JP6895374B2 - 免疫チェックポイントモジュレーターの発現用腫瘍溶解性ウイルス - Google Patents
免疫チェックポイントモジュレーターの発現用腫瘍溶解性ウイルス Download PDFInfo
- Publication number
- JP6895374B2 JP6895374B2 JP2017502212A JP2017502212A JP6895374B2 JP 6895374 B2 JP6895374 B2 JP 6895374B2 JP 2017502212 A JP2017502212 A JP 2017502212A JP 2017502212 A JP2017502212 A JP 2017502212A JP 6895374 B2 JP6895374 B2 JP 6895374B2
- Authority
- JP
- Japan
- Prior art keywords
- virus
- oncolytic virus
- oncolytic
- antibody
- cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 244000309459 oncolytic virus Species 0.000 title claims description 115
- 230000014509 gene expression Effects 0.000 title claims description 44
- 229940123309 Immune checkpoint modulator Drugs 0.000 title claims description 30
- 108090000623 proteins and genes Proteins 0.000 claims description 119
- 206010028980 Neoplasm Diseases 0.000 claims description 110
- 241000700605 Viruses Species 0.000 claims description 66
- 241000700618 Vaccinia virus Species 0.000 claims description 52
- 102000037982 Immune checkpoint proteins Human genes 0.000 claims description 48
- 108091008036 Immune checkpoint proteins Proteins 0.000 claims description 48
- 201000011510 cancer Diseases 0.000 claims description 42
- 230000003612 virological effect Effects 0.000 claims description 42
- 102000006601 Thymidine Kinase Human genes 0.000 claims description 40
- 108020004440 Thymidine kinase Proteins 0.000 claims description 40
- 230000000174 oncolytic effect Effects 0.000 claims description 40
- 230000000694 effects Effects 0.000 claims description 37
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 37
- 102000004169 proteins and genes Human genes 0.000 claims description 37
- 150000007523 nucleic acids Chemical class 0.000 claims description 34
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 32
- 230000001225 therapeutic effect Effects 0.000 claims description 30
- 108020004707 nucleic acids Proteins 0.000 claims description 29
- 102000039446 nucleic acids Human genes 0.000 claims description 29
- 239000012634 fragment Substances 0.000 claims description 27
- 229920001184 polypeptide Polymers 0.000 claims description 27
- 238000011282 treatment Methods 0.000 claims description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- 108010041388 Ribonucleotide Reductases Proteins 0.000 claims description 18
- 102000000505 Ribonucleotide Reductases Human genes 0.000 claims description 18
- 230000002062 proliferating effect Effects 0.000 claims description 15
- 230000035772 mutation Effects 0.000 claims description 14
- 108091000036 uracil phosphoribosyltransferase Proteins 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 230000000415 inactivating effect Effects 0.000 claims description 10
- 108700005077 Viral Genes Proteins 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 9
- 230000003308 immunostimulating effect Effects 0.000 claims description 9
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 101000807008 Homo sapiens Uracil phosphoribosyltransferase homolog Proteins 0.000 claims description 7
- 102100037717 Uracil phosphoribosyltransferase homolog Human genes 0.000 claims description 7
- 238000001990 intravenous administration Methods 0.000 claims description 7
- 201000001441 melanoma Diseases 0.000 claims description 7
- 229940002612 prodrug Drugs 0.000 claims description 6
- 239000000651 prodrug Substances 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 101100502554 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) FCY1 gene Proteins 0.000 claims description 5
- 102000000311 Cytosine Deaminase Human genes 0.000 claims description 4
- 108010080611 Cytosine Deaminase Proteins 0.000 claims description 4
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 claims description 4
- 108010063738 Interleukins Proteins 0.000 claims description 4
- 102000015696 Interleukins Human genes 0.000 claims description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 206010038389 Renal cancer Diseases 0.000 claims description 4
- 230000007812 deficiency Effects 0.000 claims description 4
- 229960005386 ipilimumab Drugs 0.000 claims description 4
- 201000010982 kidney cancer Diseases 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 229960003301 nivolumab Drugs 0.000 claims description 4
- 101150104910 C8L gene Proteins 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 claims description 3
- 102100040678 Programmed cell death protein 1 Human genes 0.000 claims description 3
- 101100141316 Vaccinia virus (strain Copenhagen) F4L gene Proteins 0.000 claims description 3
- 101100141318 Vaccinia virus (strain Western Reserve) VACWR043 gene Proteins 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 102000048776 human CD274 Human genes 0.000 claims description 3
- 102000043321 human CTLA4 Human genes 0.000 claims description 3
- 102000048362 human PDCD1 Human genes 0.000 claims description 3
- 229960002621 pembrolizumab Drugs 0.000 claims description 3
- 102000007469 Actins Human genes 0.000 claims description 2
- 108010085238 Actins Proteins 0.000 claims description 2
- 101000746373 Homo sapiens Granulocyte-macrophage colony-stimulating factor Proteins 0.000 claims description 2
- 101710101148 Probable 6-oxopurine nucleoside phosphorylase Proteins 0.000 claims description 2
- 102000030764 Purine-nucleoside phosphorylase Human genes 0.000 claims description 2
- 230000007547 defect Effects 0.000 claims description 2
- 229950010773 pidilizumab Drugs 0.000 claims description 2
- 229950007217 tremelimumab Drugs 0.000 claims description 2
- 101710089372 Programmed cell death protein 1 Proteins 0.000 claims 2
- 238000011319 anticancer therapy Methods 0.000 claims 1
- 102000046157 human CSF2 Human genes 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 131
- 238000000034 method Methods 0.000 description 42
- 239000000203 mixture Substances 0.000 description 34
- 241000282414 Homo sapiens Species 0.000 description 22
- 239000000047 product Substances 0.000 description 22
- 101100519207 Mus musculus Pdcd1 gene Proteins 0.000 description 21
- 238000002347 injection Methods 0.000 description 18
- 239000007924 injection Substances 0.000 description 18
- 210000002966 serum Anatomy 0.000 description 18
- 230000027455 binding Effects 0.000 description 17
- 238000004519 manufacturing process Methods 0.000 description 17
- 241000699666 Mus <mouse, genus> Species 0.000 description 16
- 230000002950 deficient Effects 0.000 description 16
- 239000002773 nucleotide Substances 0.000 description 16
- 241000701161 unidentified adenovirus Species 0.000 description 16
- 125000003729 nucleotide group Chemical group 0.000 description 15
- 206010046865 Vaccinia virus infection Diseases 0.000 description 14
- 208000015181 infectious disease Diseases 0.000 description 14
- 230000002401 inhibitory effect Effects 0.000 description 14
- 208000007089 vaccinia Diseases 0.000 description 14
- 108010074708 B7-H1 Antigen Proteins 0.000 description 13
- 102000008096 B7-H1 Antigen Human genes 0.000 description 13
- 101100174574 Mus musculus Pikfyve gene Proteins 0.000 description 13
- 125000003275 alpha amino acid group Chemical group 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 210000001744 T-lymphocyte Anatomy 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- 101150003725 TK gene Proteins 0.000 description 11
- 230000004048 modification Effects 0.000 description 11
- 238000012986 modification Methods 0.000 description 11
- 241000699800 Cricetinae Species 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 238000011161 development Methods 0.000 description 10
- 101150118483 tmk gene Proteins 0.000 description 10
- 108020004705 Codon Proteins 0.000 description 9
- 238000002965 ELISA Methods 0.000 description 9
- 101150060895 I4L gene Proteins 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 239000003446 ligand Substances 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- 238000010189 synthetic method Methods 0.000 description 9
- 239000013598 vector Substances 0.000 description 9
- 101150040913 DUT gene Proteins 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- 108060003951 Immunoglobulin Proteins 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 108010032220 cyclomaltodextrinase Proteins 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 102000018358 immunoglobulin Human genes 0.000 description 8
- 230000002458 infectious effect Effects 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 230000001105 regulatory effect Effects 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 238000002523 gelfiltration Methods 0.000 description 7
- 230000006801 homologous recombination Effects 0.000 description 7
- 238000002744 homologous recombination Methods 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 238000003780 insertion Methods 0.000 description 7
- 230000037431 insertion Effects 0.000 description 7
- 230000002601 intratumoral effect Effects 0.000 description 7
- 230000001404 mediated effect Effects 0.000 description 7
- 239000002953 phosphate buffered saline Substances 0.000 description 7
- 239000013612 plasmid Substances 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 6
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- -1 IFNα) Proteins 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- 108091028043 Nucleic acid sequence Proteins 0.000 description 6
- 241000700584 Simplexvirus Species 0.000 description 6
- 101100525041 Vaccinia virus (strain Western Reserve) VACWR073 gene Proteins 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 230000000903 blocking effect Effects 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 239000012228 culture supernatant Substances 0.000 description 6
- 230000037430 deletion Effects 0.000 description 6
- 238000012217 deletion Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 230000035755 proliferation Effects 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 230000032258 transport Effects 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- 241001529453 unidentified herpesvirus Species 0.000 description 6
- 241000711404 Avian avulavirus 1 Species 0.000 description 5
- 229940045513 CTLA4 antagonist Drugs 0.000 description 5
- 241000712079 Measles morbillivirus Species 0.000 description 5
- 108010076504 Protein Sorting Signals Proteins 0.000 description 5
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 5
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 5
- 125000000539 amino acid group Chemical group 0.000 description 5
- 230000003042 antagnostic effect Effects 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 239000000427 antigen Substances 0.000 description 5
- 210000000612 antigen-presenting cell Anatomy 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
- 102000036639 antigens Human genes 0.000 description 5
- 238000010367 cloning Methods 0.000 description 5
- 238000012258 culturing Methods 0.000 description 5
- 210000003527 eukaryotic cell Anatomy 0.000 description 5
- 238000000684 flow cytometry Methods 0.000 description 5
- 230000004927 fusion Effects 0.000 description 5
- 230000028993 immune response Effects 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 230000001613 neoplastic effect Effects 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- 241000283707 Capra Species 0.000 description 4
- 206010008342 Cervix carcinoma Diseases 0.000 description 4
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 4
- 241000287828 Gallus gallus Species 0.000 description 4
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 4
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 4
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 4
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 4
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 4
- 241000711975 Vesicular stomatitis virus Species 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 238000011394 anticancer treatment Methods 0.000 description 4
- 230000000890 antigenic effect Effects 0.000 description 4
- 210000003719 b-lymphocyte Anatomy 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 201000010881 cervical cancer Diseases 0.000 description 4
- 210000004748 cultured cell Anatomy 0.000 description 4
- 230000009089 cytolysis Effects 0.000 description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 4
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229960002949 fluorouracil Drugs 0.000 description 4
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 102000040430 polynucleotide Human genes 0.000 description 4
- 108091033319 polynucleotide Proteins 0.000 description 4
- 239000002157 polynucleotide Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 230000006798 recombination Effects 0.000 description 4
- 238000005215 recombination Methods 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 3
- RNBMPPYRHNWTMA-UAKXSSHOSA-N 5-fluorouridine 5'-monophosphate Chemical compound O1[C@H](COP(O)(O)=O)[C@@H](O)[C@@H](O)[C@@H]1N1C(=O)NC(=O)C(F)=C1 RNBMPPYRHNWTMA-UAKXSSHOSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 108700010070 Codon Usage Proteins 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- 241000206602 Eukaryota Species 0.000 description 3
- 101150067602 F4L gene Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 3
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 3
- 101000666896 Homo sapiens V-type immunoglobulin domain-containing suppressor of T-cell activation Proteins 0.000 description 3
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 3
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 3
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 3
- 102000014150 Interferons Human genes 0.000 description 3
- 108010050904 Interferons Proteins 0.000 description 3
- 102000017578 LAG3 Human genes 0.000 description 3
- 230000006044 T cell activation Effects 0.000 description 3
- 230000005867 T cell response Effects 0.000 description 3
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102100038282 V-type immunoglobulin domain-containing suppressor of T-cell activation Human genes 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000012472 biological sample Substances 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000012636 effector Substances 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 3
- 229960004413 flucytosine Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 238000003119 immunoblot Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 108091008042 inhibitory receptors Proteins 0.000 description 3
- 229940079322 interferon Drugs 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 208000037819 metastatic cancer Diseases 0.000 description 3
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 3
- 210000000822 natural killer cell Anatomy 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 230000007918 pathogenicity Effects 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 239000003053 toxin Substances 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 230000014616 translation Effects 0.000 description 3
- 102000003390 tumor necrosis factor Human genes 0.000 description 3
- 230000029812 viral genome replication Effects 0.000 description 3
- 210000002845 virion Anatomy 0.000 description 3
- 239000011534 wash buffer Substances 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- WOVKYSAHUYNSMH-UHFFFAOYSA-N BROMODEOXYURIDINE Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-UHFFFAOYSA-N 0.000 description 2
- 244000063299 Bacillus subtilis Species 0.000 description 2
- 235000014469 Bacillus subtilis Nutrition 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 108700031361 Brachyury Proteins 0.000 description 2
- 101100476210 Caenorhabditis elegans rnt-1 gene Proteins 0.000 description 2
- 102000000844 Cell Surface Receptors Human genes 0.000 description 2
- 108010001857 Cell Surface Receptors Proteins 0.000 description 2
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 2
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 2
- 230000004543 DNA replication Effects 0.000 description 2
- 230000006820 DNA synthesis Effects 0.000 description 2
- 102100023933 Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial Human genes 0.000 description 2
- 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 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 2
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 2
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 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 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 201000005505 Measles Diseases 0.000 description 2
- 206010027480 Metastatic malignant melanoma Diseases 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
- 108700019961 Neoplasm Genes Proteins 0.000 description 2
- 102000048850 Neoplasm Genes Human genes 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- 241000837158 Senecavirus A Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229930006000 Sucrose Natural products 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
- 239000012505 Superdex™ Substances 0.000 description 2
- 230000024932 T cell mediated immunity Effects 0.000 description 2
- 108010022394 Threonine synthase Proteins 0.000 description 2
- 102000002689 Toll-like receptor Human genes 0.000 description 2
- 108020000411 Toll-like receptor Proteins 0.000 description 2
- 108700019146 Transgenes Proteins 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 230000006023 anti-tumor response Effects 0.000 description 2
- 230000005975 antitumor immune response Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 102000005936 beta-Galactosidase Human genes 0.000 description 2
- 108010005774 beta-Galactosidase Proteins 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229950004398 broxuridine Drugs 0.000 description 2
- 230000036755 cellular response Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 101150093170 codA gene Proteins 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 229940104302 cytosine Drugs 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 108010011219 dUTP pyrophosphatase Proteins 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000005547 deoxyribonucleotide Substances 0.000 description 2
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 235000013681 dietary sucrose Nutrition 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 108010030074 endodeoxyribonuclease MluI Proteins 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 238000001502 gel electrophoresis Methods 0.000 description 2
- 239000005090 green fluorescent protein Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 239000000710 homodimer Substances 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000012744 immunostaining Methods 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 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 2
- 230000002934 lysing effect Effects 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 208000021039 metastatic melanoma Diseases 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000010188 recombinant method Methods 0.000 description 2
- 206010038038 rectal cancer Diseases 0.000 description 2
- 201000001275 rectum cancer Diseases 0.000 description 2
- 230000003362 replicative effect Effects 0.000 description 2
- 235000020183 skimmed milk Nutrition 0.000 description 2
- 238000005063 solubilization Methods 0.000 description 2
- 230000007928 solubilization Effects 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000012289 standard assay Methods 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 230000008093 supporting effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 230000005030 transcription termination Effects 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 241000712461 unidentified influenza virus Species 0.000 description 2
- 229940035893 uracil Drugs 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 229940055760 yervoy Drugs 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
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- DLZKEQQWXODGGZ-KCJUWKMLSA-N 2-[[(2r)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)[C@@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 DLZKEQQWXODGGZ-KCJUWKMLSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- RHKWIGHJGOEUSM-UHFFFAOYSA-N 3h-imidazo[4,5-h]quinoline Chemical class C1=CN=C2C(N=CN3)=C3C=CC2=C1 RHKWIGHJGOEUSM-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 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 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 108020005544 Antisense RNA Proteins 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 108010063104 Apoptosis Regulatory Proteins Proteins 0.000 description 1
- 102000010565 Apoptosis Regulatory Proteins Human genes 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 101001073212 Arabidopsis thaliana Peroxidase 33 Proteins 0.000 description 1
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 1
- 101150039990 B13R gene Proteins 0.000 description 1
- 101150006352 B18R gene Proteins 0.000 description 1
- 101150118897 B8R gene Proteins 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 101150017888 Bcl2 gene Proteins 0.000 description 1
- 101150008012 Bcl2l1 gene Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 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
- 102100025248 C-X-C motif chemokine 10 Human genes 0.000 description 1
- 102100025279 C-X-C motif chemokine 11 Human genes 0.000 description 1
- 102100036170 C-X-C motif chemokine 9 Human genes 0.000 description 1
- 102100027207 CD27 antigen Human genes 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 1
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 1
- 241000282836 Camelus dromedarius Species 0.000 description 1
- 241000178270 Canarypox virus Species 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102100035904 Caspase-1 Human genes 0.000 description 1
- 108090000426 Caspase-1 Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- 101150091887 Ctla4 gene 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
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 101150074155 DHFR gene Proteins 0.000 description 1
- 102000053602 DNA Human genes 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
- 206010061818 Disease progression Diseases 0.000 description 1
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 description 1
- 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 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 101150036671 FCA1 gene Proteins 0.000 description 1
- 101150078582 FCY1 gene Proteins 0.000 description 1
- 101150002048 FUR1 gene Proteins 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 101150046249 Havcr2 gene Proteins 0.000 description 1
- 101710154606 Hemagglutinin Proteins 0.000 description 1
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 1
- 101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 description 1
- 101000858060 Homo sapiens C-X-C motif chemokine 11 Proteins 0.000 description 1
- 101000947172 Homo sapiens C-X-C motif chemokine 9 Proteins 0.000 description 1
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 1
- 101001123325 Homo sapiens Peroxisome proliferator-activated receptor gamma coactivator 1-beta Proteins 0.000 description 1
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- 101100321817 Human parvovirus B19 (strain HV) 7.5K gene Proteins 0.000 description 1
- 101150076998 ICP34.5 gene Proteins 0.000 description 1
- 101150106931 IFNG gene Proteins 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108090000172 Interleukin-15 Proteins 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241000712045 Morbillivirus Species 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101001117316 Mus musculus Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- 241000186366 Mycobacterium bovis Species 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
- 241001460678 Napo <wasp> Species 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 108010077850 Nuclear Localization Signals Proteins 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010031096 Oropharyngeal cancer Diseases 0.000 description 1
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 description 1
- 241000700629 Orthopoxvirus Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 1
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 240000000220 Panda oleosa Species 0.000 description 1
- 235000016496 Panda oleosa Nutrition 0.000 description 1
- 241000711504 Paramyxoviridae Species 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102100028961 Peroxisome proliferator-activated receptor gamma coactivator 1-beta Human genes 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 101710176177 Protein A56 Proteins 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 108700005075 Regulator Genes Proteins 0.000 description 1
- 241000702247 Reoviridae Species 0.000 description 1
- 108091081062 Repeated sequence (DNA) Proteins 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- 241000724205 Rice stripe tenuivirus Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 108091058545 Secretory proteins Proteins 0.000 description 1
- 102000040739 Secretory proteins Human genes 0.000 description 1
- 241001632234 Senecavirus Species 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- 108010034546 Serratia marcescens nuclease Proteins 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 244000057717 Streptococcus lactis Species 0.000 description 1
- 235000014897 Streptococcus lactis Nutrition 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 229940126547 T-cell immunoglobulin mucin-3 Drugs 0.000 description 1
- 108700026226 TATA Box Proteins 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 102000005497 Thymidylate Synthase Human genes 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 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
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 1
- 102000006943 Uracil-DNA Glycosidase Human genes 0.000 description 1
- 108010072685 Uracil-DNA Glycosidase Proteins 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 241000700647 Variola virus Species 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 108010084455 Zeocin Proteins 0.000 description 1
- KMLCRELJHYKIIL-UHFFFAOYSA-N [1-(azanidylmethyl)cyclohexyl]methylazanide;platinum(2+);sulfuric acid Chemical compound [Pt+2].OS(O)(=O)=O.[NH-]CC1(C[NH-])CCCCC1 KMLCRELJHYKIIL-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent 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
- 230000004075 alteration Effects 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 230000001147 anti-toxic effect Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 229910052586 apatite Inorganic materials 0.000 description 1
- 230000000386 athletic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- DVQHYTBCTGYNNN-UHFFFAOYSA-N azane;cyclobutane-1,1-dicarboxylic acid;platinum Chemical compound N.N.[Pt].OC(=O)C1(C(O)=O)CCC1 DVQHYTBCTGYNNN-UHFFFAOYSA-N 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 108700000707 bcl-2-Associated X Proteins 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 210000004204 blood vessel Anatomy 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
- 239000003560 cancer drug Substances 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 210000000234 capsid Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000009134 cell regulation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 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
- 229960004630 chlorambucil Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000003184 complementary RNA Substances 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000011443 conventional therapy Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 239000013024 dilution buffer Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 101150113316 egr gene Proteins 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 201000004101 esophageal cancer Diseases 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
- 229960005420 etoposide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000013861 fat-free Nutrition 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- IJJVMEJXYNJXOJ-UHFFFAOYSA-N fluquinconazole Chemical compound C=1C=C(Cl)C=C(Cl)C=1N1C(=O)C2=CC(F)=CC=C2N=C1N1C=NC=N1 IJJVMEJXYNJXOJ-UHFFFAOYSA-N 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 238000011990 functional testing Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000005182 global health Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 239000000185 hemagglutinin Substances 0.000 description 1
- 208000014617 hemorrhoid Diseases 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
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 210000004408 hybridoma Anatomy 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
- 229960002751 imiquimod Drugs 0.000 description 1
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000008088 immune pathway Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 208000029559 malignant endocrine neoplasm Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000002609 medium Substances 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
- 229960001924 melphalan Drugs 0.000 description 1
- 210000004779 membrane envelope Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 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 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 229950010203 nimotuzumab Drugs 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229940046166 oligodeoxynucleotide Drugs 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 201000006958 oropharynx cancer Diseases 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 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
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 101710135378 pH 6 antigen Proteins 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 229960005547 pelareorep Drugs 0.000 description 1
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- 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
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229940080469 phosphocellulose Drugs 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000002745 poly(ortho ester) Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 201000005825 prostate adenocarcinoma Diseases 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960003876 ranibizumab Drugs 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 235000017709 saponins Nutrition 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 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 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
- 238000012360 testing method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000011200 topical administration Methods 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
- 235000013619 trace mineral Nutrition 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 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
- 229960002066 vinorelbine Drugs 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 239000000304 virulence factor Substances 0.000 description 1
- 230000007923 virulence factor Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Images
Classifications
-
- 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
- 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
- A61K35/765—Reovirus; Rotavirus
-
- 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
- A61K35/766—Rhabdovirus, e.g. vesicular stomatitis virus
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
- C07K14/53—Colony-stimulating factor [CSF]
- C07K14/535—Granulocyte CSF; Granulocyte-macrophage CSF
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
-
- 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
- C12N15/863—Poxviral vectors, e.g. entomopoxvirus
- C12N15/8636—Vaccina virus vectors
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y204/00—Glycosyltransferases (2.4)
- C12Y204/02—Pentosyltransferases (2.4.2)
- C12Y204/02009—Uracil phosphoribosyltransferase (2.4.2.9)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
- A61K2039/5256—Virus expressing foreign proteins
-
- 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
- A61K35/761—Adenovirus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
- A61K35/763—Herpes virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/515—Complete light chain, i.e. VL + CL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/24011—Poxviridae
- C12N2710/24111—Orthopoxvirus, e.g. vaccinia virus, variola
- C12N2710/24121—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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/24011—Poxviridae
- C12N2710/24111—Orthopoxvirus, e.g. vaccinia virus, variola
- C12N2710/24132—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2799/00—Uses of viruses
- C12N2799/02—Uses of viruses as vector
- C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
- C12N2799/023—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a poxvirus
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/1048—Glycosyltransferases (2.4)
- C12N9/1077—Pentosyltransferases (2.4.2)
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/78—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
- C12N9/80—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5) acting on amide bonds in linear amides (3.5.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y305/00—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5)
- C12Y305/01—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5) in linear amides (3.5.1)
- C12Y305/01023—Ceramidase (3.5.1.23)
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Virology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Wood Science & Technology (AREA)
- Immunology (AREA)
- Mycology (AREA)
- General Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oncology (AREA)
- Gastroenterology & Hepatology (AREA)
- Toxicology (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Inorganic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Pulmonology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
癌の進展を開始または促進させるために共にまたは別々に作用するかもしれない決定的な因子が多いため、癌は、何年も深刻で世界的な健康への脅威であり続けると予想される。さらに、悪性および特に転移性腫瘍は、しばしば、従来の療法に対して耐性であり、幾つかの癌の顕著な死亡率を裏付けている。
本願全体で使用される用語「1つ(a)」および「1つ(an)」は、本文が明確に他を指示していない限り、言及された構成要素またはステップの「少なくとも1つ」、「少なくとも第一」、「1つ以上」または「複数」を意味するという意義で使用される。例えば、用語「1つの細胞(a cell)」は、それらの混合物を含む、複数の細胞が包含される。
本発明において使用される腫瘍溶解性ウイルスは、現在同定されている任意のウイルスメンバーから得ることができるが、ただし、それらは、非分裂細胞と比べて分裂細胞を選択的に複製および破壊するその傾向によって腫瘍溶解性である。それは、生来的に腫瘍溶解性である天然ウイルスでもよく、または、腫瘍選択性および/または分裂細胞中での選択的複製を増大させるために、DNA複製、核酸代謝、宿主向性、表面付着、病原性、溶解、および伝播に関与するもの等の1つ以上のウイルス遺伝子を改変することによって操作されたものでもよい(例えば、Kirn et al., 2001, Nat. Med. 7: 781; Wong et al., 2010, Viruses 2: 78-106を参照)。1つ以上のウイルス遺伝子を、イベントの制御または組織特異的調節因子(例えば、プロモーター)下で配置することを想定してもよい。
一つの態様において、本発明の腫瘍溶解性ウイルスは、ウイルスゲノム内に挿入された、少なくとも1つの治療遺伝子をさらに発現する。「治療遺伝子」は、対象へ適切に投与された際に、抗腫瘍効果を強化するかまたはウイルスの腫瘍溶解性特性を強化することのいずれかによって、治療される病態の過程または症状に対して有益な効果を引き起こすと期待される、生物学的活性を提供できる生成物をコードする。本発明の文脈において、治療遺伝子は、哺乳類(例えば、ヒト、マウス、ウサギ等)由来であっても、そうでなくても(例えば、細菌性、酵母またはウイルス由来)よい。
用語「自殺遺伝子」とは、薬剤の前駆体を細胞傷害性化合物に転換できるタンパク質をコードする遺伝子を意味する。自殺遺伝子は、限定されることなく、シトシンデアミナーゼ活性、チミジンキナーゼ活性、ウラシルホスホリボシルトランスフェラーゼ活性、プリンヌクレオシドホスホリラーゼ活性およびチミジレートキナーゼ活性を有するタンパク質をコードする遺伝子を含んでなる。自殺遺伝子の例および1つの核酸塩基部分を含んでなる薬剤の対応する前駆体は、下記の表において開示されている。
本明細書で使用される場合、用語「免疫刺激性タンパク質」とは、特異的または非特異的様式で、免疫系を刺激する能力を有するタンパク質を意味する。当技術分野において、多数のタンパク質が、その免疫刺激効果を発揮する能力で公知である。本発明の文脈において好適な免疫刺激性タンパク質の例としては、限定されることなく、サイトカインが挙げられ、特に好ましくはインターロイキン(例えば、IL−2、IL−6、IL−12、IL−15、IL−24)、ケモカイン(例えば、CXCL10、CXCL9、CXCL11)、インターフェロン(例えば、IFNg、IFNα)、腫瘍壊死因子(TNF)、コロニー刺激因子(例えば、GM−CSF、C−CSF、M−CSF等)、APC(抗原提示細胞)暴露タンパク質(例えば、B7.1、B7.2等)、増殖因子(形質転換増殖因子TGF、線維芽細胞増殖因子FGF、血管内皮増殖因子VEGF等)、クラスIまたはIIのMHC抗原、アポトーシス誘発因子または阻害因子(例えば、Bax、Bcl2、BclX等)、細胞増殖抑制剤(p21、p16、Rb等)、抗毒素、抗原性ポリペプチド(抗原性ポリペプチド、エピトープ等)およびマーカー(β−ガラクトシダーゼ、ルシフェラーゼ等)である。好ましくは、免疫刺激性タンパク質は、インターロイキンまたはコロニー刺激因子、特に好ましくはGM−CSFである。
免疫チェックポイントおよびそれらのモジュレーター、同様にそのような化合物を用いた方法は、文献に記載されている。本発明によれば、1つ以上の免疫チェックポイントモジュレーターは、アンタゴニスト機能(即ち、免疫チェックポイント媒介阻害シグナルと拮抗することができること)またはアゴニスト機能(即ち、免疫チェックポイント媒介刺激性シグナルを高めることができること)を発揮するために、独立して、標的免疫チェックポイントを結合でき、かつ/またはリガンドの当該標的免疫チェックポイントへの結合を阻害することができるドメインを含んでなるポリペプチドであってもよい。そのような1つ以上の免疫チェックポイントモジュレーターは、ペプチド(例えば、ペプチドリガンド)、天然受容体の可溶性ドメイン、RNAi、アンチセンス分子、抗体およびタンパク質の骨組からなる群から独立して選択され得る。
i)VL、VH、CLおよびCH1ドメインからなる一価断片で表されるFab断片;
ii)ヒンジ領域で少なくとも1つのジスルフィド架橋によって結合された2つのFab断片を含んでなる二価断片で表されるF(ab’)2断片;
iii)VHおよびCH1ドメインからなるFd断片;
iv)抗体の単一アームのVLおよびVHドメインからなるFv断片、
v)単一ドメイン可変断片(VHまたはVLドメイン)からなるdAb断片;
vi)Fv断片の2つのドメインと、融合され、最終的に一本鎖タンパク質を形成するためにリンカーを有するVLおよびVHとを含んでなる一本鎖Fv(scFv)(例えば、Bird et al., 1988, Science 242: 423-6; Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85: 5879-83; US4,946,778; US5,258,498を参照);および
vii)任意の他の人工抗体
が挙げられる。
免疫チェックポイントモジュレーターをコードする核酸分子および治療遺伝子は、当技術分野において入手可能な配列データおよび本明細書で提供された情報を用いて、標準的な分子生物学技法(例えば、PCR増幅、cDNAクローニング、化学合成)によって容易に得ることができる。抗体、それらの断片および類似体をクローニングする方法は、当技術分野において公知である(例えば、Harlow and Lane, 1988, Antibodies - A laboratory manual; Cold Spring Harbor Laboratory, Cold Spring Harbor NYを参照)。例えば、抗体の軽鎖および重鎖、またはそれらのCDRをコードする核酸分子(例えば、cDNA)は、産生ハイブリドーマ(例えば、Kohler and Milstein, 1975, Nature 256: 495-7; Cote et al., 1983, Proc. Natl. Acad. Sci. USA 80: 2026-30; Cole et al. in Monoclonal antibodies and Cancer Therapy; Alan Liss pp77- 20 96を参照)、免疫グロブリン遺伝子ライブラリー、または任意の入手可能な材料(source)から分離してもよく、またはヌクレオチド配列は、化学合成によって生成させてもよい。類似体および断片は、分子生物学の標準的な技法を用いて発生させてもよい。
一つの態様において、本発明の文脈において、腫瘍溶解性ウイルスを、組換え手段によってそれがコードする1つ以上の免疫チェックポイントモジュレーターを生成するために利用してもよい。宿主細胞内の免疫チェックポイントモジュレーターをコードする核酸分子の維持、増殖または発現を可能にする1つ以上の追加的因子を含むことが有利であり得る。そのような追加的因子は、(例えば、細胞の栄養要求性の相補性または抗生物質抵抗性によって)生成宿主細胞の同定および分離を容易にするためのマーカー遺伝子を含んでなる。好適なマーカー遺伝子は、限定されることなく、メトトレキサートへの耐性を付与するジヒドロ葉酸還元酵素(dhfr)(Wigler et al., 1980, Proc. Natl. Acad. Sci. USA 77: 3567、 O'Hare et al., 1981, Proc. Natl. Acad. Sci. USA 78: 1527)、ミコフェノール酸への耐性を付与するgpt(Mulligan and Berg, 1981, Proc. Natl. Acad. Sci. USA 78: 2072)、アミノグリコシドG−418への耐性を付与するneo(Colberre-Garapin et al., 1981, J. Mol. Biol. 150: 1)、ゼオマイシン(zeomycin)への耐性を付与するzeo、カナマイシンへの耐性を付与するkana、ハイグロマイシンへの耐性を付与するhygro(Santerre et al., 1984, Gene 30: 147)を含む。機能的TKを欠失している組換えウイルス(例えば、免疫チェックポイントモジュレーターをコードする核酸分子のTK遺伝子座への挿入に起因する)を、ブロモデオキシウリジン(BrdU)を含有する培地と選択してもよい。実際に、TKウイルスは、BrdU剤に対して感度が低い一方で、該薬剤は、TK+ウイルス内でのDNA合成を妨げる。例えば、GFP(緑色蛍光タンパク質)、ルシフェラーゼおよびベータガラクトシダーゼに基づく、レポーター発光システムまたは比色システムに依存してもよい。
本発明は、場合により薬学的に許容可能な賦形剤を含む、本発明の腫瘍溶解性ウイルスの治療的有効量を含んでなる組成物も提供する。そのような組成物は、1回または数回、および同一または異なる経路を介して投与されてもよい。
本発明の腫瘍溶解性ウイルスまたは組成物は、単回投与(例えば、ボーラス注射)または複数回投与で投与してもよい。複数回投与の場合、投与は同一または異なる経路によって行ってもよく、同一の部位または異なる部位に行ってもよい。投与は、休息期間後に、繰り返し、連続的サイクルで投与することによって進めることも可能である。各投与の間隔は、数時間から1年であり得る(例えば、24時間、48時間、72時間、毎週、隔週、毎月または毎年)。間隔は、不規則であってもよい(例えば、腫瘍進行の後)。用量は、上記の範囲内で、それぞれの投与について変化させてもよい。
・例えば、マイトマイシンC、シクロホスファミド、ブスルファン、イホスファミド、イソファミド、メルファラン、ヘキサメチルメラミン、チオテパ、クロラムブシルまたはダカルバジン等のアルキル化剤;
・例えば、ゲムシタビン、カペシタビン、5−フルオロウラシル、シタラビン、2−フルオロデオキシシチジン、メトトレキサート、イダトレキサート、トムデックスまたはトリメトレキサート等の代謝拮抗物質;
・例えば、ドキソルビシン、エピルビシン、エトポシド、テニポシドまたはミトキサントロン等のトポイソメラーゼII阻害剤;
・例えば、イリノテカン(CPT−11)、7−エチル−10−ヒドロキシ−カンプトセシン(SN−38)またはトポテカン等のトポイソメラーゼI阻害剤;
・例えば、パクリタキセル、ドセタキセル、ビンブラスチン、ビンクリスチンまたはビノレルビン等の細胞分裂抑制薬;
・例えば、シスプラチン、オキサリプラチン、スピロプラチナム(spiroplatinum)またはカルボプラチナム(carboplatinum)等の白金誘導体;
・スニチニブ(Pfizer)およびソラフェニブ(Bayer)等のチロシンキナーゼ受容体の阻害剤;
・抗腫瘍抗体、具体的には、トラスツズマブ、セツキシマブ、パニツムマブ、ザルツムマブ、ニモツズマブ、マツズマブ、ベバシズマブおよびラニビズマブ等の細胞表面受容体の調節に影響する抗体;
・ゲフィチニブ、エルロチニブおよびラパチニブ等のEGFR(上皮成長因子受容体)阻害剤;ならびに
・例えば、α、βまたはγインターフェロン、インターロイキン(具体的には、IL-2、IL-6、IL-10またはIL-12)または腫瘍壊死因子等の免疫調節剤
である。
J43の重鎖は、抗CD79b IgGの重鎖と高い相同性を示した。従って、重鎖のクローン化用に保持されていた配列は、J43の可変鎖および抗CD79Bの定常鎖であった。J43の軽鎖を、抗CD79b抗体の軽鎖のシグナル配列とクローン化した。重鎖および軽鎖を、若干異なる強度を持つ、ウイルスプロモーターpH5Rまたはp7.5Kの制御下に置いた。「全」抗体コンストラクトに加えて、誘導体、それぞれHisタグ抗原結合断片(Fab)コンストラクト、同様に、Hisタグ一本鎖抗体(scFv)コンストラクトを生成した。それぞれのプロモーター下に置かれた軽鎖または重鎖の部位に依存して、Fabに対して、2つのコンストラクトフォーマットも生成した。全ての5つのコンストラクトを、TK、RR欠失WR VVの骨格に挿入した。コンストラクトは、下記のとおりまとめられる:
pH5R−HC−p7.5K−LCに対応するWRTG18618(または、mAb1)
pH5R−LC−p7.5K−HCに対応するWRTG18619(または、mAb2)
pH5R−(VH−CH1−6His)−p7.5K−LCに対応するWRTG18621(または、Fab1)
pH5R−LC−p7.5K−(VH−CH1−6His)に対応するWRTG18620(または、Fab2)
pH5R−VH−gs−VL−6His)に対応するWRTG18616(scFv)。
合成的方法(Geneart:レーゲンスブルク、ドイツ)により、p7.5Kプロモーターに続くHCを含有する断片を産生し、PstIおよびEcoRIによって制限されたワクシニア導入プラスミドpTG18496中にクローン化し、pTG18614を得た。合成的方法により、LCを含有する断片を産生し、NsiIおよびSalIによって制限されたpTG18614中にクローン化し、pTG18618を得た。
合成的方法により、p7.5Kプロモーターに続くLCを含有する断片を産生し、PstIおよびEcoRIによって制限されたワクシニア導入プラスミドpTG18496中にクローン化し、pTG18615を得た。合成的方法により、HCを含有する断片を産生し、NsiIおよびMluIによって制限されたpTG18615中にクローン化し、pTG18619を得た。
合成的方法により、p7.5Kプロモーターに続くVH−CH1−6Hisを含有する断片を産生し、PstIおよびEcoRIによって制限されたワクシニア導入プラスミドpTG18496中にクローン化し、pTG18617を得た。合成的方法により、LCを含有する断片を産生し、NsiIおよびSalIによって制限されたpTG18617中にクローン化し、pTG18621を得た。
合成的方法により、p7.5Kプロモーターに続くLCを含有する断片を産生し、PstIおよびEcoRIによって制限されたワクシニア導入プラスミドpTG18496中にクローン化し、pTG18615を得た。合成的方法により、VH−CH1−6Hisを含有する断片を産生し、NsiIおよびMluIによって制限されたpTG18615中にクローン化し、pTG18620を得た。
合成的方法により、VH−gs−VL−6Hisを含有する断片を産生し、PstIおよびEcoRIによって制限されたワクシニア導入プラスミドpTG18496中にクローン化し、pTG18616を得た。
上述の組換え腫瘍溶解性ベクターを、コードされた抗mPD−1分子の産生を評価するために試験した。これに、初代許容細胞または細胞株を感染させ、上清を集菌した。抗mPD−1分子の存在は、SDS−PAGE、ウエスタンブロット分析、質量分析、ELISAおよび機能的アッセイによって決定できる。市販の抗mPD−1抗体をコントロールとして用いた。
CEFを、F175フラスコ内で培養し、2.7×108pfuの抗PD−1発現ウイルスを感染させた。48〜72時間後、培養上清を採取し、0.2μmのろ過器で濾過した。mAb1を、Hitrap protein A(GE Healthcare)によって精製し、次いでSuperdex 200 ゲル濾過(GE Healthcare)する一方で、Fab1およびscFvを、HIS-Trap(GE Healthcare)によって精製し、次いでSuperdex 75ゲル濾過(GE Healthcare)した。scFvは、ゲル濾過により2つのピークとして溶出され、一つ目のピークは二量体、2つ目のピークは単量体に対応していた。図1において示されているように、相当量のmAb、FabおよびscFVが産生された。収量は、抗体型によって、上清1mlあたり0.5〜2μgであった。
ヒトLoVo癌細胞株を、トランス遺伝子のないTK−RR欠失WRワクシニアウイルス(WRTG18011)によって、および異なる抗mPD−1分子を発現するTK−RR欠失WRワクシニアウイルス(WRTG18616、WRTG18618およびWRTG8621)によって、0.001および0.0001のMOIの懸濁液に形質導入した。合計3×105細胞/ウェルを、6ウェル培養皿に、10%のFCSを補充した2mlの培地中に置いた。次いで、細胞を37℃で培養し、細胞生存を、5日後にトリパンブルー除去によって決定した。図3に示されているように、異なるウイルスの腫瘍溶解性活性は、それぞれ0.0001および0.001のMOIで、生存細胞数の75〜95%および99%の減少をもたらした。トランス遺伝子のないTK−RR欠失WRウイルスおよび異なる抗mPD−1分子を発現するTK−RR欠失WRウイルスは、細胞傷害活性において差異を示さなかった。従って、異なる抗mPD−1分子の発現は、ワクシニアウイルスの腫瘍溶解性活性に影響しなかった。
組換え腫瘍溶解性ベクターを、発現レベルおよび分泌された抗体の集合を評価するための免疫ブロットによって試験した。免疫ブロット分析を、CEFと上記のmAbおよびFabコンストラクトとを感染させてから24時間後に回収した細胞培養上清において行った。上清を、16000gで5分間遠心分離機にかけ、25μlを、還元剤を含まないLaemmli緩衝液中に調製し、PrecastGel4〜15%ポリアクリルアミドゲル(Biorad)にロードした。市販のモノクローナルJ43(BioXcell)を、参照分子として用いた。各分子を1μgゲル上にロードした。ゲル電気泳動を、非還元条件下で行い、軽鎖および重鎖の集合を保存して、最適な検出を可能にした(即ち、検出に用いられたポリクローナル抗体は、還元されたIgG鎖およびFab鎖を認識しなかった)。次いで、タンパク質を、予備プログラム化されたプロトコル(高分子量:10分、2.5A一定、最大25V)によるTransblot Turboシステム(Transblot Turbo Transfer pack Biorad)を用いて、PVDF膜に移した。膜を、ブロッキング液(0.05% Tween20、無脂肪粉ミルクBiorad5%を添加した、8mM NaPO4、2mM KPO4、154mM NaCl pH7.2(PBS))中で、4℃で一晩飽和させた。希釈緩衝液(PBS、0.05% Tween20、無脂肪粉ミルク5%)中の西洋ワサビペルオキシダーゼ(HRP)接合ヤギ抗アルメニアハムスターIgG(Jackson Immunoresearch)80ng/mLを、抗体免疫検出のために用いた。Amersham ECL Prime ウェスタンブロッティング検出試薬を用いて現像し、化学発光を捕らえるためにMolecular Imager ChemiDOCTMXRSを用いた。
ベクター化抗PD−1J43mAbの発現を、皮下移植したB16F10腫瘍を持つマウスおよび持たないマウスにおいてin vivoで評価した。WRTG18618(mAb1コンストラクト)を、腫瘍内または皮下のいずれかで注射し、市販のJ43(腫瘍内注射)と比較した。
より詳細には、3×105のB16F10細胞(マウス黒色腫)を6週齢雌C57BL/6マウスの右横腹に皮下(S.C.)注射した。0日目(D0)、腫瘍体積が、100〜200mm3に到達した際に、100μLの、WRTG18618(107pfu)または市販のJ43(1μgまたは10μg、BioXcell)のいずれかを腫瘍内(I.T.)に注射した。
J43濃度を、血清および腫瘍ホモジネートの両方において評価した。より具体的には、96ウェルプレート(Nunc immune plate Maxisorp)を、1ウェルあたり100μLの、コート溶液(0.05M炭酸ナトリウム pH9.6、Sigma)中の0.8μg/mLのヤギ抗ハムスターIgG(Southern Biotech)とともに、4℃で一晩培養した。プレートを、洗浄緩衝液(PBS、Tween20 0.05%、1ウェルあたり300μL)で3回洗浄し、1ウェルあたり200μLのブロッキング溶液(PBS、Tween20 0.05%、無脂肪粉ミルク5%)で、室温で1時間培養した。プレートを、洗浄緩衝液で3回洗浄した。2倍連続希釈法によって、1000〜0.488ng/mLのJ43(BioXcell)の標準範囲を、100%マウス血清(Sigma)中に調製した。次いで、各標準液を、ブロッキング溶液でさらに2倍希釈し(最終J43濃度は500〜0.244ng/mL)、血清の最終濃度を50%とした。1ウェルあたり100μLの各標準液を、プレートに二重に添加した。血清試料を、ブロッキング緩衝液で少なくとも2倍に希釈し、必要に応じて、ブロッキング緩衝液/血清の1体積/1体積混合物でさらに希釈し、プレートに100μLを添加した。プレートを、37℃で2時間インキュベートした。洗浄緩衝液で3回洗浄した後、1ウェルあたり100μLで、80ng/mLのHRP接合ヤギ抗アルメニアハムスターIgG(Jackson Immunoresearch)を添加し、プレートを、37℃で1時間インキュベートした。3回洗浄後、1ウェルあたり100μLの3,3’,5,5’−テトラメチルベンジジン(TMB、Sigma)を添加し、プレートを、室温で30分間インキュベートした。反応を、1ウェルあたり100μLの2M H2SO4で停止し、プレートリーダー(TECAN Infinite M200 PRO)により450nmの吸光を測定した。得られたOD値を、GraphPadPrismソフトウェアに転送し、試料濃度を、5つのパラメーターに適合した標準カーブを用いて逆算出した。
上記の多様な抗PD−1発現ワクシニアウイルスの抗腫瘍活性は、従来の前臨床的モデルにおいて、腫瘍の移植に続くコンストラクトの注射後に試験されてもよい。例えば、マウス癌細胞を、免疫競合性マウスの横腹中に皮下注射する。腫瘍が、50〜70mm3の体積に達したら、盲検下でランダム化し、1×107PFUの用量で指示されたワクシニアウイルスで処理した。ベクターまたはコントロール賦形剤(ウイルスを再懸濁するために使用される緩衝液)を、腫瘍移植後、10日目、12日目および14日目に腫瘍内へ直接注射した。キャリパーを用いて、1週間に2回、腫瘍サイズを計測した。具体的には、ベクター化したscFvおよびmAB1抗体は、腫瘍増殖を遅延させ、かつ生存率を増大させるために、少なくともWRベクターと市販のJ43の共投与と同じくらい効率的であった。
Claims (28)
- ゲノム内に挿入された、1つ以上の免疫チェックポイントモジュレーターをコードする核酸分子を含んでなる腫瘍溶解性ウイルスであって、前記腫瘍溶解性ウイルスが、J2Rウイルス性遺伝子中の不活性化突然変異に起因するチミジンキナーゼ(TK)の欠損を有するワクシニアウイルスであり、かつ、前記腫瘍溶解性ウイルスが、ウイルス性I4L遺伝子および/またはF4L遺伝子中の不活性化突然変異に起因するリボヌクレオチドレダクターゼ(RR)の欠損を有するワクシニアウイルスであり、かつ、前記1つ以上の免疫チェックポイントモジュレーターが、PD−1およびCTLA4のいずれかに特異的に結合するモノクローナル抗体から選択される、前記腫瘍溶解性ウイルス。
- 前記1つ以上の免疫チェックポイントモジュレーターが、PD−1に特異的に結合するモノクローナル抗体を含んでなる、請求項1に記載の腫瘍溶解性ウイルス。
- 前記腫瘍溶解性ウイルスが、ウイルス性ゲノム内に挿入された少なくとも1つの治療遺伝子をさらに含んでなる、請求項1または2に記載の腫瘍溶解性ウイルス。
- 前記治療遺伝子が、自殺遺伝子産物をコードする遺伝子および免疫刺激性タンパク質をコードする遺伝子からなる群から選択される、請求項3に記載の腫瘍溶解性ウイルス。
- 前記自殺遺伝子が、シトシンデアミナーゼ(CDase)活性、チミジンキナーゼ活性、ウラシルホスホリボシルトランスフェラーゼ(UPRTase)活性、プリンヌクレオシドホスホリラーゼ活性、チミジレートキナーゼ活性、ならびにCDaseおよびUPRTase活性の両方を有するタンパク質をコードする遺伝子からなる群から選択される、請求項4に記載の腫瘍溶解性ウイルス。
- 前記自殺遺伝子産物が、codA::upp、FCY1::FUR1およびFCY1::FUR1[デルタ]105(FCU1)およびFCU1〜8ポリペプチドからなる群から選択される、請求項5に記載の腫瘍溶解性ウイルス。
- 前記腫瘍溶解性ワクシニアウイルスが、TK活性およびRR活性の両方を欠損しているワクシニアウイルスであって、かつそのゲノム内に挿入された治療用FCU1自殺遺伝子を含んでなる、請求項5または6に記載の腫瘍溶解性ウイルス。
- 前記免疫刺激性タンパク質が、インターロイキンまたはコロニー刺激性因子である、請求項4に記載の腫瘍溶解性ウイルス。
- 前記腫瘍溶解性ワクシニアウイルスが、TK活性を欠損しているワクシニアウイルスであって、かつそのゲノム内に挿入された治療用ヒトGM−CSFを含んでなる、請求項8に記載の腫瘍溶解性ウイルス。
- 前記1つ以上の免疫チェックポイントモジュレーターが、ヒトPD−1に特異的に結合する抗体を含んでなる、請求項1〜9のいずれか一項に記載の腫瘍溶解性ウイルス。
- 前記ヒトPD−1に特異的に結合する抗体が、ニボルマブ(Nivolumab)、ペンブロリズマブ(Pembrolizumab)およびピディリズマブ(Pidilizumab)からなる群から選択される、請求項10に記載の腫瘍溶解性ウイルス。
- 前記1つ以上の免疫チェックポイントモジュレーターが、ヒトPD−L1に特異的に結合する抗体を含んでなる、請求項1〜9のいずれか一項に記載の腫瘍溶解性ウイルス。
- 前記ヒトPD−L1に特異的に結合する抗体が、MPDL3280AおよびBMS−936559からなる群から選択される、請求項12に記載の腫瘍溶解性ウイルス。
- 前記1つ以上の免疫チェックポイントモジュレーターが、ヒトCTLA−4に特異的に結合する抗体を含んでなる、請求項1〜9のいずれか一項に記載の腫瘍溶解性ウイルス。
- 前記ヒトCTLA−4に特異的に結合する抗体が、イピリムマブ(Ipilimumab)、トレメリムマブ(Tremelimumab)および一本鎖抗CTLA4抗体からなる群から選択される、請求項14に記載の腫瘍溶解性ウイルス。
- 前記抗体の重鎖またはその断片が、前記抗体の軽鎖またはその断片の発現に用いられるものより強いプロモーターの制御下に置かれる、請求項1〜15のいずれか一項に記載の腫瘍溶解性ウイルス。
- 前記重鎖の発現に用いられるプロモーターが、前記軽鎖の発現と比べて、少なくとも10%多く生成物を提供する、請求項16に記載の腫瘍溶解性ウイルス。
- ・前記重鎖の発現に用いられるプロモーターが、CMV、RSVおよびワクシニアウイルスpH5Rおよびp11K7.5プロモーターから選択され、かつ/または、
・前記軽鎖の発現に用いられるプロモーターが、PGK、β−アクチンおよびワクシニアウイルスp7.5KおよびpA35Rプロモーターから選択される、
請求項16または17に記載の腫瘍溶解性ウイルス。 - 請求項1〜18のいずれか一項に記載の腫瘍溶解性ウイルスの有効量および薬学的に許容可能な賦形剤を含んでなる、医薬組成物。
- 107pfu〜5×109pfuの前記腫瘍溶解性ウイルスを含んでなる、請求項19に記載の医薬組成物。
- 非経口投与用に製剤化された、請求項19または20に記載の医薬組成物。
- 増殖性疾患の治療のための、請求項19〜21のいずれか一項に記載の医薬組成物。
- 前記増殖性疾患が癌である、請求項22に記載の医薬組成物。
- 前記癌が、黒色腫、腎臓癌、前立腺癌、乳癌、大腸癌、肺癌および肝臓癌からなる群から選択される、請求項23に記載の医薬組成物。
- 前記腫瘍溶解性ウイルスが、静脈内または腫瘍内の経路によって投与される、請求項22〜24のいずれか一項に記載の医薬組成物。
- 1または2週間間隔で、108または109pfuの腫瘍溶解性ウイルスを2〜5回静脈内投与または腫瘍内投与することを含んでなる、請求項25に記載の医薬組成物。
- プロドラッグおよび/または抗癌治療において効果的な物質の投与をさらに含んでなる、請求項22〜26のいずれか一項に記載の医薬組成物。
- 増殖性疾患の治療のための医薬組成物を製造するための、請求項1〜18のいずれか一項に記載の腫瘍溶解性ウイルスの使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14306153.9 | 2014-07-16 | ||
EP14306153 | 2014-07-16 | ||
PCT/EP2015/066263 WO2016008976A1 (en) | 2014-07-16 | 2015-07-16 | Oncolytic virus for expression of immune checkpoint modulators |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020163305A Division JP7077377B2 (ja) | 2014-07-16 | 2020-09-29 | 免疫チェックポイントモジュレーターの発現用腫瘍溶解性ウイルス |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2017522025A JP2017522025A (ja) | 2017-08-10 |
JP2017522025A5 JP2017522025A5 (ja) | 2018-08-16 |
JP6895374B2 true JP6895374B2 (ja) | 2021-06-30 |
Family
ID=51220528
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017502212A Active JP6895374B2 (ja) | 2014-07-16 | 2015-07-16 | 免疫チェックポイントモジュレーターの発現用腫瘍溶解性ウイルス |
JP2020163305A Active JP7077377B2 (ja) | 2014-07-16 | 2020-09-29 | 免疫チェックポイントモジュレーターの発現用腫瘍溶解性ウイルス |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020163305A Active JP7077377B2 (ja) | 2014-07-16 | 2020-09-29 | 免疫チェックポイントモジュレーターの発現用腫瘍溶解性ウイルス |
Country Status (14)
Country | Link |
---|---|
US (2) | US10555981B2 (ja) |
EP (2) | EP3552615B8 (ja) |
JP (2) | JP6895374B2 (ja) |
CN (1) | CN107208069A (ja) |
AU (2) | AU2015289125B2 (ja) |
CA (2) | CA3190510A1 (ja) |
DK (2) | DK3552615T3 (ja) |
ES (2) | ES2743873T3 (ja) |
HU (1) | HUE045108T2 (ja) |
IL (1) | IL250058A0 (ja) |
PL (1) | PL3169341T3 (ja) |
PT (1) | PT3169341T (ja) |
RU (1) | RU2696312C2 (ja) |
WO (1) | WO2016008976A1 (ja) |
Families Citing this family (82)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2890714A2 (en) * | 2012-08-30 | 2015-07-08 | Amgen Inc. | A method for treating melanoma using a herpes simplex virus and an immune checkpoint inhibitor |
US10344090B2 (en) | 2013-12-12 | 2019-07-09 | Shanghai Hangrui Pharmaceutical Co., Ltd. | PD-1 antibody, antigen-binding fragment thereof, and medical application thereof |
AU2015289125B2 (en) * | 2014-07-16 | 2019-11-28 | Transgene Sa | Oncolytic virus for expression of immune checkpoint modulators |
AU2015289081B2 (en) * | 2014-07-16 | 2020-02-06 | Transgene Sa | Combination of oncolytic virus with immune checkpoint modulators |
NZ732211A (en) | 2014-10-24 | 2020-04-24 | Calidi Biotherapeutics Inc | Combination immunotherapy approach for treatment of cancer |
AU2016229408A1 (en) | 2015-02-25 | 2017-09-14 | Memorial Sloan-Kettering Cancer Center | Use of inactivated nonreplicating modified vaccinia virus ankara (mva) as monoimmunotherapy or in combination with immune checkpoint blocking agents for solid tumors |
DK3283508T3 (en) | 2015-04-17 | 2021-05-31 | Alpine Immune Sciences Inc | Immunomodulatory Proteins with Tunable Affinities |
WO2016168862A1 (en) | 2015-04-17 | 2016-10-20 | Memorial Sloan-Kettering Cancer Center | Use of mva or mvadeltae3l as immunotherapeutic agents against solid tumors |
WO2016196237A1 (en) | 2015-05-29 | 2016-12-08 | Agenus Inc. | Anti-ctla-4 antibodies and methods of use thereof |
EP3313993A4 (en) | 2015-06-29 | 2019-06-19 | Regents of the University of Minnesota | ANTI-APOBEC3 ANTIBODIES AND METHOD OF PREPARATION AND USE |
WO2017004165A1 (en) * | 2015-06-29 | 2017-01-05 | Regents Of The University Of Minnesota | Apobec3b mutagenesis and immunotherapy |
MA42447A (fr) | 2015-07-13 | 2018-05-23 | Cytomx Therapeutics Inc | Anticorps anti-pd-1, anticorps anti-pd-1 activables, et leurs procédés d'utilisation |
CN115212301A (zh) | 2015-08-11 | 2022-10-21 | 卡利迪生物治疗有限公司 | 用以癌症治疗的天花疫苗 |
CA3008279A1 (en) | 2015-12-14 | 2017-06-22 | X4 Pharmaceuticals, Inc. | Methods for treating cancer |
US10953003B2 (en) | 2015-12-14 | 2021-03-23 | X4 Pharmaceuticals, Inc. | Methods for treating cancer |
CA3009176A1 (en) | 2015-12-22 | 2017-06-29 | X4 Pharmaceuticals, Inc. | Methods for treating immunodeficiency disease |
US10612005B2 (en) | 2016-01-08 | 2020-04-07 | Replimune Limited | Modified oncolytic virus |
WO2017127811A1 (en) * | 2016-01-22 | 2017-07-27 | X4 Pharmaceuticals, Inc. | Methods for treating cancer |
KR20180136435A (ko) | 2016-01-27 | 2018-12-24 | 온코루스, 인크. | 종양 살상형 바이러스 벡터 및 그의 용도 |
EP3419662A4 (en) | 2016-02-25 | 2019-09-18 | Memorial Sloan Kettering Cancer Center | RECOMBINANT MVA OR MVADELE3L EXPRESSING FLT3L HUMAN AND THEIR USE AS IMMUNOTHERAPEUTIC AGENTS AGAINST SOLID TUMORS |
KR20180133395A (ko) | 2016-02-25 | 2018-12-14 | 메모리얼 슬로안 케터링 캔서 센터 | 암 면역요법을 위한, 인간 flt3l 또는 gm-csf의 발현이 있거나 없으며 티미딘 키나제가 결실된 복제 가능 약독화 백시니아 바이러스 |
JP2019510785A (ja) | 2016-04-08 | 2019-04-18 | エックス4 ファーマシューティカルズ, インコーポレイテッド | 癌を処置する方法 |
KR20230051602A (ko) | 2016-04-15 | 2023-04-18 | 알파인 이뮨 사이언시즈, 인코포레이티드 | Icos 리간드 변이체 면역조절 단백질 및 그의 용도 |
WO2017201281A1 (en) | 2016-05-18 | 2017-11-23 | Mayo Foundation For Medical Education And Research | Targeting pd-l1 on tumor cells |
CN109640988A (zh) | 2016-06-21 | 2019-04-16 | X4 制药有限公司 | Cxcr4抑制剂及其用途 |
CN116554168A (zh) | 2016-06-21 | 2023-08-08 | X4 制药有限公司 | Cxcr4抑制剂及其用途 |
JP6994767B2 (ja) | 2016-06-21 | 2022-01-14 | エックス4 ファーマシューティカルズ, インコーポレイテッド | Cxcr4阻害剤およびその使用 |
CA3029426A1 (en) | 2016-06-30 | 2018-01-04 | Oncorus, Inc. | Pseudotyped oncolytic viral delivery of therapeutic polypeptides |
JP6731646B2 (ja) * | 2016-07-13 | 2020-07-29 | 国立大学法人鳥取大学 | 外来遺伝子発現ワクシニアウイルスの製造方法 |
EP3494219A1 (en) * | 2016-08-03 | 2019-06-12 | Aalborg Universitet | ANTISENSE OLIGONUCLEOTIDES (ASOs) DESIGNED TO INHIBIT IMMUNE CHECKPOINT PROTEINS |
WO2018049261A1 (en) * | 2016-09-09 | 2018-03-15 | Icellhealth Consulting Llc | Oncolytic virus expressing immune checkpoint modulators |
CN110072550A (zh) | 2016-11-01 | 2019-07-30 | 德那翠丝有限公司 | 用于治疗脑癌的组合疗法 |
EP4289484A3 (en) | 2016-12-07 | 2024-03-06 | Agenus Inc. | Anti-ctla-4 antibodies and methods of use thereof |
JP2020510624A (ja) * | 2016-12-12 | 2020-04-09 | マルチビア インコーポレイテッド | がんおよび感染性疾患の治療および予防のための、ウイルス遺伝子治療および免疫チェックポイント阻害剤を含む方法および組成物 |
US11298420B2 (en) * | 2016-12-21 | 2022-04-12 | Memgen, Llc | Armed oncolytic viruses |
CN108261426B (zh) | 2017-01-04 | 2019-04-05 | 杭州康万达医药科技有限公司 | 药物组合物及其在治疗肿瘤和/或癌症的药物中的应用 |
GB201700350D0 (en) | 2017-01-09 | 2017-02-22 | Replimune Ltd | Altered virus |
BR112019015514A2 (pt) * | 2017-01-30 | 2020-04-07 | Epicentrx Inc | mutantes de tata-box e caat-box seletivos de tumor |
RU2740713C1 (ru) | 2017-02-28 | 2021-01-20 | Генемедицине Ко., Лтд. | Противораковая композиция, содержащая опухолеспецифический онколитический аденовирус и ингибитор контрольной точки иммунного ответа |
US11242509B2 (en) | 2017-05-12 | 2022-02-08 | Memorial Sloan Kettering Cancer Center | Vaccinia virus mutants useful for cancer immunotherapy |
WO2018218137A1 (en) | 2017-05-25 | 2018-11-29 | Leidos, Inc. | Pd-1 and ctla-4 dual inhibitor peptides |
BR112020001559A2 (pt) | 2017-07-26 | 2020-08-11 | Oncorus, Inc. | vetores virais oncolíticos e usos dos mesmos |
CN109576231B (zh) * | 2017-09-28 | 2022-03-25 | 北京康万达医药科技有限公司 | 分离的重组溶瘤腺病毒、药物组合物及其在治疗肿瘤和/或癌症的药物中的用途 |
EP4442268A2 (en) | 2017-10-10 | 2024-10-09 | Alpine Immune Sciences, Inc. | Ctla-4 variant immunomodulatory proteins and uses thereof |
US20200283500A1 (en) | 2017-10-18 | 2020-09-10 | Alpine Immune Sciences, Inc. | Variant icos ligand immunomodulatory proteins and related compositions and methods |
WO2019084418A1 (en) * | 2017-10-27 | 2019-05-02 | Merck Sharp & Dohme Corp. | COMPOSITIONS AND METHODS FOR THE TREATMENT OF LIVER CANCER |
US20210177921A1 (en) * | 2017-11-16 | 2021-06-17 | Virogin Biotech Canada Ltd | Targeting moiety-decorated oncolytic viruses |
CN108165536A (zh) * | 2017-12-11 | 2018-06-15 | 浙江大学 | 一种重组溶瘤痘苗病毒及其制备方法与应用 |
JP2021508477A (ja) | 2017-12-29 | 2021-03-11 | オンコラス, インコーポレイテッド | 治療用ポリペプチドの腫瘍溶解性ウイルス送達 |
EP3735466A4 (en) | 2018-01-05 | 2022-01-12 | Ottawa Hospital Research Institute | MODIFIED ORTHOPOXVIRUS VECTORS |
CA3088609C (en) * | 2018-01-19 | 2024-02-13 | Kolon Life Science, Inc. | Recombinant vaccinia virus and pharmaceutical composition comprising same |
JP2021511060A (ja) * | 2018-01-26 | 2021-05-06 | ユニバーシティ オブ ピッツバーグ − オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション | 腫瘍治療を改善するための、腫瘍微小環境における代謝モジュレーターの発現 |
WO2019151836A1 (en) * | 2018-02-05 | 2019-08-08 | Sillajen, Inc. | Oncolytic vaccinia virus expressing an immune checkpoint protein antagonist to treat cancer |
ES2976989T3 (es) * | 2018-02-28 | 2024-08-14 | Bionoxx Inc | Composición farmacéutica para prevenir o tratar el cáncer que comprende virus antineoplásicos e hidroxicarbamida como componentes eficaces |
CN108329378B (zh) * | 2018-03-12 | 2020-09-25 | 华中农业大学 | 塞内卡谷病毒vp1蛋白、编码基因、杂交瘤细胞株和单克隆抗体及其应用 |
US20210023151A1 (en) * | 2018-03-13 | 2021-01-28 | Memorial Sloan Kettering Cancer Center | Oncolytic vaccinia virus expressing immune checkpoint blockade for cancer immunotherapy |
US11505782B2 (en) | 2018-06-04 | 2022-11-22 | Calidi Biotherapeutics, Inc. | Cell-based vehicles for potentiation of viral therapy |
WO2019241758A1 (en) | 2018-06-15 | 2019-12-19 | Alpine Immune Sciences, Inc. | Pd-1 variant immunomodulatory proteins and uses thereof |
US20210196771A1 (en) * | 2018-08-16 | 2021-07-01 | Systems Oncology, Llc | Recombinant myxoma viruses and uses thereof |
US10548889B1 (en) | 2018-08-31 | 2020-02-04 | X4 Pharmaceuticals, Inc. | Compositions of CXCR4 inhibitors and methods of preparation and use |
EP3617230A1 (en) * | 2018-09-03 | 2020-03-04 | BioInvent International AB | Novel antibodies and nucleotide sequences, and uses thereof |
WO2020052551A1 (en) * | 2018-09-10 | 2020-03-19 | Genesail Biotech (Shanghai) Co. Ltd. | A modified oncolytic virus, composition and use thereof |
CN111100846A (zh) * | 2018-10-26 | 2020-05-05 | 上海元宋生物技术有限公司 | 表达pd-1结合蛋白的溶瘤病毒及其应用 |
CN113194715B (zh) * | 2018-10-31 | 2024-03-19 | 赫曼尼根公司 | 用于治疗癌症的材料和方法 |
KR20210087029A (ko) * | 2018-11-01 | 2021-07-09 | 바이오인벤트 인터내셔날 에이비 | 신규한 길항작용 항 tnfr2 항체 분자 |
EP3876951A1 (en) | 2018-11-06 | 2021-09-15 | Calidi Biotherapeutics, Inc. | Enhanced systems for cell-mediated oncolytic viral therapy |
WO2020106924A1 (en) | 2018-11-21 | 2020-05-28 | Mayo Foundation For Medical Education And Research | Adenoviruses and methods for using adenoviruses |
CN109627336A (zh) * | 2018-12-20 | 2019-04-16 | 南京昂科利医药科技创新研究院有限公司 | 一种表达pd-l1单链抗体的新城疫溶瘤病毒的制备方法及应用 |
PE20212307A1 (es) * | 2018-12-21 | 2021-12-10 | Ottawa Hospital Res Inst | Vectores de orthopoxvirus modificados |
MX2021007860A (es) * | 2018-12-28 | 2021-10-26 | Transgene | Poxvirux deficiente en m2. |
WO2020156693A1 (en) * | 2019-01-29 | 2020-08-06 | Arno Thaller | Recombinant oncolytic newcastle disease viruses with increased activity |
CN109913425B (zh) * | 2019-03-22 | 2021-05-11 | 中国人民解放军总医院第五医学中心 | 一种重组流感病毒拯救方法及其在肿瘤治疗中的应用 |
WO2020198690A1 (en) * | 2019-03-28 | 2020-10-01 | Arizona Board Of Regents, A Body Corporate Of The State Of Arizona, Acting For And On Behalf Of Arizona State University | Oncolytic myxoma virus expressing fast p14 to treat hematological cancer |
US11485767B2 (en) | 2019-04-29 | 2022-11-01 | Mayo Foundation For Medical Education And Research | Multivalent PD-L1 binding compounds for treating cancer |
AU2020279371A1 (en) | 2019-05-22 | 2021-12-23 | Leidos, Inc. | LAG 3 binding peptides |
CN114340649A (zh) * | 2019-08-26 | 2022-04-12 | 拜耳诺克斯有限公司 | 包含痘苗病毒和羟基脲作为活性成分的用于治疗癌症的药物组合物 |
US11578102B2 (en) | 2020-07-31 | 2023-02-14 | Leidos, Inc. | LAG3 binding peptides |
JP2023548662A (ja) | 2020-10-12 | 2023-11-20 | レイドス, インコーポレイテッド | 免疫調節性ペプチド |
CN112641798A (zh) * | 2020-12-29 | 2021-04-13 | 武汉博威德生物技术有限公司 | 一种提高重组柯萨奇病毒溶瘤作用的方法 |
KR20230130689A (ko) * | 2021-01-11 | 2023-09-12 | 세네카 세라퓨틱스, 인크. | 체크포인트 억제제에 불응성인 암을 치료하기 위한세네카 밸리 바이러스 조합 요법 |
WO2022159508A1 (en) * | 2021-01-19 | 2022-07-28 | Seneca Therapeutics, Inc. | Armed seneca valley virus oncolytic therapy compositions and methods thereof |
CN114934065A (zh) * | 2021-11-25 | 2022-08-23 | 浙江理工大学绍兴生物医药研究院有限公司 | 携带免疫检查点分子tim-3抗体基因的溶瘤腺病毒构建方法和应用 |
Family Cites Families (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5168062A (en) | 1985-01-30 | 1992-12-01 | University Of Iowa Research Foundation | Transfer vectors and microorganisms containing human cytomegalovirus immediate-early promoter-regulatory DNA sequence |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5258498A (en) | 1987-05-21 | 1993-11-02 | Creative Biomolecules, Inc. | Polypeptide linkers for production of biosynthetic proteins |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
FR2656800B1 (fr) | 1990-01-08 | 1992-05-15 | Roussy Inst Gustave | Nouvelles proteines produits par les lymphocytes humains, sequence d'adn codant pour ces proteines et applications pharmaceutiques et biologiques. |
US5457035A (en) | 1993-07-23 | 1995-10-10 | Immunex Corporation | Cytokine which is a ligand for OX40 |
US5856153A (en) | 1994-11-17 | 1999-01-05 | Cayla | Suicide genes and new associations of pyrimidine nucleobase and nucleoside analogs with new suicide genes for gene therapy of acquired diseases |
US5811097A (en) | 1995-07-25 | 1998-09-22 | The Regents Of The University Of California | Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling |
FR2751343B1 (fr) | 1996-07-16 | 1998-12-18 | Transgene Sa | Procede de conservation de virus recombinants infectieux, suspension aqueuse virale et utilisation comme medicament |
EP0931158A1 (en) | 1996-09-06 | 1999-07-28 | The Trustees Of The University Of Pennsylvania | An inducible method for production of recombinant adeno-associated viruses utilizing t7 polymerase |
EP0988053A1 (en) | 1997-06-11 | 2000-03-29 | Aquila Biopharmaceuticals, Inc. | Purified saponins as oral adjuvants |
FR2766091A1 (fr) | 1997-07-18 | 1999-01-22 | Transgene Sa | Composition antitumorale a base de polypeptide immunogene de localisation cellulaire modifiee |
US6312700B1 (en) | 1998-02-24 | 2001-11-06 | Andrew D. Weinberg | Method for enhancing an antigen specific immune response with OX-40L |
FR2777570A1 (fr) | 1998-04-17 | 1999-10-22 | Transgene Sa | Mutant ayant une activite phosphoribosyl transferase |
US7109003B2 (en) | 1998-12-23 | 2006-09-19 | Abgenix, Inc. | Methods for expressing and recovering human monoclonal antibodies to CTLA-4 |
US6322980B1 (en) | 1999-04-30 | 2001-11-27 | Aclara Biosciences, Inc. | Single nucleotide detection using degradation of a fluorescent sequence |
US7605238B2 (en) | 1999-08-24 | 2009-10-20 | Medarex, Inc. | Human CTLA-4 antibodies and their uses |
AU784012B2 (en) | 1999-08-24 | 2006-01-12 | E. R. Squibb & Sons, L.L.C. | Human CTLA-4 antibodies and their uses |
CA2399321C (en) | 2000-03-07 | 2013-04-30 | Robert K. Evans | Adenovirus formulations |
ATE524495T1 (de) | 2001-07-31 | 2011-09-15 | Ono Pharmaceutical Co | Pd-1-spezifische substanz |
GB0128288D0 (en) | 2001-11-27 | 2002-01-16 | Siddall & Hilton Ltd | Spring location means |
US7094412B2 (en) | 2001-12-10 | 2006-08-22 | Bavarian Nordic A/S | Poxvirus containing formulations and process for preparing stable poxvirus containing compositions |
IL164376A0 (en) | 2002-04-03 | 2005-12-18 | Applied Research Systems | Ox4or binding agents, their preparation and pharmaceutical compositions containing them |
US7550140B2 (en) | 2002-06-13 | 2009-06-23 | Crucell Holland B.V. | Antibody to the human OX40 receptor |
FI2206517T3 (fi) | 2002-07-03 | 2023-10-19 | Ono Pharmaceutical Co | Immuunopotentioivia koostumuksia käsittäen anti-PD-L1 -vasta-aineita |
US7291331B1 (en) | 2002-09-11 | 2007-11-06 | La Jolla Institute For Allergy And Immunology | Methods of treating OX40 medicated recall immune responses |
ATE514713T1 (de) | 2002-12-23 | 2011-07-15 | Wyeth Llc | Antikörper gegen pd-1 und ihre verwendung |
CN1826410B (zh) | 2003-07-21 | 2011-10-26 | 特兰斯吉恩股份有限公司 | 具有改良的胞嘧啶脱氨酶活性的多肽 |
EP1528101A1 (en) | 2003-11-03 | 2005-05-04 | ProBioGen AG | Immortalized avian cell lines for virus production |
CN101056646A (zh) | 2004-11-12 | 2007-10-17 | 拜耳先灵医药股份有限公司 | 重组新城疫病毒 |
FR2884255B1 (fr) | 2005-04-11 | 2010-11-05 | Vivalis | Utilisation de lignees de cellules souches aviaires ebx pour la production de vaccin contre la grippe |
EP2439273B1 (en) | 2005-05-09 | 2019-02-27 | Ono Pharmaceutical Co., Ltd. | Human monoclonal antibodies to programmed death 1(PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics |
LT2397156T (lt) | 2005-06-08 | 2017-02-27 | Dana-Farber Cancer Institute, Inc. | Būdai ir kompozicijos, skirti nuolatinių infekcijų ir vėžio gydymui inhibuojant užprogramuotos ląstelės mirties-1 (pd-1) kelią |
WO2007056847A1 (en) | 2005-11-21 | 2007-05-24 | Sanofi Pasteur Limited | Stabilizing formulations for recombinant viruses |
US9868961B2 (en) | 2006-03-30 | 2018-01-16 | The Regents Of The University Of California | Methods and compositions for localized secretion of anti-CTLA-4 antibodies |
AU2007263281B2 (en) | 2006-06-20 | 2012-12-06 | Transgene S.A. | Recombinant viral vaccine |
JP5456464B2 (ja) | 2006-06-20 | 2014-03-26 | トランジェーヌ、ソシエテ、アノニム | ポックスウイルスおよびポックスウイルス組成物の製造方法 |
GB0705245D0 (en) | 2007-03-19 | 2007-04-25 | Stabilitech Ltd | Stable biological products |
EP1985305A1 (en) | 2007-04-24 | 2008-10-29 | Vivalis | Duck embryonic derived stem cell lines for the production of viral vaccines |
AU2008250596C1 (en) | 2007-05-14 | 2010-11-25 | Bavarian Nordic A/S | Purification of Vaccinia virus- and recombinant Vaccinia virus-based vaccines |
BRPI0812913B8 (pt) | 2007-06-18 | 2021-05-25 | Merck Sharp & Dohme | anticorpos monoclonais ou fragmento de anticorpo para o receptor de morte programada humano pd-1, polinucleotideo, método para produzir os referidos anticorpos ou fragmentos de anticorpos, composição que os compreende e uso dos mesmos |
US8357531B2 (en) | 2007-07-03 | 2013-01-22 | Transgene S.A. | Immortalized avian cell lines |
WO2009014708A2 (en) | 2007-07-23 | 2009-01-29 | Cell Genesys, Inc. | Pd-1 antibodies in combination with a cytokine-secreting cell and methods of use thereof |
BRPI0820578A2 (pt) | 2007-11-19 | 2015-06-16 | Transgène S A | Vírus da varíola, processo para preparar um vírus da varíola, composição, uso de um vírus da varíola ou de uma composição, e, método para tratar doenças |
US9687515B2 (en) * | 2007-11-19 | 2017-06-27 | Transgene S.A. | Poxviral oncolytic vectors |
RU2503717C2 (ru) * | 2007-11-19 | 2014-01-10 | Трансжене Са | Поксвирусные онколитические векторы |
TWI661833B (zh) | 2007-11-30 | 2019-06-11 | 百慕達商艾伯維生物技術有限責任公司 | 蛋白質調配物及製造其之方法 |
MX2010008970A (es) | 2008-02-12 | 2011-05-30 | Sanofi Pasteur Ltd | Metodo que utiliza cromatografia de intercambio ionico y filtracion en gel para la purificacion de poxvirus. |
EP2262837A4 (en) | 2008-03-12 | 2011-04-06 | Merck Sharp & Dohme | PD-1 BINDING PROTEINS |
US8470977B2 (en) | 2008-03-14 | 2013-06-25 | Transgene S.A. | Antibody against the CSF-1R |
US8445270B2 (en) | 2009-05-12 | 2013-05-21 | Transgene S.A. | Immortalized avian cell lines and use thereof |
US9631018B2 (en) | 2010-03-26 | 2017-04-25 | The Trustees Of Dartmouth College | Vista regulatory T cell mediator protein, vista binding agents and use thereof |
ES2813413T3 (es) | 2011-08-05 | 2021-03-23 | Sillajen Biotherapeutics Inc | Métodos y composiciones para la producción de virus vaccina |
US20130071403A1 (en) | 2011-09-20 | 2013-03-21 | Vical Incorporated | Synergistic anti-tumor efficacy using alloantigen combination immunotherapy |
EP2879498A4 (en) | 2012-07-30 | 2016-03-30 | Alex Wah Hin Yeung | BY TREATMENT OF AT LEAST TWO OR ALL THREE OF THE FOLLOWING COMPONENTS SUCH AS TUMOR CELLS, AN ONCOLYTIC VIRUS VECTOR WITH TRANSGENIC EXPRESSION OF GM-CSF AND AN IMMUNE TEST MODULE DEVELOPED TUMOR SPECIFIC LIVING AND IN VIVO CANCER VACCINE SYSTEM |
US20150250837A1 (en) * | 2012-09-20 | 2015-09-10 | Morningside Technology Ventures Ltd. | Oncolytic virus encoding pd-1 binding agents and uses of the same |
TWI690322B (zh) | 2012-10-02 | 2020-04-11 | 法商傳斯堅公司 | 含病毒的調配物及其使用 |
AU2015289125B2 (en) * | 2014-07-16 | 2019-11-28 | Transgene Sa | Oncolytic virus for expression of immune checkpoint modulators |
CN108165536A (zh) * | 2017-12-11 | 2018-06-15 | 浙江大学 | 一种重组溶瘤痘苗病毒及其制备方法与应用 |
US20210023151A1 (en) * | 2018-03-13 | 2021-01-28 | Memorial Sloan Kettering Cancer Center | Oncolytic vaccinia virus expressing immune checkpoint blockade for cancer immunotherapy |
EP3617230A1 (en) * | 2018-09-03 | 2020-03-04 | BioInvent International AB | Novel antibodies and nucleotide sequences, and uses thereof |
CN110218707B (zh) * | 2019-05-29 | 2021-10-22 | 上海市公共卫生临床中心 | 一种新型溶瘤病毒及其制备方法和应用 |
-
2015
- 2015-07-16 AU AU2015289125A patent/AU2015289125B2/en active Active
- 2015-07-16 DK DK19174121.4T patent/DK3552615T3/da active
- 2015-07-16 JP JP2017502212A patent/JP6895374B2/ja active Active
- 2015-07-16 WO PCT/EP2015/066263 patent/WO2016008976A1/en active Application Filing
- 2015-07-16 RU RU2017103162A patent/RU2696312C2/ru active
- 2015-07-16 ES ES15738359T patent/ES2743873T3/es active Active
- 2015-07-16 DK DK15738359.7T patent/DK3169341T3/da active
- 2015-07-16 CA CA3190510A patent/CA3190510A1/en active Pending
- 2015-07-16 PL PL15738359T patent/PL3169341T3/pl unknown
- 2015-07-16 EP EP19174121.4A patent/EP3552615B8/en active Active
- 2015-07-16 PT PT15738359T patent/PT3169341T/pt unknown
- 2015-07-16 ES ES19174121T patent/ES2909957T3/es active Active
- 2015-07-16 HU HUE15738359A patent/HUE045108T2/hu unknown
- 2015-07-16 CN CN201580050076.8A patent/CN107208069A/zh active Pending
- 2015-07-16 CA CA2954841A patent/CA2954841A1/en active Pending
- 2015-07-16 EP EP15738359.7A patent/EP3169341B1/en active Active
- 2015-07-16 US US15/325,562 patent/US10555981B2/en active Active
-
2017
- 2017-01-11 IL IL250058A patent/IL250058A0/en active IP Right Grant
-
2019
- 2019-12-23 US US16/725,485 patent/US11779619B2/en active Active
-
2020
- 2020-01-24 AU AU2020200541A patent/AU2020200541B2/en active Active
- 2020-09-29 JP JP2020163305A patent/JP7077377B2/ja active Active
Also Published As
Publication number | Publication date |
---|---|
JP2021006048A (ja) | 2021-01-21 |
US11779619B2 (en) | 2023-10-10 |
EP3169341B1 (en) | 2019-06-05 |
DK3552615T3 (da) | 2022-02-14 |
CA3190510A1 (en) | 2016-01-21 |
RU2017103162A (ru) | 2018-08-16 |
DK3169341T3 (da) | 2019-08-05 |
EP3552615B1 (en) | 2022-01-26 |
AU2020200541A1 (en) | 2020-02-13 |
PL3169341T3 (pl) | 2019-12-31 |
AU2015289125B2 (en) | 2019-11-28 |
CN107208069A (zh) | 2017-09-26 |
AU2015289125A1 (en) | 2017-02-02 |
RU2017103162A3 (ja) | 2018-08-22 |
IL250058A0 (en) | 2017-03-30 |
US20200197457A1 (en) | 2020-06-25 |
WO2016008976A1 (en) | 2016-01-21 |
JP7077377B2 (ja) | 2022-05-30 |
HUE045108T2 (hu) | 2019-12-30 |
ES2743873T3 (es) | 2020-02-21 |
CA2954841A1 (en) | 2016-01-21 |
JP2017522025A (ja) | 2017-08-10 |
EP3552615A1 (en) | 2019-10-16 |
US20170157188A1 (en) | 2017-06-08 |
RU2696312C2 (ru) | 2019-08-01 |
ES2909957T3 (es) | 2022-05-11 |
US10555981B2 (en) | 2020-02-11 |
AU2020200541B2 (en) | 2021-12-16 |
EP3169341A1 (en) | 2017-05-24 |
PT3169341T (pt) | 2019-09-09 |
EP3552615B8 (en) | 2022-03-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7077377B2 (ja) | 免疫チェックポイントモジュレーターの発現用腫瘍溶解性ウイルス | |
JP7146852B2 (ja) | 腫瘍溶解性ウイルスと免疫チェックポイントモジュレーターとの組合せ | |
AU2021297349A1 (en) | Oncolytic herpes simplex viruses (HSV) expressing immunomodulatory fusion proteins | |
JP7515461B2 (ja) | 新規抗体およびヌクレオチド配列、ならびにそれらの使用 | |
TWI817159B (zh) | 重組牛痘病毒 | |
WO2023213764A1 (en) | Fusion polypeptide comprising an anti-pd-l1 sdab and a member of the tnfsf |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180706 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180706 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20190521 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190607 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190909 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20191107 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20191205 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20200529 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200929 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20200929 |
|
C11 | Written invitation by the commissioner to file amendments |
Free format text: JAPANESE INTERMEDIATE CODE: C11 Effective date: 20201009 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20201110 |
|
C21 | Notice of transfer of a case for reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C21 Effective date: 20201113 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210122 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210406 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20210514 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210607 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6895374 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |