WO2012097012A1 - Use of toll-like receptor agonist for treating cancer - Google Patents
Use of toll-like receptor agonist for treating cancer Download PDFInfo
- Publication number
- WO2012097012A1 WO2012097012A1 PCT/US2012/020844 US2012020844W WO2012097012A1 WO 2012097012 A1 WO2012097012 A1 WO 2012097012A1 US 2012020844 W US2012020844 W US 2012020844W WO 2012097012 A1 WO2012097012 A1 WO 2012097012A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cancer
- tlr
- cblb502
- mammal
- liver
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 186
- 201000011510 cancer Diseases 0.000 title claims abstract description 83
- 229940123384 Toll-like receptor (TLR) agonist Drugs 0.000 title claims abstract description 9
- 239000003970 toll like receptor agonist Substances 0.000 title claims abstract description 6
- 210000004185 liver Anatomy 0.000 claims abstract description 94
- 108010040721 Flagellin Proteins 0.000 claims abstract description 64
- 238000000034 method Methods 0.000 claims abstract description 63
- 231100000304 hepatotoxicity Toxicity 0.000 claims abstract description 23
- 230000007056 liver toxicity Effects 0.000 claims abstract description 12
- 102000002689 Toll-like receptor Human genes 0.000 claims description 124
- 108020000411 Toll-like receptor Proteins 0.000 claims description 124
- 239000000556 agonist Substances 0.000 claims description 68
- 230000000694 effects Effects 0.000 claims description 47
- 210000001519 tissue Anatomy 0.000 claims description 47
- 241000124008 Mammalia Species 0.000 claims description 44
- 210000004072 lung Anatomy 0.000 claims description 22
- 208000037819 metastatic cancer Diseases 0.000 claims description 16
- 208000011575 metastatic malignant neoplasm Diseases 0.000 claims description 16
- 230000001988 toxicity Effects 0.000 claims description 16
- 231100000419 toxicity Toxicity 0.000 claims description 16
- 238000004820 blood count Methods 0.000 claims description 12
- 210000000265 leukocyte Anatomy 0.000 claims description 12
- 238000002512 chemotherapy Methods 0.000 claims description 10
- 210000001072 colon Anatomy 0.000 claims description 10
- 210000005228 liver tissue Anatomy 0.000 claims description 10
- 230000001270 agonistic effect Effects 0.000 claims description 9
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 9
- 210000003932 urinary bladder Anatomy 0.000 claims description 9
- 229940089514 Fas agonist Drugs 0.000 claims description 8
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 claims description 8
- 230000000968 intestinal effect Effects 0.000 claims description 8
- 206010025323 Lymphomas Diseases 0.000 claims description 7
- 230000001394 metastastic effect Effects 0.000 claims description 7
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 6
- 206010027476 Metastases Diseases 0.000 claims description 6
- 108050002568 Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 claims description 6
- 210000000481 breast Anatomy 0.000 claims description 6
- 230000015788 innate immune response Effects 0.000 claims description 6
- 230000009401 metastasis Effects 0.000 claims description 6
- 238000009097 single-agent therapy Methods 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 206010066476 Haematological malignancy Diseases 0.000 claims description 5
- 208000002250 Hematologic Neoplasms Diseases 0.000 claims description 5
- 101000669460 Homo sapiens Toll-like receptor 5 Proteins 0.000 claims description 5
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
- 210000002307 prostate Anatomy 0.000 claims description 5
- 241000607142 Salmonella Species 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 206010039438 Salmonella Infections Diseases 0.000 claims description 3
- 208000036142 Viral infection Diseases 0.000 claims description 3
- 229940127089 cytotoxic agent Drugs 0.000 claims description 3
- 230000036039 immunity Effects 0.000 claims description 3
- 229960005489 paracetamol Drugs 0.000 claims description 3
- 238000001959 radiotherapy Methods 0.000 claims description 3
- 206010039447 salmonellosis Diseases 0.000 claims description 3
- 230000009385 viral infection Effects 0.000 claims description 3
- 102100039357 Toll-like receptor 5 Human genes 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- 238000011275 oncology therapy Methods 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract description 56
- 102000008234 Toll-like receptor 5 Human genes 0.000 abstract description 3
- 108010060812 Toll-like receptor 5 Proteins 0.000 abstract description 3
- 229950009493 entolimod Drugs 0.000 description 157
- 108010079458 CBLB502 Proteins 0.000 description 156
- 241000699670 Mus sp. Species 0.000 description 125
- 210000004027 cell Anatomy 0.000 description 69
- 238000002347 injection Methods 0.000 description 57
- 239000007924 injection Substances 0.000 description 57
- 238000011282 treatment Methods 0.000 description 51
- 108090000765 processed proteins & peptides Proteins 0.000 description 49
- 108010057466 NF-kappa B Proteins 0.000 description 47
- 102000003945 NF-kappa B Human genes 0.000 description 47
- 230000004913 activation Effects 0.000 description 42
- 108090000623 proteins and genes Proteins 0.000 description 40
- 235000001014 amino acid Nutrition 0.000 description 37
- 150000001413 amino acids Chemical class 0.000 description 35
- 102000004196 processed proteins & peptides Human genes 0.000 description 35
- 238000007920 subcutaneous administration Methods 0.000 description 35
- 108060001084 Luciferase Proteins 0.000 description 31
- 230000014509 gene expression Effects 0.000 description 31
- 230000001404 mediated effect Effects 0.000 description 31
- 239000005089 Luciferase Substances 0.000 description 30
- 210000003494 hepatocyte Anatomy 0.000 description 30
- 241000699666 Mus <mouse, genus> Species 0.000 description 29
- 230000004614 tumor growth Effects 0.000 description 28
- 229920001184 polypeptide Polymers 0.000 description 27
- 235000018102 proteins Nutrition 0.000 description 27
- 102000004169 proteins and genes Human genes 0.000 description 27
- 210000004881 tumor cell Anatomy 0.000 description 26
- 239000013598 vector Substances 0.000 description 21
- 230000000259 anti-tumor effect Effects 0.000 description 19
- 230000006907 apoptotic process Effects 0.000 description 19
- 102100040247 Tumor necrosis factor Human genes 0.000 description 18
- 210000000056 organ Anatomy 0.000 description 15
- 230000006698 induction Effects 0.000 description 14
- 239000003446 ligand Substances 0.000 description 14
- 238000007912 intraperitoneal administration Methods 0.000 description 13
- 230000004044 response Effects 0.000 description 13
- 241000700159 Rattus Species 0.000 description 12
- 125000003275 alpha amino acid group Chemical group 0.000 description 12
- 230000001419 dependent effect Effects 0.000 description 12
- 239000012634 fragment Substances 0.000 description 12
- 206010019851 Hepatotoxicity Diseases 0.000 description 11
- 238000011717 athymic nude mouse Methods 0.000 description 11
- 239000000284 extract Substances 0.000 description 11
- 230000007686 hepatotoxicity Effects 0.000 description 11
- 230000011664 signaling Effects 0.000 description 11
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 10
- 108700012920 TNF Proteins 0.000 description 10
- 230000001580 bacterial effect Effects 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 238000003384 imaging method Methods 0.000 description 10
- 102100022089 Acyl-[acyl-carrier-protein] hydrolase Human genes 0.000 description 9
- 102000004091 Caspase-8 Human genes 0.000 description 9
- 108090000538 Caspase-8 Proteins 0.000 description 9
- 230000001965 increasing effect Effects 0.000 description 9
- 239000002502 liposome Substances 0.000 description 9
- 238000002203 pretreatment Methods 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 8
- 108010082126 Alanine transaminase Proteins 0.000 description 8
- 102000011727 Caspases Human genes 0.000 description 8
- 108010076667 Caspases Proteins 0.000 description 8
- 108010049207 Death Domain Receptors Proteins 0.000 description 8
- 102000009058 Death Domain Receptors Human genes 0.000 description 8
- 241000021375 Xenogenes Species 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 241000894007 species Species 0.000 description 8
- 102100035100 Transcription factor p65 Human genes 0.000 description 7
- 230000000692 anti-sense effect Effects 0.000 description 7
- 238000011319 anticancer therapy Methods 0.000 description 7
- 230000034994 death Effects 0.000 description 7
- 208000014018 liver neoplasm Diseases 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- 102000004127 Cytokines Human genes 0.000 description 6
- 108090000695 Cytokines Proteins 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 101000763579 Homo sapiens Toll-like receptor 1 Proteins 0.000 description 6
- 102100027010 Toll-like receptor 1 Human genes 0.000 description 6
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 6
- 230000004071 biological effect Effects 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 150000002632 lipids Chemical group 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 238000001356 surgical procedure Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 5
- 208000032843 Hemorrhage Diseases 0.000 description 5
- 206010019695 Hepatic neoplasm Diseases 0.000 description 5
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 5
- 102000043136 MAP kinase family Human genes 0.000 description 5
- 108091054455 MAP kinase family Proteins 0.000 description 5
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 5
- 230000002424 anti-apoptotic effect Effects 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- -1 c-Flip Proteins 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- DAZSWUUAFHBCGE-KRWDZBQOSA-N n-[(2s)-3-methyl-1-oxo-1-pyrrolidin-1-ylbutan-2-yl]-3-phenylpropanamide Chemical compound N([C@@H](C(C)C)C(=O)N1CCCC1)C(=O)CCC1=CC=CC=C1 DAZSWUUAFHBCGE-KRWDZBQOSA-N 0.000 description 5
- 210000004940 nucleus Anatomy 0.000 description 5
- 239000012188 paraffin wax Substances 0.000 description 5
- 244000052769 pathogen Species 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000003757 reverse transcription PCR Methods 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 210000000952 spleen Anatomy 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 206010027457 Metastases to liver Diseases 0.000 description 4
- 101100153382 Mus musculus Tlr5 gene Proteins 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 230000001640 apoptogenic effect Effects 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 208000029742 colonic neoplasm Diseases 0.000 description 4
- 210000000805 cytoplasm Anatomy 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 239000013583 drug formulation Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 210000002889 endothelial cell Anatomy 0.000 description 4
- 210000002919 epithelial cell Anatomy 0.000 description 4
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 210000000987 immune system Anatomy 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 229960004768 irinotecan Drugs 0.000 description 4
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 4
- 210000001865 kupffer cell Anatomy 0.000 description 4
- 231100000636 lethal dose Toxicity 0.000 description 4
- 238000003468 luciferase reporter gene assay Methods 0.000 description 4
- 210000004962 mammalian cell Anatomy 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 230000002438 mitochondrial effect Effects 0.000 description 4
- 238000010172 mouse model Methods 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 230000001717 pathogenic effect Effects 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- 238000010254 subcutaneous injection Methods 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 102100032814 ATP-dependent zinc metalloprotease YME1L1 Human genes 0.000 description 3
- 102000010565 Apoptosis Regulatory Proteins Human genes 0.000 description 3
- 108010063104 Apoptosis Regulatory Proteins Proteins 0.000 description 3
- 102000047934 Caspase-3/7 Human genes 0.000 description 3
- 108700037887 Caspase-3/7 Proteins 0.000 description 3
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- 206010062016 Immunosuppression Diseases 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 101150026829 JUNB gene Proteins 0.000 description 3
- 102000005712 Keratin-8 Human genes 0.000 description 3
- 108010070511 Keratin-8 Proteins 0.000 description 3
- 206010067125 Liver injury Diseases 0.000 description 3
- 102000010168 Myeloid Differentiation Factor 88 Human genes 0.000 description 3
- 108010077432 Myeloid Differentiation Factor 88 Proteins 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- 101800000795 Proadrenomedullin N-20 terminal peptide Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 208000009956 adenocarcinoma Diseases 0.000 description 3
- 238000011394 anticancer treatment Methods 0.000 description 3
- 238000011284 combination treatment Methods 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 210000002216 heart Anatomy 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000006749 inflammatory damage Effects 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000021995 interleukin-8 production Effects 0.000 description 3
- 210000000936 intestine Anatomy 0.000 description 3
- 210000005229 liver cell Anatomy 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002105 nanoparticle Substances 0.000 description 3
- 239000002687 nonaqueous vehicle Substances 0.000 description 3
- 230000005937 nuclear translocation Effects 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- PIRWNASAJNPKHT-SHZATDIYSA-N pamp Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)N)C(C)C)C1=CC=CC=C1 PIRWNASAJNPKHT-SHZATDIYSA-N 0.000 description 3
- 230000003076 paracrine Effects 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000000861 pro-apoptotic effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 238000010911 splenectomy Methods 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000005945 translocation Effects 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 2
- 102100027211 Albumin Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 238000011725 BALB/c mouse Methods 0.000 description 2
- 102000051485 Bcl-2 family Human genes 0.000 description 2
- 108700038897 Bcl-2 family Proteins 0.000 description 2
- 238000011735 C3H mouse Methods 0.000 description 2
- 108020004635 Complementary DNA Proteins 0.000 description 2
- 102000018832 Cytochromes Human genes 0.000 description 2
- 108010052832 Cytochromes Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 108010039471 Fas Ligand Protein Proteins 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 2
- 101000852214 Homo sapiens THO complex subunit 4 Proteins 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- 102100034343 Integrase Human genes 0.000 description 2
- 102000019223 Interleukin-1 receptor Human genes 0.000 description 2
- 108050006617 Interleukin-1 receptor Proteins 0.000 description 2
- 102000052508 Lipopolysaccharide-binding protein Human genes 0.000 description 2
- 108010053632 Lipopolysaccharide-binding protein Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 206010028851 Necrosis Diseases 0.000 description 2
- 101150091206 Nfkbia gene Proteins 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- 241000392514 Salmonella enterica subsp. enterica serovar Dublin Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 108091027967 Small hairpin RNA Proteins 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000035508 accumulation Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000005775 apoptotic pathway Effects 0.000 description 2
- 239000008135 aqueous vehicle Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000003305 autocrine Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 230000000254 damaging effect Effects 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 108010052621 fas Receptor Proteins 0.000 description 2
- 102000018823 fas Receptor Human genes 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 210000003495 flagella Anatomy 0.000 description 2
- 101150078861 fos gene Proteins 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 229940014259 gelatin Drugs 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 231100000234 hepatic damage Toxicity 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 102000045719 human TLR5 Human genes 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- 230000008105 immune reaction Effects 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 238000002991 immunohistochemical analysis Methods 0.000 description 2
- 238000011532 immunohistochemical staining Methods 0.000 description 2
- 229960001438 immunostimulant agent Drugs 0.000 description 2
- 239000003022 immunostimulating agent Substances 0.000 description 2
- 230000003308 immunostimulating effect Effects 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000008818 liver damage Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 230000001926 lymphatic effect Effects 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 230000001338 necrotic effect Effects 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000003531 protein hydrolysate Substances 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 208000011581 secondary neoplasm Diseases 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000004055 small Interfering RNA Substances 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000002463 transducing effect Effects 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 230000001960 triggered effect Effects 0.000 description 2
- 230000002100 tumorsuppressive effect Effects 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 230000003827 upregulation Effects 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 108700000712 BH3 Interacting Domain Death Agonist Proteins 0.000 description 1
- 102000055105 BH3 Interacting Domain Death Agonist Human genes 0.000 description 1
- 102100026596 Bcl-2-like protein 1 Human genes 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 238000003737 Bright-Glo Luciferase Assay System Methods 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- 108090000567 Caspase 7 Proteins 0.000 description 1
- 102100026549 Caspase-10 Human genes 0.000 description 1
- 108090000572 Caspase-10 Proteins 0.000 description 1
- 102100029855 Caspase-3 Human genes 0.000 description 1
- 102100038902 Caspase-7 Human genes 0.000 description 1
- 101001026137 Cavia porcellus Glutathione S-transferase A Proteins 0.000 description 1
- 101001071697 Cavia porcellus Glutathione S-transferase B Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 208000005443 Circulating Neoplastic Cells Diseases 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 206010055114 Colon cancer metastatic Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102100033215 DNA nucleotidylexotransferase Human genes 0.000 description 1
- 108010008286 DNA nucleotidylexotransferase Proteins 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- AHCYMLUZIRLXAA-SHYZEUOFSA-N Deoxyuridine 5'-triphosphate Chemical compound O1[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C=C1 AHCYMLUZIRLXAA-SHYZEUOFSA-N 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- 102100025027 E3 ubiquitin-protein ligase TRIM69 Human genes 0.000 description 1
- 241000701832 Enterobacteria phage T3 Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102100026693 FAS-associated death domain protein Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108090000331 Firefly luciferases Proteins 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- 101150112014 Gapdh gene Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000830203 Homo sapiens E3 ubiquitin-protein ligase TRIM69 Proteins 0.000 description 1
- 101000911074 Homo sapiens FAS-associated death domain protein Proteins 0.000 description 1
- 101000977771 Homo sapiens Interleukin-1 receptor-associated kinase 4 Proteins 0.000 description 1
- 101000999079 Homo sapiens Radiation-inducible immediate-early gene IEX-1 Proteins 0.000 description 1
- 101000665442 Homo sapiens Serine/threonine-protein kinase TBK1 Proteins 0.000 description 1
- 101000831567 Homo sapiens Toll-like receptor 2 Proteins 0.000 description 1
- 101000669406 Homo sapiens Toll-like receptor 6 Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010020565 Hyperaemia Diseases 0.000 description 1
- 101150014048 IER3 gene Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102100023533 Interleukin-1 receptor-associated kinase 4 Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 244000237786 Lathyrus tuberosus Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- 101100452374 Mus musculus Ikbke gene Proteins 0.000 description 1
- 101100206904 Mus musculus Tirap gene Proteins 0.000 description 1
- 101100481581 Mus musculus Tlr13 gene Proteins 0.000 description 1
- 101100046526 Mus musculus Tnf gene Proteins 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010053159 Organ failure Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 101000870531 Pleuronectes platessa Glutathione S-transferase A Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102100024819 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 238000010240 RT-PCR analysis Methods 0.000 description 1
- 102100036900 Radiation-inducible immediate-early gene IEX-1 Human genes 0.000 description 1
- 101001026113 Rattus norvegicus Glutathione S-transferase alpha-1 Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 102100038192 Serine/threonine-protein kinase TBK1 Human genes 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 102100038803 Somatotropin Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 102100024333 Toll-like receptor 2 Human genes 0.000 description 1
- 102100039387 Toll-like receptor 6 Human genes 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 108010018242 Transcription Factor AP-1 Proteins 0.000 description 1
- 102100023132 Transcription factor Jun Human genes 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- WCHSQACWYIQTKL-XPWFQUROSA-N [[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2r,3r,4r,5r)-2-(6-aminopurin-9-yl)-4-hydroxy-5-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Chemical compound C1=NC2=C(N)N=CN=C2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1OP(O)(=O)OP(O)(=O)OC[C@H]([C@@H](O)[C@H]1O)O[C@H]1N1C(N=CN=C2N)=C2N=C1 WCHSQACWYIQTKL-XPWFQUROSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 210000002821 alveolar epithelial cell Anatomy 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 229940124650 anti-cancer therapies Drugs 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 230000005975 antitumor immune response Effects 0.000 description 1
- 230000009925 apoptotic mechanism Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 210000005068 bladder tissue Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000000424 bronchial epithelial cell Anatomy 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000008004 cell lysis buffer Substances 0.000 description 1
- 210000004671 cell-free system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 201000010897 colon adenocarcinoma Diseases 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000006552 constitutive activation Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 230000002074 deregulated effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- BFMYDTVEBKDAKJ-UHFFFAOYSA-L disodium;(2',7'-dibromo-3',6'-dioxido-3-oxospiro[2-benzofuran-1,9'-xanthene]-4'-yl)mercury;hydrate Chemical group O.[Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(Br)=C([O-])C([Hg])=C1OC1=C2C=C(Br)C([O-])=C1 BFMYDTVEBKDAKJ-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 210000004920 epithelial cell of skin Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 230000007185 extracellular pathway Effects 0.000 description 1
- 230000006624 extrinsic pathway Effects 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 210000005002 female reproductive tract Anatomy 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000005558 fluorometry Methods 0.000 description 1
- 108700025906 fos Genes Proteins 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000009650 gentamicin protection assay Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 210000002288 golgi apparatus Anatomy 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 229940127130 immunocytokine Drugs 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 210000005007 innate immune system Anatomy 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000006662 intracellular pathway Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 208000034415 irinotecan toxicity Diseases 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000001365 lymphatic vessel Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000000723 mammalian artificial chromosome Anatomy 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005776 mitochondrial apoptotic pathway Effects 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 230000001483 mobilizing effect Effects 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 238000011206 morphological examination Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 230000006654 negative regulation of apoptotic process Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 230000004942 nuclear accumulation Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 230000004983 pleiotropic effect Effects 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000035409 positive regulation of cell proliferation Effects 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000009290 primary effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 210000003456 pulmonary alveoli Anatomy 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 229940124553 radioprotectant Drugs 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 230000025915 regulation of apoptotic process Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000000754 repressing effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 231100000847 severe hepatotoxicity Toxicity 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 230000006433 tumor necrosis factor production Effects 0.000 description 1
- 238000013042 tunel staining Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 230000007923 virulence factor Effects 0.000 description 1
- 239000000304 virulence factor Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 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
-
- 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
- A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
- C07K14/255—Salmonella (G)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5158—Antigen-pulsed cells, e.g. T-cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
- A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
- A61K2039/585—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation wherein the target is cancer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/025—Enterobacteriales, e.g. Enterobacter
- A61K39/0275—Salmonella
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
Definitions
- This invention relates to methods of treating cancer in Toll- Like Receptor-expressing tissues, and to methods of protecting the liver from the effects of a liver toxicity, using a TLR agonist.
- Fas ligand is a 40 kDa physiological agonist of Fas signaling expressed on activated lymphocytes and many tumor cells which can also be secreted through metalloproteinase-mediated cleavage and kill the sensitive cells in autocrine and paracrine manner.
- Fas is a transmembrane receptor expressed on activated lymphocytes, variety of tissues and tumor cells. Fas signaling plays crucial role in regulation of the immune system by triggering autocrine suicide or paracrine death (apoptosis), suppressing immune reaction by eliminating activated lymphocytes. Upon binding, it induces p53 independent cell death through extrinsic pathway of apoptosis engaging DISC formation, caspase-8 and 10, and intrinsic (mitochondrial) apoptosis activating caspase-8 and Bid cleavage, and cytochrome release. Both apoptotic pathways lead to activation of caspase-3 and 7.
- Mitochondrial apoptosis is regulated by pro- and anti-apoptotic Bcl2 family members.
- Fas signaling is often found deregulated either by absence of Fas receptor, or by constitutive activation of NF-kB resulting in the expression of anti-apoptotic genes, such as c-Flip, Bcl-2, Bcl-xL.
- C-Flip an NF- kB responsive gene, has been demonstrated to inhibit caspase-8 and Fas mediated apoptosis in tumors (REFs, Kataoka et al 2000).
- TLRs are found to be expressed on both epithelial and endothelial cells as well as immunocytes. At present, thirteen TLRs have been identified in mammals. Upon receptor stimulation, several common signaling pathways get activated such as NF-kB, AP-1, PI3K/AKT and mitogen-activated protein kinases (MAPK) leading to increased survival, stimulation of cell proliferation and the secretion of many cytokines with chemotactic and pro-inflammatory functions. Induction of TLR in cancer cells can be used to treat cancer, however, the distribution of different TLRs varies significantly among the various organs and cell types. This affects the cytokine profile and extent of the inflammatory response of cells. Accordingly, there is a need in the art for cancer immunotherapeutic methods that do not depend on the presence of TLR5 expression.
- a method of treating cancer in a mammal which may comprise administering to a mammal in need thereof of Toll-Like Receptor (TLR) agonist.
- TLR Toll-Like Receptor
- a method of reducing cancer recurrence in a mammal which may comprise administering to a mammal in need thereof a TLR agonist.
- the cancer may be present in a tissue that expresses TLR.
- the cancer may be a metastasis or tumor regrowth.
- the TLR agonist may be flagellin.
- the cancer may not express TLR, which may be TLR5.
- the tissue may be liver, lung, bladder, or intestinal.
- the cancer may be metastatic.
- the cancer may be melanoma, colon, breast, prostate, or a hematological malignancy, which may be lymphoma.
- the cancer may be tumor.
- the agent may be administered as a monotherapy.
- the mammal may not be receiving a combination therapy.
- the mammal may also not be receiving chemotherapy or radiation therapy, but may be treated surgically.
- the mammal may have sufficient innate immunity, which may be at a level that is equivalent to the level required for eligibility for a first or subsequent round of chemotherapy.
- the mammal may have a white blood cell count within the range of normal, or may have a white blood cell count indicative of mild-immunosuppression.
- the TLR agonist may be administered to the mammal before, after or concurrent with removal of a tumor.
- the TLR agonist may be administered during tumor removal.
- a method of treating cancer in a mammal which may comprise administering to a mammal in need thereof a FAS agonist and a TLR agonist, which may be flagellin.
- the FAS agonist may be a FAS agonist antibody.
- the cancer may be metastatic, and may be a tumor.
- the cancer may not express a TLR.
- the cancer may have metastasized to an invaded tissue that expresses TLR.
- the invaded tissue may be liver, bladder, lung, or intestinal.
- a method of protecting liver tissue in a mammal from the effects of a liver toxicity which may comprise administering to a mammal in need thereof a TLR agonist.
- the toxicity may be a FAS ligand, a FAS agonistic antibody, TNFa, acetaminophen, alcohol, a viral infection of the liver, or a chemotherapeutic agent.
- the toxicity may also be a Salmonella infection, which may be from Salmonella typhimurium.
- the TLR agonist may be flagellin.
- Figure 1 shows the domain structure of bacterial flagellin.
- Side-chain atoms are color coded: Ala, yellow; Leu, He or Val, orange; Phe and Tyr, purple (carbon atoms) and red (oxygen atoms), c, Position and region of various structural features in the amino-acid sequence of flagellin.
- Figure 2 shows a schematic of Salmonella flagellin domains, its fragments, and its interaction with TLR5. Dark bars denote regions of the flagellin gene used to construct fragments comprising A, B, C, A' and B'.
- Figure 3 depicts flagellin derivatives. The domain structure and approximate boundaries (amino acid coordinates) of selected flagellin derivatives (listed on the right). FliC flagellin of Salmonella dublin is encoded within 505 amino acids (aa).
- Figure 4 shows the nucleotide and amino acid sequence for the following flagellin variants: AA' (SEQ ID NO: 7-8), AB' (SEQ ID NO: 9-10), BA' (SEQ ID NO: 11-12), BB' (SEQ ID NO: 13-14), CA' (SEQ ID NO: 15-16), CB' (SEQ ID NO: 17-18), A (SEQ ID NO: 19- 20), B (SEQ ID NO: 21-22), C (SEQ ID NO: 23-24), GST-A' (SEQ ID NO: 25-26), GST-B' (SEQ ID NO: 27-28), AA'nl-170 (SEQ ID NO: 29-30), AA'nl-163 (SEQ ID NO: 33-34), AA'n54-170 (SEQ ID NO: 31-32), AA'n54-163 (SEQ ID NO: 335-36), AB'nl-170 (SEQ ID NO: 37-38), AB'nl-163 (SEQ ID NO: 39-40
- the pRSETb leader sequence is shown in Italic (leader includes Met, which is also amino acid 1 of FliC).
- the N terminal constant domain is underlined.
- the amino acid linker sequence is in Bold.
- the C terminal constant domain is underlined. GST, if present, is highlighted.
- Figure 5 shows a comparison of amino acid sequences of the conserved amino (Fig. 5A) and carboxy (Fig. 5B) terminus from 21 species of bacteria.
- the 13 conserved amino acids important for TLR5 activity are shown with shading.
- Figure 6 shows the sequence of human TLR5.
- Figure 7 NF-kB activation in vivo in response to CBLB502 and LPS injections.
- NF-kB nuclear translocation indicative of the bioactivity of agonists LPS and CBLB502 in liver from NIH-Swiss mice injected s.c either with CBLB502 or LPS.
- Control mice were injected with PBS. Tissue samples were obtained 20, 40 and 60 min after the treatments, processed into paraffin blocks.
- P65 was stained with green fluorescence, cytokeratin-8 with red fluorescence and nuclei with non-specific Dapi blue staining. Pictures are taken at x20 magnification. Arrows indicate Kupffer and endothelial cells determined based on morphological criteria.
- FIG. 8 shows CBLB502 protection from Fas mediated hepatotoxicity.
- A Survival of NIH-Swiss mice after i.p. injection of 4 ⁇ g of anti-Fas antibodies alone or in combination with CBLB502 (1 ⁇ g/ mouse) injected 30 min, 2 hours and 6 hours prior antibodies. In parenthesis are the numbers of mice per each treatment.
- B Protection of livers from anti- Fas antibody toxicity. Apoptosis in livers 5 hours after injections of anti-Fas antibodies was detected using TUNEL technique.
- C Tissue morphology with H&E staining revealed necrotic damge to livers by anti- Fas antibody injections and protection by CBLB502.
- D Tissue morphology with H&E staining revealed necrotic damge to livers by anti- Fas antibody injections and protection by CBLB502.
- erythrocyte autofluorescence rhodamine channel, red
- mouse IgG control Cy5-conjugated anti- mouse IgG antibody, pceudocolored in purple
- DAPI nuclei blue
- E. Caspase-3/7 activity in liver samples of NIH-Swiss mice was determined in tissue protein lysates 5 hours after injection of 3 ⁇ g anti- Fas antibody with or without CBLB502 thirty minute pre-treatment. N 3. Bars represent average +/- s.d.
- ALT Alanine aminotransferase
- Figure 9 shows regulation of apopto sis-related factors by CBLB502 in liver and its effect on Fas-mediated antitumor activity in CT-26 tumor model.
- C. RNA expression of Bcl2AlB, Bcl2AlD, IER-3, Fos, Jun and JunB genes in livers of intact mice and treated with CBLB502 for 30 min and 2 hours was detected by RT-PCR.
- GAPDH was used as a control to monitor the induction of gene expression.
- Tumor growth in livers was determined using Xenogen IVIS Imaging System on the days 10, 15, 17, 22, 28 and 40 after tumor cell inoculation. Images of 3 mice from each group taken on day 15 are presented. The difference between proportions of mice with tumor- free livers in CBLB502-treated and control groups reaches statistical significance (p ⁇ 0.05) on days indicated by asterisks.
- Figure 10 Dynamics of NF-kB activation in different organs after injections with CBLB502 (5 ⁇ g, s.c.) or LPS (20 ⁇ g, s.c). Mice were euthanized 2, 6, 24 and 48 hours later by C02 inhalation. Luciferase activity in protein extracts from liver, large intestine, kidneys and lungs was normalized per ⁇ g of the protein extract and average values were calculated per organ. Luciferase fold induction was calculated as ratio between average luciferase activity in protein extract from organs of the TLR agonist treated mice and that obtained in the extracts from the corresponding organs of the PBS injected control mice (3 mice/ group). Bars represent fold induction as average + s.e.
- FIG. 11 NF-kB dependent luciferase expression in primary culture of mouse hepatocytes isolated from luciferase reporter mice and treated in vitro for 3 hours with CBLB502 (100 ng/ml), LPS (5 ⁇ g/ml) or PBS control. Then hepatocytes were rinsed with PBS and collected in cell lysis buffer (Pro mega). Luciferase activity in the protein supernatants was determined by Promega reporter system and normalized per ⁇ g of the protein extract. Bars represent luciferase units (mean + s.d.).
- FIG. 12 H&E staining of liver samples from NIH-Swiss mice treated with CBLB502, anti-Fas antibodies (3 ⁇ g) or their combination obtained at different time-points after the treatment. Samples of livers were obtained 5, 12 and 26 hours after injections of anti-Fas antibodies, fixed in 10% formalin, embedded in paraffin and stained for tissue morphology with hematoxilin and eosin.
- FIG. 13 TLR5 expression on B16 and CT-26 cells.
- B NF-kB activation in B16 and CT-26 tumor cells in response to CBLB502, mouse TNFa and LPS was tested using luciferase reporter assay. Data represent luciferase units (mean + s.d).
- FIG. 14 Shows TLR5 expresion in CT-26 tumor cells and A20 lymphoma cells.
- Figs. 14A and C total RNA was extracted from CT-26 and B16 tumor cells (Fig. 14A) and CT- 26 and A20 cells (Fig. 14C) using TRIzol reagent as described in the main text of the manuscript.
- the primers for TLR5 were designed using LaserGene software (DNASTAR, Inc., Madison, WI).
- a region of mouse TLR5 mRNA GenBank Accession No.
- NM_016928.2 was amplified using primers specific for the mouse TLR5 gene: forward (5'- AGTCCCCCAGCTCCAGTTTC-3') and reverse (5 ' -GG AGCCCCCTAGC AGTG AGT-3 ' ) .
- GAPDH was used as a control to monitor the induction of gene expression.
- cDNAs were synthesized using SuperscriptTM II Reverse Transcriptase and oligo(dT)12-18 primer
- Antitumor activity of colon HCT116 adenocarcinoma s.c. Grown as a xenograft in athymic mice.
- HCT116 were injected s.c. into 2 flanks of 8 athymic nude mice (0.5x106 /100 ml of PBS) to induce tumors.
- tumors became of about 3-5 mm in diameter (by day 6 after injections) mice were randomly distributed into 2 groups, 5 mice for CBLB502 treated group and 3 mice in PBS control group.
- Right figure represents the amount of days needed for tumors to reach 400 mm3 volume with and without treatment with CBLB502.
- FIG. 19 Fischer rats with s.c. growing syngeneic Ward colon tumors were treated with CBLB502 (0.2 mg/kg) was administered by i.p. once a day for three days.
- Right figure demonstrates IL-8 production in response to CBLB502 treatment as indicative of TLR5 function in H1299-TLR5 cells.
- FIG. 22 shows that the bladder strongly responds to CBLB502.
- FIG 23 shows that CBLB502 treatment delays tumor appearance and growth in livers, even in tumors that do not express TLR5.
- Figure 24 shows CBLB502 protection from Fas mediated hepatotoxicity.
- Figure 25 shows that the liver is protected from TNFa and LPS toxicity by CBLB502.
- Figure 26 shows that CBLB502 protects the lungs from TNF and LPS toxicity.
- Figure 27 shows that CBLB502 protects mice from legal oral administration of Salmonella.
- Figure 28 shows that irinotecan abrogates the antitumor effect of flagellin (CBLB502).
- TLR Toll- Like Receptor
- the TLR agonist may be particularly useful in treating liver, bladder, lung, and intestinal cancers, whether primary or metastatic, as well as cancer affecting other TLR5-positive tissues.
- the TLR agonist can also be used to treat cancers that originate in tissues other than the liver, bladder, lung, intestinal, and other TLR5-positive tissues, but metastasize to these tissues.
- TLR5 Even though the metastatic cancer cells do not express TLR5, the cancer may nonetheless be treatable with the TLR agonist when the cancer has metastasized to TLR5-expressing tissues such as the liver.
- TLR agonists effectively reduce or kill cancer cells affecting a tissue that has a strong innate immunity system, thereby obviating the need for any pre-existing expression of TLR5 in the cancer cells.
- the innate immune system is sufficiently triggered so as to treat cancers that are devoid of TLR5 expression.
- TLR5 does not need to be provided to the cancer cells in order for the TLR agonist to effectively reduce or kill cancer cells.
- TLR agonist can protect the liver from a liver toxicity.
- death ligands and activators of FAS-mediated apoptosis such as FAS ligand and anti-FAS agonistic antibodies, can induce does-dependent
- TLR agonists can protect the liver against such toxicities. This unexpected property of TLR agonists allows it be combined with FAS agonists or TNF for cancer treatment, such that the adverse of effects of the FAS agonist or TNF are reduced or prevented.
- each intervening number there between with the same degree of precision is explicitly contemplated.
- the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6,9, and 7.0 are explicitly contemplated.
- administering may mean a single dose or multiple doses of an agent or agent.
- Analog may mean, in the context of a peptide or polypeptide, a peptide or polypeptide comprising one or more non-standard amino acids or other structural variations from the conventional set of amino acids.
- Antibody may mean an antibody of classes IgG, IgM, IgA, IgD or IgE, or fragments, or derivatives thereof, including Fab, F(ab')2, Fd, and single chain antibodies, diabodies, bispecific antibodies, bifunctional antibodies and derivatives thereof.
- the antibody may be a monoclonal antibody, polyclonal antibody, affinity purified antibody, or mixtures thereof which exhibits sufficient binding specificity to a desired epitope or a sequence derived therefrom.
- the antibody may also be a chimeric antibody.
- the antibody may be derivatized by the attachment of one or more chemical, peptide, or polypeptide moieties known in the art.
- the antibody may be conjugated with a chemical moiety.
- a “derivative” may mean a peptide or polypeptide different other than in primary structure (amino acids and amino acid analogs). Derivatives may differ by being glycosylated, one form of post-translational modification. For example, peptides or polypeptides may exhibit glycosylation patterns due to expression in heterologous systems. If at least one biological activity is retained, then these peptides or polypeptides are derivatives according to the invention.
- Other derivatives may include fusion peptides or fusion polypeptides having a covalently modified N- or C-terminus, PEGylated peptides or polypeptides, peptides or polypeptides associated with lipid moieties, alkylated peptides or polypeptides, peptides or polypeptides linked via an amino acid side-chain functional group to other peptides, polypeptides or chemicals, and additional modifications as would be understood in the art.
- a "fragment” may mean a portion of a reference peptide or polypeptide.
- a “homo log” may mean a peptide or polypeptide sharing a common evolutionary ancestor.
- a "leader sequence” may be a nucleic acid encoding any peptide sequence that is linked and translated with a peptide or polypeptide of interest to allow the peptide or polypeptide of interest be properly routed through a eukaryotic cell' s endoplasmic reticulum and Golgi complexes for the purposed of extracellular secretion from the cell's membrane.
- the leader peptide sequence may be derived from alkaline phosphatase.
- the leader sequence may have a DNA sequence comprising atgctgctgctgctgctgctgctgggcctgaggctacagctct ccctgggc.
- a liposome may mean a tiny bubble (vesicle) made out of the same material as a cell membrane.
- a liposome be filled with drugs and used to deliver drugs for cancer and other diseases.
- a liposome may be filled with a vector.
- a liposome membrane may be made of phospholipids, which are molecules that have a head group and a tail group. The head of the liposome may be attracted to water, and the tail, which is made of a long hydrocarbon chain, is repelled by water. The tails may be repelled by water, and line up to form a surface away from the water.
- the lipids in the plasma membrane may be chiefly phospholipids like
- Liposomes may be composed of naturally- derived phospholipids with mixed lipid chains (like egg phosphatidylethanolamine), or of pure surfactant components like DOPE (dioleoylphosphatidylethanolamine).
- a "peptide” or “polypeptide” may mean a linked sequence of amino acids and may be natural, synthetic, or a modification or combination of natural and synthetic.
- substantially identical may mean that a first and second amino acid sequence are at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%,or 99% over a region of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100 amino acids .
- Treating each may mean to alleviate, suppress, repress, eliminate, prevent or slow the appearance of symptoms, clinical signs, or underlying pathology of a condition or disorder on a temporary or permanent basis.
- Preventing a condition or disorder involves administering a agent of the present invention to a subject prior to onset of the disease.
- Suppressing a condition or disorder involves administering a agent of the present invention to a subject after induction of the condition or disorder but before its clinical appearance.
- Repressing the condition or disorder involves administering a agent of the present invention to a subject after clinical appearance of the disease.
- a “variant” may mean means a peptide or polypeptide that differs in amino acid sequence by the insertion, deletion, or conservative substitution of amino acids, but retain at least one biological activity.
- Representative examples of "biological activity” include the ability to bind to a toll- like receptor and to be bound by a specific antibody.
- Variant may also mean a protein with an amino acid sequence that is substantially identical to a referenced protein with an amino acid sequence that retains at least one biological activity.
- a conservative substitution of an amino acid i.e., replacing an amino acid with a different amino acid of similar properties (e.g., hydrophilicity, degree and distribution of charged regions) is recognized in the art as typically involving a minor change.
- hydrophobicity and charge It is known in the art that amino acids of similar hydropathic indexes can be substituted and still retain protein function. In one aspect, amino acids having hydropathic indexes of +2 are substituted.
- the hydrophilicity of amino acids can also be used to reveal substitutions that would result in proteins retaining biological function. A consideration of the hydrophilicity of amino acids in the context of a peptide permits calculation of the greatest local average hydrophilicity of that peptide, a useful measure that has been reported to correlate well with antigenicity and immunogenicity.
- U.S. Patent No. 4,554,101 incorporated fully herein by reference.
- Substitution of amino acids having similar hydrophilicity values can result in peptides retaining biological activity, for example immunogenicity, as is understood in the art. Substitutions may be performed with amino acids having hydrophilicity values within +2 of each other. Both the hyrophobicity index and the hydrophilicity value of amino acids are influenced by the particular side chain of that amino acid. Consistent with that observation, amino acid substitutions that are compatible with biological function are understood to depend on the relative similarity of the amino acids, and particularly the side chains of those amino acids, as revealed by the hydrophobicity, hydrophilicity, charge, size, and other properties.
- a "vector” may mean a nucleic acid sequence containing an origin of replication.
- a vector may be a plasmid, a yeast or a mammalian artificial chromosome.
- a vector may be a RNA or DNA vector.
- a vector may be either a self-replicating extrachromosomal vector or a vector which integrates into a host genome. 2. Toll-like Receptor Agonist
- the TLR agonist may be a PAMP, which may be conserved molecular product derived from a pathogen.
- the pathogen may be a Gram-positive bacterium, Gram-negative bacterium,, fungus, or virus.
- the TLR agonist may be a damage- associated molecular pattern (DAMP) ligand, which may be an endogenous molecule released from injured or dying cells.
- DAMP or PAMP may initiate an immune response through TLR signals and recruit adapter molecules within the cytoplasm of cells in order to propagate a signal.
- the TLR agonist may be an agonist for the TLR, which may be a ligand from the following in Table 1:
- the TLR agonist may be a fragment, variant, analog, homology or derivative of a PAMP or DAMP that binds a TLR and induces TLR-mediated activity, such as activation of NF-KB activity.
- the TLR agonsist fragment, variant, analog, homolog, or derivative may be at least 30- 99% identical to amino acids of a TLR-agonist and induce TLR-mediated activity.
- the TLR agonist may target a TLR such as TLR-5.
- the TLR agonist may be an agonist of TLR-5 and stimulate TLR-5 activity.
- the TLR agonist may be an anti-TLR5 antibody or other small molecule.
- the TLR agonist may be flagellin.
- the flagellin may also be a flagellin or flagellin-related polypeptide.
- the flagellin may be from any source, including a variety of Gram-positive and Gram-negative bacterial species.
- the flagellin may be a flagellin polypeptide from any Gram-positive or Gram-negative bacterial species including, but not limited to, a flagellin polypeptide disclosed in U.S. Pat. Pub. No. 2003/000044429, the contents of which are fully incorporated herein by reference.
- the flagellin may have an amino acid sequence from a bacterial species depicted in Figure 7 of U.S. Patent Publication No. 2003/0044429.
- the nucleotide sequences encoding the flagellin polypeptides listed in Figure 7 of U.S. 2003/0044429 are publicly available at sources including the NCBI Genbank database.
- the flagellin may also be a flagellin peptide corresponding to an Accession number listed in the BLAST results shown in Fig. 25 of U.S. Patent Pub.
- the flagellin may also be a flagellin polypeptide as disclosed in U.S. Patent Appl. Publication No. 2009/0011982, the contents of which are fully incorporated herein.
- the flagellin maybe any one of a flagellin polypeptide as disclosed in Figures 3 and 4 herein.
- the flagellin may be a fragment, variant, analog, homology or derivative of a flagellin that binds TLR5 and induces TLR5-mediated activity, such as activation of NF- ⁇ activity.
- a fragment, variant, analog, homolog, or derivative of flagellin may be at least 30-99% identical to amino acids of a flagellin that binds TLR5 and induces TLR5-mediated activity.
- the flagellin may be from a species of Salmonella, a representative example of which is S.dublin (encoded by GenBank Accession Number M84972).
- the flagellin related-polypeptide may be a fragment, variant, analog, homolog, or derivative of M84972, or combination thereof, that binds to TLR5 and induces TLR5-mediated activity, such as activation of NF-kB activity.
- a fragment, variant, analog, homolog, or derivative of flagellin may be obtained by rational-based design based on the domain structure of Flagellin and the conserved structure recognized by TLR5.
- the flagellin may comprise at least 10, 11, 12, or 13 of the 13 conserved amino acids shown in Fig. 2 (positions 89, 90, 91, 95, 98, 101, 115, 422, 423, 426, 431, 436 and 452).
- the flagellin may be at least 30-99% identical to amino acids 1 174 and 418 505 of M84972.
- the flagellin may be the major component of bacterial flagellum.
- the flagellin may be composed of three domains (Fig. 1). Domain 1 (Dl) and domain 2 (D2) may be discontinuous and may be formed when residues in the amino terminus and carboxy terminus are juxtaposed by the formation of a hairpin structure.
- the amino and carboxy terminus comprising the Dl and D2 domains may be most conserved, whereas the middle hypervariable domain (D3) may be highly variable.
- Studies with a recombinant protein containing the amino Dl and D2 and carboxyl Dl and D2 separated by an Escherichia coli hinge (ND1-2/ECH/CD2) indicate that Dl and D2 may be bioactive when coupled to an ECH element.
- This chimera may induce IkBa degradation, NF-kB activation, and NO and IL-8 production in two intestinal epithelial cell lines.
- the non-conserved D3 domain may be on the surface of the flagellar filament and may contain the major antigenic epitopes.
- the potent proinflammatory activity of flagellin may reside in the highly conserved N and C Dl and D2 regions (See Figure 1).
- the flagellin may induce NF-kB activity by binding to To 11- like receptor 5 (TLR5).
- TLR5 To 11- like receptor 5
- the TLR may recognize a conserved structure that is particular to the flagellin.
- the conserved structure may be composed of a large group of residues that are somewhat permissive to variation in amino acid content.
- Smith et al., Nat Immunol. 4: 1247-53 (2003), the contents of which are incorporated herein by reference, have identified 13 conserved amino acids in flagellin that are part of the conserved structure recognized by TLR5.
- the 13 conserved amino acids of flagellin that may be important for TLR5 activity are shown in Fig. 2.
- flagellin Numerous deletional mutants of flagellin have been made that retain at least some TLR5 stimulating activity.
- the flagellin may be such a deletional mutant, and may be a deletional mutant disclosed in the Examples herein.
- the flagellin may comprise a sequence translated from GenBank Accession number D 13689 missing amino acids 185-306 or 444-492, or from
- the flagellin may comprise transposon insertions and changes to the variable D3 domain.
- the D3 domain may be substituted in part, or in whole, with a hinge or linker polypeptide that allows the Dl and D2 domains to properly fold such that the variant stimulates TLR5 activity.
- the variant hinge elements may be found in the E.coli MukB protein and may have a sequence as set forth in International Application No. PCT/US 10/51646, filed on October 6, 2010, the contents of which are incorporated herein by reference.
- the flagellin as described above may further comprise a leader sequence.
- the flagellin further comprising a leader sequence may be CBLB502S.
- This invention also relates to an agent comprising a therapeutically effective amount of a TLR agonist.
- the agent may be a polypeptide.
- the agent may also be a vector.
- the vector may comprise a nucleic acid encoding the TLR agonist.
- the vector may be capable of transducing mammalian cells.
- the vector may be delivered into a mammalian cell by a virus or liposome related vector system.
- the virus vector system may be an adenovirus or a cytomegalovirus.
- the agent may be a liposome harboring the vector.
- the liposome maybe capable of transducing mammalian cells and delivering the vector for expression.
- the agent may be a drug formulation that activates a TLR, thereby exposing tumor or infected cells to the host immune system imitating the situation of a massive penetration through the intestinal wall.
- the agent may be delivered systematically in solution for administration such as intramuscularly.
- the agent may be a drug formulation that expresses the TLR agonist in the form of a nano-particle, which may carry a functional agonist to the cell surface of a mammalian cell.
- the agent may be a pharmaceutical agent comprising the drug formulation described above, which may be produced using methods well known in the art.
- the agent may also comprise a coagent.
- the vector may comprise a nucleic acid encoding flagellin.
- the vector may be capable of expressing flagellin using a strong promoter.
- the expression vector may further comprise a leader sequence cloned upstream of the gene encoding the TLR agonist.
- the drug formulation may be an adenovirus expressing:
- the TLR agonist delivered systematically in solution for administration, such as intramuscularly; or
- the TLR agonist expressed in the form of nano-particles carrying functional TLR agonist, such as flagellin, which may be derived from CBLB502, on their surface.
- the nano- particle may be on the basis of a bacteriophage T7, or fully formed to retain its biological activity.
- the nano-formulation may provide for dose-dependent, NF-KB-responsive reporter activation, and may result in cell internalization by endocytosis for effective immunization approach (Mobian AP-A).
- Administration of the agents using the method described herein may be systemically, orally, parenterally, sublingually, transdermally, rectally, transmuco sally, topically, via inhalation, via buccal administration, or combinations thereof.
- Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, and intraarticular. Administration may also be subcutaneous, intravenous, via intra-air duct, or intra-tumoral.
- the agent may be
- the agents may be administered to a human patient, cat, dog, large animal, or an avian.
- the agent may be administered as a monotherapy or simultaneously or metronomically with other treatments, which may be a surgery or removal of a tumor.
- the term "simultaneous” or “simultaneously” as used herein, means that the agent and other treatment be administered within 48 hours, preferably 24 hours, more preferably 12 hours, yet more preferably 6 hours, and most preferably 3 hours or less, of each other.
- the term “metronomically” as used herein means the administration of the agent at times different from the other treatment and at a certain frequency relative to repeat administration.
- the agent may be administered at any point prior to another treatment including about 120 hr, 118 hr, 116 hr, 114 hr, 112 hr, l lO hr, 108 hr, 106 hr, 104 hr, 102 hr, 100 hr, 98 hr, 96 hr, 94 hr, 92 hr, 90 hr, 88 hr, 86 hr, 84 hr, 82 hr, 80 hr, 78 hr, 76 hr, 74 hr, 72 hr, 70 hr, 68 hr, 66 hr, 64 hr, 62 hr, 60 hr, 58 hr, 56 hr, 54 hr, 52 hr, 50hr, 48 hr, 46 hr, 44 hr, 42 hr, 40 hr, 38 hr, 36
- the agent may be administered at any point prior to a second treatment of the agent including about 120 hr, 118 hr, 116 hr, 114 hr, 112 hr, 110 hr, 108 hr, 106 hr, 104 hr, 102 hr, 100 hr, 98 hr, 96 hr, 94 hr, 92 hr, 90 hr, 88 hr, 86 hr, 84 hr, 82 hr, 80 hr, 78 hr, 76 hr, 74 hr, 72 hr, 70 hr, 68 hr, 66 hr, 64 hr, 62 hr, 60 hr, 58 hr, 56 hr, 54 hr, 52 hr, 50hr, 48 hr, 46 hr, 44 hr, 42 hr, 40 hr, 38 hr, 36 h
- the agent may be administered at any point after another treatment including about lmin, 2 mins., 3 mins., 4 mins., 5 mins., 6 mins., 7 mins., 8 mins., 9 mins., 10 mins., 15 mins., 20 mins., 25 mins., 30 mins., 35 mins., 40 mins., 45 mins., 50 mins., 55 mins., 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 14 hr, 16 hr, 18 hr, 20 hr, 22 hr, 24 hr, 26 hr, 28 hr, 30 hr, 32 hr, 34 hr, 36 hr, 38 hr, 40 hr, 42 hr, 44 hr, 46 hr, 48 hr, 50 hr, 52 hr, 54 hr
- the agent may be administered at any point prior after a second treatment of the agent including about 120 hr, 118 hr, 116 hr, 114 hr, 112 hr, 110 hr, 108 hr, 106 hr, 104 hr, 102 hr, 100 hr, 98 hr, 96 hr, 94 hr, 92 hr, 90 hr, 88 hr, 86 hr, 84 hr, 82 hr, 80 hr, 78 hr, 76 hr, 74 hr, 72 hr, 70 hr, 68 hr, 66 hr, 64 hr, 62 hr, 60 hr, 58 hr, 56 hr, 54 hr, 52 hr, 50hr, 48 hr, 46 hr, 44 hr, 42 hr, 40 hr, 38 hr, 36 h
- the method may comprise administering the agent.
- Agents provided herein may be in the form of tablets or lozenges formulated in a conventional manner.
- tablets and capsules for oral administration may contain conventional excipients may be binding agents, fillers, lubricants, disintegrants and wetting agents.
- Binding agents include, but are not limited to, syrup, accacia, gelatin, sorbitol, tragacanth, mucilage of starch and polyvinylpyrrolidone.
- Fillers may be lactose, sugar, microcrystalline cellulose, maizestarch, calcium phosphate, and sorbitol.
- Lubricants include, but are not limited to, magnesium stearate, stearic acid, talc, polyethylene glycol, and silica.
- Disintegrants may be potato starch and sodium starch glycollate.
- Wetting agents may be sodium lauryl sulfate. Tablets may be coated according to methods well known in the art.
- Agents provided herein may also be liquid formulations such as aqueous or oily suspensions, solutions, emulsions, syrups, and elixirs. The agents may also be formulated as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain additives such as suspending agents, emulsifying agents, nonaqueous vehicles and preservatives.
- Suspending agent may be sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydro xyethylcellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats.
- Emulsifying agents may be lecithin, sorbitan monooleate, and acacia.
- Nonaqueous vehicles may be edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol.
- Preservatives may be methyl or propyl p-hydroxybenzoate and sorbic acid.
- Agents provided herein may also be formulated as suppositories, which may contain suppository bases such as cocoa butter or glycerides. Agents provided herein may also be formulated for inhalation, which may be in a form such as a solution, suspension, or emulsion that may be administered as a dry powder or in the form of an aerosol using a propellant, such as dichlorodifluoromethane or trichlorofluoromethane. Agents provided herein may also be formulated as transdermal formulations comprising aqueous or nonaqueous vehicles such as creams, ointments, lotions, pastes, medicated plaster, patch, or membrane.
- aqueous or nonaqueous vehicles such as creams, ointments, lotions, pastes, medicated plaster, patch, or membrane.
- Agents provided herein may also be formulated for parenteral administration such as by injection, intratumor injection or continuous infusion.
- Formulations for injection may be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents including, but not limited to, suspending, stabilizing, and dispersing agents.
- the agent may also be provided in a powder form for reconstitution with a suitable vehicle including, but not limited to, sterile, pyrogen-free water.
- Agents provided herein may also be formulated as a depot preparation, which may be administered by implantation or by intramuscular injection.
- the agents may be formulated with suitable polymeric or hydrophobic materials (as an emulsion in an acceptable oil, for example), ion exchange resins, or as sparingly soluble derivatives (as a sparingly soluble salt, for example), c.
- the method may comprise administering a therapeutically effective amount of the agent to a patient in need thereof.
- the therapeutically effective amount required for use in therapy varies with the nature of the condition being treated, the length of time desired to activate TLR activity, and the age/condition of the patient.
- doses employed for adult human treatment typically are in the range of 0.001 mg/kg to about 200 mg/kg per day.
- the dose may be about 1 mg/kg to about 100 mg/kg per day.
- the desired dose may be conveniently administered in a single dose, or as multiple doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day. Multiple doses may be desired, or required.
- the dosage may be at any dosage such as about 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 225 mg/kg, 250 mg/kg, 275 mg/kg, 300 mg/kg, 325 mg/kg, 350 mg/kg, 375 mg/kg, 400 mg/kg, 425 mg/kg, 450 mg/kg, 475 mg/kg, 500 mg/kg, 525 mg/kg, 550 mg/kg, 575 mg/kg, 600 mg/kg, 625 mg/kg, 650 mg/kg, 675 mg/kg, 700 mg/kg, 725 mg/kg, 750 mg/kg, 775 mg/kg, 800 mg/kg, 825 mg/kg,
- the agent may be administered as a monotherapy, under which the agent is not administered together with any other type of cancer treatment, such as chemotherapy, radiation therapy, another biological therapy, or other combination therapies; provided that "monotherapy” may include administration of the agent together with surgical treatment.
- the agent may be administered in combination with a surgery, which may be tumor removal.
- the agent may be administered prior to, together with, or after the surgery.
- the agent may be administered during the surgery.
- a method for treating cancer which may be present in a tissue that expresses a TLR such as TLR5, by administering to a mammal in need thereof the agent.
- the cancer may be a tumor or a metastatic cancer.
- the cancer may also be present in liver, bladder, lung, or intestinal tissue, and also may have originated in another type of tissue such as colon, breast, or prostate.
- the cancer may also be melanoma or a hematological malignancy such as lymphoma.
- the cancer may also be any cancer that has metastasized to a TLR-expressing tissue, such as liver, lung, bladder, intestine, or other TLR-expressing tissue.
- the cancer may be a TLR-negative cancer, and thus lack expression of a Toll-Like Receptor.
- the cancer may lack both endogenous and exogenous expression of the Toll-Like Receptor.
- the method may comprise a step of not providing the Toll- Like Receptor to the cancer, which may include not providing the Toll- Like Receptor either exogenously or endogenously.
- the cancer may lack any and all Toll- Like Receptor expression.
- the Toll- Like Receptor may recognize molecules that are conserved molecular products derived from pathogens that include Gram-positive, Gram-negative bacteria, fungi, and viruses, but are distinguishable from host molecules, collectively referred to as pathogen- associated molecular patterns (PAMPs).
- PAMPs pathogen-associated molecular patterns
- DAMPs damage-associated molecular pattern
- a PAMP or DAMP may be a TLR agonist as further described below.
- the TLR may be a fragment, variant, analog, homo log or derivative that recruits adapter molecules within the cytoplasm of cells in order to propagate a signal.
- the TLR may be from a human or other mammalian species such as rhesus monkey, mouse, or rat.
- the TLR may be at least 30- 99% identical to a TLR that recruits adapter molecules within the cytoplasm of cells in order to propagate a signal.
- the TLR may be one of the between ten and fifteen types of TLR that are estimated to exist in most mammalian species.
- the TLR may be one of the 13 TLR (named simply TLR1 to TLR13) that have been identified in humans and mice together, or may be an equivalent form that has been found in other mammalian species.
- the TLR may be one of the 11 members (TLR1-TLR11) that have been identified in humans.
- the TLR may ordinarily be expressed by different types of immune cells, and may be located on the cell surface or in the cell cytoplasm.
- the TLR may ordinarily be expressed on cancer cells.
- the TLR may ordinarily be expressed by normal epithelial cells in the digestive system, normal keratinocytes in the skin, alveolar and bronchial epithelial cells, and epithelial cells of the female reproductive tract. These cells lining an organ may be the first line of defense against invasion of microorganisms, and TLRs ordinarily expressed in epithelial cells may have a crucial role in the regulation of proliferation and apoptosis.
- the TLR may not be expressed by the cancer cells.
- the TLR- negative cancer cells may not express any TLR mRNA, may not express any TLR protein, or may not express any functional TLR protein.
- the TLR protein may not function due to reduced ability to bind a TLR ligand or reduced ability to transmit downstream signals triggered by ligand binding.
- the TLR- negative cancer cells may also have reduced levels of TLR mRNA, protein, or TLR function. The reduction may be 100%, or by more than 99.9%, 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50%, as compared to a normal cell from the tissue from which the cancer cell originated, or as compared to another, known TLR-expressing cell type.
- the TLR- expressing cell may be a normal cell or a tumor cell, such as a tumor cell line or tumor xenograft.
- the TLR ordinarily expressed on cancer cells may upregulate the NF- ⁇ cascade and produce anti-apoptotic proteins that contribute to carcinogenesis and cancer cell proliferation.
- TLR signaling pathways are known to be involved in signaling. These proteins are known as myeloid differentiation factor 88 (MyD88), Tirap (also called Mai), Trif, and Tram.
- MyD88 myeloid differentiation factor 88
- Tirap also called Mai
- Trif Trif
- the adapters activate other molecules within the cell, including certain protein kinases (IRAKI, IRAK4, TBK1, and IKKi) that amplify the signal, and ultimately lead to the induction or suppression of genes that orchestrate the inflammatory response.
- IRAKI, IRAK4, TBK1, and IKKi protein kinases
- TLR signaling pathways during pathogen recognition may induce immune reactions via extracellular and intracellular pathways mediated by MyD88, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB), and mitogen-associated protein kinase (MAPK).
- NF-KB nuclear factor kappa-light-chain-enhancer of activated B cells
- MAPK
- TLRs together with the Interleukin- 1 receptors form a receptor superfamily, known as the "Interleukin- 1 Receptor/To 11- Like Receptor Superfamily.” All members of this family have in common a so-called TIR (Toll-IL-1 receptor) domain. Three subgroups of TIR domains may exist. Proteins with subgroup I TIR domains are receptors for interleukins that are produced by macrophages, monocytes and dendritic cells and all have extracellular Immunoglobulin (Ig) domains. Proteins with subgroup II TIR domains are classical TLRs, and bind directly or indirectly to molecules of microbial origin.
- a third subgroup of proteins containing TIR domains (III) consists of adaptor proteins that are exclusively cytosolic and mediate signaling from proteins of subgroups 1 and 2.
- the TLR may be a fragment, variant, analog, homo log or derivative that retains either a subgroup I TIR domain, subgroup II TIR domain, or subgroup III TIR domain.
- the TLR may function as a dimer.
- TLR2 forms heterodimers with TLR1 or TLR6, each dimer having a different ligand specificity.
- the TLR may also depend on other co-receptors for full ligand sensitivity, such as in the case of TLR4's recognition of LPS, which requires MD-2.
- CD 14 and LPS Binding Protein (LBP) are known to facilitate the presentation of LPS to MD-2.
- the TLR may be TLR1, which recognizes PAMPs with a specificity for gram-positive bacteria. TLR1 has also been designated as CD281.
- the TLR may be Toll- Like Receptor 5.
- the protein encoded by the TLR5 may play a fundamental role in pathogen recognition and activation of innate immunity.
- TLR5 may recognize PAMPs that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity.
- TLR5 may recognize bacterial flagellin, a principal component of bacterial flagella and a virulence factor.
- the activation of the TLR5 may mobilize the nuclear factor NF- ⁇ and stimulate tumor necrosis factor-alpha production.
- the cancer may be a primary cancer or a metastatic cancer.
- the primary cancer may be an area of cancer cells at an originating site that becomes clinically detectable, and may be a primary tumor.
- the metastatic cancer may be the spread of a disease from one organ or part to another non-adjacent organ or part.
- the metastatic cancer may be caused by a cancer cell that acquires the ability to penetrate and infiltrate surrounding normal tissues in a local area, forming a new tumor, which may be a local metastasis.
- the metastatic cancer may also be caused by a cancer cell that acquires the ability to penetrate the walls of lymphatic and/or blood vessels, after which the cancer cell is able to circulate through the bloodstream (thereby being a circulating tumor cell) to other sites and tissues in the body.
- the metastatic cancer may be due to a process such as lymphatic or hematogeneous spread.
- the metastatic cancer may also be caused by a tumor cell that comes to rest at another site, re-penetrates through the vessel or walls, continues to multiply, and eventually forms another clinically detectable tumor.
- the metastatic cancer may be this new tumor, which may be a metastatic (or secondary) tumor.
- the metastatic cancer may be caused by tumor cells that have metastasized, which may be a secondary or metastatic tumor.
- the cells of the metastatic tumor may be like those in the original tumor.
- the secondary tumor while present in the liver, is made up of abnormal breast or colon cells, not of abnormal liver cells.
- the tumor in the liver may thus be a metastatic breast cancer or a metastatic colon cancer, not liver cancer.
- the metastatic cancer may have an origin from any tissue.
- the metastatic cancer may originate from melanoma, colon, breast, or prostate, and thus may be made up of cells that were originally skin, colon, breast, or prostate, respectively.
- the metastatic cancer may also be a hematological malignancy, which may be lymphoma.
- the metastatic cancer may invade a tissue such as liver, lung, bladder, or intestinal. The invaded tissue may express a TLR, while the metastatic cancer may or may not express a TLR.
- the method may also comprise co-administration of the TLR agonist with an anti-cancer therapy.
- the anti-cancer therapy may be FAS ligand, a FAS agonistic antibody, TNFa, a TNFa agonistic antibody, TRAIL, or a TRAIL agonistic antibody.
- the TLR5 agonist may be used to sensitize the cancer to the anti-cancer therapy.
- the method may also be combined with other methods for treating cancer, including use of an immuno stimulant, cytokine, or
- the immuno stimulant may be a growth hormone, prolactin or vitamin D.
- Also provided herein is a method of reducing cancer recurrence, comprising
- the cancer may be or may have been present in a tissue that either does or does not express TLR, such as TLR5.
- TLR5 tissue that either does or does not express TLR
- the cancer, tissue, TLR, mammal, and agent may be as described above.
- the method may also prevent cancer recurrence.
- the cancer may be an oncological disease.
- the cancer may be a dormant tumor, which may result from the metastasis of a cancer.
- the dormant tumor may also be left over from surgical removal of a tumor.
- the cancer recurrence may be tumor regrowth, a lung metastasis, or a liver metastasis.
- the mammal may have a fully- functional immune system, and may not be
- the mammal may also have a level of immunity that is equivalent to the level sufficient to make the mammal eligible for a first or second round a chemotherapy.
- the mammal may not have a low white blood cell count, which may be chemotherapy- induced.
- the low white blood cell count may be caused by the loss of healthy cells during chemotherapy. The loss may be an expected side effect of a chemotherapy drug.
- the low white blood cell count may be a severe immunosuppression caused by chemotherapy.
- the low white blood cell count may compromise the antitumor effect of the agent.
- the low white blood cell count may be restored 7-14 days after a chemotherapy treatment.
- the mammal may have a white blood cell count that is within a normal range.
- the mammal may also have a white blood cell count that is indicative of mild immunosuppression.
- the mammal may have not received chemotherapy treatment for 7-14 days, or at least 14 days.
- the mammal may also have total white blood cell count of at least 3000 or 3500 cells/ml of whole blood; a granulocyte count of at least 1800 or 2100 cells/ml of whole blood; or an albumin level of at least 3.0 or 3.5 g/100 ml of whole blood.
- the white blood cell count, granulocyte count, or albumin level may also fall within +/- 5%, 10%, 20%, 30%, 40%, or 50% of these levels.
- the liver toxicity may also be a Salmonella infection, which may be from Salmonella typhimurium.
- the agent may also be used to protect against liver toxicity that may be FAS- mediated.
- the toxicity may also be FAS ligand, a FAS agonistic antibody, TNFa,
- acetaminophen a compound selected from the group consisting of acetaminophen, alcohol, a viral infection of the liver, or a chemotherapeutic agent.
- the agent may be administered to the mammal.
- TLR5 An agonist of TLR5 protects liver from hepatotoxicity
- CBLB502 which is a pharmacologically optimized TLR5 agonist, is a powerful radioprotectant due to, at least in part, inhibition of apoptosis in radiosensitive tissues.
- CBLB502 was tested for liver protection from Fas-mediated apoptosis. The following examples demonstrate that upon stimulation with CBLB502 the TLR5 pathway is active in liver hepatocytes of mice and humans leading to NF-kB -dependent induction of genes encoding anti- apoptotic proteins. Pretreatment of mice with CBLB502 protected them from lethal doses of Fas agonistic antibodies, reduced Fas-induced elevation of liver enzymes in the blood, caspase activity in liver extracts and preserved liver tissue integrity. CBLB502 did not protect tumors in syngeneic melanoma and colon carcinoma mouse models. These observations support the use of Fas agonists for cancer treatment under the protection of a TLR5 agonist, such as CBLB502.
- NF-kB response was compared in different organs after administration of TLR5 agonist CBLB502 and TLR4 agonist LPS, another known activator of NF-kB.
- CBLB502 was found to induce fast direct activation of NF-kB in hepatocytes, while LPS activation of NF-kB in hepatocytes was mediated through different types of cells. The following data thus also demonstrate that pre-treatment with CBLB502 can reduce Fas-mediated hepatotoxicity during anti-cancer therapy in mice.
- TLR5 toll- like receptor-5
- NF-kB response was investigated in different organs of mice to TLR5 agonist CBLB502 in comparison with bacterial LPS acting through TLR4.
- NF-kB dependent luciferase reporter Xenogen mouse model in which luciferase transgene is expressed under the control of NFkB- dependent natural promoter of IkBa gene (Zhang N, et al, 2005).
- NFkB- activating agents luciferase activity was increased in cells and tissues that respond to a given agent.
- detected strong activation of NF-kB in liver of mice was detected 2 hours after s.c.
- the anti-Fas antibodies can induce dose- dependent hepatotoxicity and rapidly kill mice by inducing apoptosis, liver tissue necrosis and hemorrhage (Ogasawara J et al, Nature 1993, Nishimura et al 1997).
- NF-kB activation in hepatocytes induced by TLR5 agonist CBLB502 may protect liver from Fas mediated apoptosis.
- 4 ⁇ g of anti-Fas antibodies (clone Jo2) injected i.p.
- CBLB502 injected mice had much less damage to the liver that deflected in better overall survival after injections of about than 80% of NIH-Swiss mice when injected 30 min before anti- Fas antibodies (Figure 8 A). All mice survived when CBLB502 was injected 2 hours before antibodies. The protection level then declined by 6 hours time-point of pre-treatment.
- Caspases 3 and 7 are downstream targets of both intrinsic (mitochondrial) and extrinsic (caspase) Fas-mediated apoptosis signaling. Upon activation of the receptor, first caspase-8 becomes phosphorylated and cleaved leading to activation of mitochondrial apoptotic
- caspase 8 activation was reduced to a background level, as indicated by using fluorigenic substrate assay (Fig. 8F).
- CBLB502 also quickly induced RNA expression of another anti-apoptotic protein immediate early response protein IER-3 (Figure 9C, IEX-1 is an alternative name) that was shown suppressing the production of reactive oxygen species and mitochondrial apoptotic pathway (Shen et al 2009).
- RT-PCR analysis of liver samples revealed the induction of IER-3 RNA expression by CBLB502 already 30 min after administration with significant increase by 2 hours.
- proteins of MAPK pathway were found up-regulated in livers of CBLB502 treated mice. It was demonstrated that activation of MAPK pathway in tumors mediates the resistance of these cells to Fas receptor apoptosis (REF).
- LPS is not a good candidate for clinical application, since it induces strong inflammation in many organs and can be directly cytotoxic through FADD/caspase-8 apoptotic pathway (REFs).
- CBLB502 in its turn has been tested in mice, non-human primates and human healthy volunteers and found to be a rather mild inducer of short-lasting inflammation.
- FADD/caspase-8 apoptotic pathway FADD/caspase-8 apoptotic pathway
- CBLB502 does not protect tumors from anti-Fas antibodies toxicity and can even slightly enhance Fas mediated antitumor effect against CT-26 tumors.
- the simultaneous protection of normal liver tissue from Fas mediated toxicity may allow increasing the amount of the Fas agonist reaching complete prevention of liver metastases and the therapeutic effect against s.c. growing tumors.
- mice were purchased from NCI (Frederick, MD), BALB/c and C57B1/6 female mice were purchased from Jackson Laboratory (Bar Harbor, ME). All mice were used in the experiments at the age of 10-14 weeks old.
- Balb/C-Tg(lKBa-luc)Xen mice with NF- kB inducible luciferase reporter gene were originally purchased from Xenogen (Alameda, CA) and bred in our domestic colony.
- CBLB502 a bacterial flagellin derivative, was obtained from Cleveland BioLabs, Inc.
- Bacterial lipopolysacharide (LPS) from Escherichia coli 055 :B5 was purchased from Sigma.
- samples of liver, lungs, kidney, spleen, heart and intestine from NF-kB reporter mice injected s.c. with 100 ⁇ of either PBS, CBLB502 (0.2 mg/kg) or LPS (1 mg/kg) were obtained 2, 6 and 24 h after injections (Fig. 7B, 10).
- Tissue samples were covered with lysis buffer containing proteinase inhibitor cocktail (according to manufacture's recommendation, Calbiochem) to get 100 mg tissue per 1 ml lysis buffer. This was followed by homogenization and centrifugation at 14,000 rpm for 10 min at 4C.
- Luciferase activity was measured in 20 ⁇ of samples immediately after adding 30 ⁇ of luciferin reagent (Bright-Glo Luciferase Assay System, Promega). Luciferase activity was normalized per g of the protein extract. Luciferase fold induction was calculated as ratio between average luciferase units in livers of the TLR ligand treated mice and that obtained from PBS injected control mice.
- NIH-Swiss mice were injected i.p. with 2, 3, 4, and 5 ⁇ g of anti-Fas antibodies in 200 ⁇ of PBS to determine a 100% lethal dose that was found to be 4 ⁇ g/ mouse for this mouse strain. Then CBLB502 (0.04 mg/kg, s.c.) was injected s.c. 30 min, 2 hours and 6 hours before 4 ⁇ g of anti-Fas antibodies (i.p.) (Fig. 8A). Usually death from anti-Fas hepatotoxicity occurs during first 1-2 days after antibody injections. Mouse survival was observed and recorded during 30 days.
- TUNEL indirect terminal deoxynucleotidyl transferase mediated deoxyuridine tri-phosphate nick end labeling
- liver specimens were collected from NIH-Swiss mice five hours (Fig. 2C) or in dynamics of 5, 12 and 26 hours (Fig. S3) after anti-Fas antibody injections with or without pre- treatment with CBLB502 (0.04 mg/kg) 30 minutes before antibodies. Mice that were not treated ("intact") were used as controls. Tissue specimens were fixed in 10% buffered formalin, embedded in paraffin, sectioned and processed with H&E staining.
- Livers were cut to small pieces and homogenized with a tissue grinder (Bullet Blender, NextAdvance) in the buffer (lOmM Hepes, 0.4mM EDTA, 0.2% CHAPS, 2% glycerol), supplemented with 2mM DTT. All steps were performed on ice. Liver homogenates were centrifuged for 20 min at 13,000 xg, and supernatant was stored at -20°C.
- Caspase activities were determined by incubation of liver homogenate (containing 50 ⁇ g of total protein) with 50 ⁇ of the fluorogenic substrate acetyl- Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-aminomethylcoumarin (Ac-DEVD-amc) (ENZO, LifeSciences) in 200 ⁇ cell-free system buffer containing 10 mM HEPES, 0.4mM EDTA, 0.2% CHAPS, 2% glycerol and 2 mM DTT. The release of fluorescent amc was measured after at time 0 and 2 hours of incubation at 37°C by fluorometry (Ex: 355, Em: 485) (Victor3, PerkinElmer). Data are shown as the difference between twp and zero hours ( Figure 8E).
- ALT alanine-aminotransferase
- NIH-Swiss mice (3 per group) were injected s.c. with 1 ⁇ g CBLB502 30 min before anti- Fas antibodies.
- the alanine aminotransferase (ALT) presence in mouse serum was determined using commercial enzyme assays according to the manufacturer's instructions (Stanbio
- Total protein was isolated from treated and untreated mouse liver using RIPA buffer (Sigma- Aldrich St. Louis, MO) supplemented with protease inhibitor cocktail (Sigma- Aldrich St. Louis, MO).
- the protein extracts were separated by electrophoresis in denaturing 4 to 20% polyacrylamide Novex gels (Invitrogen, Carlsbad, CA) and transferred to nylon polyvinylidene difluoride (PVDF) membranes (Immobilon-P, Millipore Billerica MA).
- PVDF nylon polyvinylidene difluoride
- the following antibodies were used: Caspase-8 antibody (Calbiochem, Darmstadt, Germany), anti-BID (AbCam,
- HRP horseradish peroxidase
- GAPDH was used as a control to monitor the induction of gene expression.
- the primers were designed using LaserGene software (DNASTAR, Inc., Madison, WI) and then UCSC Genome Browser In- Silico PCR website was used to check for locating primers.
- Primers specific for the IER3 gene GenBank Accession No. NM_133662.2
- Bcl2AlB gene GenBank Accession No.
- NM_007534.3 (sense 5 ' -TAGGTGGGCAGCAGCAGTCA-3 ' and antisense 5'- CTCCATTCCGCCGTATCCAT-3'), Bcl2AlD gene (GenBank Accession No. NM_007536.2) (sense 5 ' -TCTAGGTGGGCAGCAGCAGTC-3 ' and antisense 5'-
- CT-26 s.c. growing tumors
- experimental liver metastatic model of CT-26 tumors CT-26 cells were transduced with lentiviral vector carrying luciferase gene under CMV promoter for constitutive expression of luciferase.
- Tumors were induced by s.c. injections of CT-26 tumor cells (2.5x105/ 100 ⁇ ) in both flanks of BALB/c mice. When the tumors reached about 4-5 mm in diameter, the mice were randomly divided into three groups and treatment was initiated.
- mice One group of mice was injected i.p. with anti-Fas antibodies (4 ⁇ g/mouse), another was treated with CBLB502 (1 ⁇ g/mouse) 24 h and 1 h before anti-Fas antibody injection (4 ⁇ g/mouse).
- Control mice ('intact') received PBS injections s.c. and i.p. in replace of CBLB502 and antibodies.
- Statistical difference between tumor volumes was estimated using ANOVA one-way analysis of variances (p ⁇ 0.05).
- liver tumor growth For the development of liver tumor growth, CT-26 tumor cells (2x105 /50 ⁇ ) were injected directly into spleen followed by splenectomy 5 min later. Mice were treated with anti-Fas antibodies and combination of CBLB502 with antibodies the same way as described for s.c. tumors starting on day 5 after tumor cell inoculation.
- Noninvasive bioluminescent imaging of mice anesthetized with isoflurane and injected with D-luciferin (3 mg/ 100 ⁇ , i.p.) was performed using Xenogen IVIS Imaging System 100 series on the days 14, 17, 22 and 28 after tumor cell injection. Mice were sacrificed when tumor growth in liver was determined. Statistical comparison of liver tumor-free curves was done using log-rank (Mantel-Cox) test (p ⁇ 0.05) (Fig. 9G).
- CBLB502 Antitumor activity of CBLB502 in Fischer rats bearing s.c. advanced Ward colorectal carcinoma.
- CBLB-502 was administered by i.p. once a day for 5 days (0.2 mg/kg x 5 doses) initiated 5 days after tumor transplantation into 4 rats.
- Control 4 rats received PBS injection as a vehicle control. Tumor weight was measured daily. Complete response (tumor complete disappearance) was observed in 3 rats treated with CBLB502 ( Figure 19). The fourth rat in this group had tumor growth similar to rats in the control group.
- A549- shTLR5 vs. A549-shV The effect of CBLB502 injections on A549 tumors differing in TLR5 expression (A549- shTLR5 vs. A549-shV).
- A549 cells expressing Firefly luciferase gene under the control of NF-kB promoter (Cellecta, Mountain View, CA) were transduced with lentiviral pLKOl-puro vector expressing shRNA specific to human TLR5 gene [CCG-GCC-TTG-CCT-ACA-ACA-AGA-TAA-ACT-CGA-GTT-TAT-CTT-GTT-GTA-GGC- AAG-GTT-TTT-G] or control empty vector (shV, Sigma- Aldrich, St.
- A549-shV and A549-shTLR5 cells were tested for NF-kB activation in response to CBLB502 treatment using luciferase reporter assay according to manufacture protocol (Promega, Cat#E4530, Madison, WI). Then A549-shV and A549-shTLR5 cells (1x106 /100 ⁇ of PBS) were injected s.c. into 2 flanks of 20 athymic nude mice to induce tumors. Mice bearing s.c.
- H1299-control vs. H1299-TLR5 The effect of CBLB502 injections on H1299 tumors differing in TLR5 expression.
- H1299 cells originally TLR5 negative
- lentriviral construct expressing human TLR5 gene.
- the functional activity of TLR5 was checked by IL-8 production in response to CBLB502 treatment.
- both tumor cell types lxlO 6 /100 ⁇ of PBS
- mice bearing were treated with either CBLB502 or PBS acting as control.
- Table 2 shows the spectrum of genes transcriptionally activated by CBLB502 in target organs of mice (bladder results are shown). Genes that are strongly upregulated in bladders of mice treated with CBLB502, 1 and 3 hrs post- injection, are clustered according to their function. The largest group consists of chemokines, cytokines and their receptors indicative of activation of innate immunity mobilizing mechanisms.
- CT-26 tumor cells which do not express TLR5
- Tumor bearing mice were treated with CBLB502 (0.04 mg/kg, s.c.) given twice 24 hour apart. The volumes of s.c. growing tumors in treated mice were compared with tumors growing in the intact mice. Pre-treatment with CBLB502 did not have any effect on tumor growth.
- CT26 tumor growth was tested in the experimental model of liver metastases induced by intrasplenic injection of luciferase expressing CT-26 tumor cells ( Figures 23B and C) and A20 lymphoma cells ( Figure 23D) followed by splenectomy.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biomedical Technology (AREA)
- Communicable Diseases (AREA)
- Toxicology (AREA)
- Dermatology (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Virology (AREA)
- Zoology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (20)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/979,104 US9376473B2 (en) | 2011-01-10 | 2012-01-10 | Use of Toll-Like Receptor agonist for treating cancer |
BR112013017283A BR112013017283A2 (en) | 2011-01-10 | 2012-01-10 | use of toll-like receptor agonist for cancer treatment |
CA2824438A CA2824438A1 (en) | 2011-01-10 | 2012-01-10 | Use of toll-like receptor agonist for treating cancer |
AU2012205681A AU2012205681B2 (en) | 2011-01-10 | 2012-01-10 | Use of toll-like receptor agonist for treating cancer |
NZ612615A NZ612615B2 (en) | 2011-01-10 | 2012-01-10 | Use of toll-like receptor agonist for treating cancer |
EA201390843A EA026524B1 (en) | 2011-01-10 | 2012-01-10 | USE OF Toll-LIKE RECEPTOR AGONIST FOR TREATING CANCER |
KR1020137021035A KR20140030132A (en) | 2011-01-10 | 2012-01-10 | Use of toll-like receptor agonist for treating cancer |
MX2013007967A MX361355B (en) | 2011-01-10 | 2012-01-10 | Use of toll-like receptor agonist for treating cancer. |
SG2013051396A SG191830A1 (en) | 2011-01-10 | 2012-01-10 | Use of toll-like receptor agonist for treating cancer |
CN201280009451.0A CN103476458B (en) | 2011-01-10 | 2012-01-10 | Use of toll-like receptor agonist for treating cancer |
EP12734417.4A EP2663367A4 (en) | 2011-01-10 | 2012-01-10 | Use of toll-like receptor agonist for treating cancer |
JP2013548628A JP6041444B2 (en) | 2011-01-10 | 2012-01-10 | Use of Toll-like receptor agonists to treat cancer |
ARP120102493A AR087114A1 (en) | 2012-01-10 | 2012-07-10 | USE OF THE TOLL TYPE RECEIVER AGONIST FOR CANCER TREATMENT, TREATMENT METHOD |
IL227308A IL227308A (en) | 2011-01-10 | 2013-07-03 | Use of a toll-like receptor agonist for preparation of a medicament for treating cancer |
US14/949,441 US20160206690A1 (en) | 2011-01-10 | 2015-11-23 | Use of toll-like receptor agonist for treating cancer |
US15/241,757 US20170065692A1 (en) | 2011-01-10 | 2016-08-19 | Use of toll-like receptor agonist for treating cancer |
US15/631,427 US10034926B2 (en) | 2011-01-10 | 2017-06-23 | Use of toll-like receptor agonist for treating cancer |
US16/014,419 US10265390B2 (en) | 2011-01-10 | 2018-06-21 | Use of toll-like receptor agonist for treating cancer |
US16/279,457 US10780152B2 (en) | 2011-01-10 | 2019-02-19 | Use of toll-like receptor agonist for treating cancer |
US16/934,556 US11628201B2 (en) | 2011-01-10 | 2020-07-21 | Use of toll-like receptor agonist for treating cancer |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161431313P | 2011-01-10 | 2011-01-10 | |
US61/431,313 | 2011-01-10 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/979,104 A-371-Of-International US9376473B2 (en) | 2011-01-10 | 2012-01-10 | Use of Toll-Like Receptor agonist for treating cancer |
US14/949,441 Continuation US20160206690A1 (en) | 2011-01-10 | 2015-11-23 | Use of toll-like receptor agonist for treating cancer |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2012097012A1 true WO2012097012A1 (en) | 2012-07-19 |
Family
ID=46507417
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2012/020844 WO2012097012A1 (en) | 2011-01-10 | 2012-01-10 | Use of toll-like receptor agonist for treating cancer |
Country Status (15)
Country | Link |
---|---|
US (7) | US9376473B2 (en) |
EP (1) | EP2663367A4 (en) |
JP (1) | JP6041444B2 (en) |
KR (1) | KR20140030132A (en) |
CN (1) | CN103476458B (en) |
AU (1) | AU2012205681B2 (en) |
BR (1) | BR112013017283A2 (en) |
CA (1) | CA2824438A1 (en) |
CL (1) | CL2013002001A1 (en) |
CO (1) | CO6781506A2 (en) |
EA (1) | EA026524B1 (en) |
IL (1) | IL227308A (en) |
MX (2) | MX361355B (en) |
SG (1) | SG191830A1 (en) |
WO (1) | WO2012097012A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014098649A1 (en) * | 2012-12-18 | 2014-06-26 | Obschestvo S Ogranichennoy Otvetstvennostyu "Panacela Labs" | Compositions and methods using toll-like receptor 5 and toll-like receptor agonist |
WO2018160090A1 (en) | 2017-02-28 | 2018-09-07 | Александр Васильевич ИВАЩЕНКО | Antiviral composition and method for using same |
US10717767B2 (en) | 2017-07-20 | 2020-07-21 | Spogen Biotech, Inc. | Bioactive polypeptides for improvements in plant protection, growth and productivity |
US11419931B2 (en) | 2018-03-19 | 2022-08-23 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
Families Citing this family (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080058282A1 (en) | 2005-08-30 | 2008-03-06 | Fallon Joan M | Use of lactulose in the treatment of autism |
US8658163B2 (en) | 2008-03-13 | 2014-02-25 | Curemark Llc | Compositions and use thereof for treating symptoms of preeclampsia |
US8084025B2 (en) | 2008-04-18 | 2011-12-27 | Curemark Llc | Method for the treatment of the symptoms of drug and alcohol addiction |
US10776453B2 (en) | 2008-08-04 | 2020-09-15 | Galenagen, Llc | Systems and methods employing remote data gathering and monitoring for diagnosing, staging, and treatment of Parkinsons disease, movement and neurological disorders, and chronic pain |
KR20170005192A (en) | 2009-01-06 | 2017-01-11 | 큐어론 엘엘씨 | Compositions and methods for the treatment or prevention of staphylococcus aureus infections and for the eradication or reduction of staphylococcus aureus on surfaces |
WO2010080835A1 (en) | 2009-01-06 | 2010-07-15 | Curemark Llc | Compositions and methods for the treatment or the prevention oral infections by e. coli |
US9056050B2 (en) | 2009-04-13 | 2015-06-16 | Curemark Llc | Enzyme delivery systems and methods of preparation and use |
WO2011050135A1 (en) | 2009-10-21 | 2011-04-28 | Curemark Llc | Methods and compositions for the prevention and treatment of influenza |
AU2012205681B2 (en) * | 2011-01-10 | 2016-07-28 | Cleveland Biolabs, Inc. | Use of toll-like receptor agonist for treating cancer |
BR112013027034A8 (en) | 2011-04-21 | 2018-01-02 | Curemark Llc | "compounds for the treatment of neuropsychiatric disorders." |
GB201112091D0 (en) | 2011-07-14 | 2011-08-31 | Gt Biolog Ltd | Bacterial strains isolated from pigs |
GB201117313D0 (en) | 2011-10-07 | 2011-11-16 | Gt Biolog Ltd | Bacterium for use in medicine |
US10350278B2 (en) | 2012-05-30 | 2019-07-16 | Curemark, Llc | Methods of treating Celiac disease |
GB201306536D0 (en) | 2013-04-10 | 2013-05-22 | Gt Biolog Ltd | Polypeptide and immune modulation |
CN104258375A (en) * | 2014-09-18 | 2015-01-07 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Novel application of radiation-resistant peptide proteins |
HUE037476T2 (en) | 2014-12-23 | 2018-08-28 | 4D Pharma Res Ltd | Pirin polypeptide and immune modulation |
LT3065748T (en) | 2014-12-23 | 2018-03-12 | 4D Pharma Research Limited | A bacteroides thetaiotaomicron strain and its use in reducing inflammation |
EP3636272A1 (en) | 2015-06-15 | 2020-04-15 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
LT3650033T (en) | 2015-06-15 | 2022-04-11 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
MA41010B1 (en) | 2015-06-15 | 2020-01-31 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
RS59308B1 (en) | 2015-06-15 | 2019-10-31 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
MA41060B1 (en) | 2015-06-15 | 2019-11-29 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
GB2561748B (en) | 2015-11-20 | 2019-05-08 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
GB201520497D0 (en) | 2015-11-20 | 2016-01-06 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
GB201520638D0 (en) | 2015-11-23 | 2016-01-06 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
GB201520631D0 (en) | 2015-11-23 | 2016-01-06 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
TW201733601A (en) | 2016-03-04 | 2017-10-01 | 4D製藥有限公司 | Compositions comprising bacterial strains |
GB201612191D0 (en) | 2016-07-13 | 2016-08-24 | 4D Pharma Plc | Compositions comprising bacterial strains |
TWI802545B (en) | 2016-07-13 | 2023-05-21 | 英商4D製藥有限公司 | Compositions comprising bacterial strains |
AU2017370942A1 (en) | 2016-12-07 | 2019-06-13 | Progenity Inc. | Gastrointestinal tract detection methods, devices and systems |
GB201621123D0 (en) | 2016-12-12 | 2017-01-25 | 4D Pharma Plc | Compositions comprising bacterial strains |
US11426566B2 (en) | 2016-12-14 | 2022-08-30 | Biora Therapeutics, Inc. | Treatment of a disease of the gastrointestinal tract with a TLR modulator |
MA48940A (en) | 2017-05-22 | 2020-04-08 | 4D Pharma Res Ltd | COMPOSITIONS CONTAINING BACTERIAL STRAINS |
EP3630942B1 (en) | 2017-05-24 | 2022-11-30 | 4D Pharma Research Limited | Compositions comprising bacterial strain |
DK3804737T3 (en) | 2017-06-14 | 2022-07-25 | 4D Pharma Res Ltd | COMPOSITIONS COMPRISING BACTERIAL STRAINS |
MD3638271T2 (en) | 2017-06-14 | 2021-03-31 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
CN108404113A (en) * | 2018-05-16 | 2018-08-17 | 中国人民解放军军事科学院军事医学研究院 | The anti-peptide medicine composite of oral spoke for Antiradiation injury |
CN108478782B (en) * | 2018-05-16 | 2021-05-18 | 中国人民解放军军事科学院军事医学研究院 | Application of radio-resistant peptide in promoting liver cell regeneration |
CN111109198B (en) * | 2019-03-29 | 2021-08-20 | 成都华西海圻医药科技有限公司 | Method for constructing uveitis animal model |
CN114502573A (en) * | 2019-08-30 | 2022-05-13 | 基因组保护股份有限公司 | Method for improving efficacy of vaccines |
WO2021174024A1 (en) | 2020-02-28 | 2021-09-02 | First Wave Bio, Inc. | Methods of treating iatrogenic autoimmune colitis |
JP2023504907A (en) * | 2020-06-04 | 2023-02-07 | ザ カトリック ユニバーシティ オブ コリア インダストリー-アカデミック コーオペレイション ファウンデーション | Anticancer composition containing a flagellin-derived TLR5 agonist as an active ingredient |
JP2023532717A (en) | 2020-07-02 | 2023-07-31 | ヴィーブ ヘルスケア カンパニー | Methods of achieving HIV viral remission with long-acting antiretroviral agents |
US11541009B2 (en) | 2020-09-10 | 2023-01-03 | Curemark, Llc | Methods of prophylaxis of coronavirus infection and treatment of coronaviruses |
KR102543157B1 (en) * | 2020-11-16 | 2023-06-14 | 아주대학교산학협력단 | Toll-like receptor 1/2 and/or 4 Activating Peptides and Uses Thereof |
CN114592007B (en) * | 2022-04-29 | 2023-10-27 | 昆明理工大学 | New application of FAR1 gene |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4554101A (en) | 1981-01-09 | 1985-11-19 | New York Blood Center, Inc. | Identification and preparation of epitopes on antigens and allergens on the basis of hydrophilicity |
US20070269406A1 (en) * | 2005-12-14 | 2007-11-22 | Ichim Thomas E | Transcatheter tumor immunoembolization |
US20090081157A1 (en) * | 2006-01-09 | 2009-03-26 | Richard Syd Kornbluth | Immunostimulatory Combinations for Vaccine Adjuvants |
US20090123467A1 (en) * | 2007-07-31 | 2009-05-14 | The Johns Hopkins University | Polypeptide-Nucleic Acid Conjugate for Immunoprophylaxis or Immunotherapy for Neoplastic or Infectious Disorders |
US20090175880A1 (en) * | 2007-11-07 | 2009-07-09 | Celldex Therapeutics Inc. | Antibodies that bind human dendritic and epithelial cell 205 (dec-205) |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3007812A (en) | 1957-02-11 | 1961-11-07 | Allied Chem | Water-repellent compositions, method of water-proofing porous surfaces therewith, and resulting water-repellent surfaces |
US5399494A (en) | 1983-03-04 | 1995-03-21 | The University Of Maryland System | Vibrio cholerae strain CVD103Hgr, method of making same, and vaccines derived therefrom |
US6130082A (en) | 1988-05-05 | 2000-10-10 | American Cyanamid Company | Recombinant flagellin vaccines |
ES2088014T3 (en) | 1990-09-28 | 1996-08-01 | Sulzer Innotec Ag | HOLLOW NEEDLE FOR MEDICAL USE AND PROCEDURE FOR THE MANUFACTURE OF THIS TYPE OF HOLLOW NEEDLES. |
JP3368902B2 (en) | 1992-03-02 | 2003-01-20 | カイロン エセ.ピー.アー. | Helicobacter pylori proteins useful for vaccines and diagnostics |
US5693476A (en) | 1995-02-24 | 1997-12-02 | The Board Of Trustees Of The Leland Stanford Junior University | Methods of screening for compounds capable of modulating vesicular release |
US20020009747A1 (en) | 1997-08-25 | 2002-01-24 | Freda Diane Miller | Methods and reagents for identifying modulators of neuronal apoptosis |
US5994409A (en) | 1997-12-09 | 1999-11-30 | U.S. Bioscience, Inc. | Methods for treatment of neuro--and nephro--disorders and therapeutic toxicities using aminothiol compounds |
AU4709401A (en) | 1999-11-29 | 2001-06-12 | Inotek Corporation | Composition and method for treating a microbial infection |
IL150885A0 (en) | 2000-01-31 | 2003-02-12 | Munin Corp | Cyr61 compositions and methods |
US7300749B2 (en) | 2000-02-17 | 2007-11-27 | Millennium Pharmaceuticals, Inc. | Molecules of the pyrin domain protein family and uses thereof |
AU2002216500A1 (en) | 2000-11-28 | 2002-06-11 | Genesis Research And Development Corporation Limited | Methods for modulating apoptotic cell death |
US8703146B2 (en) | 2001-04-20 | 2014-04-22 | Institute For Systems Biology | Toll-like receptor 5 ligands and methods of use |
ATE463505T1 (en) | 2001-04-20 | 2010-04-15 | Inst Systems Biology | TOLL-LIKE RECEPTOR 5 LIGANDS AND METHODS OF USE |
WO2003028659A2 (en) | 2001-10-02 | 2003-04-10 | University Of Chicago | Methods and compositions for modulating apoptosis |
US7078165B2 (en) | 2003-03-27 | 2006-07-18 | Institut Pasteur | Method for modulating Nod1 activity, use of a MTP related molecule for modulating Nod1 activity, and therapeutic applications thereof |
US7638485B2 (en) | 2003-12-02 | 2009-12-29 | Cleveland Biolabs, Inc. | Modulating apoptosis |
EA010291B1 (en) | 2003-12-02 | 2008-08-29 | Кливлэнд Клиник Фаундейшн | Method of protecting mammals against radiation |
US8580321B2 (en) | 2003-12-02 | 2013-11-12 | The Cleveland Clinic Foundation | Method for reducing the effects of chemotherapy using flagellin related polypeptides |
WO2005056054A2 (en) | 2003-12-02 | 2005-06-23 | Cleveland Clinic Foundation | METHODS OF INHIBITING APOPTOSIS USING INDUCERS OF NF-κB |
WO2005056041A2 (en) | 2003-12-02 | 2005-06-23 | Cleveland Clinic Foundation | METHODS OF INHIBITING APOPTOSIS USING LATENT TGFβ |
US20050266391A1 (en) | 2004-01-15 | 2005-12-01 | Bennett Brydon L | Methods for preserving tissue |
WO2006039701A1 (en) * | 2004-10-01 | 2006-04-13 | University Of South Florida | Flagellin-based adjuvants and vaccines |
EP1824510B1 (en) | 2004-12-16 | 2012-10-31 | Wake Forest University Health Sciences | Use of flagellin in the immunotherapy of yersinia pestis |
WO2006069198A1 (en) | 2004-12-22 | 2006-06-29 | Cleveland Clinic Foundation | Flagellin related polypeptides and uses thereof |
WO2007030581A2 (en) | 2005-09-09 | 2007-03-15 | Oregon Health & Science University | Neuroprotectants |
WO2008094275A1 (en) | 2007-01-30 | 2008-08-07 | New York University | Peptides for treatment of conditions associated with nitric oxide |
AU2008265911B2 (en) * | 2007-06-15 | 2013-05-16 | Immurx, Inc. | Use of TLR agonists and/or type 1 interferons to alleviate toxicity of TNF-R agonist therapeutic regimens |
US8324163B2 (en) | 2008-08-01 | 2012-12-04 | Cleveland Biolabs, Inc. | Methods for treating reperfusion injuries using flagellin |
MX2011012337A (en) | 2009-05-21 | 2011-12-08 | Dainippon Sumitomo Pharma Co | Novel pyrimidine derivatives and their use in the treatment of cancer and further diseases. |
ES2443952T3 (en) | 2009-09-02 | 2014-02-21 | Novartis Ag | Immunogenic compositions that include modulators of TLR activity |
CA2777198C (en) | 2009-10-06 | 2018-07-24 | Panacela Labs, Inc. | Use of toll-like receptor and agonist for treating cancer |
AU2012205681B2 (en) * | 2011-01-10 | 2016-07-28 | Cleveland Biolabs, Inc. | Use of toll-like receptor agonist for treating cancer |
-
2012
- 2012-01-10 AU AU2012205681A patent/AU2012205681B2/en not_active Ceased
- 2012-01-10 SG SG2013051396A patent/SG191830A1/en unknown
- 2012-01-10 BR BR112013017283A patent/BR112013017283A2/en active Search and Examination
- 2012-01-10 CN CN201280009451.0A patent/CN103476458B/en not_active Expired - Fee Related
- 2012-01-10 WO PCT/US2012/020844 patent/WO2012097012A1/en active Application Filing
- 2012-01-10 CA CA2824438A patent/CA2824438A1/en not_active Abandoned
- 2012-01-10 EP EP12734417.4A patent/EP2663367A4/en not_active Withdrawn
- 2012-01-10 EA EA201390843A patent/EA026524B1/en not_active IP Right Cessation
- 2012-01-10 KR KR1020137021035A patent/KR20140030132A/en not_active Application Discontinuation
- 2012-01-10 MX MX2013007967A patent/MX361355B/en active IP Right Grant
- 2012-01-10 JP JP2013548628A patent/JP6041444B2/en not_active Expired - Fee Related
- 2012-01-10 US US13/979,104 patent/US9376473B2/en active Active
-
2013
- 2013-07-03 IL IL227308A patent/IL227308A/en active IP Right Grant
- 2013-07-08 CL CL2013002001A patent/CL2013002001A1/en unknown
- 2013-07-08 MX MX2018014998A patent/MX2018014998A/en unknown
- 2013-07-29 CO CO13178553A patent/CO6781506A2/en not_active Application Discontinuation
-
2015
- 2015-11-23 US US14/949,441 patent/US20160206690A1/en not_active Abandoned
-
2016
- 2016-08-19 US US15/241,757 patent/US20170065692A1/en not_active Abandoned
-
2017
- 2017-06-23 US US15/631,427 patent/US10034926B2/en active Active
-
2018
- 2018-06-21 US US16/014,419 patent/US10265390B2/en active Active
-
2019
- 2019-02-19 US US16/279,457 patent/US10780152B2/en active Active
-
2020
- 2020-07-21 US US16/934,556 patent/US11628201B2/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4554101A (en) | 1981-01-09 | 1985-11-19 | New York Blood Center, Inc. | Identification and preparation of epitopes on antigens and allergens on the basis of hydrophilicity |
US20070269406A1 (en) * | 2005-12-14 | 2007-11-22 | Ichim Thomas E | Transcatheter tumor immunoembolization |
US20090081157A1 (en) * | 2006-01-09 | 2009-03-26 | Richard Syd Kornbluth | Immunostimulatory Combinations for Vaccine Adjuvants |
US20090123467A1 (en) * | 2007-07-31 | 2009-05-14 | The Johns Hopkins University | Polypeptide-Nucleic Acid Conjugate for Immunoprophylaxis or Immunotherapy for Neoplastic or Infectious Disorders |
US20090175880A1 (en) * | 2007-11-07 | 2009-07-09 | Celldex Therapeutics Inc. | Antibodies that bind human dendritic and epithelial cell 205 (dec-205) |
Non-Patent Citations (8)
Title |
---|
BURDELYA ET AL., SCIENCE, vol. 320, 2008, pages 226 - 230 |
KATAOKA ET AL., REFS, 2000 |
KYTE ET AL., J. MOL. BIOL., vol. 157, 1982, pages 105 - 132 |
OFFRINGA R.: "Tumour immunology - Exploitation of the weapon of immune destruction for cancer therapy: taking aim before firing", CURRENT OPINION IN IMMUNOLOGY, vol. 17, 2005, pages 159 - 162, XP027787173 * |
OGASAWARA J ET AL., NATURE, 1993 |
RHEE ET AL., GASTROENTEROLOGY, vol. 135, 2008, pages 518 - 528 |
See also references of EP2663367A4 |
SMITH ET AL., NAT IMMUNOL, vol. 4, 2003, pages 1247 - 53 |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014098649A1 (en) * | 2012-12-18 | 2014-06-26 | Obschestvo S Ogranichennoy Otvetstvennostyu "Panacela Labs" | Compositions and methods using toll-like receptor 5 and toll-like receptor agonist |
WO2018160090A1 (en) | 2017-02-28 | 2018-09-07 | Александр Васильевич ИВАЩЕНКО | Antiviral composition and method for using same |
US10717767B2 (en) | 2017-07-20 | 2020-07-21 | Spogen Biotech, Inc. | Bioactive polypeptides for improvements in plant protection, growth and productivity |
US11046735B2 (en) | 2017-07-20 | 2021-06-29 | Spogen Biotech Inc. | Bioactive polypeptides for improvements in plant protection, growth and productivity |
US11419931B2 (en) | 2018-03-19 | 2022-08-23 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
EP4046644A1 (en) | 2018-03-19 | 2022-08-24 | 4D Pharma Research Limited | Compositions of entrecoccus flagellin for use in therapy |
US11857614B2 (en) | 2018-03-19 | 2024-01-02 | Cj Bioscience, Inc. | Enterococcus gallinarum flagellin polypeptides |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10265390B2 (en) | Use of toll-like receptor agonist for treating cancer | |
AU2010303464B2 (en) | Use of toll-like receptor and agonist for treating cancer | |
US8211864B2 (en) | Compositions and methods for the intracellular disruption of VEGF and VEGFR-2 by intraceptors | |
KR20220015375A (en) | Treatment of cancer using SPS4P fusion protein | |
Maio et al. | Structure, distribution, and functional role of protectin (CD59) in complement-susceptibility and in immunotherapy of human malignancies | |
RU2682762C2 (en) | Improved vector expressing toll-like receptor and agonist, and use in cancer therapy | |
WO2018088933A1 (en) | Anti-tumor effects of a viral vector encoding a toll-like receptor and a toll-like receptor agonist | |
WO2012122943A1 (en) | Anti-hepatitis b virus x protein polypeptide drug | |
WO2012122942A1 (en) | Polypeptide drug against hepatitis b virus x protein | |
NZ612615B2 (en) | Use of toll-like receptor agonist for treating cancer | |
WO2024064288A1 (en) | Tlr4 inhibitors for cancer treatment | |
WO2012052995A2 (en) | Treatment and prevention of hepatocellular carcinoma with chemokine receptor modulators |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12734417 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2013548628 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12013501422 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 201390843 Country of ref document: EA |
|
ENP | Entry into the national phase |
Ref document number: 2824438 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2013002001 Country of ref document: CL Ref document number: MX/A/2013/007967 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 001538-2013 Country of ref document: PE |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2012205681 Country of ref document: AU Date of ref document: 20120110 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13178553 Country of ref document: CO |
|
ENP | Entry into the national phase |
Ref document number: 20137021035 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: A201309873 Country of ref document: UA Ref document number: 2012734417 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112013017283 Country of ref document: BR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13979104 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref document number: 112013017283 Country of ref document: BR Kind code of ref document: A2 Effective date: 20130704 |