr ligands |
JP3887346B2 (ja) * | 2003-04-28 | 2007-02-28 | 株式会社東芝 | 映像信号処理装置及び映像信号処理方法、映像表示装置 |
AU2004241093B2 (en) | 2003-05-16 | 2009-08-27 | Idera Pharmaceuticals, Inc. | Synergistic treatment of cancer using immunomers in conjunction with chemotherapeutic agents |
EP1484336A1 (en) * | 2003-06-02 | 2004-12-08 | Pevion Biotech Ltd. | Methods for synthesizing conformationally constrained peptides, peptidometics and the use thereof as synthetic vaccines |
EP2371834B1 (en) | 2003-06-11 | 2016-02-17 | Idera Pharmaceuticals, Inc. | Stabilized immunomodulatory oligonucleotides |
JPWO2004110489A1 (ja) * | 2003-06-13 | 2006-07-20 | 第一アスビオファーマ株式会社 | Th1型免疫疾患予防又は治療用医薬組成物 |
EP2356999A1 (en) * | 2003-06-17 | 2011-08-17 | Mannkind Corporation | Compositions to elicit, enhance and sustain immune responses against MHC class I-restricted epitopes, for prophylactic or therapeutic purposes |
JP2007524615A (ja) * | 2003-06-20 | 2007-08-30 | コーリー ファーマシューティカル ゲーエムベーハー | 低分子トール様レセプター(tlr)アンタゴニスト |
US20040265833A1 (en) | 2003-06-23 | 2004-12-30 | Cathy Lofton-Day | Methods and nucleic acids for the analysis of colorectal cell proliferative disorders |
KR20060031607A (ko) | 2003-07-10 | 2006-04-12 | 사이토스 바이오테크놀로지 아게 | 패킹된 바이러스-양 입자 |
US20050013812A1 (en) * | 2003-07-14 | 2005-01-20 | Dow Steven W. | Vaccines using pattern recognition receptor-ligand:lipid complexes |
AU2004259204B2 (en) | 2003-07-15 | 2010-08-19 | Idera Pharmaceuticals, Inc. | Synergistic stimulation of the immune system using immunostimulatory oligonucleotides and/or immunomer compounds in conjunction with cytokines and/or chemotherapeutic agents or radiation therapy |
CA2544240A1 (en) * | 2003-07-22 | 2005-02-17 | Cytos Biotechnology Ag | Cpg-packaged liposomes |
WO2005021726A2 (en) | 2003-08-28 | 2005-03-10 | The Immune Response Corporation | Immunogenic hiv compositions and related methods |
US7576068B2 (en) * | 2003-09-05 | 2009-08-18 | Anadys Pharmaceuticals, Inc. | Administration of TLR7 ligands and prodrugs thereof for treatment of infection by hepatitis C virus |
EP1671643A1 (en) | 2003-09-08 | 2006-06-21 | Intellectual Property Consulting Inc. | Medicinal composition for treating chronic hepatitis c |
GB0321615D0 (en) * | 2003-09-15 | 2003-10-15 | Glaxo Group Ltd | Improvements in vaccination |
WO2005027920A1 (en) * | 2003-09-19 | 2005-03-31 | Pfizer Products Inc. | 2-alkylidene-19-nor-vitamin d derivatives for the treatment of rickets or vitamin d deficiency |
CA2536139A1 (en) * | 2003-09-25 | 2005-04-07 | Coley Pharmaceutical Group, Inc. | Nucleic acid-lipophilic conjugates |
WO2005034979A2 (en) | 2003-10-11 | 2005-04-21 | Inex Pharmaceuticals Corporation | Methods and compositions for enhancing innate immunity and antibody dependent cellular cytotoxicity |
US20050087538A1 (en) * | 2003-10-23 | 2005-04-28 | Wolfe Darrell R. | Iceless multiple can cooler |
US20050215501A1 (en) | 2003-10-24 | 2005-09-29 | Coley Pharmaceutical Group, Inc. | Methods and products for enhancing epitope spreading |
CA2540949A1 (en) | 2003-10-30 | 2005-05-12 | Coley Pharmaceutical Gmbh | C-class oligonucleotide analogs with enhanced immunostimulatory potency |
US20050239733A1 (en) | 2003-10-31 | 2005-10-27 | Coley Pharmaceutical Gmbh | Sequence requirements for inhibitory oligonucleotides |
US20050100983A1 (en) * | 2003-11-06 | 2005-05-12 | Coley Pharmaceutical Gmbh | Cell-free methods for identifying compounds that affect toll-like receptor 9 (TLR9) signaling |
JP4088246B2 (ja) * | 2003-12-05 | 2008-05-21 | 富士通株式会社 | リングネットワークのマスタ設定方法及び装置 |
WO2005060377A2 (en) | 2003-12-08 | 2005-07-07 | Hybridon, Inc. | Modulation of immunostimulatory properties by small oligonucleotide-based compounds |
US9090673B2 (en) | 2003-12-12 | 2015-07-28 | City Of Hope | Synthetic conjugate of CpG DNA and T-help/CTL peptide |
US20070172315A1 (en) * | 2003-12-18 | 2007-07-26 | Barrett Robert K | Method and Apparatus for Creating Soil or Rock Subsurface Support |
EP1550458A1 (en) | 2003-12-23 | 2005-07-06 | Vectron Therapeutics AG | Synergistic liposomal adjuvants |
KR100558851B1 (ko) | 2004-01-08 | 2006-03-10 | 학교법인연세대학교 | 면역조절능력이 증가된 CpG 올리고데옥시뉴클레오티드변형체 |
AU2005213460A1 (en) * | 2004-02-06 | 2005-08-25 | Mayo Foundation For Medical Education And Research | Complexed polypeptide and adjuvant for improved vaccines |
US20050181035A1 (en) | 2004-02-17 | 2005-08-18 | Dow Steven W. | Systemic immune activation method using non CpG nucleic acids |
EP1720568A2 (en) | 2004-02-19 | 2006-11-15 | Coley Pharmaceutical Group, Inc. | Immunostimulatory viral rna oligonucleotides |
CN1918293A (zh) | 2004-02-20 | 2007-02-21 | 莫洛根股份公司 | 用于对人及高等动物进行治疗性和预防性免疫刺激的取代的非编码核酸分子 |
AU2005222909B2 (en) | 2004-03-12 | 2010-03-11 | Idera Pharmaceuticals, Inc. | Enhanced activity of HIV vaccine using a second generation immunomodulatory oligonucleotide |
EP1730281A2 (en) * | 2004-04-02 | 2006-12-13 | Coley Pharmaceutical Group, Inc. | Immunostimulatory nucleic acids for inducing il-10 responses |
US7303881B2 (en) * | 2004-04-30 | 2007-12-04 | Pds Biotechnology Corporation | Antigen delivery compositions and methods of use |
WO2005115449A1 (en) * | 2004-05-28 | 2005-12-08 | Alk-Abelló A/S | Method of treating allergy and infection by eliciting an iga antibody response |
US8399025B2 (en) * | 2004-06-04 | 2013-03-19 | Board Of Regents, The University Of Texas System | Polyamine modified particles |
AU2005326144A1 (en) | 2004-06-08 | 2006-08-03 | Coley Pharmaceutical Gmbh | Abasic oligonucleotide as carrier platform for antigen and immunostimulatory agonist and antagonist |
US7756043B1 (en) * | 2004-06-09 | 2010-07-13 | Sprint Communications Company L.P. | Method for identifying high traffic origin-destination node pairs in a packet based network |
US7427405B2 (en) | 2004-06-15 | 2008-09-23 | Idera Pharmaceuticals, Inc. | Immunostimulatory oligonucleotide multimers |
EP2901856B1 (en) | 2004-06-15 | 2017-08-09 | Idera Pharmaceuticals, Inc. | Immunostimulatory oligonucleotide multimers |
US8175282B2 (en) * | 2004-06-25 | 2012-05-08 | The Tc Group A/S | Method of evaluating perception intensity of an audio signal and a method of controlling an input audio signal on the basis of the evaluation |
US7534449B2 (en) * | 2004-07-01 | 2009-05-19 | Yale University | Targeted and high density drug loaded polymeric materials |
EP1781325A2 (en) | 2004-07-18 | 2007-05-09 | CSL Limited | Immuno stimulating complex and oligonucleotide formulations for inducing enhanced interferon-gamma responses |
CA2574090A1 (en) * | 2004-07-18 | 2006-12-21 | Coley Pharmaceutical Group, Ltd. | Methods and compositions for inducing innate immune responses |
WO2006015560A1 (de) | 2004-08-09 | 2006-02-16 | Mologen Ag | Immunmodulierendes mittel in verbindung mit chemotherapeutischen massnahmen |
US20060058261A1 (en) * | 2004-09-15 | 2006-03-16 | Andre Aube | Chitin derivatives for hyperlipidemia |
MY159370A (en) * | 2004-10-20 | 2016-12-30 | Coley Pharm Group Inc | Semi-soft-class immunostimulatory oligonucleotides |
KR100721928B1 (ko) * | 2004-11-05 | 2007-05-28 | 주식회사 바이오씨에스 | CpG 올리고데옥시뉴클레오티드를 함유하는 피부질환의치료 또는 예방용 약학적 조성물 |
US20060105979A1 (en) | 2004-11-08 | 2006-05-18 | Hybridon, Inc. | Synergistic inhibition of VEGF and modulation of the immune response |
US20060171968A1 (en) | 2005-01-07 | 2006-08-03 | Alk-Abello A/S | Method of preventive treatment of allergy by oromucosal administration of an allergy vaccine |
WO2007042554A2 (en) * | 2005-10-12 | 2007-04-19 | Cancer Research Technology Ltd. | Methods and compositions for treating immune disorders |
CN101160401A (zh) * | 2005-02-24 | 2008-04-09 | 科勒制药集团公司 | 免疫刺激寡核苷酸 |
EP1874325A2 (en) | 2005-04-08 | 2008-01-09 | Coley Pharmaceutical Group, Inc. | Methods for treating infectious disease exacerbated asthma |
US20060241076A1 (en) | 2005-04-26 | 2006-10-26 | Coley Pharmaceutical Gmbh | Modified oligoribonucleotide analogs with enhanced immunostimulatory activity |
US7325152B2 (en) * | 2005-06-30 | 2008-01-29 | Infineon Technologies Ag | Synchronous signal generator |
NZ565311A (en) * | 2005-07-07 | 2009-10-30 | Pfizer | Anti-ctla-4 antibody and cpg-motif-containing synthetic oligodeoxynucleotide combination therapy for cancer treatment |
CA2620582C (en) * | 2005-08-31 | 2015-11-10 | Dennis M. Klinman | Methods of altering an immune response induced by cpg oligodeoxynucleotides |
EA013375B1 (ru) | 2005-09-16 | 2010-04-30 | Коли Фармасьютикал Гмбх | МОДУЛЯЦИЯ ИММУНОСТИМУЛИРУЮЩИХ СВОЙСТВ КОРОТКОЙ ИНТЕРФЕРИРУЮЩЕЙ РИБОНУКЛЕИНОВОЙ КИСЛОТЫ (siРНК) С ПОМОЩЬЮ МОДИФИКАЦИИ НУКЛЕОТИДОВ |
WO2007088423A2 (en) | 2005-09-16 | 2007-08-09 | Coley Pharmaceutical Gmbh | Immunostimulatory single-stranded ribonucleic acid with phosphodiester backbone |
BRPI0616770A2 (pt) | 2005-09-27 | 2011-06-28 | Coley Pharm Gmbh | modulação de respostas imunes mediadas por tlr empregando oligonucleotìdeos adaptadores |
US20070093439A1 (en) | 2005-10-25 | 2007-04-26 | Idera Pharmaceuticals, Inc. | Short immunomodulatory oligonucleotides |
US20070243209A1 (en) * | 2005-10-28 | 2007-10-18 | Health Research, Inc. | Compositions and methods for prevention and treatment of fungal diseases |
AU2006306805A1 (en) * | 2005-10-28 | 2007-05-03 | Index Pharmaceuticals Ab | Composition and method for the prevention, treatment and/or alleviation of an inflammatory disease |
CA2628328A1 (en) | 2005-11-04 | 2007-05-10 | Novartis Vaccines And Diagnostics S.R.L. | Influenza vaccines including combinations of particulate adjuvants and immunopotentiators |
CA2628424A1 (en) | 2005-11-04 | 2007-05-10 | Novartis Vaccines And Diagnostics S.R.L. | Adjuvanted influenza vaccines including cytokine-inducing agents |
US7776834B2 (en) | 2005-11-07 | 2010-08-17 | Idera Pharmaceuticals, Inc. | Immunostimulatory properties of oligonucleotide-based compounds comprising modified immunostimulatory dinucleotides |
EP2371956A3 (en) | 2005-11-07 | 2012-01-04 | Idera Pharmaceuticals | Immunostimulatory properties of oligonucleotide-based compounds comprising modified immunostimulatory dinucleotides |
US7470674B2 (en) | 2005-11-07 | 2008-12-30 | Idera Pharmaceuticals, Inc. | Immunostimulatory properties of oligonucleotide-based compounds comprising modified immunostimulatory dinucleotides |
CA2630118A1 (en) | 2005-11-07 | 2007-05-18 | Sudhir Agrawal | Immunostimulatory properties of oligonucleotide-based compounds comprising modified immunostimulatory dinucleotides |
DK1957647T3 (en) * | 2005-11-25 | 2015-04-07 | Zoetis Belgium S A | Immunostimulatory oligoribonucleotides |
JP2009521218A (ja) | 2005-12-20 | 2009-06-04 | イデラ ファーマシューティカルズ インコーポレイテッド | 異なる長さのパリンドロームセグメントを含むパリンドローム免疫調節オリゴヌクレオチド(imo(tm))の免疫賦活作用 |
EP2405002B1 (en) * | 2006-02-15 | 2014-09-24 | AdiuTide Pharmaceuticals GmbH | Compositions and methods for oligonucleotide formulations |
DE102006007433A1 (de) | 2006-02-17 | 2007-08-23 | Curevac Gmbh | Adjuvanz in Form einer Lipid-modifizierten Nukleinsäure |
WO2008019018A2 (en) * | 2006-08-03 | 2008-02-14 | William Soo Hoo | Bioactive molecular matrix and methods of use in the treatment of disease |
US20080124366A1 (en) * | 2006-08-06 | 2008-05-29 | Ohlfest John R | Methods and Compositions for Treating Tumors |
EP2056880A4 (en) * | 2006-08-16 | 2010-10-13 | Protiva Biotherapeutics Inc | NUCLEIC ACID MODULATION OF IMMUNE STIMULATION FACILITATED BY A RECIPTOR SIMILAR TO THE TOLL RECEIVER |
US8027888B2 (en) | 2006-08-31 | 2011-09-27 | Experian Interactive Innovation Center, Llc | Online credit card prescreen systems and methods |
WO2008033432A2 (en) | 2006-09-12 | 2008-03-20 | Coley Pharmaceutical Group, Inc. | Immune modulation by chemically modified ribonucleosides and oligoribonucleotides |
US20090181078A1 (en) * | 2006-09-26 | 2009-07-16 | Infectious Disease Research Institute | Vaccine composition containing synthetic adjuvant |
EP2486938B1 (en) * | 2006-09-26 | 2018-05-09 | Infectious Disease Research Institute | Vaccine composition containing synthetic adjuvant |
MX2009003398A (es) | 2006-09-27 | 2009-08-12 | Coley Pharm Gmbh | Analogos de oligonucleotidos cpg que contienen analogos t hidrofobos con actividad inmunoestimuladora mejorada. |
MX2009003403A (es) | 2006-09-27 | 2009-04-09 | Coley Pharm Group Inc | Composiciones de ligandos de tlr y antivirales. |
RU2009115687A (ru) * | 2006-10-26 | 2010-11-10 | Коли Фармасьютикал Гмбх (De) | Олигорибонуклеотиды и их применения |
US20090142362A1 (en) * | 2006-11-06 | 2009-06-04 | Avant Immunotherapeutics, Inc. | Peptide-based vaccine compositions to endogenous cholesteryl ester transfer protein (CETP) |
AU2007329375A1 (en) * | 2006-12-04 | 2008-06-12 | The Board Of Trustees Of The University Of Illinois | Compositions and methods to treat cancer with cupredoxins and CpG rich DNA |
US8057804B2 (en) * | 2006-12-28 | 2011-11-15 | The Trustees Of The University Of Pennsylvania | Herpes simplex virus combined subunit vaccines and methods of use thereof |
JP6144448B2 (ja) * | 2006-12-28 | 2017-06-07 | ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア | 単純ヘルペスウイルス複合サブユニットワクチンおよびその使用方法 |
PE20090146A1 (es) * | 2007-04-20 | 2009-03-23 | Glaxosmithkline Biolog Sa | Composicion inmunogenica contra el virus influenza |
US20100285041A1 (en) | 2007-05-17 | 2010-11-11 | Eugen Uhlmann | Class A Oligonucleotides with Immunostimulatory Potency |
WO2009022215A1 (en) * | 2007-08-13 | 2009-02-19 | Pfizer Inc. | Combination motif immune stimulatory oligonucleotides with improved activity |
KR20100075843A (ko) * | 2007-08-21 | 2010-07-05 | 다이나박스 테크놀로지 코퍼레이션 | 인플루엔자 단백질 조성물 및 그 제조 및 사용 방법 |
WO2009027105A2 (en) * | 2007-08-31 | 2009-03-05 | Neurimmune Therapeutics Ag | Method of providing patient specific immune response in amyloidoses and protein aggregation disorders |
US7892567B2 (en) * | 2007-10-01 | 2011-02-22 | Board Of Regents, The University Of Texas System | Methods and compositions for immunization against chlamydial infection and disease |
KR20100068422A (ko) | 2007-10-09 | 2010-06-23 | 콜리 파마슈티칼 게엠베하 | 변경된 당 잔기를 함유하는 면역자극성 올리고뉴클레오티드 유사체 |
TW200932274A (en) * | 2007-12-18 | 2009-08-01 | Alcon Res Ltd | Interfering RNA delivery system and uses thereof |
US7720322B2 (en) * | 2008-06-30 | 2010-05-18 | Intuitive Surgical, Inc. | Fiber optic shape sensor |
TWI351288B (en) * | 2008-07-04 | 2011-11-01 | Univ Nat Pingtung Sci & Tech | Cpg dna adjuvant in avian vaccines |
US20100166782A1 (en) * | 2008-07-25 | 2010-07-01 | Martha Karen Newell | Clip inhibitors and methods of modulating immune function |
US8053422B2 (en) * | 2008-12-04 | 2011-11-08 | The United States Of America As Represented By The Department Of Health And Human Services | Anti-cancer oligodeoxynucleotides |
-
1996
- 1996-10-30 US US08/738,652 patent/US6207646B1/en not_active Expired - Lifetime
-
1997
- 1997-10-30 ES ES97947311T patent/ES2268736T3/es not_active Expired - Lifetime
- 1997-10-30 WO PCT/US1997/019791 patent/WO1998018810A1/en active IP Right Grant
- 1997-10-30 CN CNA2007101300520A patent/CN101265285A/zh active Pending
- 1997-10-30 AU AU52424/98A patent/AU5242498A/en not_active Abandoned
- 1997-10-30 DK DK97947311T patent/DK0948510T3/da active
- 1997-10-30 KR KR1019997003873A patent/KR100689942B1/ko not_active IP Right Cessation
- 1997-10-30 ES ES10186177.1T patent/ES2624859T3/es not_active Expired - Lifetime
- 1997-10-30 NZ NZ335397A patent/NZ335397A/xx not_active IP Right Cessation
- 1997-10-30 EP EP06115792A patent/EP1714969A3/en not_active Withdrawn
- 1997-10-30 PT PT97947311T patent/PT948510E/pt unknown
- 1997-10-30 CN CNB971993521A patent/CN100338086C/zh not_active Expired - Lifetime
- 1997-10-30 AT AT97947311T patent/ATE332966T1/de active
- 1997-10-30 CA CA2270345A patent/CA2270345C/en not_active Expired - Lifetime
- 1997-10-30 EP EP06115801A patent/EP1746159A3/en not_active Withdrawn
- 1997-10-30 JP JP52078498A patent/JP2001503267A/ja active Pending
- 1997-10-30 DE DE69736331T patent/DE69736331T2/de not_active Revoked
- 1997-10-30 EP EP10186177.1A patent/EP2360252B8/en not_active Expired - Lifetime
- 1997-10-30 EP EP97947311A patent/EP0948510B1/en not_active Revoked
- 1997-10-30 EP EP10186108A patent/EP2322615A1/en not_active Withdrawn
-
2001
- 2001-03-27 US US09/818,918 patent/US20030050261A1/en not_active Abandoned
- 2001-12-14 AU AU97249/01A patent/AU775185B2/en not_active Expired
-
2003
- 2003-03-03 JP JP2003056446A patent/JP2003286174A/ja not_active Withdrawn
- 2003-05-09 US US10/435,656 patent/US20050277604A1/en not_active Abandoned
- 2003-07-03 US US10/613,916 patent/US20050070491A1/en not_active Abandoned
- 2003-09-10 JP JP2003319045A patent/JP2004041224A/ja not_active Withdrawn
- 2003-10-03 US US10/679,710 patent/US20040147468A1/en not_active Abandoned
- 2003-12-22 US US10/743,625 patent/US20040132685A1/en not_active Abandoned
-
2004
- 2004-01-30 US US10/769,282 patent/US7674777B2/en not_active Expired - Fee Related
- 2004-04-02 US US10/817,165 patent/US20040198688A1/en not_active Abandoned
- 2004-04-23 US US10/831,647 patent/US7402572B2/en not_active Expired - Fee Related
- 2004-05-17 US US10/847,642 patent/US20050004061A1/en not_active Abandoned
- 2004-06-24 US US10/877,407 patent/US20040229835A1/en not_active Abandoned
- 2004-07-02 US US10/884,852 patent/US20050059625A1/en not_active Abandoned
- 2004-07-09 US US10/888,785 patent/US7517861B2/en not_active Expired - Fee Related
- 2004-07-09 US US10/888,449 patent/US20050049215A1/en not_active Abandoned
- 2004-07-16 US US10/894,862 patent/US8058249B2/en not_active Expired - Fee Related
- 2004-07-16 US US10/894,657 patent/US20050054602A1/en not_active Abandoned
- 2004-08-26 US US10/928,762 patent/US20050123523A1/en not_active Abandoned
- 2004-10-01 US US10/956,745 patent/US20050239732A1/en not_active Abandoned
- 2004-10-01 US US10/956,494 patent/US7879810B2/en not_active Expired - Fee Related
- 2004-10-13 AU AU2004218696A patent/AU2004218696B2/en not_active Expired
- 2004-10-22 US US10/972,301 patent/US20050215500A1/en not_active Abandoned
- 2004-11-12 US US10/987,146 patent/US20050148537A1/en not_active Abandoned
-
2005
- 2005-01-07 US US11/031,460 patent/US8158592B2/en not_active Expired - Fee Related
- 2005-01-14 US US11/036,527 patent/US7723022B2/en not_active Expired - Fee Related
- 2005-02-25 US US11/067,587 patent/US8129351B2/en not_active Expired - Fee Related
- 2005-05-23 US US11/134,918 patent/US20050267064A1/en not_active Abandoned
- 2005-12-07 US US11/296,572 patent/US20060089326A1/en not_active Abandoned
-
2006
- 2006-08-11 US US11/503,483 patent/US7723500B2/en not_active Expired - Fee Related
- 2006-09-22 US US11/526,197 patent/US20070078104A1/en not_active Abandoned
- 2006-11-10 US US11/598,207 patent/US8258106B2/en not_active Expired - Fee Related
-
2007
- 2007-06-05 US US11/810,353 patent/US20080026011A1/en not_active Abandoned
-
2008
- 2008-07-25 JP JP2008192729A patent/JP5082063B2/ja not_active Expired - Lifetime
- 2008-10-09 US US12/248,493 patent/US20090202575A1/en not_active Abandoned
-
2009
- 2009-03-25 US US12/383,824 patent/US7888327B2/en not_active Expired - Fee Related
-
2010
- 2010-03-10 JP JP2010053784A patent/JP2010150280A/ja active Pending
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100438908C (zh) * | 2001-10-06 | 2008-12-03 | 梅瑞尔有限公司 | CpG制剂及相关方法 |
CN100546657C (zh) * | 2002-11-21 | 2009-10-07 | 贝希尔治疗学股份有限公司 | 预防和治疗疾病的方法及免疫调节核酸组合物 |
CN100439386C (zh) * | 2003-03-05 | 2008-12-03 | 长春华普生物技术有限公司 | 增强蛋白类疫苗免疫效果的含CpG单链脱氧寡核苷酸 |
CN1307196C (zh) * | 2004-01-08 | 2007-03-28 | 延世大学校 | 具有改善的免疫调节功能的经修饰的CpG寡聚脱氧核苷酸 |
CN1296378C (zh) * | 2004-05-17 | 2007-01-24 | 中国人民解放军第三军医大学 | 高免疫活性 CpG-S ODN 和拮抗 CpG-S ODN 作用的 CpG-N ODN 的基因序列及其应用 |
WO2007012285A1 (fr) * | 2005-07-28 | 2007-02-01 | Changchun Huapu Biotechnology Co., Ltd. | Desoxynucleosides monocatenaires resistant aux infections virales |
CN102864152B (zh) * | 2005-11-07 | 2015-11-18 | 艾德拉药物股份有限公司 | 包含经修饰的免疫刺激性二核苷酸的基于寡核苷酸的化合物之免疫刺激特性 |
CN101932707B (zh) * | 2008-01-31 | 2013-08-21 | 库瑞瓦格有限责任公司 | 作为免疫刺激剂/佐剂的式(I)(NuGlXmGnNv)a的核酸及其衍生物 |
CN103550783A (zh) * | 2013-04-27 | 2014-02-05 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 一种核酸类药物靶向递送系统及其制备方法 |
CN105530957A (zh) * | 2013-07-19 | 2016-04-27 | 财团法人国家卫生研究院 | CpG寡脱氧核苷酸、包含其的免疫组合物及制备组合物并通过其刺激免疫反应的方法 |
CN112263675A (zh) * | 2013-07-19 | 2021-01-26 | 财团法人卫生研究院 | CpG寡脱氧核苷酸、包含其的免疫组合物及制备组合物并通过其刺激免疫反应的方法 |
CN105530957B (zh) * | 2013-07-19 | 2022-03-29 | 台湾卫生研究院 | CpG寡脱氧核苷酸、包含其的免疫组合物及组合物用于制备治疗以刺激免疫反应的药物的应用 |
CN112263675B (zh) * | 2013-07-19 | 2024-02-27 | 财团法人卫生研究院 | CpG寡脱氧核苷酸、包含其的免疫组合物及制备组合物并通过其刺激免疫反应的方法 |
CN112107693A (zh) * | 2013-12-03 | 2020-12-22 | 西北大学 | 脂质体颗粒、制备所述脂质体颗粒的方法以及其用途 |
CN112107693B (zh) * | 2013-12-03 | 2023-05-26 | 西北大学 | 脂质体颗粒、制备所述脂质体颗粒的方法以及其用途 |
CN110004150A (zh) * | 2018-08-01 | 2019-07-12 | 中国农业科学院兰州兽医研究所 | 一种具有免疫增强活性的CpG寡聚核苷酸序列及其应用 |
CN110004150B (zh) * | 2018-08-01 | 2023-03-10 | 中国农业科学院兰州兽医研究所 | 一种具有免疫增强活性的CpG寡聚核苷酸序列及其应用 |
CN110646557A (zh) * | 2019-10-12 | 2020-01-03 | 北京航空航天大学 | 携带idh基因突变的胶质母细胞瘤患者的尿液代谢标志物及其用途 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100338086C (zh) | 免疫刺激性核酸分子 | |
US7713529B2 (en) | Methods for treating and preventing infectious disease | |
US7524828B2 (en) | Immunostimulatory nucleic acid molecules |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C41 | Transfer of patent application or patent right or utility model | ||
TR01 | Transfer of patent right |
Effective date of registration: 20090220 Address after: The United States Iowa Co-patentee after: The United States of America, Represented by the Secretary, Department of Health Patentee after: University of Iowa Research Foundation Address before: The United States Iowa Patentee before: The Univ. of Iowa Research Foundation |
|
CX01 | Expiry of patent term | ||
CX01 | Expiry of patent term |
Granted publication date: 20070919 |