WO2000074629A2 - Composition destinee a la mise en oeuvre d'un traitement cytotoxique, notamment antitumoral ou antiviral, chez un mammifere - Google Patents
Composition destinee a la mise en oeuvre d'un traitement cytotoxique, notamment antitumoral ou antiviral, chez un mammifere Download PDFInfo
- Publication number
- WO2000074629A2 WO2000074629A2 PCT/FR2000/001559 FR0001559W WO0074629A2 WO 2000074629 A2 WO2000074629 A2 WO 2000074629A2 FR 0001559 W FR0001559 W FR 0001559W WO 0074629 A2 WO0074629 A2 WO 0074629A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- polypeptide
- nucleic acid
- vector
- composition according
- activity
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 74
- 230000001472 cytotoxic effect Effects 0.000 title claims abstract description 40
- 238000011282 treatment Methods 0.000 title claims abstract description 32
- 231100000433 cytotoxic Toxicity 0.000 title claims abstract description 17
- 241000124008 Mammalia Species 0.000 title claims abstract description 13
- 230000000259 anti-tumor effect Effects 0.000 title description 15
- 230000000840 anti-viral effect Effects 0.000 title description 7
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 69
- 229920001184 polypeptide Polymers 0.000 claims abstract description 66
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 66
- 150000007523 nucleic acids Chemical group 0.000 claims abstract description 45
- 102000019034 Chemokines Human genes 0.000 claims abstract description 26
- 108010012236 Chemokines Proteins 0.000 claims abstract description 26
- 108091028043 Nucleic acid sequence Proteins 0.000 claims abstract description 25
- 230000014509 gene expression Effects 0.000 claims abstract description 18
- 239000013598 vector Substances 0.000 claims description 69
- 108090000623 proteins and genes Proteins 0.000 claims description 43
- 230000000694 effects Effects 0.000 claims description 37
- 230000003612 virological effect Effects 0.000 claims description 32
- 239000002245 particle Substances 0.000 claims description 28
- 102000000311 Cytosine Deaminase Human genes 0.000 claims description 25
- 108010080611 Cytosine Deaminase Proteins 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 23
- 108091000036 uracil phosphoribosyltransferase Proteins 0.000 claims description 23
- 102100028748 Transportin-1 Human genes 0.000 claims description 19
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 17
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims description 17
- 229960002949 fluorouracil Drugs 0.000 claims description 17
- 229960004413 flucytosine Drugs 0.000 claims description 16
- 238000009472 formulation Methods 0.000 claims description 13
- 108010002350 Interleukin-2 Proteins 0.000 claims description 12
- 102000000588 Interleukin-2 Human genes 0.000 claims description 12
- 102000004127 Cytokines Human genes 0.000 claims description 11
- 108090000695 Cytokines Proteins 0.000 claims description 11
- 230000001772 anti-angiogenic effect Effects 0.000 claims description 9
- 239000013612 plasmid Substances 0.000 claims description 9
- 102000004169 proteins and genes Human genes 0.000 claims description 9
- 108010074328 Interferon-gamma Proteins 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000013603 viral vector Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 5
- 229940002612 prodrug Drugs 0.000 claims description 5
- 239000000651 prodrug Substances 0.000 claims description 5
- 101000815628 Homo sapiens Regulatory-associated protein of mTOR Proteins 0.000 claims description 4
- 101000652747 Homo sapiens Target of rapamycin complex 2 subunit MAPKAP1 Proteins 0.000 claims description 4
- 101000648491 Homo sapiens Transportin-1 Proteins 0.000 claims description 4
- 102100037850 Interferon gamma Human genes 0.000 claims description 4
- 102000008070 Interferon-gamma Human genes 0.000 claims description 4
- 101000686934 Mus musculus Prolactin-7D1 Proteins 0.000 claims description 3
- 101710101148 Probable 6-oxopurine nucleoside phosphorylase Proteins 0.000 claims description 3
- 102000030764 Purine-nucleoside phosphorylase Human genes 0.000 claims description 3
- 102000006601 Thymidine Kinase Human genes 0.000 claims description 3
- 108020004440 Thymidine kinase Proteins 0.000 claims description 3
- 239000002254 cytotoxic agent Substances 0.000 claims description 3
- 229940127089 cytotoxic agent Drugs 0.000 claims description 3
- 229940044627 gamma-interferon Drugs 0.000 claims description 3
- 102400000068 Angiostatin Human genes 0.000 claims description 2
- 108010079709 Angiostatins Proteins 0.000 claims description 2
- 102000007644 Colony-Stimulating Factors Human genes 0.000 claims description 2
- 108010071942 Colony-Stimulating Factors Proteins 0.000 claims description 2
- 102400001047 Endostatin Human genes 0.000 claims description 2
- 108010079505 Endostatins Proteins 0.000 claims description 2
- 101000582950 Homo sapiens Platelet factor 4 Proteins 0.000 claims description 2
- 108010091358 Hypoxanthine Phosphoribosyltransferase Proteins 0.000 claims description 2
- 102000018251 Hypoxanthine Phosphoribosyltransferase Human genes 0.000 claims description 2
- 108010050904 Interferons Proteins 0.000 claims description 2
- 102000014150 Interferons Human genes 0.000 claims description 2
- 102000015696 Interleukins Human genes 0.000 claims description 2
- 108010063738 Interleukins Proteins 0.000 claims description 2
- 108010006035 Metalloproteases Proteins 0.000 claims description 2
- 102000005741 Metalloproteases Human genes 0.000 claims description 2
- 102100030304 Platelet factor 4 Human genes 0.000 claims description 2
- 102000007614 Thrombospondin 1 Human genes 0.000 claims description 2
- 108010046722 Thrombospondin 1 Proteins 0.000 claims description 2
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 claims description 2
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 claims description 2
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 claims description 2
- 238000004113 cell culture Methods 0.000 claims description 2
- 229940047120 colony stimulating factors Drugs 0.000 claims description 2
- 229940047124 interferons Drugs 0.000 claims description 2
- 229940047122 interleukins Drugs 0.000 claims description 2
- 229960005356 urokinase Drugs 0.000 claims description 2
- 102100021503 ATP-binding cassette sub-family B member 6 Human genes 0.000 claims 1
- 101000742140 Foeniculum vulgare Pathogenesis-related protein Proteins 0.000 claims 1
- 101000924727 Homo sapiens Alternative prion protein Proteins 0.000 claims 1
- 101000740685 Homo sapiens C4b-binding protein alpha chain Proteins 0.000 claims 1
- 101001090065 Homo sapiens Peroxiredoxin-2 Proteins 0.000 claims 1
- 101000830596 Homo sapiens Tumor necrosis factor ligand superfamily member 15 Proteins 0.000 claims 1
- 101000633277 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Peroxiredoxin TSA1 Proteins 0.000 claims 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims 1
- 102100024587 Tumor necrosis factor ligand superfamily member 15 Human genes 0.000 claims 1
- 108010032220 cyclomaltodextrinase Proteins 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 102000003390 tumor necrosis factor Human genes 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 69
- 206010028980 Neoplasm Diseases 0.000 description 49
- 241000699670 Mus sp. Species 0.000 description 22
- 241000701161 unidentified adenovirus Species 0.000 description 22
- 241000282414 Homo sapiens Species 0.000 description 15
- 238000001415 gene therapy Methods 0.000 description 15
- 241000588724 Escherichia coli Species 0.000 description 14
- 210000004881 tumor cell Anatomy 0.000 description 13
- 201000011510 cancer Diseases 0.000 description 12
- 239000002773 nucleotide Substances 0.000 description 12
- 125000003729 nucleotide group Chemical group 0.000 description 12
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- 241000700605 Viruses Species 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 229940088598 enzyme Drugs 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 238000010276 construction Methods 0.000 description 8
- 238000012217 deletion Methods 0.000 description 8
- 230000037430 deletion Effects 0.000 description 8
- 239000012634 fragment Substances 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 230000004927 fusion Effects 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 230000010076 replication Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- 241001430294 unidentified retrovirus Species 0.000 description 7
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000001747 exhibiting effect Effects 0.000 description 6
- 210000001616 monocyte Anatomy 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- 230000035755 proliferation Effects 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 241001529936 Murinae Species 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 239000002870 angiogenesis inducing agent Substances 0.000 description 5
- 230000002950 deficient Effects 0.000 description 5
- 229960002963 ganciclovir Drugs 0.000 description 5
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 230000035945 sensitivity Effects 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- 229940035893 uracil Drugs 0.000 description 5
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 4
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000002299 complementary DNA Substances 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 230000002255 enzymatic effect Effects 0.000 description 4
- 230000003394 haemopoietic effect Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000002458 infectious effect Effects 0.000 description 4
- 210000004962 mammalian cell Anatomy 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- 230000006798 recombination Effects 0.000 description 4
- 238000005215 recombination Methods 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- 230000002792 vascular Effects 0.000 description 4
- -1 1TL-4 IL -6 Proteins 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 102100031102 C-C motif chemokine 4 Human genes 0.000 description 3
- 101100054773 Caenorhabditis elegans act-2 gene Proteins 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 102100021519 Hemoglobin subunit beta Human genes 0.000 description 3
- 108091005904 Hemoglobin subunit beta Proteins 0.000 description 3
- 101000807008 Homo sapiens Uracil phosphoribosyltransferase homolog Proteins 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 108010065805 Interleukin-12 Proteins 0.000 description 3
- 101150021395 JUND gene Proteins 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000000481 breast Anatomy 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000010367 cloning Methods 0.000 description 3
- 230000000295 complement effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 3
- 229940104302 cytosine Drugs 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 208000037803 restenosis Diseases 0.000 description 3
- 230000001177 retroviral effect Effects 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- PQGCEDQWHSBAJP-TXICZTDVSA-N 5-O-phosphono-alpha-D-ribofuranosyl diphosphate Chemical compound O[C@H]1[C@@H](O)[C@@H](O[P@](O)(=O)OP(O)(O)=O)O[C@@H]1COP(O)(O)=O PQGCEDQWHSBAJP-TXICZTDVSA-N 0.000 description 2
- SYMHUEFSSMBHJA-UHFFFAOYSA-N 6-methylpurine Chemical compound CC1=NC=NC2=C1NC=N2 SYMHUEFSSMBHJA-UHFFFAOYSA-N 0.000 description 2
- RJOXFJDOUQJOMQ-UHFFFAOYSA-N 6-sulfanylidene-3,7-dihydropurin-2-one Chemical compound S=C1NC(=O)NC2=C1NC=N2 RJOXFJDOUQJOMQ-UHFFFAOYSA-N 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 101100263837 Bovine ephemeral fever virus (strain BB7721) beta gene Proteins 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 241000282465 Canis Species 0.000 description 2
- 108010055166 Chemokine CCL5 Proteins 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 101100316840 Enterobacteria phage P4 Beta gene Proteins 0.000 description 2
- 241000206602 Eukaryota Species 0.000 description 2
- 101150002048 FUR1 gene Proteins 0.000 description 2
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 2
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 2
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 2
- 101710151805 Mitochondrial intermediate peptidase 1 Proteins 0.000 description 2
- 241000713869 Moloney murine leukemia virus Species 0.000 description 2
- 241000713862 Moloney murine sarcoma virus Species 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 102000011755 Phosphoglycerate Kinase Human genes 0.000 description 2
- 101001099217 Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8) Triosephosphate isomerase Proteins 0.000 description 2
- 108010022394 Threonine synthase Proteins 0.000 description 2
- 108700019146 Transgenes Proteins 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 241000700618 Vaccinia virus Species 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 229960004150 aciclovir Drugs 0.000 description 2
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 230000001889 chemoattractive effect Effects 0.000 description 2
- 230000035605 chemotaxis Effects 0.000 description 2
- 101150093170 codA gene Proteins 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 230000009615 deamination Effects 0.000 description 2
- 238000006481 deamination reaction Methods 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 239000005549 deoxyribonucleoside Substances 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 210000003979 eosinophil Anatomy 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 238000010353 genetic engineering Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 231100000636 lethal dose Toxicity 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 210000004897 n-terminal region Anatomy 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000030786 positive chemotaxis Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000001057 smooth muscle myoblast Anatomy 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 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 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 241000710929 Alphavirus Species 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- 102100036153 C-X-C motif chemokine 6 Human genes 0.000 description 1
- 101710085504 C-X-C motif chemokine 6 Proteins 0.000 description 1
- 101150104494 CAV1 gene Proteins 0.000 description 1
- 101100504320 Caenorhabditis elegans mcp-1 gene Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 101150047856 Cav2 gene Proteins 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 241000724252 Cucumber mosaic virus Species 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 102000003849 Cytochrome P450 Human genes 0.000 description 1
- 102000004594 DNA Polymerase I Human genes 0.000 description 1
- 108010017826 DNA Polymerase I Proteins 0.000 description 1
- 244000187656 Eucalyptus cornuta Species 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 101710115997 Gamma-tubulin complex component 2 Proteins 0.000 description 1
- 101710166358 Globin-1 Proteins 0.000 description 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 101000777471 Homo sapiens C-C motif chemokine 4 Proteins 0.000 description 1
- 101000973997 Homo sapiens Nucleosome assembly protein 1-like 4 Proteins 0.000 description 1
- 101000947178 Homo sapiens Platelet basic protein Proteins 0.000 description 1
- 241000341655 Human papillomavirus type 16 Species 0.000 description 1
- 241000714192 Human spumaretrovirus Species 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 102000004890 Interleukin-8 Human genes 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102100035304 Lymphotactin Human genes 0.000 description 1
- 108010059343 MM Form Creatine Kinase Proteins 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
- 102000009571 Macrophage Inflammatory Proteins Human genes 0.000 description 1
- 108010009474 Macrophage Inflammatory Proteins Proteins 0.000 description 1
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 1
- 101710091439 Major capsid protein 1 Proteins 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010027202 Meningitis bacterial Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 108010008707 Mucin-1 Proteins 0.000 description 1
- 101100264116 Mus musculus Xcl1 gene Proteins 0.000 description 1
- 241000186366 Mycobacterium bovis Species 0.000 description 1
- 108010089610 Nuclear Proteins Proteins 0.000 description 1
- 102000029785 Orotate phosphoribosyltransferase Human genes 0.000 description 1
- 108010055012 Orotidine-5'-phosphate decarboxylase Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 102100036154 Platelet basic protein Human genes 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 101100502554 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) FCY1 gene Proteins 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
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 102000005497 Thymidylate Synthase Human genes 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 208000010165 Tyrosinosis Diseases 0.000 description 1
- 102100037717 Uracil phosphoribosyltransferase homolog Human genes 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 102000015395 alpha 1-Antitrypsin Human genes 0.000 description 1
- 108010050122 alpha 1-Antitrypsin Proteins 0.000 description 1
- 229940024142 alpha 1-antitrypsin Drugs 0.000 description 1
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 1
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000006023 anti-tumor response Effects 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 230000007503 antigenic stimulation Effects 0.000 description 1
- 230000005975 antitumor immune response Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 108010018755 aquaporin 0 Proteins 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 201000009904 bacterial meningitis Diseases 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 201000008274 breast adenocarcinoma Diseases 0.000 description 1
- 230000000981 bystander Effects 0.000 description 1
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 1
- 210000000234 capsid Anatomy 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000005025 clonogenic survival Effects 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000005757 colony formation Effects 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- GYOZYWVXFNDGLU-XLPZGREQSA-N dTMP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)C1 GYOZYWVXFNDGLU-XLPZGREQSA-N 0.000 description 1
- 230000002074 deregulated effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003114 enzyme-linked immunosorbent spot assay Methods 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 102000052292 human CCL4 Human genes 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 231100000568 intoxicate Toxicity 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000003580 lung surfactant Substances 0.000 description 1
- 108010019677 lymphotactin Proteins 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 201000006512 mast cell neoplasm Diseases 0.000 description 1
- 208000006971 mastocytoma Diseases 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- 230000002956 necrotizing effect Effects 0.000 description 1
- 230000021616 negative regulation of cell division Effects 0.000 description 1
- 230000030648 nucleus localization Effects 0.000 description 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 208000003154 papilloma Diseases 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000003014 totipotent stem cell Anatomy 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/195—Chemokines, e.g. RANTES
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2013—IL-2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/217—IFN-gamma
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
Definitions
- composition intended for the implementation of a cytotoxic treatment, in particular antitumor or antiviral, in a mammal
- the present invention relates to a cytotoxic composition
- a cytotoxic composition comprising a first nucleic acid sequence coding for all or part of a MIP chemokine and a second nucleic acid sequence coding for all or part of a polypeptide having at least one cytotoxic activity, in particular antitumor or antiviral.
- the present invention is particularly useful in the context of the implementation of a treatment by gene therapy of proliferative or infectious diseases.
- Recent research in the cancer field has proposed adapting gene therapy protocols to tumor therapy.
- one can for example cite the work of Meneguzzi et al., 1991, Nirology, 181, 61-69 relating to immunization against tumor cells using a recombinant vaccinia vector expressing the genes E6 and E7 of the human papilloma virus type 16.
- Mention may also be made of the content of French patent FR 92/03120 relating to the use of a recombinant adenovirus expressing a cytokine in the context of anti-tumor gene therapy.
- Cytokines are molecules naturally produced following antigenic stimulation or an inflammatory reaction (Gillis and Williams, 1998, Curr. Opin. Immunol., 10, 501-503) whose usefulness in the context of treatment of certain cancers has been shown in particular by Oettger (Curr. Opin. Immunol., 1991, 3, 699-705).
- Oettger a mechanism for preventing the production of cytokines at tumor sites after intra-tumor administration of recombinant viral vectors.
- this anti-tumor response although encouraging, does not allow the definitive disappearance of the tumor cells, and consequently the implementation of a satisfactory anti-tumor treatment.
- Chemokines are a subclass of the cytokine family. They are distinguished from other cytokines by their chemo-attractive property, in particular during the natural processes of chemotaxis, and in particular of attraction of the cells of the immune system towards the tissues in which the inflammation or infection takes place, as well as their properties anti-angiogenic. Chemokines are proteins of low molecular weight (between 8 and 10 kd), of small size (from 70 to 80 amino acids) whose amino acid sequences have a low homology rate (varying from 10 to 70% depending on the chemokines considered ) allowing to define about 50 different chemokines to date. These chemokines can nevertheless be subdivided into 4 main families relating to the position of the cysteine residues which they contain.
- compositions whose various constituents are chosen so as to obtain a synergistic effect of their respective activities and of the improved properties of said constituents. More particularly, such compositions make it possible to inhibit or delay cell proliferation by inducing the specific death of cells, in particular tumor cells, better presentation of the antigens and / or stimulation of the immune cells of the host organism.
- the present invention provides an advantageous and effective alternative to the techniques of the prior art, in particular for treating human or animal cancer.
- the invention relates firstly to a composition intended for the implementation of a cytotoxic treatment, for example anti-tumor or antiviral, or any applications requiring cell death, in a mammal comprising: (i) a nucleic acid sequence encoding for all or part of a MIP chemokine,
- nucleic acid sequence coding for all or part of a polypeptide having at least one cytotoxic activity, said nucleic acid sequences being placed under the control of the elements necessary for their expression in a host cell of said mammal .
- the preferred MIP chemokine is the MIP 1 type chemokine, and more particularly selected from the group consisting of the chemokines MlPl ⁇ and MlPl ⁇ , the properties of which have been demonstrated by Wolpe et al, 1988, J Exp. Med, 167, 570-581.
- MIP 1 the nucleic acid and peptide sequences of which are described in Obaru et al. 1986, J. Biochem. 99, 885-894, the content of which is incorporated by reference into the present application, is produced by T lymphocytes and monocytes. It allows chemo-attraction of eosinophils and T lymphocytes during respiratory tract infections; monocytes and neutrophils in rheumatoid arthritis, inflammation of the digestive system or meningitis of bacterial origin. In addition, it inhibits the proliferation of hematopoietic precursors.
- MlPl ⁇ whose nucleic acid and peptide sequences are described in Brown et al. 1989, J. Immunol. 142, 679-68, the content of which is incorporated by reference in the present application, is also produced by T lymphocytes and monocytes. It exerts its chemo-attractive properties on monocytes and neutrophils in cases of bone arthritis and bacterial meningitis. Like MlPl ⁇ , it inhibits the proliferation of hematopoietic precursors.
- Act-2 Lipes et al., 1988, PNAS, 85, 9704-9708, the content of which is incorporated herein by reference.
- polypeptide having at least one cytotoxic activity is intended to denote any peptide substance capable of inducing or activating an immune response directed specifically against a tumor cell (the cytotoxic activity is then called anti-tumor activity) or a cell infected with a virus (cytotoxic activity is then called antiviral activity) or to inhibit the growth and / or division of such a cell, in particular tumor or infected. According to a preferred case, said cytotoxic activity results in the death of said cell. According to a particular case, it would also be possible to use compositions according to the present invention in pathological cases associated with cell proliferation, such as for example the phenomena of restenosis.
- chemo-attraction activity of a given polypeptide in particular derived from the chemokine MIP
- cells involved in immune reactions such as for example eosinophils, T lymphocytes, monocytes or neutrophils
- a chemotaxis test Magnhazachi, 1993, Nature Immunity, 12, 57.
- this type of chemokine inhibiting the proliferation of hematopoietic precursors it is possible to evaluate such a property in vitro according to Graham et al., 1992, Growth Factors, 7, 151.
- the cytotoxic activity of a given polypeptide in particular an antitumor activity, can be evaluated in vitro by measuring cell survival either by short-term viability tests (such as for example the tryptan blue test or MTT), either by clonogenic survival tests (colony formation) (Brown and Wouters, 1999, Cancer Research, 59, 1391-1399) or in vivo by measuring tumor growth (size and / or volume) in an animal model (Ovejera and Houchens, 1981, Semin. Oncol., 8, 386-393).
- short-term viability tests such as for example the tryptan blue test or MTT
- clonogenic survival tests colony formation
- tumor growth size and / or volume
- the invention relates to a composition characterized in that said polypeptide having cytotoxic activity is chosen from cytokines, proteins encoded by a gene called “suicide gene” and antiangiogenic protein factors. More particularly, when said polypeptide in (ii) is a cytokine, it is preferably a cytokine chosen from interferons ⁇ , ⁇ and ⁇ , interleukins, and in particular IL-2, 1TL-4 IL -6, IL-10 or IL-12, tumor necrotizing factors (TNF) and colony stimulating factors (GM-CSF, C-CSF, M-CSF ).
- cytokine chosen from interferons ⁇ , ⁇ and ⁇ , interleukins, and in particular IL-2, 1TL-4 IL -6, IL-10 or IL-12, tumor necrotizing factors (TNF) and colony stimulating factors (GM-CSF, C-CSF, M-CSF .
- said cytokine is selected from interleukin-2 (IL-2) and interferon gamma (IFN- ⁇ ).
- Interleukin-2 is in particular responsible for the proliferation of activated T lymphocytes, for the multiplication and activation of cells of the immune system (for the nucleic acid sequence see in particular FR 85 09480).
- LTFN- ⁇ activates phagocytic cells and increases the expression of class I and II surface antigens of the major histocompatibility complex (for the nucleic acid sequence see in particular FR 85 09225). Said nucleic acid sequences are incorporated by reference into the present application.
- composition according to the invention is characterized in that it comprises in (ii) at least two nucleic acid sequences coding for all or part of interleukin-2 (IL-2) and all or part of gamma interferon (IFN- ⁇ ).
- IL-2 interleukin-2
- IFN- ⁇ gamma interferon
- the invention also relates to such a composition characterized in that said polypeptide in ( ⁇ ) exhibits at least one enzymatic activity selected from thymidine kinase activity, purine nucleoside phosphorylase activity, guanine or uracil activity or orotate phosphoribosyl transferase and cytosine deaminase activity.
- polypeptides which are not toxic as such but which exhibit catalytic enzymatic properties capable of transforming an inactive substance (predrogue), for example a nucleoside or a nucleoside analog, into a substance which is highly toxic for the cell, for example a modified nucleoside which can be incorporated into elongated DNA or RNA chains, with the consequence, in particular, of the inhibition of cell division or of cellular dysfunctions leading to the death of the cell containing such polypeptides.
- the genes coding for such polypeptides are called "suicide genes". Many suicide / predrug gene pairs are currently available. We can cite more particularly, the couples:
- TK HSV-1 herpes simplex virus type 1 thymidine kinase
- GCV acyclovir or ganciclovir
- CDase is an enzyme which intervenes in the metabolic pathway of pyrimidines by which the exogenous cytosine is transformed by means of hydrolytic deamination into uracil.
- CDase activities have been demonstrated in prokaryotes and lower eukaryotes (Jund and Lacroute, 1970, J. Bacteriol. 102, 607-615; Beck et al., 1972, J. Bacteriol. 110, 219-228; De Haan et al., 1972, Antonie van Leeuwenhoek 38, 257-263; Hoeprich et al., 1974, J. Inf. Dis. 130, 112-118; Esders and Lynn, 1985, J. Biol. Chem.
- FCY1 genes of Saccharomyces cerevisiae (S. cerevisiae) and cod ⁇ of E. coli coding respectively for the CDase of these two organisms are known and their sequences published (EP 402 108; Erbs et al., 1997, Curr. Genêt. 31, 1-6; WO93 / 01281).
- CDase also deaminates a cytosine analog, 5-fluorocytosine (5-FC) into 5-fluorouracil (5-FU) which is a highly cytotoxic compound especially when it is converted into 5-fluoro-UMP (5-FUMP ).
- Cells lacking CDase activity either because of an inactivating mutation of the gene coding for the enzyme, or because of their natural deficiency for this enzyme (for example mammalian cells) are resistant to 5-FC (Jund and Lacroute, 1970, J. Bacteriol. 102, 607-615; Kilstrup et al., 1989, J. Bacteriol. 1989 171, 2124-2127).
- This phenomenon is due to the excretion by cells expressing CDase activity, of 5-FU which intoxicates neighboring cells by simple diffusion through the cell membrane.
- This passive diffusion property of 5-FU constitutes an advantage over the rfc / GCV reference system for which the neighborhood effect requires contact with the cells which express tk (Mesnil et al., 1996, Proc. Natl. Acad Sci. USA 93,
- sensitivity to 5-FC varies widely across cell lines. Low sensitivity is observed, for example, in human tumor lines PANC-1 (pancreatic carcinoma) and SK-BR-3 (breast adenocarcinoma) transduced by a retrovirus expressing the E codA gene. Coli (Harris et al., 1994, Gene Therapy 1, 170-175). This undesirable phenomenon could be explained by the absence or the weak endogenous conversion of 5-FU formed by the enzymatic action of CDase into cytotoxic 5-FUMP.
- This step normally performed in mammalian cells by the orotate phosphorybosyl transferase (Peters et al., 1991, Cancer 68, 1903-1909), can be absent in certain tumors and thus render gene therapy, based on CDase, ineffective.
- uracil In prokaryotes and lower eukaryotes, uracil is transformed into UMP by the action of uracil phosphoribosyl transferase (consequently exhibiting UPRTase activity). This enzyme also converts 5-FU to 5-FUMP.
- furl mutants of the yeast S. cerevisiae are resistant to high concentrations of 5-FU (10 mM) and 5-FC (10 mM) because in the absence of UPRTase activity, 5-FU, originating from deamination of 5-FC by CDase, is not transformed into cytotoxic 5-FUMP (Jund and Lacroute, 1970, J. Bacteriol. 102, 607-615).
- the upp and FUR1 genes encoding lTJPRTase respectively from E. coli and S. cerevisiae have been cloned and sequenced (Andersen et al., 1992, ⁇ ur. J. Biochem. 204, 51-56; Kern et al., 1990, Gene 88, 149-157).
- a polypeptide having UPRTase activity denotes a polypeptide capable of converting uracil or one of its derivatives into a monophosphated analogue and, in particular 5-FU into 5-FUMP.
- mutant is meant the addition, deletion and / or substitution of one or more residues at any location of said polypeptide.
- the native LTJPRTase in question in the present invention can be of any origin, in particular prokaryotic, fungal or yeast.
- Lactococcus lactis (Martinussen and Hammer, 1994, J. Bacteriol. 176, 6457-
- yeast UPRTase and in particular that encoded by the FUR1 gene from S. cerevisiae, the sequence of which is disclosed in
- Kern et al. (1990, Gene 88, 149-157) is introduced here by reference.
- the gene sequences and those of the corresponding UPRTases can be found in the literature and specialized databases (SWISSPROT, ⁇ MBL, Genbank, Medline ).
- application PCT / FR99 / 00904 describes a FUR1 gene devoid of 105 nucleotides 5 ′ of the coding part allowing the synthesis of a UPRTase deleted from the first 35 residues in the N-terminal position and starting with methionine in position 36 in native protein.
- the expression product of the mutant gene, designated FUR1 ⁇ 105 is capable of complementing a furl mutant of S. cerevisiae.
- the polypeptide encoded according to the invention is a deletion mutant of a native UPRTase.
- the deletion is preferably located in the N-terminal region of the original UPRTase. It can be total (concern all the residues of said N-terminal region) or partial (concern one or more residues, whether continuous or not, in the primary structure).
- a polypeptide is made up of N-terminal, central and C-terminal parts, each representing approximately one third of the molecule. For example, the UPRTase of S.
- N-terminal part consists of the first 83 residues starting with the so-called initiator methionine located in the first position of the native form.
- initiator methionine located in the first position of the native form.
- N-terminal part covers positions 1 to 69.
- patent applications WO96 / 16183 and PCT / FR99 / 00904 describe the use of a fusion protein coding for a two-domain enzyme having the CDase and UPRTase activities and demonstrate that the transfer of a hybrid gene codA :: upp or FCYlr.FURl or FCYl :: FUR1 ⁇ 105 carried by an expression plasmid increases the sensitivity to 5-FC of transfected B16 cells.
- the protein and nucleic acid sequences described in these two applications are incorporated into the description of the present application.
- the polypeptide is a polypeptide fused in phase with at least one second polypeptide.
- the fusion can take place at any location of the first polypeptide, the N or C-terminal ends are preferred and in particular the N-terminal end.
- a fusion of CDase and UPRTase activities improves the sensitivity of target cells to 5-FC and 5-FU.
- a person skilled in the art is able to clone the CDase or UPRTase sequences from the published data, to carry out possible mutations, to test the enzymatic activities of the mutant forms in an acellular or cellular system according to l technology. art or by following the protocol indicated in application PCT / FR99 / 00904 and to merge, in particular in phase, the polypeptides of CDase and UPRTase activity, and consequently all or part of the corresponding genes.
- the composition of the invention is characterized in that the nucleic acid sequence (ii) is selected from the nucleic sequences of the CodA, upp, FUR1 genes; FCYl and FUR1 ⁇ 105, or by a combination of all or part of said sequences.
- the invention relates more particularly to a said composition characterized in that said polypeptide in (ii) has at least one CDase activity and one UPRTase activity.
- nucleic acid sequences are intended to denote both distinct sequences which code for at least two distinct polypeptides as well as fused sequences which code for fusion polypeptides, it being understood that the production of such polypeptides can be carried out under the control of the same regulatory elements (polycistronic cassette) or of independent, identical or different elements, homologous or heterologous with respect to the vector containing them, constitutive or inducible.
- the composition of the invention comprises at least one nucleic acid sequence (ii) coding for a fusion polypeptide in which a first polypeptide exhibiting UPRTase or CDase activity is fused in phase with at least one second polypeptide, said second polypeptide exhibiting CDase or UPRTase activity, respectively.
- a polypeptide is characterized in that the fusion with the second polypeptide is carried out at the N-terminal end of said first polypeptide.
- said composition is characterized in that the nucleic acid sequence coding for said fusion polypeptide is a hybrid sequence comprising:
- hybrid nucleic acid sequence coding for said fusion polypeptide may also contain an IRES type sequence.
- the invention relates in particular to such a composition for which the first nucleic acid sequence is selected from upp, FUR1 and FUR1 ⁇ 105, and in that the second nucleic acid sequence is selected from CodA and FCYl, and vice versa.
- a hybrid nucleic acid sequence is chosen from the hybrid sequences described in patent applications WO96 / 16183 and PCT / FR99 / 00904.
- the composition according to the present invention is characterized in that said polypeptide having cytotoxic activity (ii) is an anti-angiogenic protein factor.
- Angiogenesis is the process responsible for the formation of new capillaries from the already existing vascular network. This complex process is finely regulated in healthy tissue by the balance of the effects of many angiogenic and anti-angiogenic factors. However, in certain pathologies, and in particular during the formation of a tumor, this process is deregulated: the angiogenic factors take precedence over the anti-angiogenic factors which allows an important vascularization of the tumors and consequently their rapid development and / or the appearance of metastases.
- an anti-angiogenic factor is considered to be a cytotoxic agent, in particular an anti-tumor agent.
- angiostatin for angiostatin, endostatin, the factor platelet PF4, thrombospondin-1, PRP (for Proliferin Related Protein), VEGI (for Vascular Endothelial Growth Inhibitor) metalloproteases and urokinase.
- the nucleic acid sequences (i) or ( ⁇ ) can be easily obtained by cloning, by PCR or by chemical synthesis according to the conventional techniques in use. They may be native genes or derivatives thereof by mutation, deletion, substitution and / or addition of one or more nucleotides. Furthermore, their sequences are widely described in the literature available to those skilled in the art.
- the present invention also relates to a composition as presented above, characterized in that said nucleic acid sequences (i) and (ii) are inserted into a recombinant vector of plasmid or viral origin, as well as to a such a recombinant vector carrying such nucleotide sequences placed under the control of the elements necessary for their expression in a host cell.
- the nucleic acid sequences (i) and (ii) may be present in one or more copies on the same vector.
- compositions of the invention can comprise said nucleic acid sequences (i) and (ii) inserted in the same recombinant vector or in distinct recombinant vectors.
- recombinant vector according to the invention is intended to denote a
- Vector of plasmid or viral origin and optionally such a vector associated with one or more substances improving the transfection efficiency and / or the stability of said vector and / or the protection of said vector in vivo with respect to the immune system of the host organism.
- substances are widely documented in the literature accessible to those skilled in the art (see for example Felgner et al., 1987, Proc. West. Pharmacol. Soc. 32, 115-121; Hodgson and Solaiman, 1996, Nature Biotechnology 14, 339-342; Remy et al., 1994, Bioconjugate Chemistry 5, 647-654).
- they may be polymers, lipids in particular cationic, liposomes, nuclear or viral proteins or even neutral lipids. These substances can be used alone or in combination. Examples of such compounds are available in particular in WO patent applications 98/08489, WO 98/17693, WO 98/34910, WO 98/37916, WO 98/53853, EP 890362 or WO 99/05183.
- a possible combination is a recombinant plasmid vector associated with cationic lipids (DOGS, DC-CHOL, spermine-chol, spermidine-chol etc.) and neutral lipids (DOPE).
- plasmids which can be used in the context of the present invention are vast. They may be cloning and / or expression vectors. In general, they are known to those skilled in the art and many of them are commercially available, but it is also possible to construct or modify them by genetic manipulation techniques. Mention may be made, as examples, of the plasmids derived from pBR322 (Gibco BRL), pUC (Gibco BRL), pBluescript (Stratagene), pREP4, pCEP4 (Invitrogene) or also p Poly (Lathe et al., 1987, Gene 57, 193-201).
- a plasmid used in the context of the present invention contains an origin of replication ensuring the initiation of replication in a producer cell and / or a host cell (for example, the ColEl origin will be retained for a plasmid intended to be produced in E. coli and the oriP / EBNAl system if it is desired to be self-replicating in a mammalian host cell, Lupton and Levine, 1985, Mol. Cell. Biol. 5, 2533-2542; Yates and al., Nature 313, 812-815). It can also comprise a selection gene making it possible to select or identify the transfected cells (complementation of an auxotrophy mutation, gene coding for resistance to an antibiotic, etc.).
- cer sequence which promotes the monomeric maintenance of a plasmid (Summers and Sherrat, 1984, Cell 36, 1097-1103, sequences of integration into the cell genome).
- a viral vector Being a viral vector, one can envisage a vector deriving from a poxvirus (vaccinia virus, in particular MVA, canaripox, etc.), from an adenovirus, from a retrovirus, from a virus herpes, an alphavirus, a foamyvirus or a virus associated with the adenovirus.
- a non-replicative and non-integrative vector will be used.
- the adenoviral vectors are very particularly suitable for the implementation of the present invention. However, it should be noted here that as part of the implementation of the present invention, the nature of the vector is of little importance.
- Retroviruses have the property of infecting and integrating mainly in dividing cells and in this respect are particularly suitable for cancer application.
- a recombinant retrovirus according to the invention generally comprises the LTR sequences, an encapsidation region and the nucleotide sequence according to the invention placed under the control of the retroviral LTR or of an internal promoter such as those described below. It can be derived from a retrovirus of any origin (murine, primate, feline, human, etc.) and in particular from MoMuLV (Moloney murine leukemia virus), MVS (Murine sarcoma virus) or Friend murine retrovirus (Fb29).
- MoMuLV Moloney murine leukemia virus
- MVS Murine sarcoma virus
- Fb29 Friend murine retrovirus
- the retroviral vector according to the invention may include modifications in particular at the level of the LTRs (replacement of the promoter region with a eukaryotic promoter) or of the packaging region (replacement with a heterologous packaging region, for example of the VL30 type). (see French applications 94 08300 and 97 05203).
- a defective adenoviral vector for replication that is to say devoid of all or part of at least one region essential for replication selected from regions E1, E2, E4 and.
- a deletion from the El region is preferred.
- it can be combined with other modification (s) / deletion (s) affecting in particular all or part of the regions E2, E4 and / or L1-L5, insofar as the defective essential functions are complemented in trans by means of 'a line of complementation and / or an auxiliary virus in order to ensure the production of the viral particles of interest.
- use may be made of second generation vectors of the state of the art (see for example international applications WO94 / 28152 and WO97 / 04119).
- the deletion of the majority of the region E1 and of the transcription unit E4 is very particularly advantageous.
- the adenoviral vector can also be devoid of all or part of the non-essential E3 region.
- the origin of the adenoviral vector according to the invention can be varied both from the point of view of the species and of the serotype.
- adenovirus of human or animal origin canine, avian, bovine, murine, ovine, porcine, simian .
- Mention may more particularly be made of the adenoviruses CAV-1 or CAV-2 of canine origin, DAV of avian origin or else Bad of type 3 of bovine origin (Zakharchuk et al., Arch. Virol., 1993, 128: 171 -176; Spibey and Cavanagh, J. Gen.
- an adenoviral vector of human origin preferably deriving from a serotype C adenovirus, in particular of type 2 or 5, will be preferred.
- An adenoviral vector according to the present invention can be generated in vitro in Escherichia coli (E. coli) by homologous ligation or recombination (see for example international application WO96 / 17070) or alternatively by recombination in a complementation line.
- the different adenoviral vectors and their preparation techniques are known (see for example Graham and Prevect, t
- the elements necessary for expression consist of all of the elements allowing the transcription of the nucleotide sequence into AR ⁇ and the translation of AR ⁇ m into polypeptide, in particular the promoter sequences and / or efficient regulatory sequences in said cell, and optionally the sequences required to allow excretion or expression on the surface of target cells of said polypeptide.
- These elements can be regulable or constitutive.
- the promoter is adapted to the vector selected and to the host cell. Mention may be made, by way of examples, of the eukaryotic promoters of the PGK (Phospho Glycerate Kinase), MT (metallothioneine; Me Ivor et al., 1987, Mol . Cell Biol.
- ⁇ -1 antitrypsin CFTR
- promoters of the gene coding for muscle creatine kinase, for actin, for the pulmonary surfactant immunoglobulin, ⁇ -actin (Tabin et al., 1982, Mol. Cell Biol. 2, 426-436), SR ⁇ (Takebe et al., 1988, Mol. Cell. Biol.
- the early promoter of the SV40 virus (Simian Virus), the RSV LTR (Rous Sarcoma Virus), the promoter of MPSV, the promoter TK-HSV-1, the early promoter of the CMV virus (Cytomegalovirus), the promoters of the vaccinia virus p7.5K pH5R, pKlL, p28, pl i and the adenoviral promoters El A and MLP or a combination of said promoters. It can also be a promoter stimulating expression in a tumor or cancer cell.
- the promoters of the MUC-1 genes overexpressed in breast and prostate cancers (Chen et al., 1995, J. Clin. Invest.
- the necessary elements may, in addition, include additional elements improving the expression of the nucleotide sequence according to the invention or its maintenance in the host cell. Mention may in particular be made of the intronic sequences (WO 94/29471), secretion signal sequences, nuclear localization sequences, internal sites of translation initiation of IRES type, poly A sequences for transcription termination.
- the invention relates more particularly to a recombinant vector, in particular a viral vector, and more specifically to an adenoviral vector defective for replication, comprising: (i) a nucleic acid sequence coding for all or part of a MIP chemokine,
- nucleic acid sequence coding for all or part of a polypeptide having at least one cytotoxic activity, said nucleic acid sequences being placed under the control of the elements necessary for their expression in a host cell and being defined as indicated above.
- the present invention also relates to a viral particle, in particular adenoviral, comprising a recombinant viral vector according to the invention.
- a viral particle can be generated from a viral vector according to any conventional technique in the art. Its propagation is carried out in particular in a complementation cell adapted to the deficiencies of said vector.
- an adenoviral vector use will be made, for example, of a complementation line as described in application WO 94/28152, to line 293 established from human embryonic kidney cells, which effectively complements the El function (Graham et al., 1977, J. Gen. Virol.
- complementation cell is meant a cell capable of providing in trans the early and / or late factors necessary for the packaging of the genome.
- the invention also relates to a process for preparing a viral particle, according to which: (i) a recombinant vector according to the invention is introduced into a cell, in particular a complementation cell capable of complementing said vector in trans, so as to obtain a said transfected cell, (ii) culturing said transfected cell under appropriate conditions to allow the production of said viral particle, and
- the viral particle can be recovered from the culture supernatant but also from the cells.
- One of the commonly used methods is to lyse the cells by consecutive freeze / thaw cycles to collect the virions in the lysis supernatant. These can be amplified and purified according to the techniques of the art (chromatographic process, ultracentrifugation in particular through a gradient of cesium chloride ).
- the invention also relates to a eukaryotic host cell comprising the DNA fragments present in the composition according to the invention.
- Said host cell is advantageously a mammalian cell and, preferably, a human cell. It will preferably be a 293 cell, LCA4 or PERC6. Such a cell is particularly useful for producing viral particles at high titer, without generating particles competent for replication.
- the invention also relates to a host cell comprising a nucleotide sequence, a recombinant vector according to the invention or infected with a viral particle according to the invention.
- a host cell consists of any cell transfectable by a recombinant vector or infectable by a viral particle, as defined above.
- a mammalian and in particular human cell is particularly suitable. It can comprise said vector in a form integrated into the genome or not (episome). It may be a primary or tumor cell of any origin, in particular hematopoietic (totipotent stem cell, leukocyte, lymphocyte, monocyte or macrophage ...) (satellite cell, myocyte, myoblast, smooth muscle ...), cardiac, pulmonary, tracheal, hepatic, epithelial or fibroblast.
- hematopoietic totipotent stem cell, leukocyte, lymphocyte, monocyte or macrophage
- satellite cell myocyte, myoblast, smooth muscle
- cardiac pulmonary, tracheal, hepatic, epithelial or fibroblast.
- the invention also relates to a composition intended for the implementation of an antitumor or antiviral treatment, or any applications requiring cell death, in a mammal comprising:
- Another object according to the invention consists of a formulation intended for the implementation of a cytotoxic treatment, in particular antitumor or antiviral, in a mammal characterized in that it comprises a composition (based on nucleic acids or polypeptides as described above), an adenoviral vector or a viral particle according to the invention, as well as a support which is acceptable from a pharmaceutical point of view.
- a support is preferably isotonic, hypotonic or weakly hypertonic and has a relatively low ionic strength, such as for example a sucrose solution.
- such a support can contain any solvent, or aqueous or partially aqueous liquid such as sterile non-pyrogenic water.
- the pH of the formulation is also adjusted and buffered in order to meet the requirements for use in vivo.
- the formulation may also include a pharmaceutically acceptable diluent, adjuvant or excipient, as well as solubilizers, stabilizers, preservatives.
- a pharmaceutically acceptable diluent for injectable administration, an aqueous, non-aqueous or isotonic solution formulation is preferred. It can be presented as a single dose or in multidose in liquid or dry form (powder, lyophilisate, etc.) capable of being reconstituted extemporaneously with an appropriate diluent.
- said formulation also comprises pharmaceutically acceptable amounts of a prodrug capable of being transformed into cytotoxic molecule by a polypeptide having at least one cytotoxic activity.
- Such a prodrug will be selected in particular from the group consisting of acyclovir or ganciclovir (GCV), cyclophosphophamide, 6-methylpurine deoxyribonucleoside, 6-thioxanthine, cytosine or one of its derivatives or uracil or one of its derivatives.
- said prodrug is 5-fluorocytosine (5FC) or 5-fluorouracil (5-FU).
- said formulation may also comprise one or more substances potentiating the cytotoxic effect of 5-FU.
- drugs which inhibit the enzymes of the de novo biosynthesis pathway for pyrimidines (for example those cited below), drugs such as Leucovorin (Waxman et al., 1982, Eur. J.
- a formulation according to the invention is more particularly intended for the preventive or curative treatment of diseases by gene therapy and is more particularly intended for proliferative diseases (cancers, tumors, restenosis, etc.) and for diseases of infectious origin, in particular viral for which it is necessary to limit the proliferation of infected cells (induced by hepatitis B or C viruses, HIV, herpes, retroviruses, etc.).
- a formulation according to the invention can be manufactured in a conventional manner for administration by the local, parenteral or digestive route.
- routes of administration We can cite for example the intragastric, subcutaneous, intracardiac, intramuscular, intravenous, intraperitoneal, intratumoral, intranasal, intrapulmonary or intratracheal route.
- administration by aerosol or instillation is advantageous.
- the administration can take place in single dose or repeated one or more times after a certain interval of interval.
- the appropriate route of administration and dosage vary according to various parameters, for example, the individual, the disease to be treated or the gene (s) of interest to be transferred.
- the preparations based on viral particles according to the invention can be formulated in doses of between 10 4 and 10 14 pfu (units forming plaques), advantageously 10 5 and 10 13 pfu and, preferably, 10 6 and 10 12 ufp.
- doses comprising from 0.01 to 100 mg of DNA, preferably 0.05 to 10 mg and, most preferably, 0.5 to 5 mg may be considered.
- a composition based on polypeptides preferably comprises from 0.05 to 10 g and, most preferably, from 0.5 to 5 g of said polypeptide.
- the doses can be adjusted by the clinician.
- the present invention also relates to the therapeutic or prophylactic use of a composition, of a recombinant vector or of a viral particle according to the invention for the preparation of a medicament intended for the treatment of the human or animal body by therapy gene, in particular for the preparation of a cytotoxic drug, in particular an antitumor or antiviral drug, intended to inhibit the growth or cause the rejection of a tumor or the death of an infected cell.
- the drug can be administered directly in vivo (for example by intravenous injection, in an accessible tumor or at its periphery, in the lungs by aerosol, in the vascular system by means of an appropriate probe ...) .
- a preferred use is to treat or prevent cancers, tumors and diseases resulting from unwanted cell proliferation.
- possible applications include breast, uterine (in particular those induced by papillomas virus), prostate, lung, bladder, liver, colon, pancreas, stomach cancers , esophagus, larynx of the central nervous system and blood (lymphomas, leukemia etc.). It is also useful in the context of cardiovascular diseases, for example to inhibit or delay the proliferation of smooth muscle cells of the vascular wall (restenosis).
- infectious diseases application to AIDS can be considered.
- the invention also extends to a method for the treatment of diseases by gene therapy, characterized in that a nucleotide sequence, a recombinant vector, is administered to an organism or to a host cell in need of such treatment.
- a viral particle or a host cell according to the invention.
- the treatment method uses a nucleotide sequence, a recombinant vector or a viral particle allowing the expression of a polypeptide according to the invention having a UPRTase activity
- the administration of the UPRTase and CDase sequences can be simultaneous or consecutive, the order of administration being unimportant.
- the therapeutic use or the method of treatment also comprises an additional stage according to which the organism or the host cell is administered pharmaceutically acceptable amounts of a pre-drug, advantageously an analog of cytosine and, in particular of 5-FC.
- a dose of 50 to 500 mg / kg / day can be used with a preference for 200 mg / kg / day.
- the predrogue is administered according to standard practices and this in a prior, concomitant or even after that of the therapeutic agent according to the invention.
- the oral route is preferred.
- Either a single dose of the pre-drug or repeated doses may be administered long enough to allow the production of the toxic metabolite within the host organism or cell.
- the therapeutic use or the method of treatment is associated with a second treatment of the patient by surgery (in particular by removal of the tumor partially or totally), by radiotherapy or chemotherapy.
- the treatment according to the invention is applied beforehand, concomitantly or following said second treatment.
- this treatment will be applied following said second treatment.
- FIG. 1 represents the evolution of the tumor volume in B6D2 mice implanted with B16F0 tumor cells.
- FIG. 2 represents the survival rate of these same mice.
- Groups of 15 mice are treated using compositions comprising adenoviruses expressing the following genes: huMIP ⁇ , huIL2, huMIPl ⁇ + huIL2, empty Ad.
- FIG. 3 represents the evolution of the tumor volume in mice
- FIG. 4 represents the survival rate of these same mice.
- Groups of 15 mice are treated using compositions comprising adenoviruses expressing the following genes: huMIP ⁇ , huIL2, huMIP ⁇ + huIL2, empty Ad.
- FIG. 5 represents the evolution of the tumor volume in B6D2 mice implanted with P815 tumor cells.
- FIG. 6 represents the survival rate of these same mice. Groups of 15 mice are treated using compositions comprising adenoviruses expressing the following genes: Tris buffer, huMIP ⁇ + huIL2, huMIPl ⁇ + muIFN ⁇ , huIL2 + muIFN ⁇ .
- FIG. 7 represents the evolution of the tumor volume in mice
- mice implanted with RENCA tumor cells. These mice are treated with the aid of compositions comprising adenoviruses expressing the human MlPl ⁇ gene (huMIPl ⁇ ) in combination with adenoviruses expressing the murine IL12 gene (muIL12), or adenoviruses expressing the muIL12 gene, or adenoviruses containing no transgene (Ad empty).
- adenoviruses expressing the human MlPl ⁇ gene huMIPl ⁇
- muIL12 murine IL12 gene
- muIL12 muIL12 gene
- Ad empty adenoviruses containing no transgene
- the constructions described below are carried out according to the general techniques of genetic engineering and molecular cloning, detailed in Maniatis et al., (1989, Laboratory Manual, Cold Spring Harbor, Laboratory Press, Cold Spring Harbor, NY) or according to the recommendations from the manufacturer when using a commercial kit.
- the homologous recombination steps are preferably carried out in the E. coli BJ 5183 strain (Hanahan, 1983, J. Mol. Biol. 166, 557-580).
- the technique used consists of filling the protruding 5 ′ ends with the large fragment of DNA polymerase I from E. coli (Klenow).
- the adenoviral genome fragments used in the various constructions described below are indicated precisely according to their position in the nucleotide sequence of the Ad5 genome as disclosed in the Genbank database under the reference M73260.
- the cells are transfected or transduced and cultured according to standard techniques well known to those skilled in the art.
- Tumor models Three tumor cell models were chosen in order to evaluate the activity of the composition of the invention: P815 (mastocytoma H-2d, described in Dunn et al, 1957, J. Natl. Cancer Inst., 18 , 587-590), B16FO (melanoma H-2b, described in Wu et al, 1996, Cancer Res., 56, 21-26) and RENCA (renal cell carcinoma H-2d, described in Murphy et al, 1973, J. Natl. Cancer Inst., 50 (4 ), 1023-1025).
- the cells (3E + 5 for each tumor model) are implanted on D-7 / Dl 1 subcutaneously in the right flank of B6D2 mice aged 6 to 8 weeks.
- cytotoxic compositions of the invention A volume of 100 ⁇ l of adenoviral vectors (5 ⁇ 10 8 infectious units) is injected directly into the tumors when their volume is close to 4 to 10 mm 3 (D0). This injection is repeated under the same conditions on D1 and D2.
- composition of the invention administered is controlled by measuring the size of the tumors as well as by measuring the survival time of the mice treated with, if necessary, a control of the animal's immunological status by ELISPOT, test CTL, ...
- the animals can also be then subjected to a counter-lateral challenge during which a lethal dose of tumor cells is administered to the pre-treated animal.
- the human MIP cDNA (Accession number with GenBank: X03754; sequence incorporated on request by reference) was assembled by synthetic oligonucleotides according to the sequence described by Obaru, K. & al. 1986, J. Biochem. 99 (3), 885-894. This cDNA was introduced into a vector derived from pBluescript to give the vector pTG 13006.
- pTG8347 is a p polyll vector (Lathe et al., 1987, Gene 57, 193-201) into which are inserted the Ad5 sequences 1 to 458, the RSV promoter, the rabbit beta-globin 1 intron 2 splicing sequences, the beta polyadenylation sequences - rabbit globin 1 and the Ad5 sequences 3328-5788.
- Ad5 sequences 1 to 458 the Ad5 sequences 1 to 458
- the RSV promoter the rabbit beta-globin 1 intron 2 splicing sequences
- beta polyadenylation sequences - rabbit globin 1 and the Ad5 sequences 3328-5788.
- the adènoviral vector pTG13010 is reconstituted by recombination in the E. coli BJ 5183 strain between the P ⁇ cI-BsiEII fragment of pTG 13008 and the vector pTG6624 (described in French application 97 06757) linearized by CZ ⁇ l.
- pTG6624 corresponds to the plasmid p poly II carrying the genome Ad5 deleted from the regions El (nt 459 to 3327) and E3 (nt 28592 to 30470), the MIP expression cassette being inserted in place of El.
- the final construction pTG13010 contains the genome Ad5 deleted from most of the regions El (nt 459 to 3328) and E3 (nt 28249 to 30758) and, in place of El, a cassette for the expression of the MlPl ⁇ gene placed under the control of the RSV promoter and of the rabbit beta-globin 1 intron 2 splicing sequences.
- the adenoviral particles are generated by transfection into a line for complementing the El function, for example line 293 (ATCC CRL1573) according to the techniques of the art (Graham and Prevec, 1991, Methods in Molecular Biology Vol7, Gene Transfer and
- the cDNA of human MIP1 ⁇ (GenBank accession number: J04130; sequence incorporated on request by reference) was assembled by synthetic oligonucleotides according to the sequence described by Lipes, M.A. et al.
- the Nofl-Asp718 fragment of M13TG13013 containing the MIP1 ⁇ gene is isolated and introduced into the vector pTG8347 cleaved by these same enzymes, to give the transfer vector pTG13015.
- the adenoviral vector pTG13023 is reconstituted by recombination in the E. coli BJ 5183 strain between the P ⁇ cI-BstEII fragment of pTG13015 and the vector pTG6624 (described in French application 97 06757) linearized by CZ ⁇ l.
- the final construction pTG 13023 contains the genome Ad5 deleted from most of the regions El (nt 459 to 3328) and E3 (nt 28249 to 30758) and instead and place of E1, a cassette for the expression of the MIP1 ⁇ gene placed under the control of the RSV promoter and of the splice sequences of intron 2 of rabbit ⁇ globin 1.
- the adenoviral particles are generated by transfection into a line for complementing the El function, for example line 293 (ATCC CRL1573) according to the techniques of the art (Graham and Prevec, 1991, Methods in Molecular Biology Vol7, Gene Transfer and Expression Protocols; Ed EJ Murray, The Human Press Inc, Clinton, NJ).
- mice thus treated are then subjected to a counter lateral challenge consisting in the administration under the conditions described above of a lethal dose (3.10 5 cells) of tumor cells on D80 / D100. It was thus found that the results described above are also accompanied by an immune state of the mouse such that no tumor is capable of developing after this challenge step.
- huMIPl ⁇ 2.10 8 infectious units
- muIL12 murine gene IL12
- empty Ad empty
- the adenoviruses are in a solution containing 100 mM Tris and 10 mM MgCl 2 . It was moreover verified that the mice treated under the same conditions with a composition comprising only the adenoviruses expressing the MlP1 gene exhibited tumors of identical or even greater volume than those observed in mice treated with a composition comprising empty Ad.
- the results obtained according to this example demonstrate a drop in tumor volumes in mice treated with the compositions of the invention comprising an adenovirus expressing MlP1 associated with an adenovirus expressing 1TL12, very particularly by comparison with the results observed during treatment of mice with muIL12 alone.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002339900A CA2339900A1 (fr) | 1999-06-08 | 2000-06-07 | Composition destinee a la mise en oeuvre d'un traitement cytotoxique, notamment antitumoral ou antiviral, chez un mammifere |
EP00942167A EP1100916A2 (fr) | 1999-06-08 | 2000-06-07 | Composition destinee a la mise en oeuvre d'un traitement cytotoxique, notamment antitumoral ou antiviral, chez un mammifere |
JP2001501166A JP2003501367A (ja) | 1999-06-08 | 2000-06-07 | 哺乳類における細胞傷害、特に抗腫瘍または抗ウイルスの治療用の組成物 |
AU56883/00A AU780074B2 (en) | 1999-06-08 | 2000-06-07 | Composition for implementing a cytotoxic, in particular an antitumoral or antiviral, treatment in a mammal |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9907181 | 1999-06-08 | ||
FR99/07181 | 1999-06-08 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2000074629A2 true WO2000074629A2 (fr) | 2000-12-14 |
WO2000074629A3 WO2000074629A3 (fr) | 2001-03-22 |
Family
ID=9546486
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR2000/001559 WO2000074629A2 (fr) | 1999-06-08 | 2000-06-07 | Composition destinee a la mise en oeuvre d'un traitement cytotoxique, notamment antitumoral ou antiviral, chez un mammifere |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1100916A2 (fr) |
JP (1) | JP2003501367A (fr) |
AU (1) | AU780074B2 (fr) |
CA (1) | CA2339900A1 (fr) |
WO (1) | WO2000074629A2 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7893033B2 (en) | 2002-05-06 | 2011-02-22 | Board Of Regents, The University Of Texas System | Targeting proteins to deliver therapeutic or diagnostic reagents |
US8846401B2 (en) | 2000-11-17 | 2014-09-30 | Vascular Biogenics Ltd. | Promoters exhibiting endothelial cell specificity and methods of using same |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8071740B2 (en) * | 2000-11-17 | 2011-12-06 | Vascular Biogenics Ltd. | Promoters exhibiting endothelial cell specificity and methods of using same for regulation of angiogenesis |
DE60237777D1 (de) | 2001-10-19 | 2010-11-04 | Vascular Biogenics Ltd | Etzungen und verfahren zur gezielten herunterregulierung von angiogenese und zur krebstherapie |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994013321A1 (fr) * | 1992-12-09 | 1994-06-23 | Indiana University Foundation | Suppression des cellules myeloides |
WO1997015595A1 (fr) * | 1995-10-24 | 1997-05-01 | Smithkline Beecham Corporation | Procede de mobilisation de cellules souches hematopoietiques |
-
2000
- 2000-06-07 EP EP00942167A patent/EP1100916A2/fr not_active Withdrawn
- 2000-06-07 WO PCT/FR2000/001559 patent/WO2000074629A2/fr not_active Application Discontinuation
- 2000-06-07 CA CA002339900A patent/CA2339900A1/fr not_active Abandoned
- 2000-06-07 JP JP2001501166A patent/JP2003501367A/ja active Pending
- 2000-06-07 AU AU56883/00A patent/AU780074B2/en not_active Ceased
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994013321A1 (fr) * | 1992-12-09 | 1994-06-23 | Indiana University Foundation | Suppression des cellules myeloides |
WO1997015595A1 (fr) * | 1995-10-24 | 1997-05-01 | Smithkline Beecham Corporation | Procede de mobilisation de cellules souches hematopoietiques |
Non-Patent Citations (2)
Title |
---|
DATABASE MEDLINE [en ligne] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; LU Y ET AL: "Macrophage inflammatory protein -1alpha ( MIP -1alpha) expression plasmid enhances DNA vaccine-induced immune response against HIV-1." retrieved from STN Database accession no. 1999132267 XP002133388 & CLINICAL AND EXPERIMENTAL IMMUNOLOGY, (1999 FEB) 115 (2) 335-41., * |
DILLOO ET AL: "COMBINED CHEMOKINE AND CYTOKINE GENE TRANSFER ENHANCES ANTITUMOR IMMUNITY" NATURE MEDICINE, vol. 2, 1996, pages 1090-1095, XP002133387 cité dans la demande * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8846401B2 (en) | 2000-11-17 | 2014-09-30 | Vascular Biogenics Ltd. | Promoters exhibiting endothelial cell specificity and methods of using same |
US8859745B2 (en) | 2000-11-17 | 2014-10-14 | Vascular Biogenics Ltd. | Promoters exhibiting endothelial cell specificity and methods of using same |
US7893033B2 (en) | 2002-05-06 | 2011-02-22 | Board Of Regents, The University Of Texas System | Targeting proteins to deliver therapeutic or diagnostic reagents |
US7906628B2 (en) | 2002-05-06 | 2011-03-15 | The Board Of Regents, The University Of Texas System | Targeting proteins to deliver therapeutic or diagnostic reagents |
Also Published As
Publication number | Publication date |
---|---|
CA2339900A1 (fr) | 2000-12-14 |
JP2003501367A (ja) | 2003-01-14 |
WO2000074629A3 (fr) | 2001-03-22 |
EP1100916A2 (fr) | 2001-05-23 |
AU5688300A (en) | 2000-12-28 |
AU780074B2 (en) | 2005-02-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0998568B1 (fr) | Mutant ayant une activite uracile phosphoribosyl transferase | |
US8226954B2 (en) | Polypeptide having an improved cytosine deaminase activity | |
JP5372374B2 (ja) | 哺乳類における抗腫瘍または抗ウイルス治療を行う目的において設計された要素のキット | |
FR2794025A1 (fr) | Composition destinee a la mise en oeuvre d'un traitement antitumoral ou antiviral chez un mammifere | |
WO2000074629A2 (fr) | Composition destinee a la mise en oeuvre d'un traitement cytotoxique, notamment antitumoral ou antiviral, chez un mammifere | |
EP1683807A1 (fr) | Produits de combinaison utilisable dans le cadre d'un traitement antitumoral comprenant un anticoprs capable d'inhiber l'activité de CSF-1 | |
CA2435949A1 (fr) | Materiel biologique pour la preparation de compositions pharmaceutiques destinees au traitement de mammiferes |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AU CA JP US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2000942167 Country of ref document: EP |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref document number: 2339900 Country of ref document: CA Ref country code: CA Ref document number: 2339900 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09762573 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 56883/00 Country of ref document: AU |
|
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AU CA JP US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
WWP | Wipo information: published in national office |
Ref document number: 2000942167 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2000942167 Country of ref document: EP |