JP7227654B2 - 固形癌及び微生物感染を治療するための方法及び組成物 - Google Patents
固形癌及び微生物感染を治療するための方法及び組成物 Download PDFInfo
- Publication number
- JP7227654B2 JP7227654B2 JP2021507574A JP2021507574A JP7227654B2 JP 7227654 B2 JP7227654 B2 JP 7227654B2 JP 2021507574 A JP2021507574 A JP 2021507574A JP 2021507574 A JP2021507574 A JP 2021507574A JP 7227654 B2 JP7227654 B2 JP 7227654B2
- Authority
- JP
- Japan
- Prior art keywords
- hsv
- socs4
- mice
- virus
- cells
- 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.)
- Active
Links
- 206010028980 Neoplasm Diseases 0.000 title claims description 41
- 238000000034 method Methods 0.000 title description 48
- 208000015181 infectious disease Diseases 0.000 title description 33
- 239000000203 mixture Substances 0.000 title description 16
- 230000000813 microbial effect Effects 0.000 title description 8
- 241000700588 Human alphaherpesvirus 1 Species 0.000 claims description 63
- 102000004127 Cytokines Human genes 0.000 claims description 60
- 108090000695 Cytokines Proteins 0.000 claims description 60
- 239000012634 fragment Substances 0.000 claims description 47
- 108091033319 polynucleotide Proteins 0.000 claims description 27
- 102000040430 polynucleotide Human genes 0.000 claims description 27
- 239000002157 polynucleotide Substances 0.000 claims description 27
- 230000011664 signaling Effects 0.000 claims description 19
- 201000011510 cancer Diseases 0.000 claims description 18
- 239000003112 inhibitor Substances 0.000 claims description 17
- 230000000174 oncolytic effect Effects 0.000 claims description 10
- 206010005003 Bladder cancer Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 5
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 4
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 201000004101 esophageal cancer Diseases 0.000 claims description 4
- 239000002955 immunomodulating agent Substances 0.000 claims description 3
- 230000003308 immunostimulating effect Effects 0.000 claims description 3
- 101000652220 Homo sapiens Suppressor of cytokine signaling 4 Proteins 0.000 claims 4
- 101000652226 Homo sapiens Suppressor of cytokine signaling 6 Proteins 0.000 claims 3
- 102100030524 Suppressor of cytokine signaling 4 Human genes 0.000 claims 3
- 102000044264 human SOCS4 Human genes 0.000 claims 1
- 241000699670 Mus sp. Species 0.000 description 154
- 210000004027 cell Anatomy 0.000 description 106
- 241000700605 Viruses Species 0.000 description 78
- 108090000623 proteins and genes Proteins 0.000 description 56
- 244000309459 oncolytic virus Species 0.000 description 54
- 210000004072 lung Anatomy 0.000 description 32
- 239000013598 vector Substances 0.000 description 29
- 230000000694 effects Effects 0.000 description 27
- 210000002966 serum Anatomy 0.000 description 24
- 241000700584 Simplexvirus Species 0.000 description 21
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 20
- 102000000018 Chemokine CCL2 Human genes 0.000 description 20
- 102000004889 Interleukin-6 Human genes 0.000 description 20
- 108090001005 Interleukin-6 Proteins 0.000 description 20
- 102000004169 proteins and genes Human genes 0.000 description 20
- 230000010076 replication Effects 0.000 description 20
- 239000013603 viral vector Substances 0.000 description 20
- 150000007523 nucleic acids Chemical class 0.000 description 19
- 230000003612 virological effect Effects 0.000 description 19
- 241000282414 Homo sapiens Species 0.000 description 18
- 102100037850 Interferon gamma Human genes 0.000 description 18
- 108010074328 Interferon-gamma Proteins 0.000 description 18
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 18
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 18
- 238000004519 manufacturing process Methods 0.000 description 18
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 17
- 206010052015 cytokine release syndrome Diseases 0.000 description 16
- 238000011282 treatment Methods 0.000 description 15
- 206010050685 Cytokine storm Diseases 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 108020004414 DNA Proteins 0.000 description 13
- 102000039446 nucleic acids Human genes 0.000 description 13
- 108020004707 nucleic acids Proteins 0.000 description 13
- 101001018097 Homo sapiens L-selectin Proteins 0.000 description 12
- 102100033467 L-selectin Human genes 0.000 description 12
- 201000010099 disease Diseases 0.000 description 12
- 230000016396 cytokine production Effects 0.000 description 11
- 238000006467 substitution reaction Methods 0.000 description 11
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 10
- 102100022338 Integrin alpha-M Human genes 0.000 description 10
- 125000003275 alpha amino acid group Chemical group 0.000 description 10
- 230000037430 deletion Effects 0.000 description 10
- 238000012217 deletion Methods 0.000 description 10
- 210000002540 macrophage Anatomy 0.000 description 10
- 210000004881 tumor cell Anatomy 0.000 description 10
- 206010020565 Hyperaemia Diseases 0.000 description 9
- -1 IL-1β Proteins 0.000 description 9
- 238000000684 flow cytometry Methods 0.000 description 9
- 230000014509 gene expression Effects 0.000 description 9
- 238000003780 insertion Methods 0.000 description 9
- 230000037431 insertion Effects 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000002560 therapeutic procedure Methods 0.000 description 9
- 210000002865 immune cell Anatomy 0.000 description 8
- 238000012261 overproduction Methods 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 241000701161 unidentified adenovirus Species 0.000 description 8
- 241000288906 Primates Species 0.000 description 7
- 210000001744 T-lymphocyte Anatomy 0.000 description 7
- 210000000822 natural killer cell Anatomy 0.000 description 7
- 229920001184 polypeptide Polymers 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 230000000451 tissue damage Effects 0.000 description 7
- 231100000827 tissue damage Toxicity 0.000 description 7
- 241001430294 unidentified retrovirus Species 0.000 description 7
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 6
- 101100508081 Human herpesvirus 1 (strain 17) ICP34.5 gene Proteins 0.000 description 6
- 241000713666 Lentivirus Species 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 108091028043 Nucleic acid sequence Proteins 0.000 description 6
- 101150027249 RL1 gene Proteins 0.000 description 6
- 101150098386 SOCS4 gene Proteins 0.000 description 6
- 208000036142 Viral infection Diseases 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- 230000008595 infiltration Effects 0.000 description 6
- 238000001764 infiltration Methods 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 210000003501 vero cell Anatomy 0.000 description 6
- 230000009385 viral infection Effects 0.000 description 6
- 241000713704 Bovine immunodeficiency virus Species 0.000 description 5
- 241000700626 Cowpox virus Species 0.000 description 5
- 241000702421 Dependoparvovirus Species 0.000 description 5
- 241000713730 Equine infectious anemia virus Species 0.000 description 5
- 241000713800 Feline immunodeficiency virus Species 0.000 description 5
- 208000004852 Lung Injury Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 206010069363 Traumatic lung injury Diseases 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 230000004071 biological effect Effects 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 230000028709 inflammatory response Effects 0.000 description 5
- 231100000515 lung injury Toxicity 0.000 description 5
- 231100000915 pathological change Toxicity 0.000 description 5
- 230000036285 pathological change Effects 0.000 description 5
- 210000000952 spleen Anatomy 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- 230000004580 weight loss Effects 0.000 description 5
- 241000713756 Caprine arthritis encephalitis virus Species 0.000 description 4
- 238000012286 ELISA Assay Methods 0.000 description 4
- 241000209094 Oryza Species 0.000 description 4
- 235000007164 Oryza sativa Nutrition 0.000 description 4
- 102000006601 Thymidine Kinase Human genes 0.000 description 4
- 108020004440 Thymidine kinase Proteins 0.000 description 4
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 4
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 230000019189 interleukin-1 beta production Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 238000010827 pathological analysis Methods 0.000 description 4
- 235000009566 rice Nutrition 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 4
- 238000013518 transcription Methods 0.000 description 4
- 230000035897 transcription Effects 0.000 description 4
- 230000029812 viral genome replication Effects 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 208000035143 Bacterial infection Diseases 0.000 description 3
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010017533 Fungal infection Diseases 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 208000031888 Mycoses Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 206010039491 Sarcoma Diseases 0.000 description 3
- 241000713311 Simian immunodeficiency virus Species 0.000 description 3
- 241000713325 Visna/maedi virus Species 0.000 description 3
- 208000009956 adenocarcinoma Diseases 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 208000022362 bacterial infectious disease Diseases 0.000 description 3
- 238000012790 confirmation Methods 0.000 description 3
- 239000002612 dispersion medium Substances 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 206010022000 influenza Diseases 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 208000024191 minimally invasive lung adenocarcinoma Diseases 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 210000001616 monocyte Anatomy 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 210000004988 splenocyte Anatomy 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000002103 transcriptional effect Effects 0.000 description 3
- 241000701447 unidentified baculovirus Species 0.000 description 3
- 101150043982 44 gene Proteins 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 239000013607 AAV vector Substances 0.000 description 2
- 241000714175 Abelson murine leukemia virus Species 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 102000019034 Chemokines Human genes 0.000 description 2
- 108010012236 Chemokines Proteins 0.000 description 2
- 101150082208 DIABLO gene Proteins 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 2
- 241000714475 Fujinami sarcoma virus Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 208000009889 Herpes Simplex Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000617830 Homo sapiens Sterol O-acyltransferase 1 Proteins 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 241000713869 Moloney murine leukemia virus Species 0.000 description 2
- 241000713862 Moloney murine sarcoma virus Species 0.000 description 2
- 241000714177 Murine leukemia virus Species 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 102000000505 Ribonucleotide Reductases Human genes 0.000 description 2
- 108010041388 Ribonucleotide Reductases Proteins 0.000 description 2
- 241000714474 Rous sarcoma virus Species 0.000 description 2
- 102100021993 Sterol O-acyltransferase 1 Human genes 0.000 description 2
- 101000697584 Streptomyces lavendulae Streptothricin acetyltransferase Proteins 0.000 description 2
- 108700019146 Transgenes Proteins 0.000 description 2
- 101150054371 UL24 gene Proteins 0.000 description 2
- 101150015312 UL56 gene Proteins 0.000 description 2
- 239000003070 absorption delaying agent Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 206010069351 acute lung injury Diseases 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229960005091 chloramphenicol 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
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 208000035850 clinical syndrome Diseases 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000000120 cytopathologic effect Effects 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000001476 gene delivery Methods 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000017306 interleukin-6 production Effects 0.000 description 2
- 230000002601 intratumoral effect Effects 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 230000002101 lytic effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 210000004882 non-tumor cell Anatomy 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 150000008298 phosphoramidates Chemical group 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000013615 primer Substances 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 210000003456 pulmonary alveoli Anatomy 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 230000006798 recombination Effects 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- 230000003362 replicative effect Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000003118 sandwich ELISA Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 239000002356 single layer Substances 0.000 description 2
- 210000004989 spleen cell Anatomy 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- 208000037816 tissue injury Diseases 0.000 description 2
- 101150046896 trm1 gene Proteins 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 230000006433 tumor necrosis factor production Effects 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 description 1
- 241000702423 Adeno-associated virus - 2 Species 0.000 description 1
- 241001634120 Adeno-associated virus - 5 Species 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 241000711404 Avian avulavirus 1 Species 0.000 description 1
- 238000011725 BALB/c mouse Methods 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 102000001765 Bcl-2-Like Protein 11 Human genes 0.000 description 1
- 108010040168 Bcl-2-Like Protein 11 Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010006417 Bronchial carcinoma Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 102000004039 Caspase-9 Human genes 0.000 description 1
- 108090000566 Caspase-9 Proteins 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 102000000311 Cytosine Deaminase Human genes 0.000 description 1
- 108010080611 Cytosine Deaminase Proteins 0.000 description 1
- 239000003155 DNA primer Substances 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 102100033189 Diablo IAP-binding mitochondrial protein Human genes 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 108091029865 Exogenous DNA Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 208000000666 Fowlpox Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101100310579 Homo sapiens SOCS4 gene Proteins 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- 101150027427 ICP4 gene Proteins 0.000 description 1
- 241000712431 Influenza A virus Species 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 241000713895 Murine osteosarcoma virus Species 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000005890 Neuroma Diseases 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 208000008601 Polycythemia Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- 108010039491 Ricin Proteins 0.000 description 1
- 108050003452 SH2 domains Proteins 0.000 description 1
- 102000014400 SH2 domains Human genes 0.000 description 1
- 108050008939 SOCS box domains Proteins 0.000 description 1
- 102000000369 SOCS box domains Human genes 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 208000000389 T-cell leukemia Diseases 0.000 description 1
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 1
- 101150003725 TK gene Proteins 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 241000030538 Thecla Species 0.000 description 1
- 108091061763 Triple-stranded DNA Proteins 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 101150066971 UL49 gene Proteins 0.000 description 1
- 102000006943 Uracil-DNA Glycosidase Human genes 0.000 description 1
- 108010072685 Uracil-DNA Glycosidase Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 241000711975 Vesicular stomatitis virus Species 0.000 description 1
- 208000014070 Vestibular schwannoma Diseases 0.000 description 1
- 108700005077 Viral Genes Proteins 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 108010084455 Zeocin Proteins 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
- 238000010521 absorption reaction Methods 0.000 description 1
- 208000004064 acoustic neuroma Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 210000005006 adaptive immune system Anatomy 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 210000001552 airway epithelial cell Anatomy 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000007321 biological mechanism Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229940023860 canarypox virus HIV vaccine Drugs 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 210000000234 capsid Anatomy 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 201000003740 cowpox Diseases 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 208000037828 epithelial carcinoma Diseases 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 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 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000003630 growth substance Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 230000007236 host immunity Effects 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000000544 hyperemic effect Effects 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 229940091204 imlygic Drugs 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000005931 immune cell recruitment Effects 0.000 description 1
- 230000008076 immune mechanism Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001524 infective effect Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 210000005007 innate immune system Anatomy 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000516 lung damage Toxicity 0.000 description 1
- 208000037829 lymphangioendotheliosarcoma Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 210000003071 memory t lymphocyte Anatomy 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000023185 monocyte chemotactic protein-1 production Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 208000025189 neoplasm of testis Diseases 0.000 description 1
- 244000309711 non-enveloped viruses Species 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- 201000004123 pineal gland cancer Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 230000036515 potency Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 101150040247 rl gene Proteins 0.000 description 1
- 201000008407 sebaceous adenocarcinoma Diseases 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 230000003393 splenic effect Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000013595 supernatant sample Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 210000002437 synoviocyte Anatomy 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 230000002463 transducing effect Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
- A61K35/763—Herpes virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- 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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/16011—Herpesviridae
- C12N2710/16611—Simplexvirus, e.g. human herpesvirus 1, 2
- C12N2710/16632—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
-
- 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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/16011—Herpesviridae
- C12N2710/16611—Simplexvirus, e.g. human herpesvirus 1, 2
- C12N2710/16641—Use of virus, viral particle or viral elements as a vector
- C12N2710/16643—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Virology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Microbiology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Mycology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biotechnology (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
[項1]
サイトカインシグナル伝達阻害因子4(SOCS4)又はその機能的断片をコードする外因性ポリヌクレオチド断片を含む組換えウイルスであって、
一旦細胞内で複製されると、SOCS4又は前記機能的断片を発現する組換えウイルス。
[項2]
前記ウイルスは腫瘍溶解性ウイルス又はウイルスベクターである、上記項1に記載の組換えウイルス。
[項3]
前記腫瘍溶解性ウイルスは腫瘍溶解性1型単純ヘルペスウイルス(oHSV-1)である、上記項2に記載の組換えウイルス。
[項4]
前記外因性ポリヌクレオチド断片は、oHSV-1のUL3とUL4遺伝子の間に位置する、上記項3に記載の組換えウイルス。
[項5]
前記ウイルスベクターは、レトロウイルス、アデノウイルス、アデノ随伴ウイルス、単純ヘルペスウイルス、牛痘ウイルス、又はバキュロウイルスに由来する、上記項2に記載の組換えウイルス。
[項6]
前記細胞は癌細胞である、上記項1に記載の組換えウイルス。
[項7]
前記癌細胞は、食道癌細胞、肺癌細胞、前立腺癌細胞、又は膀胱癌細胞である、上記項6に記載の組換えウイルス。
[項8]
前記SOCS4は、GenBank登録番号がNC_000014.9であるホモサピエンス由来であるか、又はホモサピエンスと少なくとも80%の同一性を有する配列由来である、上記項1~7のいずれか1項に記載の組換えウイルス。
[項9]
免疫刺激剤及び/又は免疫治療剤をコードする追加の外因性ポリヌクレオチド断片を含む、上記項1~8のいずれか1項に記載の組換えウイルス。
[項10]
上記項1~9のいずれか1項に記載の組換えウイルスと、薬学的に許容される担体とを含む医薬組成物。
[項11]
治療有効量の組換え腫瘍溶解性ウイルスを対象に投与することを含む、対象において癌を治療する方法であって、
前記組換え腫瘍溶解性ウイルスは、サイトカインシグナル伝達阻害因子4(SOCS4)又はその機能的断片をコードする外因性ポリヌクレオチド断片を含み、一旦癌細胞内で複製されると、SOCS4又は前記機能的断片を発現する方法。
[項12]
前記腫瘍溶解性ウイルスは腫瘍溶解性1型単純ヘルペスウイルス(oHSV-1)である、上記項11に記載の方法。
[項13]
前記癌細胞は、食道癌細胞、肺癌細胞、前立腺癌細胞、又は膀胱癌細胞である、上記項11又は12に記載の方法。
[項14]
SOCS4は、GenBank登録番号がNC_000014.9であるホモサピエンス由来であるか、又はホモサピエンスと少なくとも80%の同一性を有する配列由来である、上記項11~13のいずれか1項に記載の方法。
[項15]
前記組換え腫瘍溶解性ウイルスは、免疫刺激剤及び/又は免疫治療剤をコードする追加の外因性ポリヌクレオチド断片を含む、上記項11~14のいずれか1項に記載の方法。
[項16]
治療有効量の組換え腫瘍溶解性ウイルスを対象に投与することを含む、対象において腫瘍溶解性ウイルス療法の副作用を低減又は解消する方法であって、
前記組換え腫瘍溶解性ウイルスは、サイトカインシグナル伝達阻害因子4(SOCS4)又はその機能的断片をコードする外因性ポリヌクレオチド断片を含み、一旦癌細胞内で複製されると、SOCS4又は前記機能的断片を発現する方法。
[項17]
前記組換え腫瘍溶解性ウイルスは、腫瘍溶解性1型単純ヘルペスウイルス(oHSV-1)である、上記項16に記載の方法。
[項18]
前記癌細胞は、食道癌細胞、肺癌細胞、前立腺癌細胞、又は膀胱癌細胞である、上記項16又は17に記載の方法。
[項19]
SOCS4は、GenBank登録番号がNC_000014.9であるホモサピエンス由来であるか、又はホモサピエンスと少なくとも80%の同一性を有する配列由来である、上記項16~18のいずれか1項に記載の方法。
[項20]
前記副作用は、サイトカインの過剰産生である、上記項16~19のいずれか1項に記載の方法。
[項21]
前記副作用は肺組織損傷である、上記項16~20のいずれか1項に記載の方法。
[項22]
治療有効量の組換えウイルスを対象に投与することを含む、対象において微生物感染治療の副作用を低減又は解消する方法であって、
前記組換えウイルスは、サイトカインシグナル伝達阻害因子4(SOCS4)又はその機能的断片をコードする外因性ポリヌクレオチド断片を含み、一旦細胞内で複製されると、SOCS4又は前記機能的断片を発現する方法。
[項23]
前記組換えウイルスはウイルスベクターである、上記項22に記載の方法。
[項24]
前記ウイルスベクターは、レトロウイルス、アデノウイルス、アデノ随伴ウイルス、単純ヘルペスウイルス、牛痘ウイルス、又はバキュロウイルスに由来する、上記項22又は23に記載の方法。
[項25]
SOCS4は、GenBank登録番号がNC_000014.9であるホモサピエンス由来であるか、又はホモサピエンスと少なくとも80%の同一性を有する配列由来である、上記項22~24のいずれか1項に記載の方法。
[項26]
前記微生物感染は、ウイルス感染、細菌感染、又は真菌感染である、上記項22~25のいずれか1項に記載の方法。
[項27]
前記副作用は、サイトカインの過剰産生である、上記項22~26のいずれか1項に記載の方法。
[項28]
前記副作用は肺組織損傷である、上記項22~27のいずれか1項に記載の方法。
本発明の他の態様は、以下の本発明の詳細な説明から容易に把握できる。
なお、用語「一」又は「1つ」の実体は、その実体のうちの1つ又は複数を意味し、たとえば、「癌細胞」は、1つ又は複数の癌細胞を表すものとして理解される。したがって、用語「1つ」(又は「一」)、「1つ又は複数」、及び「少なくとも1つ」は、本明細書において交換的に使用され得る。
本分野においては、多くの腫瘍溶解性ウイルスが知られ、記載されており、これらのいずれかが本発明に使用されることが考えられる。たとえば、適切な腫瘍溶解性ウイルスは、1型単純ヘルペスウイルス、2型単純ヘルペスウイルス、水疱性口炎ウイルス、腫瘍溶解性アデノウイルス、ニューカッスル病ウイルス、牛痘ウイルス、及びこれらのウイルスの突然変異株を含む。一実施形態では、腫瘍溶解性ウイルスは、複製選択的であるか、又は複製能を有する。一実施形態では、腫瘍溶解性ウイルスは複製能を有しない。
本発明の一実施形態では、組換えウイルスはSOCS4をコードするポリヌクレオチドを担持する組換えウイルスベクターである。ウイルスベクターはベクター、ベクターウイルス粒子又はベクター粒子と呼ぶこともできる。別の実施形態では、ウイルスベクターは、レトロウイルス、アデノウイルス、アデノ随伴ウイルス、単純ヘルペスウイルス、牛痘ウイルス、又はバキュロウイルスから誘導される。本発明に使用される「ウイルスベクター」という用語は、ウイルスから誘導された、ベクターであって、ポリヌクレオチド(たとえば、SOCS4又はそのバリアントをコードする)を正常細胞に送達し、該細胞内で該ポリヌクレオチドを発現させるためのベクターを指す。
本明細書に記載の腫瘍溶解性ウイルス又はウイルスベクターは、SOCS4又はその生物学的に活性な断片をコードする核酸配列を含み、該核酸配列は、ウイルスゲノム中に発現可能な形態で組み込まれる。したがって、このウイルスは、SOCS4を感染細胞に送達するためのベクターとして使用される。本発明は、様々な形態のSOCS4(たとえば、本明細書に記載の形態のSOCS4)の使用を期待しており、様々な形態のSOCS4は、SOCS4の機能的ドメイン又は治療的SOCS4ドメイン又は治療的SOCS4バリアント、ならびにそれらの断片、バリアント及び誘導体、これらの形態のSOCS4(本明細書に記載のもの)の1つを含む融合タンパク質を含むが、これらに限定されない。
SOCS4核酸を含む組換え腫瘍溶解性ウイルス又はウイルスベクターは、本明細書では第2の異種核酸配列、第3の異種核酸配列などと称される追加の異種核酸配列(たとえば、発現可能な形態で)をさらに含むことができる。あるいは、組換え腫瘍溶解性ウイルス又はウイルスベクターは、追加の異種核酸配列を含まなくてもよい。
本発明の別の態様は、治療有効量の組換えウイルス及び薬学的に許容される担体を含む医薬組成物を提供する。この医薬組成物は、対象において腫瘍を治療する、又は腫瘍溶解性腫瘍療法又は抗ウイルス治療の副作用を解消又は低減するためのものである。組換えウイルスは、適切な薬学的に許容される担体又は賦形剤中で製造することができる。これらの製剤は、通常の保存及び使用の条件下で、微生物の成長を防止するために防腐剤を含むことができる。注射用途に適した薬物形態は、無菌水溶液又は分散液と、無菌注射液又は分散液を一時的に製造するための無菌粉末とを含む。いずれの場合も、この形態は無菌でなければならず、注射を容易にするために流体でなければならない。生産及び保存の条件下で安定していなければならず、微生物(たとえば、細菌や真菌)による汚染から保護されていなければならない。
本発明の別の態様は、対象において増殖性障害を治療する方法に関する。この方法は、本明細書に記載のSOCS4核酸配列を含む組換え腫瘍溶解性ウイルスを対象に投与することによって、望ましくない増殖を示す細胞を有効量の組換え腫瘍溶解性ウイルスと接触させることを含む。
本発明の別の態様は、対象において腫瘍溶解性ウイルス療法の副作用を低減又は解消するための方法に関し、この方法は、治療有効量の組換え腫瘍溶解性ウイルスを該対象に投与することを含み、該組換え腫瘍溶解性ウイルスは、サイトカインシグナル伝達阻害因子4(SOCS4)又はその機能的断片をコードする外因性ポリヌクレオチド断片を含み、一旦癌細胞内で複製されると、SOCS4又はその機能的断片を発現する。
材料及び方法
動物:6週齢の雌Balb/cマウスは広東省実験動物センターから購入し、微生物病原体なしで、広州医科大学動物センターで飼育した。マウスに関するすべての手順は、広州医科大学動物保護及び使用委員会により承認されている。
HSV-SOCS4組換えウイルスの構築
SOCS4遺伝子挿入断片を用いて新しいHSV-1株を再構築し、HSV-SOCS4と命名し、SOCS4タンパク質の発現を証明することに成功し、HSV-SOCS4を鼻内感染マウスに用いて、サイトカインストームに対するHSV-SOCS4の作用を評価した。HSV-SOCS4ウイルスを再構築するために、SOCS4遺伝子をBACに挿入した。SOCS4遺伝子のPCR産物とシークエンシング同定のいずれによっても、この組換え体が確認された。図2Aは、pReveiver-M02からのSOCS4(1397bp)のPCR産物を示し、図2Bに示すように、最後のPCRは、UL2(1492bp)、UL3(1319bp)、及びSOCS4(1397bp)の断片を含むことを確認した。
肺に灌流されたサイトカインは血流に入ることができるので、局所的な反応と全身的な反応との間の直接的な交流を提供でき、そのため、感染後1日目、3日目、及び7日目にBALFと血清サンプルを収集し、サイトカインストームの核心にあるいくつかのサイトカインを検出した。
BALFと血清中のサイトカインのレベルの違いが免疫細胞の数に関係しているか否かを調べるために、BALFから細胞を収集し、感染したマウスから脾臓を収集してフローサイトメトリー解析を行った。1日目と7日目にサイトカイン産量の差が明らかになったので、1日目と7日目から細胞を収集して比較した。マクロファージ、好中球、及びNK細胞を含むCD11b陽性細胞がBALFに存在する主要な細胞集団を構成していることを考慮し、HSV-1(F)に感染したマウスとHSV-SOCS4に感染したマウスとの間のCD11b+細胞数の変化を解析するようにした。その結果から明らかなように、HSV-1(F)マウスからのCD11b+細胞はHSV-SOCS4マウスからのCD11b+細胞よりも優れており、2群では、7日目よりも1日目に染色された陽性細胞が多かった(図5)。脾臓からのCD4+細胞とCD8+細胞の両方を染色し、CD62Lを活性化マーカーとして使用した。図6に示すように、2群のマウスでは、1日目に二重陽性細胞はほとんどなかったが、7日目に有意に増加したCD8+及びCD62L+細胞が検出され、HSV-1(F)マウスとHSV-SOCS4マウスとの間で陽性細胞数の差が有意であった。CD4+及びCD62L+細胞にも同様のパターンが観察された(図6)。
サイトカインとウイルス複製/除去との相関性を評価するために、感染マウス肺からのウイルス力価を定量化した。1日目には、最大ウイルス力価が観察されたが、その後大幅に低下し、7日目には、ウイルスが検出されず、さらに、3日目には、HSV-1(F)マウスとHSV-SOCS4マウスとの間でウイルス除去率に有意差が見られた(図7A)。BALFを収集していないマウスの肺を組織病理学的に解析し、典型的な200倍写真を図7Bに示す。1日目には、HSV-SOCS4マウスでは、肺の病理学的変化はほとんどなかった。しかし、HSV-1(F)マウスの肺部には有意な細胞浸潤を示し、局所毛細血管の軽微な拡張と充血を伴っていた。7日目には、HSV-SOCS4に感染したマウスの肺にはいくつかの免疫細胞の浸潤、及び毛細血管の軽度から中等度の拡張と充血が観察されたが、肺胞壁の構造は破裂しなかった。HSV-1(F)マウスの肺部には、重篤な病理学的変化が見られ、つまり、肺胞壁は厚くなって破裂し、周囲は厳重に充血し、免疫細胞が満たされている。
鼻内経路で感染した後、体重と発症死亡率(onset of mortality)を確認するために、すべてのマウスを1日に2回、12日間検出した。HSV-1(F)に感染したマウスは、2日目から体重が徐々に減少し始め、7日目にはその減少が急激になり、最後に生存したマウスは10日目に50%体重が減少し(図8A)、それと同様に、生存率の百分率は7日目から減少し始め(図8B)、その後、マウスは急速に死亡したが、11日目には、HSV-1(F)群のマウスは生存しなかった。HSV-SOCS4群マウスはわずかに体重が減少し、一般的に12日目に80%の体重を維持した。HSV-SOCS4マウスの生存率は100%に維持されており、HSV-1(F)感染群の生存率とは有意に異なっていた。模擬マウスは体重減少も死亡もなかった。
Claims (7)
- サイトカインシグナル伝達阻害因子4(SOCS4)をコードする外因性ポリヌクレオチド断片を含む組換え腫瘍溶解性1型単純ヘルペスウイルス(oHSV-1)であって、
一旦癌細胞内で複製されると、SOCS4を発現する組換えoHSV-1。 - 前記外因性ポリヌクレオチド断片は、oHSV-1のUL3とUL4遺伝子の間に位置する、請求項1に記載の組換えoHSV-1。
- 前記癌細胞は、食道癌細胞、肺癌細胞、前立腺癌細胞、又は膀胱癌細胞である、請求項1に記載の組換えoHSV-1。
- 前記SOCS4は、ヒトSOCS4である、請求項1に記載の組換えoHSV-1。
- 免疫刺激剤及び/又は免疫治療剤をコードする追加の外因性ポリヌクレオチド断片を含む、請求項1に記載の組換えoHSV-1。
- 請求項1に記載の組換えoHSV-1と、薬学的に許容される担体とを含む医薬組成物。
- 癌の治療用である、請求項6に記載の医薬組成物。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2018/096152 WO2020034051A1 (en) | 2018-08-16 | 2018-08-16 | Methods and compositions for treatment of solid cancers and microbial infection |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2021533768A JP2021533768A (ja) | 2021-12-09 |
JP7227654B2 true JP7227654B2 (ja) | 2023-02-22 |
Family
ID=69524575
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021507574A Active JP7227654B2 (ja) | 2018-08-16 | 2018-08-16 | 固形癌及び微生物感染を治療するための方法及び組成物 |
Country Status (5)
Country | Link |
---|---|
US (1) | US20210268049A1 (ja) |
EP (1) | EP3837355A4 (ja) |
JP (1) | JP7227654B2 (ja) |
CN (1) | CN112639084A (ja) |
WO (1) | WO2020034051A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117373547B (zh) * | 2023-12-08 | 2024-02-27 | 四川省医学科学院·四川省人民医院 | 一种可视化癌症基因关系显示方法和系统 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005103237A1 (ja) | 2004-03-31 | 2005-11-03 | Tomoki Todo | 組換え単純ヘルペスウイルスの作製方法 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2373502A (en) * | 2000-11-08 | 2002-09-25 | Smithkline Beecham Corp | Suppressor of cytokine signalling 4 (SOCS4) |
US8507445B2 (en) * | 2001-09-07 | 2013-08-13 | Board Of Regents, The University Of Texas System | Compositions and methods of use of targeting peptides for diagnosis and therapy of human cancer |
EP2573185A3 (en) * | 2005-02-16 | 2013-06-05 | Lentigen Corporation | Lentiviral vectors and their use |
CN101160055A (zh) * | 2005-02-16 | 2008-04-09 | 莱蒂恩公司 | 慢病毒载体及其用途 |
GB201002409D0 (en) * | 2010-02-12 | 2010-03-31 | Univ Nottingham | Methods |
WO2011113048A2 (en) * | 2010-03-12 | 2011-09-15 | Vanderbilt University | Modulation of cytokine signaling |
US10821140B2 (en) * | 2016-04-22 | 2020-11-03 | Immvira Co., Limited | Construction of oncolytic herpes simplex viruses (oHSV) obligate vector and constructs for cancer therapy |
CN107164338A (zh) * | 2017-06-27 | 2017-09-15 | 镇江市卫克生物科技有限公司 | 一种重组溶瘤病毒及其应用 |
-
2018
- 2018-08-16 CN CN201880096445.0A patent/CN112639084A/zh active Pending
- 2018-08-16 EP EP18930448.8A patent/EP3837355A4/en active Pending
- 2018-08-16 US US17/268,908 patent/US20210268049A1/en active Pending
- 2018-08-16 WO PCT/CN2018/096152 patent/WO2020034051A1/en unknown
- 2018-08-16 JP JP2021507574A patent/JP7227654B2/ja active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005103237A1 (ja) | 2004-03-31 | 2005-11-03 | Tomoki Todo | 組換え単純ヘルペスウイルスの作製方法 |
Non-Patent Citations (2)
Title |
---|
Exp. Ther. Med.,2018年04月,Vol. 15,p. 3523-3529 |
PLoS Pathog.,2014年,Volume 10, Issue 5, e1004134,p. 1-13 |
Also Published As
Publication number | Publication date |
---|---|
EP3837355A4 (en) | 2022-07-06 |
WO2020034051A1 (en) | 2020-02-20 |
JP2021533768A (ja) | 2021-12-09 |
US20210268049A1 (en) | 2021-09-02 |
CN112639084A (zh) | 2021-04-09 |
EP3837355A1 (en) | 2021-06-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4910077B2 (ja) | 腫瘍の療法のためのlcmv−gpシュードタイプ化vsvベクターおよび腫瘍浸潤性ウイルス産生細胞 | |
RU2703438C2 (ru) | Расширенная адоптивная клеточная терапия | |
JP7159304B2 (ja) | 腫瘍および/または癌の処置のための医薬のための単離された組換え体腫瘍溶解性アデノウイルス、医薬組成物、およびそれらの使用 | |
KR102409147B1 (ko) | 종양분해성 백시니아 바이러스 | |
RU2711371C2 (ru) | Аденовирус, содержащий альбумин-связывающий участок | |
CN110499297B (zh) | 一种新型溶瘤病毒及其制备方法和应用 | |
JP4024830B2 (ja) | Hhv−7由来の組換ウイルスベクター、その製造方法、それを用いた宿主細胞の形質転換方法、それにより形質転換された宿主細胞およびそれを用いた遺伝子治療方法 | |
JP2019504635A (ja) | Vcnエンハンサー組成物およびその使用方法 | |
JPH06508039A (ja) | 抗腫瘍治療のためのサイトカインを発現する組換え型欠損アデノウイルス | |
CN112584849A (zh) | 包含核酸及car修饰的免疫细胞的治疗剂及其应用 | |
JP2021519747A (ja) | 腫瘍を治療するための仮性狂犬病ウイルス | |
US20140286905A1 (en) | Recombinant adenovirus comprising trans-splicing ribozyme and cancer-treating gene, and use thereof | |
US10265357B2 (en) | Compositions, methods and uses for treating solid tumors using LCMV-GP-VSV pseudotype vectors | |
JP7227654B2 (ja) | 固形癌及び微生物感染を治療するための方法及び組成物 | |
WO1998046778A1 (en) | Transgenomic viruses and the use thereof | |
KR20220125806A (ko) | 재조합 백시니아 바이러스 | |
JP2022552870A (ja) | 改変型アデノウイルスヘキソンタンパク質を有するアデノウイルス | |
US20240165175A1 (en) | Muc16 promoter containing virus | |
JP2024515290A (ja) | 癌治療用アデノウイルス | |
JP2016160249A (ja) | 腫瘍溶解改変アデノウイルス、疾患治療用改変ウイルス及びこれらを含むウイルス製剤 | |
CA3156880A1 (en) | Replication-enhanced oncolytic adenoviruses | |
TW202102677A (zh) | 經修飾腺病毒及含有其之醫藥 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210226 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210226 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220308 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220527 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220913 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221209 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20230110 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20230203 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7227654 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |