WO2020185293A1 - Synthetic oncolytic lnp-replicon rna and uses for cancer immunotherapy - Google Patents
Synthetic oncolytic lnp-replicon rna and uses for cancer immunotherapy Download PDFInfo
- Publication number
- WO2020185293A1 WO2020185293A1 PCT/US2020/013069 US2020013069W WO2020185293A1 WO 2020185293 A1 WO2020185293 A1 WO 2020185293A1 US 2020013069 W US2020013069 W US 2020013069W WO 2020185293 A1 WO2020185293 A1 WO 2020185293A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- vims
- replicon rna
- synthetic oncolytic
- synthetic
- self
- Prior art date
Links
- 230000000174 oncolytic effect Effects 0.000 title claims description 55
- 238000002619 cancer immunotherapy Methods 0.000 title description 5
- 150000002632 lipids Chemical class 0.000 claims abstract description 71
- 239000002105 nanoparticle Substances 0.000 claims abstract description 55
- 244000309459 oncolytic virus Species 0.000 claims abstract description 33
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 134
- 206010028980 Neoplasm Diseases 0.000 claims description 105
- 102000013462 Interleukin-12 Human genes 0.000 claims description 72
- 108010065805 Interleukin-12 Proteins 0.000 claims description 72
- 238000002347 injection Methods 0.000 claims description 38
- 239000007924 injection Substances 0.000 claims description 38
- 239000008194 pharmaceutical composition Substances 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 33
- -1 cationic lipid Chemical class 0.000 claims description 31
- 230000037449 immunogenic cell death Effects 0.000 claims description 30
- 201000011510 cancer Diseases 0.000 claims description 25
- 108091027544 Subgenomic mRNA Proteins 0.000 claims description 16
- 108091026890 Coding region Proteins 0.000 claims description 14
- 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 claims description 14
- 230000002601 intratumoral effect Effects 0.000 claims description 12
- 102000011681 Lumican Human genes 0.000 claims description 11
- 108010076371 Lumican Proteins 0.000 claims description 11
- 230000035772 mutation Effects 0.000 claims description 9
- 235000012000 cholesterol Nutrition 0.000 claims description 7
- 201000001441 melanoma Diseases 0.000 claims description 7
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 102000009027 Albumins Human genes 0.000 claims description 5
- 108010088751 Albumins Proteins 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000003729 nucleotide group Chemical group 0.000 claims description 5
- 102000015696 Interleukins Human genes 0.000 claims description 4
- 108010063738 Interleukins Proteins 0.000 claims description 4
- 239000002773 nucleotide Substances 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 208000000832 Equine Encephalomyelitis Diseases 0.000 claims description 3
- 208000005176 Hepatitis C Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 230000008975 immunomodulatory function Effects 0.000 claims description 2
- 238000010255 intramuscular injection Methods 0.000 claims description 2
- 239000007927 intramuscular injection Substances 0.000 claims description 2
- 238000010253 intravenous injection Methods 0.000 claims description 2
- 238000010254 subcutaneous injection Methods 0.000 claims description 2
- 239000007929 subcutaneous injection Substances 0.000 claims description 2
- KIOSQLHXJYTPDN-UHFFFAOYSA-N 1-N,3-N,5-N-tris[3-(didodecylamino)propyl]benzene-1,3,5-tricarboxamide Chemical compound C(CCCCCCCCCCC)N(CCCNC(=O)C1=CC(=CC(=C1)C(=O)NCCCN(CCCCCCCCCCCC)CCCCCCCCCCCC)C(=O)NCCCN(CCCCCCCCCCCC)CCCCCCCCCCCC)CCCCCCCCCCCC KIOSQLHXJYTPDN-UHFFFAOYSA-N 0.000 claims 1
- 230000002519 immonomodulatory effect Effects 0.000 abstract description 9
- 210000004027 cell Anatomy 0.000 description 62
- 239000000203 mixture Substances 0.000 description 55
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 54
- 108090000623 proteins and genes Proteins 0.000 description 43
- 201000010099 disease Diseases 0.000 description 35
- 102000004169 proteins and genes Human genes 0.000 description 29
- 235000018102 proteins Nutrition 0.000 description 26
- 230000014509 gene expression Effects 0.000 description 22
- 241000700605 Viruses Species 0.000 description 20
- 208000035475 disorder Diseases 0.000 description 19
- 238000011282 treatment Methods 0.000 description 19
- 102000004127 Cytokines Human genes 0.000 description 17
- 108090000695 Cytokines Proteins 0.000 description 16
- 210000004881 tumor cell Anatomy 0.000 description 16
- 238000009472 formulation Methods 0.000 description 14
- 101000941029 Homo sapiens Endoplasmic reticulum junction formation protein lunapark Proteins 0.000 description 13
- 102100030991 Nucleolar and spindle-associated protein 1 Human genes 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 238000000338 in vitro Methods 0.000 description 13
- KSXTUUUQYQYKCR-LQDDAWAPSA-M 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KSXTUUUQYQYKCR-LQDDAWAPSA-M 0.000 description 12
- 101710172711 Structural protein Proteins 0.000 description 12
- 208000002687 Venezuelan Equine Encephalomyelitis Diseases 0.000 description 12
- 210000002865 immune cell Anatomy 0.000 description 12
- 230000001225 therapeutic effect Effects 0.000 description 12
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 11
- 206010014611 Encephalitis venezuelan equine Diseases 0.000 description 11
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 11
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 11
- 210000001744 T-lymphocyte Anatomy 0.000 description 11
- 201000009145 Venezuelan equine encephalitis Diseases 0.000 description 11
- 238000001727 in vivo Methods 0.000 description 11
- 238000001890 transfection Methods 0.000 description 11
- 101000831496 Homo sapiens Toll-like receptor 3 Proteins 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 10
- 102100024324 Toll-like receptor 3 Human genes 0.000 description 10
- 230000028993 immune response Effects 0.000 description 10
- 230000001965 increasing effect Effects 0.000 description 10
- 230000011664 signaling Effects 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- 238000002560 therapeutic procedure Methods 0.000 description 10
- 101001032341 Homo sapiens Interferon regulatory factor 9 Proteins 0.000 description 9
- 102100038251 Interferon regulatory factor 9 Human genes 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- 108010071390 Serum Albumin Proteins 0.000 description 9
- 102000007562 Serum Albumin Human genes 0.000 description 9
- 239000002246 antineoplastic agent Substances 0.000 description 9
- 230000030833 cell death Effects 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 238000011161 development Methods 0.000 description 9
- 230000018109 developmental process Effects 0.000 description 9
- 239000002502 liposome Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- 230000010076 replication Effects 0.000 description 9
- 230000009885 systemic effect Effects 0.000 description 9
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 8
- 108700008625 Reporter Genes Proteins 0.000 description 8
- 210000003714 granulocyte Anatomy 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 210000000822 natural killer cell Anatomy 0.000 description 8
- 238000013518 transcription Methods 0.000 description 8
- 230000035897 transcription Effects 0.000 description 8
- 102100031256 Cyclic GMP-AMP synthase Human genes 0.000 description 7
- 101710118064 Cyclic GMP-AMP synthase Proteins 0.000 description 7
- 101001011382 Homo sapiens Interferon regulatory factor 3 Proteins 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 230000017074 necrotic cell death Effects 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 230000003612 virological effect Effects 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 102100029843 Interferon regulatory factor 3 Human genes 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 230000005975 antitumor immune response Effects 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 210000004443 dendritic cell Anatomy 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- 239000005090 green fluorescent protein Substances 0.000 description 6
- 239000003102 growth factor Substances 0.000 description 6
- 238000009169 immunotherapy Methods 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 210000004379 membrane Anatomy 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 5
- 102100029968 Calreticulin Human genes 0.000 description 5
- 108090000549 Calreticulin Proteins 0.000 description 5
- 108010012236 Chemokines Proteins 0.000 description 5
- 102000019034 Chemokines Human genes 0.000 description 5
- 101000797762 Homo sapiens C-C motif chemokine 5 Proteins 0.000 description 5
- 102000002227 Interferon Type I Human genes 0.000 description 5
- 108010014726 Interferon Type I Proteins 0.000 description 5
- 102000014150 Interferons Human genes 0.000 description 5
- 108010050904 Interferons Proteins 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 102000002689 Toll-like receptor Human genes 0.000 description 5
- 108020000411 Toll-like receptor Proteins 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 210000000234 capsid Anatomy 0.000 description 5
- 229960004679 doxorubicin Drugs 0.000 description 5
- 238000004520 electroporation Methods 0.000 description 5
- 230000005965 immune activity Effects 0.000 description 5
- 230000003308 immunostimulating effect Effects 0.000 description 5
- 230000008595 infiltration Effects 0.000 description 5
- 238000001764 infiltration Methods 0.000 description 5
- 210000002540 macrophage Anatomy 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- 210000001616 monocyte Anatomy 0.000 description 5
- 102000039446 nucleic acids Human genes 0.000 description 5
- 108020004707 nucleic acids Proteins 0.000 description 5
- 150000007523 nucleic acids Chemical class 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 108090000672 Annexin A5 Proteins 0.000 description 4
- 102000004121 Annexin A5 Human genes 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 108010002350 Interleukin-2 Proteins 0.000 description 4
- 102100020873 Interleukin-2 Human genes 0.000 description 4
- 108090001074 Nucleocapsid Proteins Proteins 0.000 description 4
- 210000003719 b-lymphocyte Anatomy 0.000 description 4
- 239000007979 citrate buffer Substances 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- OGQYPPBGSLZBEG-UHFFFAOYSA-N dimethyl(dioctadecyl)azanium Chemical compound CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC OGQYPPBGSLZBEG-UHFFFAOYSA-N 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 108091006047 fluorescent proteins Proteins 0.000 description 4
- 102000034287 fluorescent proteins Human genes 0.000 description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 229940079322 interferon Drugs 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- 210000001165 lymph node Anatomy 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000001959 radiotherapy Methods 0.000 description 4
- 230000001603 reducing effect Effects 0.000 description 4
- 230000004936 stimulating effect Effects 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- 210000002845 virion Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 241000710929 Alphavirus Species 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 101710132601 Capsid protein Proteins 0.000 description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
- 241000256113 Culicidae Species 0.000 description 3
- 102000003972 Fibroblast growth factor 7 Human genes 0.000 description 3
- 108090000385 Fibroblast growth factor 7 Proteins 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 102000000849 HMGB Proteins Human genes 0.000 description 3
- 108010001860 HMGB Proteins Proteins 0.000 description 3
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 3
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 description 3
- 101000884271 Homo sapiens Signal transducer CD24 Proteins 0.000 description 3
- 102000004889 Interleukin-6 Human genes 0.000 description 3
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- 239000000232 Lipid Bilayer Substances 0.000 description 3
- 102100038081 Signal transducer CD24 Human genes 0.000 description 3
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 3
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 230000001086 cytosolic effect Effects 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 239000003925 fat Substances 0.000 description 3
- 229940100601 interleukin-6 Drugs 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 210000000581 natural killer T-cell Anatomy 0.000 description 3
- 229910052754 neon Inorganic materials 0.000 description 3
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 230000002459 sustained effect Effects 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 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 3
- 238000012546 transfer Methods 0.000 description 3
- 230000032258 transport Effects 0.000 description 3
- NMWKYTGJWUAZPZ-WWHBDHEGSA-N (4S)-4-[[(4R,7S,10S,16S,19S,25S,28S,31R)-31-[[(2S)-2-[[(1R,6R,9S,12S,18S,21S,24S,27S,30S,33S,36S,39S,42R,47R,53S,56S,59S,62S,65S,68S,71S,76S,79S,85S)-47-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-4-oxobutanoyl]amino]-3-carboxypropanoyl]amino]-18-(4-aminobutyl)-27,68-bis(3-amino-3-oxopropyl)-36,71,76-tribenzyl-39-(3-carbamimidamidopropyl)-24-(2-carboxyethyl)-21,56-bis(carboxymethyl)-65,85-bis[(1R)-1-hydroxyethyl]-59-(hydroxymethyl)-62,79-bis(1H-imidazol-4-ylmethyl)-9-methyl-33-(2-methylpropyl)-8,11,17,20,23,26,29,32,35,38,41,48,54,57,60,63,66,69,72,74,77,80,83,86-tetracosaoxo-30-propan-2-yl-3,4,44,45-tetrathia-7,10,16,19,22,25,28,31,34,37,40,49,55,58,61,64,67,70,73,75,78,81,84,87-tetracosazatetracyclo[40.31.14.012,16.049,53]heptaoctacontane-6-carbonyl]amino]-3-methylbutanoyl]amino]-7-(3-carbamimidamidopropyl)-25-(hydroxymethyl)-19-[(4-hydroxyphenyl)methyl]-28-(1H-imidazol-4-ylmethyl)-10-methyl-6,9,12,15,18,21,24,27,30-nonaoxo-16-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29-nonazacyclodotriacontane-4-carbonyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid Chemical compound CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CSSC[C@H](NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](Cc4ccccc4)NC3=O)[C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N3CCC[C@H]3C(=O)N[C@@H](C)C(=O)N2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2c[nH]cn2)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)C(C)C)C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1)C(=O)N[C@@H](C)C(O)=O NMWKYTGJWUAZPZ-WWHBDHEGSA-N 0.000 description 2
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 2
- WALUVDCNGPQPOD-UHFFFAOYSA-M 2,3-di(tetradecoxy)propyl-(2-hydroxyethyl)-dimethylazanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCOCC(C[N+](C)(C)CCO)OCCCCCCCCCCCCCC WALUVDCNGPQPOD-UHFFFAOYSA-M 0.000 description 2
- JTTIOYHBNXDJOD-UHFFFAOYSA-N 2,4,6-triaminopyrimidine Chemical compound NC1=CC(N)=NC(N)=N1 JTTIOYHBNXDJOD-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- 231100000582 ATP assay Toxicity 0.000 description 2
- 102400001318 Adrenomedullin Human genes 0.000 description 2
- 101800004616 Adrenomedullin Proteins 0.000 description 2
- 101100339431 Arabidopsis thaliana HMGB2 gene Proteins 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- CJLHTKGWEUGORV-UHFFFAOYSA-N Artemin Chemical compound C1CC2(C)C(O)CCC(=C)C2(O)C2C1C(C)C(=O)O2 CJLHTKGWEUGORV-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000178568 Aura virus Species 0.000 description 2
- 241000231314 Babanki virus Species 0.000 description 2
- 241000710946 Barmah Forest virus Species 0.000 description 2
- 241000608319 Bebaru virus Species 0.000 description 2
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 description 2
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 description 2
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 2
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 2
- 102100035294 Chemokine XC receptor 1 Human genes 0.000 description 2
- 241001502567 Chikungunya virus Species 0.000 description 2
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 2
- 102100031614 Ciliary neurotrophic factor Human genes 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- 102000003951 Erythropoietin Human genes 0.000 description 2
- 108090000394 Erythropoietin Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 description 2
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 2
- 102100028412 Fibroblast growth factor 10 Human genes 0.000 description 2
- 102100028417 Fibroblast growth factor 12 Human genes 0.000 description 2
- 102100035292 Fibroblast growth factor 14 Human genes 0.000 description 2
- 102100035307 Fibroblast growth factor 16 Human genes 0.000 description 2
- 108050002072 Fibroblast growth factor 16 Proteins 0.000 description 2
- 102100035308 Fibroblast growth factor 17 Human genes 0.000 description 2
- 102100035323 Fibroblast growth factor 18 Human genes 0.000 description 2
- 102100031734 Fibroblast growth factor 19 Human genes 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
- 102100031361 Fibroblast growth factor 20 Human genes 0.000 description 2
- 102000003973 Fibroblast growth factor 21 Human genes 0.000 description 2
- 108090000376 Fibroblast growth factor 21 Proteins 0.000 description 2
- 102100024804 Fibroblast growth factor 22 Human genes 0.000 description 2
- 102100024802 Fibroblast growth factor 23 Human genes 0.000 description 2
- 102100028043 Fibroblast growth factor 3 Human genes 0.000 description 2
- 102100028072 Fibroblast growth factor 4 Human genes 0.000 description 2
- 102100028073 Fibroblast growth factor 5 Human genes 0.000 description 2
- 102100028075 Fibroblast growth factor 6 Human genes 0.000 description 2
- 102100037680 Fibroblast growth factor 8 Human genes 0.000 description 2
- 102100037665 Fibroblast growth factor 9 Human genes 0.000 description 2
- 102100037362 Fibronectin Human genes 0.000 description 2
- 241000710781 Flaviviridae Species 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 241000231322 Fort Morgan virus Species 0.000 description 2
- 241000608297 Getah virus Species 0.000 description 2
- 102000034615 Glial cell line-derived neurotrophic factor Human genes 0.000 description 2
- 108091010837 Glial cell line-derived neurotrophic factor Proteins 0.000 description 2
- 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 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 2
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 102000004858 Growth differentiation factor-9 Human genes 0.000 description 2
- 108090001086 Growth differentiation factor-9 Proteins 0.000 description 2
- 102100039939 Growth/differentiation factor 8 Human genes 0.000 description 2
- 108700010013 HMGB1 Proteins 0.000 description 2
- 101150021904 HMGB1 gene Proteins 0.000 description 2
- 102000003745 Hepatocyte Growth Factor Human genes 0.000 description 2
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 2
- 102100031000 Hepatoma-derived growth factor Human genes 0.000 description 2
- 102100037907 High mobility group protein B1 Human genes 0.000 description 2
- 241000710948 Highlands J virus Species 0.000 description 2
- 101000804783 Homo sapiens Chemokine XC receptor 1 Proteins 0.000 description 2
- 101001027128 Homo sapiens Fibronectin Proteins 0.000 description 2
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 2
- 101001076292 Homo sapiens Insulin-like growth factor II Proteins 0.000 description 2
- 101000724418 Homo sapiens Neutral amino acid transporter B(0) Proteins 0.000 description 2
- 101000595923 Homo sapiens Placenta growth factor Proteins 0.000 description 2
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 description 2
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 2
- 102100025947 Insulin-like growth factor II Human genes 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- 102000004388 Interleukin-4 Human genes 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 102000004058 Leukemia inhibitory factor Human genes 0.000 description 2
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241000608292 Mayaro virus Species 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 241000710949 Middelburg virus Species 0.000 description 2
- 101100182715 Mus musculus Ly6c2 gene Proteins 0.000 description 2
- 102000010168 Myeloid Differentiation Factor 88 Human genes 0.000 description 2
- 108010077432 Myeloid Differentiation Factor 88 Proteins 0.000 description 2
- 108010056852 Myostatin Proteins 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
- 108010025020 Nerve Growth Factor Proteins 0.000 description 2
- 102000015336 Nerve Growth Factor Human genes 0.000 description 2
- 102400000058 Neuregulin-1 Human genes 0.000 description 2
- 108090000556 Neuregulin-1 Proteins 0.000 description 2
- 101800000675 Neuregulin-2 Proteins 0.000 description 2
- 101800000673 Neuregulin-3 Proteins 0.000 description 2
- 101800002641 Neuregulin-4 Proteins 0.000 description 2
- 102000004230 Neurotrophin 3 Human genes 0.000 description 2
- 108090000742 Neurotrophin 3 Proteins 0.000 description 2
- 102000003683 Neurotrophin-4 Human genes 0.000 description 2
- 108090000099 Neurotrophin-4 Proteins 0.000 description 2
- 102100028267 Neutral amino acid transporter B(0) Human genes 0.000 description 2
- 101800000515 Non-structural protein 3 Proteins 0.000 description 2
- 102000011931 Nucleoproteins Human genes 0.000 description 2
- 108010061100 Nucleoproteins Proteins 0.000 description 2
- 241000710944 O'nyong-nyong virus Species 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102100035194 Placenta growth factor Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 102100022668 Pro-neuregulin-2, membrane-bound isoform Human genes 0.000 description 2
- 102100022659 Pro-neuregulin-3, membrane-bound isoform Human genes 0.000 description 2
- 102100022658 Pro-neuregulin-4, membrane-bound isoform Human genes 0.000 description 2
- 101800000980 Protease nsP2 Proteins 0.000 description 2
- 101150006932 RTN1 gene Proteins 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 102000013272 Renalase Human genes 0.000 description 2
- 108010090629 Renalase Proteins 0.000 description 2
- 102000004389 Ribonucleoproteins Human genes 0.000 description 2
- 108010081734 Ribonucleoproteins Proteins 0.000 description 2
- 241000608282 Sagiyama virus Species 0.000 description 2
- 102100027287 Serpin H1 Human genes 0.000 description 2
- 108050008290 Serpin H1 Proteins 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 101710196623 Stimulator of interferon genes protein Proteins 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 108700012920 TNF Proteins 0.000 description 2
- 102000036693 Thrombopoietin Human genes 0.000 description 2
- 108010041111 Thrombopoietin Proteins 0.000 description 2
- 241000710924 Togaviridae Species 0.000 description 2
- 102000008235 Toll-Like Receptor 9 Human genes 0.000 description 2
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 description 2
- 102100039390 Toll-like receptor 7 Human genes 0.000 description 2
- 102400001320 Transforming growth factor alpha Human genes 0.000 description 2
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 241000608278 Una virus Species 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 description 2
- 241000710959 Venezuelan equine encephalitis virus Species 0.000 description 2
- HIHOWBSBBDRPDW-PTHRTHQKSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] n-[2-(dimethylamino)ethyl]carbamate Chemical compound C1C=C2C[C@@H](OC(=O)NCCN(C)C)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 HIHOWBSBBDRPDW-PTHRTHQKSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000004721 adaptive immunity Effects 0.000 description 2
- ULCUCJFASIJEOE-NPECTJMMSA-N adrenomedullin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(=O)N[C@@H]1C(N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)NCC(=O)N[C@H](C(=O)N[C@@H](CSSC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)[C@@H](C)O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 ULCUCJFASIJEOE-NPECTJMMSA-N 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 210000001106 artificial yeast chromosome Anatomy 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229940112869 bone morphogenetic protein Drugs 0.000 description 2
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 230000022534 cell killing Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000004700 cellular uptake Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical group NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 230000001934 delay Effects 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 239000012055 enteric layer Substances 0.000 description 2
- 102000012803 ephrin Human genes 0.000 description 2
- 108060002566 ephrin Proteins 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 229940105423 erythropoietin Drugs 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 102000003684 fibroblast growth factor 13 Human genes 0.000 description 2
- 108090000047 fibroblast growth factor 13 Proteins 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 108010021843 fluorescent protein 583 Proteins 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 108010052188 hepatoma-derived growth factor Proteins 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000015788 innate immune response Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 229940068935 insulin-like growth factor 2 Drugs 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- RGLRXNKKBLIBQS-XNHQSDQCSA-N leuprolide acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 RGLRXNKKBLIBQS-XNHQSDQCSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 102000049853 macrophage stimulating protein Human genes 0.000 description 2
- 108010053292 macrophage stimulating protein Proteins 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000001565 modulated differential scanning calorimetry Methods 0.000 description 2
- 229940053128 nerve growth factor Drugs 0.000 description 2
- 229940032018 neurotrophin 3 Drugs 0.000 description 2
- 229940097998 neurotrophin 4 Drugs 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 229960005079 pemetrexed Drugs 0.000 description 2
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 2
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000007115 recruitment Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 239000002047 solid lipid nanoparticle Substances 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 230000007761 synergistic anti-cancer Effects 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 239000012096 transfection reagent Substances 0.000 description 2
- 239000013638 trimer Substances 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 244000052613 viral pathogen Species 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- XMQUEQJCYRFIQS-YFKPBYRVSA-N (2s)-2-amino-5-ethoxy-5-oxopentanoic acid Chemical compound CCOC(=O)CC[C@H](N)C(O)=O XMQUEQJCYRFIQS-YFKPBYRVSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- 108010058566 130-nm albumin-bound paclitaxel Proteins 0.000 description 1
- LDGWQMRUWMSZIU-LQDDAWAPSA-M 2,3-bis[(z)-octadec-9-enoxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC LDGWQMRUWMSZIU-LQDDAWAPSA-M 0.000 description 1
- FLPJVCMIKUWSDR-UHFFFAOYSA-N 2-(4-formylphenoxy)acetamide Chemical compound NC(=O)COC1=CC=C(C=O)C=C1 FLPJVCMIKUWSDR-UHFFFAOYSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- 101710196690 Actin B Proteins 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 102000009840 Angiopoietins Human genes 0.000 description 1
- 108010009906 Angiopoietins Proteins 0.000 description 1
- 102100026376 Artemin Human genes 0.000 description 1
- 101710205806 Artemin Proteins 0.000 description 1
- 241001292006 Arteriviridae Species 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 241000238421 Arthropoda Species 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241001533362 Astroviridae Species 0.000 description 1
- 108091005950 Azurite Proteins 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 229920002799 BoPET Polymers 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 101710117545 C protein Proteins 0.000 description 1
- 102100023705 C-C motif chemokine 14 Human genes 0.000 description 1
- 102100036842 C-C motif chemokine 19 Human genes 0.000 description 1
- 102100036848 C-C motif chemokine 20 Human genes 0.000 description 1
- 102100036846 C-C motif chemokine 21 Human genes 0.000 description 1
- 102100021933 C-C motif chemokine 25 Human genes 0.000 description 1
- 102100021936 C-C motif chemokine 27 Human genes 0.000 description 1
- 102100025248 C-X-C motif chemokine 10 Human genes 0.000 description 1
- 102100025277 C-X-C motif chemokine 13 Human genes 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- 241000714198 Caliciviridae Species 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- SHHKQEUPHAENFK-UHFFFAOYSA-N Carboquone Chemical compound O=C1C(C)=C(N2CC2)C(=O)C(C(COC(N)=O)OC)=C1N1CC1 SHHKQEUPHAENFK-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 108091005944 Cerulean Proteins 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 241000579895 Chlorostilbon Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- 108091005943 CyPet Proteins 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 241000255925 Diptera Species 0.000 description 1
- 108091005941 EBFP Proteins 0.000 description 1
- 108091005947 EBFP2 Proteins 0.000 description 1
- 108091005942 ECFP Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 208000006825 Eastern Equine Encephalomyelitis Diseases 0.000 description 1
- 201000005804 Eastern equine encephalitis Diseases 0.000 description 1
- 206010014587 Encephalitis eastern equine Diseases 0.000 description 1
- 206010014614 Encephalitis western equine Diseases 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 101710091045 Envelope protein Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102100023688 Eotaxin Human genes 0.000 description 1
- 102100033919 Ephrin-A2 Human genes 0.000 description 1
- 108010043942 Ephrin-A2 Proteins 0.000 description 1
- 102100033940 Ephrin-A3 Human genes 0.000 description 1
- 108010043940 Ephrin-A3 Proteins 0.000 description 1
- 102100033942 Ephrin-A4 Human genes 0.000 description 1
- 108010043938 Ephrin-A4 Proteins 0.000 description 1
- 102100033941 Ephrin-A5 Human genes 0.000 description 1
- 102100023721 Ephrin-B2 Human genes 0.000 description 1
- 108010044090 Ephrin-B2 Proteins 0.000 description 1
- 102100023733 Ephrin-B3 Human genes 0.000 description 1
- 108010044085 Ephrin-B3 Proteins 0.000 description 1
- 206010066919 Epidemic polyarthritis Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 108050001049 Extracellular proteins Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 108090000569 Fibroblast Growth Factor-23 Proteins 0.000 description 1
- 108090001047 Fibroblast growth factor 10 Proteins 0.000 description 1
- 108050003239 Fibroblast growth factor 12 Proteins 0.000 description 1
- 108090000046 Fibroblast growth factor 14 Proteins 0.000 description 1
- 101710153363 Fibroblast growth factor 15 Proteins 0.000 description 1
- 108050002074 Fibroblast growth factor 17 Proteins 0.000 description 1
- 101710153349 Fibroblast growth factor 19 Proteins 0.000 description 1
- 108050002085 Fibroblast growth factor 20 Proteins 0.000 description 1
- 108050002062 Fibroblast growth factor 22 Proteins 0.000 description 1
- 108090000378 Fibroblast growth factor 3 Proteins 0.000 description 1
- 108090000381 Fibroblast growth factor 4 Proteins 0.000 description 1
- 108090000380 Fibroblast growth factor 5 Proteins 0.000 description 1
- 108090000382 Fibroblast growth factor 6 Proteins 0.000 description 1
- 102100028071 Fibroblast growth factor 7 Human genes 0.000 description 1
- 108090000368 Fibroblast growth factor 8 Proteins 0.000 description 1
- 108090000367 Fibroblast growth factor 9 Proteins 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- 101710177291 Gag polyprotein Proteins 0.000 description 1
- 101000766307 Gallus gallus Ovotransferrin Proteins 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102100031132 Glucose-6-phosphate isomerase Human genes 0.000 description 1
- 108010070600 Glucose-6-phosphate isomerase Proteins 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 208000012766 Growth delay Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101000978381 Homo sapiens C-C motif chemokine 14 Proteins 0.000 description 1
- 101000713106 Homo sapiens C-C motif chemokine 19 Proteins 0.000 description 1
- 101000713099 Homo sapiens C-C motif chemokine 20 Proteins 0.000 description 1
- 101000713085 Homo sapiens C-C motif chemokine 21 Proteins 0.000 description 1
- 101000897486 Homo sapiens C-C motif chemokine 25 Proteins 0.000 description 1
- 101000897494 Homo sapiens C-C motif chemokine 27 Proteins 0.000 description 1
- 101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 description 1
- 101000858064 Homo sapiens C-X-C motif chemokine 13 Proteins 0.000 description 1
- 101000883515 Homo sapiens Chitinase-3-like protein 1 Proteins 0.000 description 1
- 101000978392 Homo sapiens Eotaxin Proteins 0.000 description 1
- 101000925251 Homo sapiens Ephrin-A5 Proteins 0.000 description 1
- 101000917237 Homo sapiens Fibroblast growth factor 10 Proteins 0.000 description 1
- 101000917234 Homo sapiens Fibroblast growth factor 12 Proteins 0.000 description 1
- 101000878181 Homo sapiens Fibroblast growth factor 14 Proteins 0.000 description 1
- 101000878124 Homo sapiens Fibroblast growth factor 17 Proteins 0.000 description 1
- 101000878128 Homo sapiens Fibroblast growth factor 18 Proteins 0.000 description 1
- 101000846394 Homo sapiens Fibroblast growth factor 19 Proteins 0.000 description 1
- 101000846532 Homo sapiens Fibroblast growth factor 20 Proteins 0.000 description 1
- 101001051971 Homo sapiens Fibroblast growth factor 22 Proteins 0.000 description 1
- 101001051973 Homo sapiens Fibroblast growth factor 23 Proteins 0.000 description 1
- 101001060280 Homo sapiens Fibroblast growth factor 3 Proteins 0.000 description 1
- 101001060274 Homo sapiens Fibroblast growth factor 4 Proteins 0.000 description 1
- 101001060267 Homo sapiens Fibroblast growth factor 5 Proteins 0.000 description 1
- 101001060265 Homo sapiens Fibroblast growth factor 6 Proteins 0.000 description 1
- 101001060261 Homo sapiens Fibroblast growth factor 7 Proteins 0.000 description 1
- 101001027382 Homo sapiens Fibroblast growth factor 8 Proteins 0.000 description 1
- 101001027380 Homo sapiens Fibroblast growth factor 9 Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101000844245 Homo sapiens Non-receptor tyrosine-protein kinase TYK2 Proteins 0.000 description 1
- 101000617130 Homo sapiens Stromal cell-derived factor 1 Proteins 0.000 description 1
- 101000595548 Homo sapiens TIR domain-containing adapter molecule 1 Proteins 0.000 description 1
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical class C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102100034349 Integrase Human genes 0.000 description 1
- 102100034353 Integrase Human genes 0.000 description 1
- 102000004560 Interleukin-12 Receptors Human genes 0.000 description 1
- 108010017515 Interleukin-12 Receptors Proteins 0.000 description 1
- 102000003816 Interleukin-13 Human genes 0.000 description 1
- 108090000176 Interleukin-13 Proteins 0.000 description 1
- 108050003558 Interleukin-17 Proteins 0.000 description 1
- 102000013691 Interleukin-17 Human genes 0.000 description 1
- 102000003810 Interleukin-18 Human genes 0.000 description 1
- 108090000171 Interleukin-18 Proteins 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 description 1
- 102400000704 Intracellular domain 1 Human genes 0.000 description 1
- 101800001559 Intracellular domain 1 Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 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
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 101710125418 Major capsid protein Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101000793654 Mus musculus Calreticulin Proteins 0.000 description 1
- 101100390675 Mus musculus Fgf15 gene Proteins 0.000 description 1
- 239000005041 Mylar™ Substances 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 102100022691 NACHT, LRR and PYD domains-containing protein 3 Human genes 0.000 description 1
- 102100021584 Neurturin Human genes 0.000 description 1
- 108010015406 Neurturin Proteins 0.000 description 1
- 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 102100036660 Persephin Human genes 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 229920000362 Polyethylene-block-poly(ethylene glycol) Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 101710188315 Protein X Proteins 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 description 1
- 101150025038 RIPK3 gene Proteins 0.000 description 1
- 108091034057 RNA (poly(A)) Proteins 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- 101800001758 RNA-directed RNA polymerase nsP4 Proteins 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 241000710942 Ross River virus Species 0.000 description 1
- 108010044012 STAT1 Transcription Factor Proteins 0.000 description 1
- 102000004265 STAT2 Transcription Factor Human genes 0.000 description 1
- 108010081691 STAT2 Transcription Factor Proteins 0.000 description 1
- 108010019992 STAT4 Transcription Factor Proteins 0.000 description 1
- 102000005886 STAT4 Transcription Factor Human genes 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 190014017285 Satraplatin Chemical compound 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 102100029904 Signal transducer and activator of transcription 1-alpha/beta Human genes 0.000 description 1
- 241000710960 Sindbis virus Species 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 102100036073 TIR domain-containing adapter molecule 1 Human genes 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 101150050472 Tfr2 gene Proteins 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 102000000887 Transcription factor STAT Human genes 0.000 description 1
- 108050007918 Transcription factor STAT Proteins 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 102100026143 Transferrin receptor protein 2 Human genes 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- YCPOZVAOBBQLRI-WDSKDSINSA-N Treosulfan Chemical compound CS(=O)(=O)OC[C@H](O)[C@@H](O)COS(C)(=O)=O YCPOZVAOBBQLRI-WDSKDSINSA-N 0.000 description 1
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- 208000005466 Western Equine Encephalomyelitis Diseases 0.000 description 1
- 201000005806 Western equine encephalitis Diseases 0.000 description 1
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 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
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- RGHILYZRVFRRNK-UHFFFAOYSA-N anthracene-1,2-dione Chemical class C1=CC=C2C=C(C(C(=O)C=C3)=O)C3=CC2=C1 RGHILYZRVFRRNK-UHFFFAOYSA-N 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000000340 anti-metabolite Effects 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
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- LNHWXBUNXOXMRL-VWLOTQADSA-N belotecan Chemical compound C1=CC=C2C(CCNC(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 LNHWXBUNXOXMRL-VWLOTQADSA-N 0.000 description 1
- 229950011276 belotecan Drugs 0.000 description 1
- 229960002707 bendamustine Drugs 0.000 description 1
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- HUTDDBSSHVOYJR-UHFFFAOYSA-H bis[(2-oxo-1,3,2$l^{5},4$l^{2}-dioxaphosphaplumbetan-2-yl)oxy]lead Chemical compound [Pb+2].[Pb+2].[Pb+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O HUTDDBSSHVOYJR-UHFFFAOYSA-H 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 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(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[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 OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 108091005948 blue fluorescent proteins Proteins 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 238000002725 brachytherapy Methods 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N butyl alcohol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229960002115 carboquone Drugs 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000034303 cell budding Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 229940074979 cetyl palmitate Drugs 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 229960000928 clofarabine Drugs 0.000 description 1
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 238000011498 curative surgery Methods 0.000 description 1
- 108010082025 cyan fluorescent protein Proteins 0.000 description 1
- PZAQDVNYNJBUTM-UHFFFAOYSA-L cyclohexane-1,2-diamine;7,7-dimethyloctanoate;platinum(2+) Chemical compound [Pt+2].NC1CCCCC1N.CC(C)(C)CCCCCC([O-])=O.CC(C)(C)CCCCCC([O-])=O PZAQDVNYNJBUTM-UHFFFAOYSA-L 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 108010057085 cytokine receptors Proteins 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000005860 defense response to virus Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- PSLWZOIUBRXAQW-UHFFFAOYSA-M dimethyl(dioctadecyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC PSLWZOIUBRXAQW-UHFFFAOYSA-M 0.000 description 1
- UAKOZKUVZRMOFN-JDVCJPALSA-M dimethyl-bis[(z)-octadec-9-enyl]azanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC[N+](C)(C)CCCCCCCC\C=C/CCCCCCCC UAKOZKUVZRMOFN-JDVCJPALSA-M 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000010894 electron beam technology Methods 0.000 description 1
- 239000010976 emerald Substances 0.000 description 1
- 229910052876 emerald Inorganic materials 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 108010078428 env Gene Products Proteins 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 108090000370 fibroblast growth factor 18 Proteins 0.000 description 1
- 229940098448 fibroblast growth factor 7 Drugs 0.000 description 1
- 229940029303 fibroblast growth factor-1 Drugs 0.000 description 1
- 238000009459 flexible packaging Methods 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000011990 functional testing Methods 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 150000004676 glycans Chemical group 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- PXDJXZJSCPSGGI-UHFFFAOYSA-N hexadecanoic acid hexadecyl ester Natural products CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC PXDJXZJSCPSGGI-UHFFFAOYSA-N 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000000710 homodimer Substances 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 102000054350 human CHI3L1 Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 230000002766 immunoenhancing effect Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 238000012606 in vitro cell culture Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000010468 interferon response 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
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000002357 laparoscopic surgery Methods 0.000 description 1
- 238000002430 laser surgery Methods 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 239000002960 lipid emulsion Substances 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 229950008991 lobaplatin Drugs 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 229940087857 lupron Drugs 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229960000733 mannosulfan Drugs 0.000 description 1
- UUVIQYKKKBJYJT-ZYUZMQFOSA-N mannosulfan Chemical compound CS(=O)(=O)OC[C@@H](OS(C)(=O)=O)[C@@H](O)[C@H](O)[C@H](OS(C)(=O)=O)COS(C)(=O)=O UUVIQYKKKBJYJT-ZYUZMQFOSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Chemical class 0.000 description 1
- 229940071648 metered dose inhaler Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- XVUQPECVOGMPRU-ZPPAUJSGSA-N n,n-dimethyl-1,2-bis[(9z,12z)-octadeca-9,12-dienoxy]propan-1-amine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCOC(C)C(N(C)C)OCCCCCCCC\C=C/C\C=C/CCCCC XVUQPECVOGMPRU-ZPPAUJSGSA-N 0.000 description 1
- OZBZDYGIYDRTBV-RSLAUBRISA-N n,n-dimethyl-1,2-bis[(9z,12z,15z)-octadeca-9,12,15-trienoxy]propan-1-amine Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCCOC(C)C(N(C)C)OCCCCCCCC\C=C/C\C=C/C\C=C/CC OZBZDYGIYDRTBV-RSLAUBRISA-N 0.000 description 1
- NFQBIAXADRDUGK-KWXKLSQISA-N n,n-dimethyl-2,3-bis[(9z,12z)-octadeca-9,12-dienoxy]propan-1-amine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCOCC(CN(C)C)OCCCCCCCC\C=C/C\C=C/CCCCC NFQBIAXADRDUGK-KWXKLSQISA-N 0.000 description 1
- 230000021597 necroptosis Effects 0.000 description 1
- 229950007221 nedaplatin Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229960001420 nimustine Drugs 0.000 description 1
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 1
- 108091027963 non-coding RNA Proteins 0.000 description 1
- 102000042567 non-coding RNA Human genes 0.000 description 1
- 238000013546 non-drug therapy Methods 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 201000002628 peritoneum cancer Diseases 0.000 description 1
- 108010070453 persephin Proteins 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- IIMIOEBMYPRQGU-UHFFFAOYSA-L picoplatin Chemical compound N.[Cl-].[Cl-].[Pt+2].CC1=CC=CC=N1 IIMIOEBMYPRQGU-UHFFFAOYSA-L 0.000 description 1
- 229950005566 picoplatin Drugs 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 230000004983 pleiotropic effect Effects 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 108010089520 pol Gene Products Proteins 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000017363 positive regulation of growth Effects 0.000 description 1
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 210000004777 protein coat Anatomy 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000002661 proton therapy Methods 0.000 description 1
- 239000000649 purine antagonist Substances 0.000 description 1
- 239000003790 pyrimidine antagonist Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 229960002185 ranimustine Drugs 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 108010054624 red fluorescent protein Proteins 0.000 description 1
- 230000033458 reproduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 201000003804 salivary gland carcinoma Diseases 0.000 description 1
- 229910052594 sapphire Inorganic materials 0.000 description 1
- 239000010980 sapphire Substances 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 210000003786 sclera Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 108091069025 single-strand RNA Proteins 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 208000017572 squamous cell neoplasm Diseases 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- SFVFIFLLYFPGHH-UHFFFAOYSA-M stearalkonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 SFVFIFLLYFPGHH-UHFFFAOYSA-M 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000001797 sucrose acetate isobutyrate Substances 0.000 description 1
- 235000010983 sucrose acetate isobutyrate Nutrition 0.000 description 1
- UVGUPMLLGBCFEJ-SWTLDUCYSA-N sucrose acetate isobutyrate Chemical compound CC(C)C(=O)O[C@H]1[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O[C@@]1(COC(C)=O)O[C@@H]1[C@H](OC(=O)C(C)C)[C@@H](OC(=O)C(C)C)[C@H](OC(=O)C(C)C)[C@@H](COC(C)=O)O1 UVGUPMLLGBCFEJ-SWTLDUCYSA-N 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229940022511 therapeutic cancer vaccine Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229960003181 treosulfan Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 229960004560 triaziquone Drugs 0.000 description 1
- GWBUNZLLLLDXMD-UHFFFAOYSA-H tricopper;dicarbonate;dihydroxide Chemical compound [OH-].[OH-].[Cu+2].[Cu+2].[Cu+2].[O-]C([O-])=O.[O-]C([O-])=O GWBUNZLLLLDXMD-UHFFFAOYSA-H 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 230000014567 type I interferon production Effects 0.000 description 1
- 235000002374 tyrosine Nutrition 0.000 description 1
- 150000003668 tyrosines Chemical class 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 208000023747 urothelial carcinoma Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 208000012991 uterine carcinoma Diseases 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 108091005957 yellow fluorescent proteins Proteins 0.000 description 1
Classifications
-
- 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
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
-
- 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
-
- 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
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
-
- 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
- A61K35/768—Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/208—IL-12
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/5434—IL-12
-
- 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
-
- 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
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C12N15/88—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using amphiphile liposome vesicle
-
- 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
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/36011—Togaviridae
- C12N2770/36111—Alphavirus, e.g. Sindbis virus, VEE, EEE, WEE, Semliki
- C12N2770/36121—Viruses as such, e.g. new isolates, mutants or their genomic sequences
-
- 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
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/36011—Togaviridae
- C12N2770/36111—Alphavirus, e.g. Sindbis virus, VEE, EEE, WEE, Semliki
- C12N2770/36132—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
Definitions
- the present disclosure relates to synthetic oncolytic viruses comprising a lipid nanoparticle comprising one or more types of lipid and a self-amplifying replicon RNA comprising a sequence that encodes an immunomodulatory molecule.
- the present disclosure is based, at least in part, on the unexpected discovery that upon injection at a tumor site, a synthetic oncolytic vims successfully triggers anti-cancer immune response of local tumors and enables systemic immunity against distal tumors.
- one aspect of the present disclosure provides a synthetic oncolytic virus comprising a lipid nanoparticle comprising one or more types of lipid and a self-amplifying replicon RNA comprising a sequence that encodes an interleukin (IL)-12 molecule.
- the lipid nanoparticle is capable of triggering immunogenic cell death.
- the IL-12 molecule is expressed by the self-amplifying replicon RNA.
- the synthetic oncolytic vims comprises a lipid nanoparticle.
- the lipid nanoparticle comprises one or more types of lipids.
- the one or more types of lipids comprises a cationic lipid.
- the cationic lipid is Nl,N3,N5-tris(3- (didodecylamino)propyl)benzene-l, 3, 5-tricarboxamide (TT3).
- the lipid nanoparticle comprises TT3, l,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), cholesterol, and C14-PEG2000.
- DOPE dioleoyl-sn-glycero-3-phosphoethanolamine
- the synthetic oncolytic vims comprises a self-amplifying replicon RNA.
- the self-amplicon RNA is derived from an alphavims or other Group IV vimses (positive single strand RNA vimses, such as a hepatitis C vims (HCV)).
- the alphavims can be Venezuela Equine Encephalitis vims, Semliki Forest vims, or Sindbis vims.
- the self-amplifying replicon RNA comprises a sequence encoding an IL-12 molecule.
- the sequence that encodes the IL-12 molecule is located in a subgenomic region of the self-amplifying replicon RNA.
- the self-amplifying replicon RNA comprises a nucleotide sequence that is at least 90% identical of the wild type (WT) replicon RNA having a sequence of SEQ ID NO: 1.
- the self-amplifying replicon RNA is not identical to SEQ ID NO: 1 and is capable of expressing the IL-12 molecule at a higher level compared to the self-amplifying replicon RNA comprising SEQ ID NO: 1.
- replicon RNA that is capable of expressing the IL-12 molecule at a higher level comprises a point mutations of G3936C and/or A4758G of SEQ ID NO: 1.
- the self-amplifying replicon RNA further comprises a serum albumin coding sequence. In some embodiments, the self-amplifying replicon RNA further comprises a Lumican coding sequence.
- self-amplifying replicon RNA comprises a sequence encoding a IL- 12 molecule.
- the IL-12 molecule is selected from the group consisting of IL-12, an IL-12 subunit, or a mutant IL-12 molecule that retains the immunomodulatory function.
- the IL-12 molecule comprises IL12a and/or I LI 2 b subunits.
- the lipid nanoparticle has a diameter of about 100-120 nm. In some embodiments, the lipid nanoparticle has a zeta potential of about 3-6 mv.
- the lipid and the self-amplifying replicon RNA have a mass ratio of about 1:2 to 2:1.
- the present disclosure at least in part, relates to a pharmaceutical composition, comprising the synthetic oncolytic vims and a pharmaceutically acceptable carrier.
- pharmaceutical composition is formulated for intratumoral injection.
- the present disclosure at least in part, relates to a method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of the synthetic oncolytic vims of any or the synthetic oncolytic virus-containing pharmaceutical composition.
- the subject is a human patient having or suspected of having a cancer.
- target cancers include, but are not limited to melanoma, breast cancer and colon cancer.
- the pharmaceutical composition is administered to the subject in a single dose. In some embodiments, the pharmaceutical composition is administered to the subject by intratumoral injection.
- FIGs. 1A-1H are charts showing the effects of B16F10 cells transfected with DOTAP, lipofectamine (Lipo), TT3 nanoparticle (TT3), mutant replicon RNA (RNA), DOTAP, Lipo, and TT3 nanoparticle encapsulate mutant replicon RNA (DOTAP-mtRep, Lipo-mtRep, and TT3-mtRep), electroporation (Electro), and electroporation with mutant replicon RNA (Electro-mtRep).
- FIG. 1A is a graph showing B16F10 cell viability 3 days post transfection.
- FIG. IB is a graph showing GFP expression in B16F10 cells transfected with lipid
- FIG. 1C is a graph showing percentages of PI+ Annexin V+ dead B16F10 cells transfected with lipid
- FIG. 1G shows the diameter of the lipid
- FIG. 1H shows the zeta potential of the lipid nanoparticles and lipid nanoparticle loaded with mutant replicon RNAs.
- FIGs. 2A-2J are charts showing mtRep and deRep trigger TFR3 signaling and induce ISGF3 complex to necrotic cell death.
- FNP-replicon RNA trigger TFR3 signaling (FIG. 2B and FIG. 2E) and activates the expression of interferon stimulated genes Stat 1, Stat2, IRF9, IRF3 and cGAS (FIGs. 2F-2J), but does not activate TFR2 (FIG. 2A), TFR7 (FIG. 2C) or TFR9 (FIG. 2D).
- FIG. 3A-3K are charts showing TT3-mtRep recruits immune cells and regresses tumor growth.
- FIG. 3A shows mtRep recruits more Ly6clo Ly6G+ granulocytes 3 days post injection.
- FIG. 3B shows the percentages of mCherry+ cells in CD45+ and CD45- cells in tumors injected with TT3-mtRep 3 days post injection.
- FIG. 3C shows the expression of ISGF3 complex (Statl/Stat2/IRF9) as well as IRF3 and cGAS at 1 day post TT3-mtRep injection.
- 3D-3F show the immune cell infiltration (granulocytes, M-MDSC, monocytes, macrophages, CD4 T, CD8 T, NK, NKT, conventional DC1 (cDCl), and conventional DC2 (cDC2)) into the tumor at day 1 (FIG. 3D), and at day 3 (FIG. 3E) post one injection of TT3-mtRep, and at day 1 post 3 sequential injection (FIG. 3F) of TT3-mtRep.
- FIGs. 3G-3H show TT3-mtRep induces more cell death (FIG. 3G), more immune cell infiltration (FIG. 3H), reduced tumor weight (FIG. 31), tumor area (FIG. 3J) and increased expression of CCL5 (FIG. 3K) at one day after 3 sequential injection of TT3-mtRep.
- FIGs. 4A-4G are charts showing TT3-mtRep encoding IL12-MSA or IL12-MSA- Lumican effectively modulates tumor microenvironments and immune cell infiltration.
- FIGs. 4A and 4B show quantification of IFNoc2 by ELISA in tumor (FIG. 4A) and in serum (FIG. 4B) one day and three days post TT3-mtRep injection.
- FIG. 4C shows B16F10 cells transfected with mtRep-IL12-MSA and mtRep-IL12-MSA-Lumican can produce IL-12.
- FIG. 4A-4G are charts showing TT3-mtRep encoding IL12-MSA or IL12-MSA- Lumican effectively modulates tumor microenvironments and immune cell infiltration.
- FIGs. 4A and 4B show quantification of IFNoc2 by ELISA in tumor (FIG. 4A) and in serum (FIG. 4B) one
- FIG. 4D shows IL-12 level in tumor one day and three days post single injection of TT3-mtRep, TT3-mtRep-IL12-MSA, or TT3-mtRep-IL12-MSA-lumican.
- FIG. 4E-4F shows immune cell infiltration in tumor one day (FIG. 4E) and three days (FIG. 4F) post single injection of TT3- mtRep, TT3-mtRep-IL12-MSA, or TT3-mtRep-IL12-MSA-lumican.
- FIG. 4E-4F shows immune cell infiltration in tumor one day (FIG. 4E) and three days (FIG. 4F) post single injection of TT3- mtRep, TT3-mtRep-IL12-MSA, or TT3-mtRep-IL12-MSA-lumican.
- 4G shows numbers of conventional DC1 (cDCl) in tumor draining lymph node one day and three days post single injection of TT3-mtRep, TT3-mtRep-IL12-MSA, or TT3-mtRep-IL12-MSA-lumican.
- FIGs. 5A-5E are charts showing in vivo synergistic anti-cancer effects of
- FIG. 5A shows that TT3-mtRep-IL12 treatment can prevent the recurrence of tumor in cured mice.
- the present disclosure is based, at least in part, on the unexpected discovery that upon injection at a tumor site, a synthetic oncolytic virus comprising a lipid nanoparticle comprising one or more types of lipid and a self-amplifying replicon RNA comprising a sequence that encodes an IL-12 molecule successfully triggers anti-cancer immune response of local tumors and enables systemic immunity against distal tumors.
- the present disclosure at least in part, relates to a synthetic oncolytic virus.
- synthetic refers to a non-natural or engineered oncolytic virus as disclosed herein, which includes a lipid nanoparticle and a self-amplifying replicon RNA comprising a sequence that encodes an IL-12 molecule.
- the present disclosure relates to utilizing lipid nanoparticles (LNPs), which are capable of inducing immunogenic cell death by themselves, to facilitate the delivery of biologically active agent (e.g., a self-amplifying replicon RNA encoding an IL-12 molecule) into the tumor cells.
- LNPs lipid nanoparticles
- the present disclosure relates to the delivery of biologically active molecules to cells using lipid nanoparticles.
- the invention relates to a synthetic oncolytic virus comprising IL-12 expressing self-amplifying replicon RNA encapsulated by lipid nanoparticles, the composition thereof, and methods of using the synthetic oncolytic virus, and the composition thereof to treat a subject having cancer or suspected of having cancer.
- a lipid nanoparticle refers to vesicle, such as a spherical vesicle, having a contiguous lipid bilayer. Lipid nanoparticles can be used in methods by which pharmaceutical therapies are delivered to targeted locations.
- Non-limiting examples of LNPs include liposomes, bolaamphiphiles, solid lipid nanoparticles (SLN), nano structured lipid carriers (NLC), and monolayer membrane structures (e.g., archaeosomes and micelles).
- the lipid nanoparticle comprises one or more types of lipids.
- a lipid refers to a group of organic compounds that include, but are not limited to, esters of fatty acids and in some embodiments are characterized by being insoluble in water, but soluble in many organic solvents. They are usually divided into at least three classes: (1) “simple lipids” which include fats and oils as well as waxes; (2)“compound lipids” which include phospholipids and glycolipids; (3)“derived lipids” such as steroids.
- Non-limiting examples of lipids include triglycerides (e.g. tristearin), diglycerides (e.g.
- the one or more types of lipids in the LNP comprises a cationic lipid.
- a cationic lipid refers to any of a number of lipid species that carry a net positive charge at a selected pH, such as physiological pH.
- Such lipids include, but are not limited to Nl,N3,N5-tris(3-(didodecylamino)propyl)benzene-l, 3, 5 -tricarboxamide (TT3), N-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP); lipofectamine;
- DLinDMA 1 ,2-DiLinoleyloxy-N,N-dimethylaminopropane
- DLenDMA 1 ,2-Dilinolenyloxy-N,N- dimethylaminopropane
- DODMA dioctadecyldimethylammonium
- DSDMA Distearyldimethylammonium
- DODAC N,N-dioleyl-N,N-dimethylammonium chloride
- DOTMA N,N-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride
- DDAB N,N- distearyl-N,N-dimethylammonium bromide
- DC-Chol 3-(N— (N',N'-dimethylaminoethane)- carbamoyl)cholesterol (DC-Chol) and N-(l,2-dimyristyloxyprop-3-yl)-N,N-dimethyl-N- hydroxyethyl ammonium bromide (DMRIE).
- the cationic lipid is TT3.
- TT3 as used herein, is capable of forming lipid nanoparticles for delivery of various biologic active agents into the cells.
- the present disclosure also demonstrates that an unloaded TT3-LNP can induce immunogenic cell death (ICD) in cancer cells in vivo and in vitro.
- Immunogenic cell death refers to a form of cell death that can induce an effective immune response through activation of dendritic cells (DCs) and consequent activation of specific T cell response.
- the cells that undergo immunogenic cell death (ICD) are tumor cells. Immunogenic tumor cell death can trigger an effective anti-tumor immune response.
- the synthetic oncolytic vims comprises TT3-LNP encapsulating a self-amplifying replicon RNA encoding only a reporter gene (TT3-LNP- replicon RNA).
- the self-amplifying replicon RNA can work synergistically with the TT3- LNP to induce higher level of ICD in tumor cells compared to TT3-LNP alone.
- the synthetic oncolytic vims comprises a TT3-LNP encapsulating a self- amplifying replicon RNA encoding an IL-12 molecule.
- IL-12 which is an immunoregulatory cytokine, elicits potent immune response against the local tumor.
- TT3-LNP self-amplifying replicon RNA and IL-12 expression
- IL-12 IL-12 expression
- the cationic lipid is DOTAP.
- DOTAP as used herein, is also capable of forming lipid nanoparticles.
- DOTAP can be used for the highly efficient transfection of DNA including yeast artificial chromosomes (YACs) into eukaryotic cells for transient or stable gene expression, and is also suitable for the efficient transfer of other negatively charged molecules, such as RNA, oligonucleotides, nucleotides, ribonucleo- protein (RNP) complexes, and proteins into research samples of mammalian cells.
- YACs yeast artificial chromosomes
- RNP ribonucleo- protein
- the cationic lipid is lipofectamine.
- Lipofectamine as used herein, is a common transfection reagent, produced and sold by Invitrogen, used in molecular and cellular biology. It is used to increase the transfection efficiency of RNA (including mRNA and siRNA) or plasmid DNA into in vitro cell cultures by lipofection.
- RNA including mRNA and siRNA
- Lipofectamine contains lipid subunits that can form liposomes or lipid nanoparticles in an aqueous environment, which entrap the transfection payload, e.g. self-amplifying replicon RNA.
- RNA-containing liposomes (positively charged on their surface) can fuse with the negatively charged plasma membrane of living cells, due to the neutral co-lipid mediating fusion of the liposome with the cell membrane, allowing nucleic acid cargo molecules to cross into the cytoplasm for replication or expression.
- LNPs are composed primarily of cationic lipids along with other lipid ingredients. These typically include other lipid molecules belonging but not limited to the phosphatidylcholine (PC) class (e.g., l,2-Distearoyl-sn-glycero-3- phosphocholine (DSPC), and l,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), sterols (e.g., cholesterol) and Polyethylene glycol (PEG)-lipid conjugates (e.g., 1,2- distearoyl-sn-glycero-3-phosphoethanolamine-N-[folate(polyethylene glycol)-2000 (DSPE- PEG2000) and l,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000 (C14-PEG2000).
- PC phosphatidylcholine
- DSPC l,2-Dist
- Particle size of lipid nanoparticles can affect drug release rate, bio-distribution, mucoadhesion, cellular uptake of water and buffer exchange to the interior of the
- the diameter of the LNPs ranges from 30 to 150 nm. In some embodiments, the diameter of the LNPs ranges from 100-120 nm. In some embodiments, the diameter of the LNPs can be 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 101 nm, 102 nm, 103 nm, 104 nm, 105 nm, 106 nm, 107 nm, 108 nm, 109 nm, 110 nm, 111 nm, 112 nm, 113 nm, 114 nm, 115 nm, 116 nm, 117 nm, 118 nm, 119 nm, or 120 nm.
- Zeta potential is a measure of the effective electric charge on the lipid nanoparticle surface. The magnitude of the zeta potential provides information about particle stability.
- the zeta potential of the LNPs ranges from -10 millivolts (mv) to 25 mv. In some embodiments, the zeta potential of the LNPs ranges from 3-6 mv.
- the zeta potential of the LNPs can be 3 mv, 3.1 mv, 3.2 mv, 3.3 mv, 3.4 mv, 3.5mv, 3.6 mv, 3.7 mv, 3.8 mv, 3.9 mv, 4 mv, 4.1 mv, 4.2 mv, 4.3 mv, 4.4 mv, 4.5mv, 4.6 mv, 4.7 mv, 4.8 mv, 4.9 mv, 5 mv, 5.1 mv, 5.2 mv, 5.3 mv, 5.4 mv, 5.5mv, 5.6 mv, 5.7 mv, 5.8 mv, 5.9 mv, and 6 mv.
- the present disclosure is related to encapsulating replicon RNA with the lipid nanoparticles.
- the mass ratio between the LNPs and the replicon RNA ranges from 1:2 to 2:1.
- the mass ratio between the LNPs and the replicon RNA can be 1:2, 1:1.5, 1:1.2, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1,
- the mass ratio between the LNPs and the replicon RNA can be 1:1.
- a self-amplifying replicon RNA encoding IL-12 molecule under the subgenomic promoter, in place of the structural proteins required for virus replication are of substantial interest in cancer immunotherapy.
- the term “self-amplifying replicon RNA” refers to a self-replicating genetic element comprised a RNA that replicates from one origin of replication.
- the terms“replicon RNA” and“self-amplifying replicon RNA” are used interchangeably herein.
- the self-amplifying replicon RNA is a viral replicon.
- a virus is a small pathogen that is only capable of replication inside a living host cell (e.g ., prokaryotic and eukaryotic cells).
- viruses exist as independent particles (e.g., viral particles or virions), which comprise genetic material in the form of DNA or RNA, the latter of which can be single-stranded or double-stranded.
- DNA viruses e.g., viruses with DNA
- RNA viruses e.g., viruses with RNA viruses.
- the virus comprises nucleic acid-associated proteins and the combination of the vims and nucleic acid-associated proteins is referred to as nucleoprotein.
- viruses In addition to the genetic material, viruses have a single or double protein coat, also known as a capsid, which facilitates attachment of the virus to a living host cell’s receptors during infection and protects the genetic material of the vims from enzymatic degradation.
- the combination of nucleoprotein and the capsid is referred to as a nucleocapsid.
- viruses have a lipid bilayer envelope, studded with virus-coded, glycosylated (trans-) membrane-associated proteins. Once a virus has infected a living host cell, the virus is dependent on the living host cell to supply the machinery for its replication, and propagation thereafter.
- the viral genome codes for some structural proteins and non- structural regulatory proteins.
- subgenome refers to a smaller section of the whole replicon genome. Accordingly, subgenomic transcription, as used herein, refers to the transcription of one or more genes in the replicon genome but not all the genes constituting the replicon genome. In one embodiment, subgenomic transcription refers to transcription of the genes of experimental or therapeutic interest, which are described elsewhere herein.
- structural protein refers to proteins that constitute the structural components of mature assembled vims particles or virions.
- structural proteins include nucleocapsid core proteins (e.g ., gag proteins), enzymes packaged within the virus particle (e.g., pol proteins), and membrane components (e.g., env proteins).
- non-stmctural protein refers to proteins that are expressed within the host cell but do not constitute structural components of the vims particle or virion.
- the self-amplifying replicon RNA is derived from an alphavims. Distinct from host mRNA, alphavims replicon RNAs encode a set of four nonstmctural proteins (nsPs 1-4) that are responsible both for genome replication and, when engineered to include genes encoding non- vims products, such as IL-12 molecules, provide for transcription of such non- viral products under the subgenomic promoter.
- Alphavimses are part of the Group IV Togaviridae family of viruses, possess a positive sense, single-stranded RNA genome, and are characterized by an icosahedral nucleocapsid.
- Group IV vimses can be Astroviridae, Caliciviridae, Coronaviridae, Flaviviridae, Picomaviridae, Arteriviridae, and Togaviridae.
- the alphavims genus includes 26 enveloped vimses that infect eukaryotes. Alphavimses have a broad host range and are transmitted by mosquitos and hematophagous arthropods.
- Non-limiting examples of alphavimses include Venezuelan equine encephalitis vims (VEE), Semliki Forest vims (SF), Sindbis vims (SIN), Eastern Equine Encephalitis vims (EEE), Western equine encephalitis vims (WEE), Everglades vims (EVE), Mucambo vims (MUC), Pixuna vims (PIX), Semliki Forest vims (SF), Middelburg virus (MID), Chikungunya virus (CHIK), O’Nyong-Nyong virus (ONN), Ross River virus (RR), Barmah Forest virus (BF), Getah virus (GET), Sagiyama virus (SAG), Bebaru virus (BEB), Mayaro virus (MAY), Una virus (UNA), Aura virus (AURA), Babanki virus (BAB), Highlands J virus (HJ), and Fort Morgan virus (FM).
- VEE Venezuelan equine encephalitis vims
- the alphavirus replicon is a VEE alphavirus replicon.
- the VEE virus is a viral pathogen typically carried by mosquitos that causes VEE or encephalomyelitis predominately in equine species. Humans, however, may also contract VEE, and people with weakened immune systems are especially at risk of having severe complications if infected with VEE.
- the virion of VEE is spherical and possesses a lipid membrane with glycoprotein surface proteins spread around the outer surface. Typically,
- VEE has a genome of approximately 11.45 kb, excluding the 5’-terminal cap and 3’-terminal poly(A) tract, and comprises 4 nonstructural proteins (nsPs) and 5 structural proteins.
- the non-structural proteins include nsPl, nsP2, nsP3, and nsP4, while the structural region encodes proteins C, E3, E2, 6K, and El.
- the self-amplifying replicon RNA is a WT replicon RNA derived from VEE.
- the sequence of the VEE virus WT replicon RNA is set forth in SEQ ID NO: 1:
- the self-amplifying replicon RNA comprises a nucleotide sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to SEQ ID NO: 1. In some embodiments, the self-amplifying replicon RNA is at least 90% identical to SEQ ID NO: 1.
- RNA Self- amplifying RNA
- An in vitro evolution synthetic replicon RNA provides a potentially powerful strategy for modifying and enhancing replicon expression both in vitro and in vivo.
- mutations were identified in nsP2 and nsP3 of Venezuelan equine encephalitis (VEE) replicon that promoted subgenomic expression in human cells.
- VEE Venezuelan equine encephalitis
- the self-amplifying replicon RNA comprises mutations that render the replicon RNA capable of expressing the IL-12 molecule at a higher level compared to the replicon RNA comprising SEQ ID NO: 1.
- the self-amplifying replicon RNA comprises at least one point mutation in a nucleic acid position 3936 and/or 4758 of WT replicon of SEQ ID NO: 1.
- the self-amplifying replicon RNA comprises at least one of the following point mutations: guanine to cytosine at position 3936 (G3936C) and adenine to guanine at position 4758 (A4758G) of WT replicon sequence of SEQ ID NO:l.
- the G3936C mutation would result in a glycine to arginine change at amino acid residue 1309 (G1309R).
- the A4758G mutation would result in a serine to glycine change at amino acid residue 1583 (S1583G).
- the sequence of the mutant self-amplifying replicon RNA is set forth in SEQ ID NO: 2 with the mutations highlighted (bold, underlined text):
- the self-amplifying replicon RNA is derived from a Hepatitis C vims (HCV).
- HCV are part of the Group IV Flaviviridae family of viruses, possessing monopartite, linear, single- stranded RNA genomes of positive polarity, 9.6 to 12.3 kil phase in length.
- the 5'-termini of flaviviruses carry a methylated nucleotide cap, while other members of this family are uncapped and encode an internal ribosome entry site.
- the alphavims is a SF vims.
- the SF vims is a viral pathogen typically carried by mosquitos that causes encephalitis.
- the Semliki Forest vims is a positive- stranded RNA vims with a genome of approximately 13,000 base pairs which encodes nine proteins. The 5’ two thirds of the genome encode four non- structural proteins concerned with RNA synthesis and the structural proteins are encoded in the 3’ third. Of the structural proteins, the C proteins makes up the icosahedral capsid which is enveloped by a lipid bilayer, derived from the host cell.
- the alphavims is a SIN vims.
- the virus is transmitted by mosquitoes. SIN virus causes Sindbis fever in humans and the symptoms include arthralgia, rash and malaise. Sindbis viruses are enveloped particles with an icosahedral capsid. Its genome is a single stranded RNA approximately 11.7kb long.
- RNA messenger RNA
- the genome encodes four non-stmctural proteins at the 5' end and the capsid and two envelope proteins at the 3' end. This is characteristic of all Togaviruses. Replication is cytoplasmic and rapid.
- the genomic RNA is partially translated at the 5’ end to produce the non-stmctural proteins which are then involved in genome replication and the production of new genomic RNA and a shorter sub-genomic RNA strand. This sub-genomic strand is translated into the structural proteins.
- the viruses assemble at the host cell surfaces and acquire their envelope through budding.
- a non-coding RNA element has been found to be essential for Sindbis vims genome replication.
- the viral replicon RNA is capable of stimulating immune response via toll like receptors (TLRs).
- TLRs toll like receptors
- IFNs type I interferons
- TLR3 responds to double stranded RNA, a replication intermediary for many viruses.
- TLR7/8 recognize viral single-stranded RNAs
- TLR9 recognizes unmethylated CpG motifs within viral DNA.
- TLRs involved in vims recognition are expressed on endosomal membranes and can be separated according to their requirement for the adaptor protein MyD88: TLR3 activity is MyD 88 -independent while TLRs7/8/9 depend on MyD88.
- the activation of TLR3 leads to the production of Type I Interferon (IFN).
- IFN Type I Interferon
- Type-I interferon signaling through ISGF3 (STAT1/STAT2/IRF9) complex is required for sustained Rip3 activation and necroptosis.
- the LNP-replicon RNA are capable of stimulating TLR3 signaling in tumor cells, which leads to necrotic cell death of tumor cells.
- the LNP-replicon RNA can enhance the immunogenic cell death (ICD) induced by the LNPs.
- ICD immunogenic cell death
- TT3-LNP-Replicon RNA can exert tumor inhibition by synergistically induce ICD in tumor cells and trigger an anti-tumor immune response (e.g., recmiting of immune cells such as granulocytes, monocytes, macrophages, myeloid derived suppressive cells, dendritic cells, T cells, and NK cells).
- an anti-tumor immune response e.g., recmiting of immune cells such as granulocytes, monocytes, macrophages, myeloid derived suppressive cells, dendritic cells, T cells, and NK cells.
- the synthetic oncolytic vims comprises TT3-LNP-mtReplicon RNA.
- the replicon RNA comprises a coding sequence for a detectable molecule in the subgenomic region.
- the detectable molecule is a nucleic acid or a polypeptide.
- the polypeptide is a fluorescent protein. Fluorescent proteins are known in the art, and are a subclass of fluorophores, which are fluorescent chemical compounds with the ability to re-emit light upon excitation. The fluorophore will absorb excitation light energy of a first specific wavelength, and then will re-emit light energy at a second, longer specific wavelength. Each type of fluorophore responds to and emits differing wavelengths of light, depending on the nature of its chemical structure and environment.
- the fluorescent protein includes, but is not limited to, wt-GFP, green fluorescent protein (e.g., EGFP, Emerald, Superfolder GFP, Azami Green, mWasabi, TagGFP, TurboGFP, AcGFP, ZsGreen, T-Sapphire, etc.), blue fluorescent protein, (e.g., EBFP, EBFP2, Azurite, mTagBFP, etc.), cyan fluorescent protein (e.g., ECFP, mECFP, Cerulean, mTurquoise, CyPet, AmCyanl, Midori-Ishi Cyan, TagCFP, mTFPl (Teal), etc.), yellow fluorescent protein (e.g., EYFP, Topaz, Venus, mCitrine, YPet, TagYFP, PhiYFP, ZsYellowl, mBanana, etc.), orange fluorescent protein (e.g., Kusabira Orange, Kusa), Kusa
- the self-amplifying replicon RNA comprises a coding sequence for expression of IL-12 in the subgenomic region.
- An exemplary coding sequence for IL-12 is set forth in SEQ ID NO: 3:
- IL-12 belongs to type I cytokines and has a four a-helical bundle structure.
- IL-12 acts in a form of a heterodimeric protein (IL-12-p70; IL-12-p30/p40) consisting of two covalently linked p30 and p40 subunits. Contrary to the heterodimeric form, IL-12-p40/p40 homodimer acts mostly as a competitive suppressant of IL-12-p70 actions.
- IL-12 is a pleiotropic cytokine, the actions of which create an interconnection between the innate and adaptive immunity. IL-12 was first described as a factor secreted from PMA-induced EBV-transformed B-cell lines.
- IL-12 was initially designated as“cytotoxic lymphocyte maturation factor” and“natural killer cell stimulatory factor”. Due to bridging the innate and adaptive immunity and potently stimulating the production of ILN-g, a cytokine coordinating natural mechanisms of anticancer defense, IL- 12 seemed an ideal candidate for tumor immunotherapy in humans. However, severe side effects associated with systemic administration of IL-12 in clinical investigations and the very narrow therapeutic index of this cytokine markedly tempered enthusiasm for the use of this cytokine in cancer patients.
- IL-12 is a ligand of a receptor composed of two amino acid chains, IL- 12R-P 1 and IL-12R- b2.
- IL-12 receptor is expressed in a constitutive (e.g., IL- 12R-P 1 in B cells) or inducible (IL- 12R-P2) manner in a variety of immune cells, including NK cells, T, and B lymphocytes.
- Ligand-bound IL-12R-P2 becomes phosphorylated on tyrosines, which provides harboring sites for two kinases, JAK2 and TYK2.
- STAT4 is considered to be the most specific mediator of cellular responses elicited by IL-12.
- IL-12 actions are as follows: increasing production of ILN-g, which is the most potent mediator of IL-12 actions, from NK and T cells; stimulation of growth and cytotoxicity of activated NK cells, CD8+ and CD4+ T cells, shifting differentiation of CD4+ ThO cells toward the Thl phenotype; enhancement of antibody-dependent cellular cytotoxicity (ADCC) against tumor cells; and the induction of IgG and suppression of IgE production from B cells.
- ILN-g which is the most potent mediator of IL-12 actions, from NK and T cells
- ADCC antibody-dependent cellular cytotoxicity
- the main source of IL-12 in humans is the activated antigen-presenting cells, such as dendritic cells, especially of the CDlc-i- phenotype, as well as the hematopoietic phagocytes (monocytes, macrophages, and also neutrophils), but IL-12 can also be produced by other cell types. While IL-12 acts on a variety of immune cells, the overall physiological role for IL-12 seems to be orchestrating the Thl-type immune response against certain pathogens.
- the present disclosure in some aspect, describes local delivery of IL-12 by a LNP encapsulated viral replicon RNA, which encodes an IL-12 molecule in its subgenomic region.
- a LNP encapsulated viral replicon RNA which encodes an IL-12 molecule in its subgenomic region.
- the expression of IL12 in the tumor microenvironment can lead to further immunostimulation and results in an enhancement of anti-tumor immune response.
- the combination of LNP-replicon RNA-IL-12 in the tumor microenvironment is capable of induce a systemic anti-tumor immune response.
- the combination of LNP-replicon RNA-IL-12 in the tumor microenvironment is capable of eradicate the tumor cells and prevent the recurrence of the tumor.
- the synthetic oncolytic vims comprises TT3-LNP-mtReplicon RNA-IL12.
- the replicon RNA-IL12 further comprises a coding sequence for serum albumin.
- a biological environment e.g., serum, tumor microenvironment
- the half-life of proteins in biological environment can be roughly correlated with their size.
- Peptides and proteins smaller than approximately 70 kDa e.g., cytokines
- the serum albumin is human serum albumin.
- the serum albumin is mouse serum albumin (MSA).
- An exemplary coding sequence for replicon RNA-IL12-MSA is set forth in SEQ ID NO: 4:
- the replicon RNA-IL-12 is fused with a serum albumin coding sequence.
- the IL- 12-albumin fusion molecule has a longer half live in tumor microenvironment.
- the IL- 12-albumin fusion protein can persist in tumor microenvironment for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, or longer.
- the synthetic oncolytic virus comprises LNP-replicon RNA- IL- 12-serum albumin.
- the synthetic oncolytic vims comprises TT3- LNP-repliconRNA-IL- 12-serum albumin.
- the synthetic oncolytic virus comprises TT3-LNP-mtReplicon RNA-IL- 12-serum albumin.
- the persist presence of IL-12 in the tumor microenvironment may prolong the anti-tumor immune response exerted by the synthetic oncolytic vims.
- the replicon RNA-IL12-semm albumin further comprises a coding sequence for lumican.
- Lumican is one of the major extracellular proteins in the interstitial extracellular matrix (ECM) of the skin, comeal stroma, sclera, aorta, muscle, lung, kidney, bone, cartilage and intervertebral discs. It is a member of the family of small, leucine- rich proteoglycans (SLRP), with a core protein of 30-50 kDa comprising a signal peptide, a negatively charged N-terminal domain, a highly conserved leucine-rich internal domain and a carboxyl-terminal domain.
- SLRP small, leucine- rich proteoglycans
- the protein core and the glycan chains of lumican can interact with various cellular effectors, including cytokines, growth factors and cell surface receptors, to modulate cell adhesion, proliferation and migration.
- cytokines including cytokines, growth factors and cell surface receptors
- the presence of lumican in tumor microenvironment would promote local retention of
- the replicon RNA-IL- 12-MS A comprises a coding sequence for lumican.
- the mtReplicon RNA-IL-12-MSA comprises a coding sequence for lumican.
- MSA-lumican (mtRep-IL12-MSA-Lumican) is set forth in SEQ ID NO: 5:
- the synthetic oncolytic vims comprises TT3-LNP-repliconRNA-IL- 12- serum albumin-lumican. In other embodiments, the synthetic oncolytic vims comprises TT3-LNP-mtReplicon RNA-IL-12-semm albumin-lumican. The retention of IL-12 in the tumor microenvironment may improve the efficacy and safety of the synthetic oncolytic vims.
- the replicon RNA may comprise one or more gene(s) of experimental or therapeutic interest.
- the gene(s) of experimental or therapeutic interest encode cytokines, chemokines, or growth factors other than IL-12.
- Cytokines are known in the art, and the term itself refers to a generalized grouping of small proteins that are secreted by certain cells within the immune system and have an effect on other cells. Cytokines are known to enhance the cellular immune response and, as used herein, can include, but are not limited to, TNFa, IFN-g, IFN-a, TGF-b, IL-1, IL-2, IL-4, IL- 10, IL-13, IL-17, IL-18, and chemokines. Chemokines are useful for studies investigating response to infection, immune responses, inflammation, trauma, sepsis, cancer, and reproduction, among other applications.
- Chemokines are known in the art, and are a type of cytokines that induce chemotaxis in nearby responsive cells, typically of white blood cells, to sites of infection.
- Non-limiting examples of chemokines include, CCL14, CCL19, CCL20, CCL21, CCL25, CCL27, CXCL12, CXCL13, CXCL-8, CCL2, CCL3, CCL4, CCL5,
- growth factors are known in the art, and the term itself is sometimes interchangeable with the term cytokines.
- growth factors refers to a naturally occurring substance capable of signaling between cells and stimulating cellular growth. While cytokines may be growth factors, certain types of cytokines may also have an inhibitory effect on cell growth, thus differentiating the two terms.
- Non-limiting examples of growth factors include Adrenomedullin (AM), Angiopoietin (Ang), Autocrine motility factor, Bone morphogenetic proteins (BMPs), Ciliary neurotrophic factor (CNTF), Leukemia inhibitory factor (LIF), Interleukin-6 (IL-6), Macrophage colony-stimulating factor (m-CSF), Granulocyte colony- stimulating factor (G-CSF), Granulocyte macrophage colony-stimulating factor (GM-CSF), Epidermal growth factor (EGF), Ephrin Al, Ephrin A2, Ephrin A3, Ephrin A4, Ephrin A5, Ephrin B l, Ephrin B2, Ephrin B3, Erythropoietin (EPO), Fibroblast growth factor 1(FGF1), Fibroblast growth factor 2(FGF2), Fibroblast growth factor 3(FGF3), Fibroblast growth factor 4(FGF4), Fibroblast growth factor 5(FGF5),
- MSP Macrophage- stimulating protein
- GDF-8 Myostatin
- NGF1 Neuregulin 1
- Neuregulin 2 (NRG2), Neuregulin 3 (NRG3), Neuregulin 4 (NRG4), Brain-derived neurotrophic factor (BDNF), Nerve growth factor (NGF), Neurotrophin-3 (NT-3),
- Neurotrophin-4 (NT-4), Placental growth factor (PGF), Platelet-derived growth factor (PDGF), Renalase (RNLS), T-cell growth factor (TCGF), Thrombopoietin (TPO),
- TGF-a Transforming growth factor alpha
- TGF-b Transforming growth factor beta
- TNF-a Tumor necrosis factor- alpha
- VEGF Vascular endothelial growth factor
- the present disclosure at least in part, relates to a pharmaceutical composition, comprising the synthetic oncolytic virus, as described herein.
- composition described herein may further comprise a pharmaceutically acceptable carrier (excipient) to form a pharmaceutical composition for use in treating a target disease.
- a pharmaceutically acceptable carrier excipient
- “Acceptable” means that the carrier must be compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject to be treated.
- compositions to be used for in vivo administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes.
- the synthetic oncolytic vims -containing compositions may be placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
- the pharmaceutical composition to be used herein can be formulated for intratumoral injection.
- Intratumoral injection refers to direct injections into the tumor, an anti-tumor composition (e.g. immuno stimulatory synthetic oncolytic virus).
- an anti-tumor composition e.g. immuno stimulatory synthetic oncolytic virus.
- a high concentration of composition can be achieved in situ, while using small amounts of drugs.
- Local delivery of immunotherapies allows multiple combination therapies, while preventing significant systemic exposure and off-target toxicities.
- the pharmaceutical composition can be formulated for intra muscular injection, intravenous injection, or subcutaneous injection.
- compositions to be used in the present methods can comprise pharmaceutically acceptable carriers, buffer agents, excipients, salts, or stabilizers in the form of lyophilized formulations or aqueous solutions. See, e.g., Remington: The Science and Practice of Pharmacy 20th Ed. (2000) Lippincott Williams and Wilkins, Ed. K. E. Hoover). Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations used, and may comprise buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as
- octadecyldimethylbenzyl ammonium chloride hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrans; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbi
- the pharmaceutical composition described herein comprises lipid nanoparticles which can be prepared by methods known in the art, such as described in Epstein, et al., Proc. Natl. Acad. Sci. USA 82:3688 (1985); Hwang, et al., Proc. Natl. Acad. Sci. USA 77:4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545.
- Liposomes with enhanced circulation time are disclosed in U.S. Pat. No. 5,013,556.
- Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid
- composition comprising phosphatidylcholine, cholesterol and PEG-derivatized
- phosphatidylethanolamine PEG-PE
- Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.
- sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the synthetic oncolytic virus which matrices are in the form of shaped articles, e.g., films, or
- sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.
- polyesters for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)
- polylactides U.S. Pat. No. 3,773,919
- Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g., TWEENTM 20, 40, 60, 80 or 85) and other sorbitans (e.g., SPANTM 20, 40, 60, 80 or 85).
- Compositions with a surface- active agent will conveniently comprise between 0.05 and 5% surface-active agent, and can be between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other
- compositions described herein can be in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.
- the principal active ingredient can be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof.
- a pharmaceutical carrier e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
- preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
- the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
- Suitable emulsions may be prepared using commercially available fat emulsions, such as INTRALIPIDTM, LIPOSYNTM, INFONUTROLTM, LIPOFUNDINTM and
- the active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, com oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water.
- an oil e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, com oil or almond oil
- a phospholipid e.g., egg phospholipids, soybean phospholipids or soybean lecithin
- Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%.
- the fat emulsion can comprise fat droplets having a suitable size and can have a pH in the range of 5.5 to 8.0.
- compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
- the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
- the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
- compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be
- compositions disclosed herein comprising a synthetic oncolytic virus, can be used to treat cancer, for example, cancer immunotherapy.
- compositions described herein can be administered to a subject (e.g., a human) in need of the treatment via a suitable route, such as intratumoral administration, by intravenous administration, e.g., as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerebrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, inhalation or topical routes.
- nebulizers for liquid formulations including jet nebulizers and ultrasonic nebulizers are useful for administration. Liquid formulations can be directly nebulized and lyophilized powder can be nebulized after reconstitution.
- synthetic oncolytic vims containing pharmaceutical composition can be aerosolized using a fluorocarbon formulation and a metered dose inhaler, or inhaled as a lyophilized and milled powder.
- the pharmaceutical composition described herein is formulated for intratumoral injection.
- the pharmaceutical composition may be administered to a subject (e.g., a human patient) via a local route, for example, injected to a local site such as a tumor site or an infectious site.
- an effective amount refers to the amount of each active agent required to confer therapeutic effect on the subject, either alone or in combination with one or more other active agents.
- the therapeutic effect is reduced tumor burden, reduction of cancer cells, or increased immune activity. Determination of whether an amount of synthetic oncolytic vims achieved the therapeutic effect would be evident to one of skill in the art. Effective amounts vary, as recognized by those skilled in the art, depending on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size, gender and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment.
- Empirical considerations such as the half-life, generally will contribute to the determination of the dosage.
- Frequency of administration may be determined and adjusted over the course of therapy, and is generally, but not necessarily, based on treatment and/or suppression and/or amelioration and/or delay of a target disease/disorder.
- sustained continuous release formulations of a synthetic oncolytic virus may be appropriate.
- Various formulations and devices for achieving sustained release are known in the art.
- the treatment is a single injection of the synthetic oncolytic vims containing pharmaceutical composition.
- the single injection is administered intratumorally to the subject in need thereof.
- dosages for a synthetic oncolytic virus as described herein may be determined empirically in individuals who have been given one or more administration(s) of synthetic oncolytic. Individuals are given incremental dosages of the synthetic oncolytic containing composition. To assess efficacy of the synthetic oncolytic virus, an indicator of the disease/disorder can be followed. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of symptoms occurs or until sufficient therapeutic levels are achieved to alleviate a target disease or disorder, or a symptom thereof.
- dosing frequency is once every week, every 2 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, or every 10 weeks; or once every month, every 2 months, or every 3 months, or longer.
- the progress of this therapy is easily monitored by conventional techniques and assays.
- the dosing regimen of the synthetic oncolytic vims used can vary over time.
- the method described herein comprises administering to a subject in need of the treatment (e.g., a human patient) one or multiple doses of synthetic oncolytic virus-containing pharmaceutical composition.
- the appropriate dosage synthetic oncolytic vims as described herein will depend on the specific synthetic oncolytic vims, the type and severity of the disease/disorder, the synthetic oncolytic vims is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the synthetic oncolytic vims, and the discretion of the attending physician.
- a clinician may administer a synthetic oncolytic vims, until a dosage is reached that achieves the desired result.
- the desired result is a decrease in tumor burden, a decrease in cancer cells, or increased immune activity. Methods of determining whether a dosage resulted in the desired result would be evident to one of skill in the art.
- Administration of one or more synthetic oncolytic vims can be continuous or intermittent, depending, for example, upon the recipient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners.
- administration synthetic oncolytic vims may be essentially continuous over a preselected period of time or may be in a series of spaced dose, e.g., either before, during, or after developing a target disease or disorder.
- the term“treating” refers to the application or administration of a composition including one or more active agents to a subject, who has a target disease or disorder, a symptom of the disease/disorder, or a predisposition toward the disease/disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disorder, the symptom of the disease, or the predisposition toward the disease or disorder.
- Alleviating a target disease/disorder includes delaying the development or progression of the disease, or reducing disease severity. Alleviating the disease does not necessarily require curative results.
- “delaying” the development of a target disease or disorder means to defer, hinder, slow, retard, stabilize, and/or postpone progression of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individuals being treated.
- a method that“delays” or alleviates the development of a disease, or delays the onset of the disease is a method that reduces probability of developing one or more symptoms of the disease in a given time frame and/or reduces extent of the symptoms in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a number of subjects sufficient to give a statistically significant result.
- “Development” or“progression” of a disease means initial manifestations and/or ensuing progression of the disease. Development of the disease can be detectable and assessed using standard clinical techniques as well known in the art. However, development also refers to progression that may be undetectable. For purpose of this disclosure, development or progression refers to the biological course of the symptoms. “Development” includes occurrence, recurrence, and onset. As used herein“onset” or“occurrence” of a target disease or disorder includes initial onset and/or recurrence.
- a synthetic oncolytic virus-containing pharmaceutical composition as described herein are administered to a subject in need of the treatment at an amount sufficient to reduce tumor burden or cancer cell growth, by at least 5% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) in vivo.
- the synthetic oncolytic virus-containing pharmaceutical compositions as described herein can be administered in an amount effective in increasing immune activity by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater.
- the subject to be treated by the methods described herein can be a mammal, such as a human, farm animals, sport animals, pets, primates, horses, dogs, cats, mice and rats.
- the subject is a human.
- the synthetic oncolytic vims -containing composition as described herein may be used for enhancing immune activity, for example, T cell activity, in a subject in need of the treatment.
- the subject may be a human patient having, suspected of having, or at risk for a cancer.
- cancers include melanoma, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, gastric cancer, and various types of head and neck cancer, including squamous cell head and neck cancer.
- the cancer can be melanoma, lung cancer, colorectal cancer, renal-cell cancer, urothelial carcinoma, or
- a subject having a target disease or disorder can be identified by routine medical examination, e.g., laboratory tests, organ functional tests, CT scans, or ultrasounds.
- a subject suspected of having any of such target disease/disorder might show one or more symptoms of the disease/disorder.
- a subject at risk for the disease/disorder can be a subject having one or more of the risk factors associated with that disease/disorder. Such a subject can also be identified by routine medical practices.
- a synthetic oncolytic virus-containing pharmaceutical composition may be co-used with another suitable therapeutic agent (e.g., an anti-cancer agent an anti-viral agent, or an anti-bacterial agent) and/or other agents that serve to enhance and/or complement the immunostimulatory effect of a synthetic oncolytic virus.
- another suitable therapeutic agent e.g., an anti-cancer agent an anti-viral agent, or an anti-bacterial agent
- the a synthetic oncolytic virus-containing composition and the additional therapeutic agent e.g., an anti-cancer therapeutic agent or others described herein
- the additional therapeutic agent e.g., an anti-cancer therapeutic agent or others described herein
- therapeutic agent is administered at a different time.
- these therapeutic agents, or at least two of the agents, are administered to the subject in a substantially simultaneous manner.
- Combination therapy can also embrace the administration of the agents described herein (e.g., a synthetic oncolytic vims containing pharmaceutical composition and an anti cancer agent) in further combination with other biologically active ingredients (e.g., a different anti-cancer agent) and non-drug therapies (e.g., surgery).
- agents described herein e.g., a synthetic oncolytic vims containing pharmaceutical composition and an anti cancer agent
- other biologically active ingredients e.g., a different anti-cancer agent
- non-drug therapies e.g., surgery.
- any combination of a synthetic oncolytic vims - containing composition and another anti-cancer agent may be used in any sequence for treating a cancer.
- the combinations described herein may be selected on the basis of a number of factors, which include but are not limited to the effectiveness of reducing tumor formation or tumor growth, reducing cancer cells, increasing immune activity, and/or alleviating at least one symptom associated with the cancer, or the effectiveness for mitigating the side effects of another agent of the combination.
- a combined therapy described herein may reduce any of the side effects associated with each individual members of the combination, for example, a side effect associated with the anti-cancer agent.
- another anti-cancer therapeutic agent is a chemotherapy, a radiation therapy, a surgical therapy and/or an immunotherapy. Examples of the
- chemotherapeutic agents include, but are not limited to, Carboplatin or Cisplatin, Docetaxel, Gemcitabine, Nab-Paclitaxel, Paclitaxel, Pemetrexed, and Vinorelbine.
- radiation therapy include, but are not limited to, ionizing radiation, gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic radioactive isotopes and radiosensitizers.
- a surgical therapy include, but are not limited to, a curative surgery (e.g., tumor removal surgery), a preventive surgery, a laparoscopic surgery, and a laser surgery.
- an immunotherapy include, but are not limited to, adoptive cell transfer and therapeutic cancer vaccines.
- chemotherapy include, but are not limited to, platinating agents, such as Carboplatin, Oxaliplatin, Cisplatin, Nedaplatin, Satraplatin, Lobaplatin, Triplatin, Tetranitrate, Picoplatin, Prolindac, Aroplatin and other derivatives; Topoisomerase I inhibitors, such as Camptothecin, Topotecan, irinotecan/SN38, mbitecan, Belotecan, and other derivatives; Topoisomerase II inhibitors, such as Etoposide (VP- 16), Daunombicin, a doxorubicin agent (e.g., doxorubicin, doxorubicin HC1, doxorubicin analogs, or doxorubicin and salts or analogs thereof in liposomes), Mitoxantrone, Aclambicin, Epirubicin, Idambicin, Ammbicin, Amsacrine, Pirarubicin, Valmbicin, Zombici
- kits for use in immunotherapy against cancer e.g., melanoma, lung cancer, colorectal cancer, or renal-cell cancer
- Such kits can include one or more containers comprising a a synthetic oncolytic vims -containing pharmaceutical composition, e.g., any of those described herein.
- the kit can comprise instructions for use in accordance with any of the methods described herein.
- the included instructions can comprise a description of administration of the a synthetic oncolytic virus-containing composition to treat, delay the onset, or alleviate a target disease as those described herein.
- the kit may further comprise a description of selecting an individual suitable for treatment based on identifying whether that individual has the target disease.
- the instructions comprise a description of administering the synthetic oncolytic vims -containing composition to an individual at risk of the target disease.
- the instructions relating to the use of a synthetic oncolytic virus-containing composition generally include information as to dosage, dosing schedule, and route of administration for the intended treatment.
- the containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses.
- Instmctions supplied in the kits of the invention are typically written instmctions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instmctions (e.g., instmctions carried on a magnetic or optical storage disk) are also acceptable.
- the label or package insert indicates that the composition is used for treating, delaying the onset and/or alleviating a disease or disorder associated with cancer, such as those described herein. Instmctions may be provided for practicing any of the methods described herein.
- kits as described herein are in suitable packaging.
- suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like.
- packages for use in combination with a specific device such as an inhaler, nasal administration device (e.g., an atomizer) or an infusion device such as a minipump.
- a kit may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
- the container may also have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
- a sterile access port for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle.
- At least one active agent in the composition is a synthetic oncolytic vims - containing composition such as those described herein.
- Kits may optionally provide additional components such as buffers and interpretive information.
- the kit comprises a container and a label or package insert(s) on or associated with the container.
- the invention provides articles of manufacture comprising contents of the kits described above.
- Monoclonal antibodies a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using antibodies: a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J. D.
- Antibodies against mouse Ly6c (HK1.4), CDl lb (Ml/70), CDl lc (N418), F4/80 (BM8), MHC-II (M5/114.15.2), CD45 (30-F11), CD3 (17A2), CD4 (GK1.5), CD8 (53-6.7), NK1.1 (PK136), CD45.2 (104), CD24 (30-F1), XCR1 (ZET), CD64 (X54-5/7.1) were from Biolegend.
- Antibodies against mouse Ly6G (1A8), CD16/32 (2.4G2) and CD103 (M290) were from BD Biosciences.
- Antibodies against mouse Calreticulin (ab2907) was from Abeam.
- the live/dead dye (L34966) were from ThermoFisher.
- the B16F10 melanoma tumor bearing mice were sacrificed and necropsied following federal, state, and local guidelines under an IACUC-approved animal protocol by Committee of Animal Care at MIT. Then the tumor draining lymph nodes were ground, and the tumors were sliced and digested by collagenase IV (1 mg/ml) for one hour for single cell
- the single cells suspensions were filtered by 70 pm nylon constrainer and stained as described 10 .
- the stained samples were analyzed by FACS analyzer (LSR-II or LSR-ITFortessa) from BD Biosciences analyzed on a BD-LSRII Fortessa analyzer. All flow cytometry data were analyzed by FlowJo (Flowjo LLC) and the plots were prepared using GraphPad Prism.
- mutant replicon constructs were from an in vitro evolution in a previous study (in revision).
- the IL12-MSA and IL12-MSA-Lumican were amplified from plasmids from Prof. Dane Wittrup Lab, and engineered in the subgenomic region of mutant replicon.
- Replicon RNAs were in vitro transcribed (IVT) from the templates of linearized VEE- constructs above using the MEGAscriptTM T7 Transcription Kit (ThermoFisher) following the manufacturer’s instructions. Resulting replicon RNAs were capped and methylated using the ScriptCapTM m7G Capping System and ScriptCapTM 2'-0-Methyltransferase Kit
- RNA purity was assessed by gel electrophoresis.
- a lipid mixture composed of 16.9375 pi DOTAP (Avanti, Cat#890890, 10 mg/ml), 15.965 pi DSPC (Avanti, Cat#850365, 3mg/ml), 18.7675 pi cholesterol (Sigma-Aldrich, Cat#C8667, 6 mg/ml), 13.6 pi DSPE-PEG2000 (Avanti Cat#880128, 2.5 mg/ml) in a molar ratio of 40:10:48:2 was prepared in ethanol and evaporated under N2 till one third of the total initial volume remained.
- Encapsulating replicon RNA into lipofectamine nanoparticle was following the instruction of LipofectamineTM MessengerMAXTM Transfection Reagent
- a lipid mixture composed of 10 pi TT3 (10 mg/ml) n , 8.04 pi DOPE (Avanti, Cat# 850725, 10 mg/ml), 5.572 m ⁇ cholesterol (Sigma-Aldrich, Cat#C8667, 10 mg/ml), 3.452 m ⁇ C14-PEG2000 (Avanti Cat# 880150, 2 mg/ml) in a molar ratio of 20:30:40:0.75 was prepared in 10.437 m ⁇ ethanol. The mixture were added 4.167 m ⁇ citrate buffer (PH 3.0, 10 mM).
- lipid nanoparticles were aliquoted in appropriate dosages for intratumoral injection (10 pg/mouse) and for transfection in vitro (5 pg/0.5 million cells in 500 m ⁇ media).
- RNA transcripts total RNA was extracted from cells or tumors transfected with LNP-replicon RNA as indicated and reverse transcribed by a TaqManTM Reverse Transcription Reagents Kit (ABI Catalog No. N8080234), followed by amplification with Sybr Green Master Mix (Roche) and specific primers for Statl (Cat#MP215434), Stat2 (Cat#MP215434), IRF9 (Cat#MP206708), IRF3 (Cat#MP206702), cGAS (Cat#MP214711) and detected by a Roche LightCycler 480. The Ct values were normalized with housekeeping gene mouse Actin B for comparison.
- Therapeutic processes can be simplified and therapeutic efficacy can be amplified by synthetic multifunctional lipid nanoparticles (LNPs) encapsulating replicon RNA, with the lipid and RNA components each serving multiple roles: a lipid formulation that both promotes cellular uptake/cytosolic delivery of RNA while also directly triggering
- this LNP delivers self-amplifying replicon RNA that both encodes immunomodulatory therapeutic proteins and directly provides
- this synthetic LNP replicon RNA should induce local immunogenic cell death in tumor and also express immunomodulatory decently in transfected cells. Immunogenic cell death could enhance tumor infiltration by immune cells and provide a reservoir of tumor- specific antigens that could be cross presented to prime new T cells responses.
- LNP formulations containing the cationic lipid TT3 was identified as being especially relevant for these goals: 3 cationic lipid nanoparticles, each comprising a key cationic lipid- DOTAP, Lipofectamine (Lipo) or TT3, were compared.
- RNA cargo an alphavirus replicon, derived from Venezuela Equine Encephalitis virus where the structural proteins were replaced by a cargo gene of interest inserted under the subgenomic promoter, was employed.
- LNP-mtRep self- amplifying replicon RNA
- the DOTAP, lipo, and TT3 lipid formulations formed particles with mean diameters of 97, 46, and 105 nm nanoparticles, with zeta potentials of +22.9, -6.7, and +4.3 mv, respectively (Fig. 1G-1H).
- RNA-loaded (mtRep) LNPs was assessed by incubating each formulation with B16F10 melanoma tumor cells in vitro. This assay revealed that viability significantly decreased for cells treated with TT3 LNPs, and mtRep synergized with TT3 to promote further tumor cell killing at 3-day post transfection (Fig. 1A).
- TT3 LNPs were more effective than DOTAP or Lipo in promoting tumor cell death.
- electroporation of replicon directly into tumor cells was relatively nontoxic, indicating that cell killing is promoted by the LNP delivery.
- To determine whether TT3 LNP-delivered replicons could drive cargo gene expression prior to cell death we evaluated expression of the reporter gene GFP following LNP(mtRep) treatment.
- TT3-mtRep treatment led to -35.4% of B16F10 cells to express GFP 12 hours post transfection, lower than electroporation (-90%), but significantly better than DOTAP-mtRep (-0.05%) or Lipo-mtRep (-7.6%) treatments (Fig. IB). Consistent with Figure 1A, the cells transfected with TT3 nanoparticles showed a large population of Annexin V+/PI+ dead cells and mtRep again synergized to this cell death (Fig. 1C).
- TT3(mtRep) is a type of immunogenic cell death (ICD), calreticulin (CRT), which generally stays on endoplasmic reticulum (ER) and traffics to cell surface as an eat- me signal during ICD1, was measured.
- ICD immunogenic cell death
- CRT calreticulin
- ER endoplasmic reticulum
- TT3 and mtRep synergized to promote the CRT trafficking to cell surfaces
- Extracellular ATP activates the NLRP3 inflammasome2 and extracellular HMGB 1 mediates inflammation3 during ICD.
- TT3, TT3-mtRep, and TT3-deRep effectively induced ATP and HMGB1 release. (Fig. IE and IF).
- TT3-mtRep RNA is a promising oncolytic formulation that could induce immunogenic cell death while also leading to transient expression of cargo genes encoded by the replicon.
- TT3 LNP DOTAP, Lipo, or TT3 nanoparticles with or without encapsulated mtRep encoding a reporter gene (or encapsulating a mutant“dead” replicon (deRep) that lacks functional gene expression) were transfected into reporter cells HEK-TLR2, HEK-TLR3, HEK-TLR7, or HEK-TLR9 (invivogen.com). Both Lipo and TT3 LNPs carrying mtRep or deRep activated TLR3 signaling, but none of the other TLRs tested were stimulated (Fig. 2A- D).
- DOTAP and Lipo formulations failed to induce the ISGF3 complex, likely because of low transfection efficiency of replicon RNA by these nanoparticles (Fig. IB). These data suggested that mtRep and deRep likely activate TLR3 signaling and induce ISGF3 complex to promote necrotic cell death, a type of immunogenic cell death.
- TT3-mtRep has effects on immunogenic cell death and expression of cargo genes in vivo was of interest.
- the absolute number of Ly6c l0 Ly6G + granulocytic populations, which are associated with responses to necrotic cell death 6 was measured in tumors at 3-day post intratumoral injection of TT3 nanoparticles encapsulating wild type replicon RNA (wtRep), with another mutant replicon RNA (mt2Rep), and the mutant replicon (mtRep) used above.
- TT3-mtRep induces immunogenic cell death with decent cargo gene expression. In vivo studies using TT3-mtRep were carried out subsequently.
- immune cells such as granulocytes (CD45 + CDl lb + Ly6c l0 Ly6G + ), M-MDSC (CD45 + CDl lb + Ly6c hl Ly6G + ), Monocytes (D45 + CDl lb + Ly6c l0 Ly6G ), Macrophages (CD45 + CDl lb + Ly6c Ly6G F4/80 + ), CD4 T (CD45 + CD3e + CD4 + ), CD8 T (CD45 + CD3e + CD8 + ), NK (CD45 + CD3e NK1.1 + ), NKT (CD45 + CD3e + NK1.1 + ), conventional DC1 (cDCl,
- TT3-mtRep induced immunogenic cell death in tumors with expression of cargo genes as observed in Fig. 1 and Fig. 2 in vitro. Most importantly, TT3-mtRep significantly modulated the tumor
- Example 4 TT3-mtRep Encoding with IL12-MSA or IL12-MSA-Lumican Effectively
- IL-12 which could polarize CD4 T helpers to Thl and enhance cytotoxicity effects of NK and CD8 T cells 8 .
- IL12b One of the subunit of IL12, also named as IL12b or
- IL12p40 is mainly secreted from antigen presentation cells (CD8 + DCs)
- interferon a2 IFNa2
- Fig. 4 A the serum
- Fig. 4B the tumors
- IL-12 secreted by DCs may still be low in the tumor
- TEE microenvironment
- Lumican is an endogenous collagen-binding protein, which we reasoned would promote retention of expressed IL-12 in the TME to enhance efficacy and safety of the replicon therapy.
- the replicon constructs were transfected in B 16F10 cells in vitro by NEON transfection and we validated IL12 secretion in these transfected cells by ELISA (Fig. 4C).
- tumors injected with TT3-mtRep encoding IL12-MSA (TT3-mtRep- IL12-MSA) or IL12-MSA-Lumican (TT3-mtRep-IL12-MSA-Lumican) expressed high levels of IL12 in vivo, reaching 40 ng/mg in tumors (Fig. 4D).
- granulocytes was 1.5-3 times increased in the tumors treated with TT3-mtRep expressing IL12-MSA and IL12-MSA-Lumican, in contrast to the group treated with TT3-mtRep encoding with reporter gene mCherry (Fig.
- IL12- MSA and IL12-MSA-Lumican groups recruited ⁇ 2-3 times higher granulocytes, CD8 T cells, and cDC2 cells to tumors compared to replicons encoding an irrelevant reporter gene (Fig. 4F).
- tumors treated with TT3-mtRep encoding reporter genes, IL12-MSA, or IL12-MSA-Lumican all showed decreases of cDCl cells in comparison to the untreated group (Fig. 4E-4F).
- mice were challenged with 0.1 million B 16F10 cells in opposite flank. As expected, all of the cured mice rejected the B 16F10 tumor in comparison of the naive mice that quickly development of B 16F10 tumor.
- inventive embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed.
- inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein.
- a reference to“A and/or B”, when used in conjunction with open-ended language such as“comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
- “or” should be understood to have the same meaning as“and/or” as defined above.
- “or” or“and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as“only one of’ or“exactly one of,” or, when used in the claims,“consisting of,” will refer to the inclusion of exactly one element of a number or list of elements.
- the phrase“at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
- This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase“at least one” refers, whether related or unrelated to those elements specifically identified.
- “at least one of A and B” can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Virology (AREA)
- Microbiology (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Toxicology (AREA)
- Oncology (AREA)
- Mycology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2021010808A MX2021010808A (es) | 2019-03-08 | 2020-01-10 | Ácido ribonucleico replicón-nanopartículas sinteticas oncolítico y sintético y usos para inmunoterapia de cáncer. |
SG11202109514VA SG11202109514VA (en) | 2019-03-08 | 2020-01-10 | Synthetic oncolytic lnp-replicon rna and uses for cancer immunotherapy |
EP20704372.0A EP3934673A1 (en) | 2019-03-08 | 2020-01-10 | Synthetic oncolytic lnp-replicon rna and uses for cancer immunotherapy |
CA3132714A CA3132714A1 (en) | 2019-03-08 | 2020-01-10 | Synthetic oncolytic lnp-replicon rna and uses for cancer immunotherapy |
JP2021553767A JP2022524391A (ja) | 2019-03-08 | 2020-01-10 | 合成腫瘍溶解性lnpレプリコンrnaおよびがん免疫治療のための使用 |
AU2020233788A AU2020233788A1 (en) | 2019-03-08 | 2020-01-10 | Synthetic oncolytic LNP-replicon RNA and uses for cancer immunotherapy |
BR112021017637A BR112021017637A8 (pt) | 2019-03-08 | 2020-01-10 | Vírus oncolítico sintético, composição farmacêutica, e, método para tratar câncer |
CN202080034343.3A CN113966221A (zh) | 2019-03-08 | 2020-01-10 | 合成溶瘤lnp复制子rna和用于癌症免疫治疗的用途 |
KR1020217032460A KR20220006041A (ko) | 2019-03-08 | 2020-01-10 | 합성 종양용해성 lnp-레플리콘 rna 및 암 면역요법을 위한 용도 |
IL285963A IL285963A (en) | 2019-03-08 | 2021-08-30 | Synthetic oncolytic replicon-lnp RNA and uses for cancer immunotherapy |
CONC2021/0013417A CO2021013417A2 (es) | 2019-03-08 | 2021-10-07 | Arn del replicón-lnp oncolítico sintético y usos para la inmunoterapia contra el cáncer |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201962815611P | 2019-03-08 | 2019-03-08 | |
US62/815,611 | 2019-03-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020185293A1 true WO2020185293A1 (en) | 2020-09-17 |
Family
ID=69526302
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2020/013069 WO2020185293A1 (en) | 2019-03-08 | 2020-01-10 | Synthetic oncolytic lnp-replicon rna and uses for cancer immunotherapy |
Country Status (13)
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113509542A (zh) * | 2021-04-20 | 2021-10-19 | 嘉晨西海(杭州)生物技术有限公司 | 一种基于mRNA的表达白介素12针对肿瘤的药物及其制备方法 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023212618A1 (en) | 2022-04-26 | 2023-11-02 | Strand Therapeutics Inc. | Lipid nanoparticles comprising venezuelan equine encephalitis (vee) replicon and uses thereof |
CN115227674B (zh) * | 2022-08-05 | 2023-07-04 | 武汉滨会生物科技股份有限公司 | 包封的溶瘤病毒遗传物质及其应用 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
US4485045A (en) | 1981-07-06 | 1984-11-27 | Research Corporation | Synthetic phosphatidyl cholines useful in forming liposomes |
US4544545A (en) | 1983-06-20 | 1985-10-01 | Trustees University Of Massachusetts | Liposomes containing modified cholesterol for organ targeting |
US5013556A (en) | 1989-10-20 | 1991-05-07 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
WO2012006376A2 (en) * | 2010-07-06 | 2012-01-12 | Novartis Ag | Virion-like delivery particles for self-replicating rna molecules |
WO2016037053A1 (en) * | 2014-09-05 | 2016-03-10 | Novartis Ag | Lipids and lipid compositions for the delivery of active agents |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016187531A1 (en) * | 2015-05-21 | 2016-11-24 | Ohio State Innovation Foundation | Benzene-1,3,5-tricarboxamide derivatives and uses thereof |
-
2020
- 2020-01-10 MX MX2021010808A patent/MX2021010808A/es unknown
- 2020-01-10 CA CA3132714A patent/CA3132714A1/en active Pending
- 2020-01-10 CN CN202080034343.3A patent/CN113966221A/zh active Pending
- 2020-01-10 WO PCT/US2020/013069 patent/WO2020185293A1/en active Application Filing
- 2020-01-10 SG SG11202109514VA patent/SG11202109514VA/en unknown
- 2020-01-10 AU AU2020233788A patent/AU2020233788A1/en active Pending
- 2020-01-10 JP JP2021553767A patent/JP2022524391A/ja active Pending
- 2020-01-10 US US16/739,407 patent/US11717548B2/en active Active
- 2020-01-10 EP EP20704372.0A patent/EP3934673A1/en active Pending
- 2020-01-10 KR KR1020217032460A patent/KR20220006041A/ko unknown
- 2020-01-10 BR BR112021017637A patent/BR112021017637A8/pt unknown
-
2021
- 2021-08-30 IL IL285963A patent/IL285963A/en unknown
- 2021-10-07 CO CONC2021/0013417A patent/CO2021013417A2/es unknown
-
2023
- 2023-06-14 US US18/334,449 patent/US20240024394A1/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
US4485045A (en) | 1981-07-06 | 1984-11-27 | Research Corporation | Synthetic phosphatidyl cholines useful in forming liposomes |
US4544545A (en) | 1983-06-20 | 1985-10-01 | Trustees University Of Massachusetts | Liposomes containing modified cholesterol for organ targeting |
US5013556A (en) | 1989-10-20 | 1991-05-07 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
WO2012006376A2 (en) * | 2010-07-06 | 2012-01-12 | Novartis Ag | Virion-like delivery particles for self-replicating rna molecules |
WO2016037053A1 (en) * | 2014-09-05 | 2016-03-10 | Novartis Ag | Lipids and lipid compositions for the delivery of active agents |
Non-Patent Citations (34)
Title |
---|
"Antibodies: a practical approach", 1988, IRL PRESS |
"Cell and Tissue Culture: Laboratory Procedures", August 1993, J. WILEY AND SONS |
"Current Protocols in Immunology", 1991 |
"Gene Transfer Vectors for Mammalian Cells", 1987 |
"Handbook of Experimental Immunology", 1994, ACADEMIC PRESS, INC. |
"Introduction to Cell and Tissue Culture", 1998, ACADEMIC PRESS |
"Oligonucleotide Synthesis", 1984 |
"Remington: The Science and Practice of Pharmacy", 2000, LIPPINCOTT WILLIAMS AND WILKINS |
"The Antibodies", 1995, HARWOOD ACADEMIC PUBLISHERS |
"Using antibodies: a laboratory manual", 1999, COLD SPRING HARBOR LABORATORY PRESS |
ANONYMOUS: "Koch Institute Immune Engineering Symposium 2019", 6 February 2019 (2019-02-06), XP055682910, Retrieved from the Internet <URL:https://acir.org/weekly-digests/2019/february/koch-institute-immune-engineering-symposium-2019> [retrieved on 20200403] * |
BOTTCHER, J. P. ET AL.: "NK Cells Stimulate Recruitment of cDCl into the Tumor Microenvironment Promoting Cancer Immune Control", CELL, vol. 172, 2018, pages 1022 - 1037 el014 |
C. A. JANEWAYP. TRAVERS, IMMUNOBIOLOGY, 1997 |
EPSTEIN ET AL., PROC. NATL. ACAD. SCI. USA, vol. 82, 1985, pages 3688 |
H. REN ET AL: "Immunogene therapy of recurrent glioblastoma multiforme with a liposomally encapsulated replication-incompetent Semliki forest virus vector carrying the human interleukin-12 gene - a phase I/II clinical protocol", JOURNAL OF NEURO-ONCOLOGY., vol. 64, no. 1-2, 1 August 2003 (2003-08-01), US, pages 147 - 154, XP055682947, ISSN: 0167-594X, DOI: 10.1007/BF02700029 * |
HAVERKAMP, J. M. ET AL.: "Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways", IMMUNITY, vol. 41, 2014, pages 947 - 959, XP055356248, DOI: 10.1016/j.immuni.2014.10.020 |
HWANG ET AL., PROC. NATL. ACAD. SCI. USA, vol. 77, 1980, pages 4030 |
IAN LAI ET AL: "Lipid nanoparticles that deliver IL-12 messenger RNA suppress tumorigenesis in MYC oncogene-driven hepatocellular carcinoma", JOURNAL FOR IMMUNOTHERAPY OF CANCER, BIOMED CENTRAL LTD, LONDON, UK, vol. 6, no. 1, 20 November 2018 (2018-11-20), pages 1 - 11, XP021262851, DOI: 10.1186/S40425-018-0431-X * |
KAWAI, T.AKIRA, S.: "TLR signaling", CELL DEATH DIFFER, vol. 13, 2006, pages 816 - 825 |
KENNETH LUNDSTROM: "Replicon RNA Viral Vectors as Vaccines", VACCINES, vol. 4, no. 4, 7 November 2016 (2016-11-07), pages 39, XP055552221, DOI: 10.3390/vaccines4040039 * |
LASEK, W.ZAGOZDZON, R.JAKOBISIAK, M.: "Interleukin 12: still a promising candidate for tumor immunotherapy?", CANCER IMMUNOL IMMUNOTHER, vol. 63, 2014, pages 419 - 435, XP055656186, DOI: 10.1007/s00262-014-1523-1 |
LI, B. ET AL.: "An Orthogonal Array Optimization of Lipid-like Nanoparticles for mRNA Delivery in Vivo", NANO LETT, vol. 15, 2015, pages 8099 - 8107, XP055536347, DOI: 10.1021/acs.nanolett.5b03528 |
LI, Y. ET AL.: "Persistent Antigen and Prolonged AKT-mTORC 1 Activation Underlie Memory CD8 T Cell Impairment in the Absence of CD4 T Cells", J IMMUNOL, vol. 195, 2015, pages 1591 - 1598 |
LUNDSTROM KENNETH ED - ORTEGO JAVIER ET AL: "Alphavirus vectors as tools in neuroscience and gene therapy", VIRUS RESEARCH, AMSTERDAM, NL, vol. 216, 22 August 2015 (2015-08-22), pages 16 - 25, XP029472298, ISSN: 0168-1702, DOI: 10.1016/J.VIRUSRES.2015.08.015 * |
LUNDSTROM KENNETH: "Alphavirus-based vaccines", CURRENT OPINION IN MOLECULAR THERAPEUTICS, CURRENT DRUGS, LONDON, GB, vol. 4, no. 1, 1 February 2002 (2002-02-01), pages 28 - 34, XP008095711, ISSN: 1464-8431 * |
MAGNA, M.PISETSKY, D. S.: "The role of HMGB 1 in the pathogenesis of inflammatory and autoimmune diseases", MOL MED, vol. 20, 2014, pages 138 - 146, XP055237917, DOI: 10.2119/molmed.2013.00164 |
MCCOMB, S. ET AL.: "Type-I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in macrophages", PROC NATL ACAD SCI U S A, vol. 111, 2014, pages E3206 - 3213 |
MONTOYA, M. ET AL.: "Type I interferons produced by dendritic cells promote their phenotypic and functional activation", BLOOD, vol. 99, 2002, pages 3263 - 3271 |
NOOR MOMIN ET AL: "Anchoring of intratumorally administered cytokines to collagen safely potentiates systemic cancer immunotherapy", SCIENCE TRANSLATIONAL MEDICINE, vol. 11, no. 498, 26 June 2019 (2019-06-26), US, pages eaaw2614, XP055655658, ISSN: 1946-6234, DOI: 10.1126/scitranslmed.aaw2614 * |
P. FINCH, ANTIBODIES, 1997 |
SAMBROOK ET AL.: "Molecular Cloning: A Laboratory Manual", 1989, COLD SPRING HARBOR PRESS |
WEIYU ZHAO ET AL: "Lipid Polymer Hybrid Nanomaterials for mRNA Delivery", CELLULAR AND MOLECULAR BIOENGINEERING, vol. 11, no. 5, 19 June 2018 (2018-06-19), Boston, pages 397 - 406, XP055536695, ISSN: 1865-5025, DOI: 10.1007/s12195-018-0536-9 * |
YUN, Y. R. ET AL.: "Fibroblast growth factors: biology, function, and application for tissue regeneration", J TISSUE ENG, vol. 218142, 2010 |
ZHA, Q. B. ET AL.: "ATP-Induced Inflammasome Activation and Pyroptosis Is Regulated by AMP-Activated Protein Kinase in Macrophages", FRONT IMMUNOL, vol. 7, 2016, pages 597 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113509542A (zh) * | 2021-04-20 | 2021-10-19 | 嘉晨西海(杭州)生物技术有限公司 | 一种基于mRNA的表达白介素12针对肿瘤的药物及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CA3132714A1 (en) | 2020-09-17 |
US20200281994A1 (en) | 2020-09-10 |
SG11202109514VA (en) | 2021-09-29 |
US20240024394A1 (en) | 2024-01-25 |
IL285963A (en) | 2021-10-31 |
CN113966221A (zh) | 2022-01-21 |
JP2022524391A (ja) | 2022-05-02 |
BR112021017637A2 (US08063081-20111122-C00044.png) | 2021-11-09 |
BR112021017637A8 (pt) | 2022-08-16 |
MX2021010808A (es) | 2021-12-15 |
EP3934673A1 (en) | 2022-01-12 |
US11717548B2 (en) | 2023-08-08 |
CO2021013417A2 (es) | 2022-01-17 |
KR20220006041A (ko) | 2022-01-14 |
AU2020233788A1 (en) | 2021-10-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20240024394A1 (en) | Synthetic oncolytic lnp-replicon rna and uses for cancer immunotherapy | |
Pardi et al. | mRNA vaccines—a new era in vaccinology | |
ES2279580T3 (es) | Composiciones para administrar genes a celulas de la piel que presentan antigenos. | |
US20210322545A1 (en) | Smc combination therapy for the treatment of cancer | |
US10329570B2 (en) | Antagonistic PD-1 aptamer and its applications in cancer therapy related applications | |
Li et al. | Enhancing the immunogenicity of lipid-nanoparticle mRNA vaccines by adjuvanting the ionizable lipid and the mRNA | |
US20210205475A1 (en) | Mitochondrial optogenetics-based gene therapy for treating cancer | |
D’haese et al. | Off the beaten path: Novel mRNA-nanoformulations for therapeutic vaccination against HIV | |
Meng et al. | Nucleic acid and oligonucleotide delivery for activating innate immunity in cancer immunotherapy | |
KR20240009419A (ko) | 바이러스 백신 | |
US20100285055A1 (en) | Activation of natural killer (NK) cells and methods of use | |
Pascolo | Nonreplicating synthetic mRNA vaccines: A journey through the European (Journal of Immunology) history | |
JP2024503000A (ja) | 発現構築物およびその使用 | |
JP6702938B2 (ja) | アンタゴニストic ctla−4アプタマー及びその免疫活性増強への応用 | |
US20220403416A1 (en) | Polymer-Encapsulated Viral Vectors for In Vivo Genetic Therapy | |
Brown | Development of Genetic Medicines for the Treatment and Prevention of Infectious Disease, Cancer, and Aging | |
US20230321230A1 (en) | Compositions and Methods for Adjuvanted Vaccines | |
WO2023109961A1 (en) | Interleukin-12 self-replicating rna and methods | |
WO2023212618A1 (en) | Lipid nanoparticles comprising venezuelan equine encephalitis (vee) replicon and uses thereof | |
Zhong | Development of a self-replicating mRNA vaccine against Zika virus | |
Monet et al. | The Emergence of the Next-Generation Vaccines | |
Hasan | Messenger RNA Based Vaccines and Their immunological effect on diseases | |
CN116574685A (zh) | 一种装载抗菌肽ll-37的外泌体及其在抗寨卡病毒中的应用 | |
JP2000072693A (ja) | 脾臓に注入するための薬剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 20704372 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 285963 Country of ref document: IL |
|
ENP | Entry into the national phase |
Ref document number: 3132714 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2021553767 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112021017637 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 2020233788 Country of ref document: AU Date of ref document: 20200110 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2020704372 Country of ref document: EP Effective date: 20211008 |
|
ENP | Entry into the national phase |
Ref document number: 112021017637 Country of ref document: BR Kind code of ref document: A2 Effective date: 20210906 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 521430266 Country of ref document: SA |