JP2013533222A - 新規抗cMET抗体 - Google Patents
新規抗cMET抗体 Download PDFInfo
- Publication number
- JP2013533222A JP2013533222A JP2013512928A JP2013512928A JP2013533222A JP 2013533222 A JP2013533222 A JP 2013533222A JP 2013512928 A JP2013512928 A JP 2013512928A JP 2013512928 A JP2013512928 A JP 2013512928A JP 2013533222 A JP2013533222 A JP 2013533222A
- Authority
- JP
- Japan
- Prior art keywords
- seq
- antibody
- amino acid
- met
- sequence
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 86
- 201000011510 cancer Diseases 0.000 claims abstract description 42
- 230000004913 activation Effects 0.000 claims abstract description 35
- 238000011282 treatment Methods 0.000 claims abstract description 33
- 238000006471 dimerization reaction Methods 0.000 claims abstract description 32
- 239000003446 ligand Substances 0.000 claims abstract description 31
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 239000000203 mixture Substances 0.000 claims abstract description 30
- 230000002018 overexpression Effects 0.000 claims abstract description 24
- 230000002265 prevention Effects 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 15
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 13
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 195
- 239000012634 fragment Substances 0.000 claims description 132
- 108090000623 proteins and genes Proteins 0.000 claims description 48
- 230000035755 proliferation Effects 0.000 claims description 18
- 230000012010 growth Effects 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 8
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 230000000694 effects Effects 0.000 abstract description 137
- 238000000034 method Methods 0.000 abstract description 67
- 239000005557 antagonist Substances 0.000 abstract description 32
- 150000007523 nucleic acids Chemical group 0.000 abstract description 26
- 150000001413 amino acids Chemical class 0.000 abstract description 25
- 230000001225 therapeutic effect Effects 0.000 abstract description 10
- 239000003053 toxin Substances 0.000 abstract description 10
- 231100000765 toxin Toxicity 0.000 abstract description 10
- 108700012359 toxins Proteins 0.000 abstract description 10
- 230000001419 dependent effect Effects 0.000 abstract description 9
- 201000010099 disease Diseases 0.000 abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
- 230000001976 improved effect Effects 0.000 abstract description 7
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 238000003745 diagnosis Methods 0.000 abstract description 4
- 206010027476 Metastases Diseases 0.000 abstract description 3
- 230000009401 metastasis Effects 0.000 abstract description 3
- 230000000069 prophylactic effect Effects 0.000 abstract description 3
- 206010061309 Neoplasm progression Diseases 0.000 abstract description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 abstract description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 abstract description 2
- 239000003102 growth factor Substances 0.000 abstract description 2
- 230000005751 tumor progression Effects 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 199
- 102000003745 Hepatocyte Growth Factor Human genes 0.000 description 80
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 80
- 241001529936 Murinae Species 0.000 description 58
- 239000000556 agonist Substances 0.000 description 48
- 102000005962 receptors Human genes 0.000 description 41
- 108020003175 receptors Proteins 0.000 description 41
- 238000006366 phosphorylation reaction Methods 0.000 description 40
- 230000026731 phosphorylation Effects 0.000 description 39
- 238000000225 bioluminescence resonance energy transfer Methods 0.000 description 34
- 238000001727 in vivo Methods 0.000 description 33
- 241000699666 Mus <mouse, genus> Species 0.000 description 28
- 235000001014 amino acid Nutrition 0.000 description 26
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 25
- 238000002474 experimental method Methods 0.000 description 25
- 102000004169 proteins and genes Human genes 0.000 description 25
- 238000000338 in vitro Methods 0.000 description 23
- 238000012360 testing method Methods 0.000 description 23
- 241000699670 Mus sp. Species 0.000 description 22
- 230000005764 inhibitory process Effects 0.000 description 21
- 239000002773 nucleotide Substances 0.000 description 21
- 125000003729 nucleotide group Chemical group 0.000 description 21
- 108020004414 DNA Proteins 0.000 description 20
- 108020004707 nucleic acids Proteins 0.000 description 20
- 102000039446 nucleic acids Human genes 0.000 description 20
- 230000006870 function Effects 0.000 description 19
- 230000014509 gene expression Effects 0.000 description 19
- 235000018102 proteins Nutrition 0.000 description 19
- 238000002965 ELISA Methods 0.000 description 16
- 108060003951 Immunoglobulin Proteins 0.000 description 16
- 102000018358 immunoglobulin Human genes 0.000 description 16
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 15
- 239000002953 phosphate buffered saline Substances 0.000 description 15
- 239000013598 vector Substances 0.000 description 15
- -1 estramustine Nitrogen mustard Chemical class 0.000 description 14
- 108090000765 processed proteins & peptides Proteins 0.000 description 14
- 238000001262 western blot Methods 0.000 description 14
- 210000004602 germ cell Anatomy 0.000 description 13
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 12
- 210000004408 hybridoma Anatomy 0.000 description 12
- 230000000638 stimulation Effects 0.000 description 12
- 239000000427 antigen Substances 0.000 description 10
- 239000002254 cytotoxic agent Substances 0.000 description 10
- 231100000673 dose–response relationship Toxicity 0.000 description 10
- 239000012636 effector Substances 0.000 description 10
- 238000011156 evaluation Methods 0.000 description 10
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 9
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 9
- 108091028043 Nucleic acid sequence Proteins 0.000 description 9
- 108091007433 antigens Proteins 0.000 description 9
- 102000036639 antigens Human genes 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 229960003330 pentetic acid Drugs 0.000 description 9
- 229920001223 polyethylene glycol Polymers 0.000 description 9
- 102000004196 processed proteins & peptides Human genes 0.000 description 9
- 230000002285 radioactive effect Effects 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 8
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 8
- 229930182816 L-glutamine Natural products 0.000 description 8
- 239000012980 RPMI-1640 medium Substances 0.000 description 8
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- 239000011651 chromium Substances 0.000 description 8
- 231100000599 cytotoxic agent Toxicity 0.000 description 8
- 239000005090 green fluorescent protein Substances 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 229920001184 polypeptide Polymers 0.000 description 8
- 239000012679 serum free medium Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000002054 transplantation Methods 0.000 description 8
- 230000004544 DNA amplification Effects 0.000 description 7
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 7
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 7
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 7
- 239000012472 biological sample Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 229940127089 cytotoxic agent Drugs 0.000 description 7
- 238000009396 hybridization Methods 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- 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 6
- 102000003992 Peroxidases Human genes 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000013592 cell lysate Substances 0.000 description 6
- 230000004663 cell proliferation Effects 0.000 description 6
- 238000012217 deletion Methods 0.000 description 6
- 230000037430 deletion Effects 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000004031 partial agonist Substances 0.000 description 6
- 108040007629 peroxidase activity proteins Proteins 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 5
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 5
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- 230000004071 biological effect Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 230000003828 downregulation Effects 0.000 description 5
- 238000002060 fluorescence correlation spectroscopy Methods 0.000 description 5
- 238000003364 immunohistochemistry Methods 0.000 description 5
- 239000000411 inducer Substances 0.000 description 5
- 239000013642 negative control Substances 0.000 description 5
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 5
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 5
- 230000006798 recombination Effects 0.000 description 5
- 230000011664 signaling Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- YHIPILPTUVMWQT-UHFFFAOYSA-N Oplophorus luciferin Chemical compound C1=CC(O)=CC=C1CC(C(N1C=C(N2)C=3C=CC(O)=CC=3)=O)=NC1=C2CC1=CC=CC=C1 YHIPILPTUVMWQT-UHFFFAOYSA-N 0.000 description 4
- 230000001270 agonistic effect Effects 0.000 description 4
- 230000003042 antagnostic effect Effects 0.000 description 4
- 239000000051 antiandrogen Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 238000010367 cloning Methods 0.000 description 4
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 235000018417 cysteine Nutrition 0.000 description 4
- 231100000433 cytotoxic Toxicity 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000000328 estrogen antagonist Substances 0.000 description 4
- 102000037865 fusion proteins Human genes 0.000 description 4
- 108020001507 fusion proteins Proteins 0.000 description 4
- 238000010353 genetic engineering Methods 0.000 description 4
- 238000005567 liquid scintillation counting Methods 0.000 description 4
- 239000012139 lysis buffer Substances 0.000 description 4
- 230000011278 mitosis Effects 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 108091033319 polynucleotide Chemical group 0.000 description 4
- 102000040430 polynucleotide Human genes 0.000 description 4
- 239000002157 polynucleotide Chemical group 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 4
- 230000009452 underexpressoin Effects 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 108091005957 yellow fluorescent proteins Proteins 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 241000283707 Capra Species 0.000 description 3
- 102000014914 Carrier Proteins Human genes 0.000 description 3
- 108010077544 Chromatin Proteins 0.000 description 3
- 102000003915 DNA Topoisomerases Human genes 0.000 description 3
- 108090000323 DNA Topoisomerases Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 3
- 238000012452 Xenomouse strains Methods 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 239000004037 angiogenesis inhibitor Substances 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940046836 anti-estrogen Drugs 0.000 description 3
- 230000001833 anti-estrogenic effect Effects 0.000 description 3
- 230000000340 anti-metabolite Effects 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 229940100197 antimetabolite Drugs 0.000 description 3
- 239000002256 antimetabolite Substances 0.000 description 3
- 108091008324 binding proteins Proteins 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 238000004422 calculation algorithm Methods 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000001516 cell proliferation assay Methods 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 210000003483 chromatin Anatomy 0.000 description 3
- 230000000295 complement effect Effects 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 230000009089 cytolysis Effects 0.000 description 3
- 239000000824 cytostatic agent Substances 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 229960002584 gefitinib Drugs 0.000 description 3
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 3
- 208000005017 glioblastoma Diseases 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 239000002955 immunomodulating agent Substances 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 210000000822 natural killer cell Anatomy 0.000 description 3
- 208000026886 papillary lung adenocarcinoma Diseases 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 238000010647 peptide synthesis reaction Methods 0.000 description 3
- 238000003566 phosphorylation assay Methods 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 229940121649 protein inhibitor Drugs 0.000 description 3
- 239000012268 protein inhibitor Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229910052702 rhenium Inorganic materials 0.000 description 3
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 235000020183 skimmed milk Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 125000006850 spacer group Chemical group 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 229910052714 tellurium Inorganic materials 0.000 description 3
- PORWMNRCUJJQNO-UHFFFAOYSA-N tellurium atom Chemical compound [Te] PORWMNRCUJJQNO-UHFFFAOYSA-N 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 230000004565 tumor cell growth Effects 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical compound [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 description 2
- BHNQPLPANNDEGL-UHFFFAOYSA-N 2-(4-octylphenoxy)ethanol Chemical compound CCCCCCCCC1=CC=C(OCCO)C=C1 BHNQPLPANNDEGL-UHFFFAOYSA-N 0.000 description 2
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- XHNXJRVXHHTIKS-UHFFFAOYSA-N 6-hydrazinylpyridine-3-carboxamide Chemical compound NNC1=CC=C(C(N)=O)C=N1 XHNXJRVXHHTIKS-UHFFFAOYSA-N 0.000 description 2
- 108010032595 Antibody Binding Sites Proteins 0.000 description 2
- 101100447914 Caenorhabditis elegans gab-1 gene Proteins 0.000 description 2
- 102000003952 Caspase 3 Human genes 0.000 description 2
- 108090000397 Caspase 3 Proteins 0.000 description 2
- 108091035707 Consensus sequence Proteins 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 230000006820 DNA synthesis Effects 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 108010087819 Fc receptors Proteins 0.000 description 2
- 102000009109 Fc receptors Human genes 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 101000961156 Homo sapiens Immunoglobulin heavy constant gamma 1 Proteins 0.000 description 2
- 101000961146 Homo sapiens Immunoglobulin heavy constant gamma 2 Proteins 0.000 description 2
- 101000604674 Homo sapiens Immunoglobulin kappa variable 4-1 Proteins 0.000 description 2
- 102100039345 Immunoglobulin heavy constant gamma 1 Human genes 0.000 description 2
- 102100039346 Immunoglobulin heavy constant gamma 2 Human genes 0.000 description 2
- 102100038198 Immunoglobulin kappa variable 4-1 Human genes 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 101100179471 Mus musculus Ighg1 gene Proteins 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 239000000020 Nitrocellulose Substances 0.000 description 2
- 108091034117 Oligonucleotide Chemical group 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 241000276498 Pollachius virens Species 0.000 description 2
- 229920002873 Polyethylenimine Polymers 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 108010052090 Renilla Luciferases Proteins 0.000 description 2
- 108091008874 T cell receptors Proteins 0.000 description 2
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 2
- 229910052775 Thulium Inorganic materials 0.000 description 2
- 108700019146 Transgenes Proteins 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 2
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 2
- PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000008484 agonism Effects 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- 230000002280 anti-androgenic effect Effects 0.000 description 2
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 2
- 229960000961 floxuridine Drugs 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 238000002292 fluorescence lifetime imaging microscopy Methods 0.000 description 2
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 229910052733 gallium Inorganic materials 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 2
- 230000008105 immune reaction Effects 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 229940127121 immunoconjugate Drugs 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- HWYHZTIRURJOHG-UHFFFAOYSA-N luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 230000010311 mammalian development Effects 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 238000003032 molecular docking Methods 0.000 description 2
- LWGJTAZLEJHCPA-UHFFFAOYSA-N n-(2-chloroethyl)-n-nitrosomorpholine-4-carboxamide Chemical compound ClCCN(N=O)C(=O)N1CCOCC1 LWGJTAZLEJHCPA-UHFFFAOYSA-N 0.000 description 2
- 229920001220 nitrocellulos Polymers 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 238000006384 oligomerization reaction Methods 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 229960002340 pentostatin Drugs 0.000 description 2
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 229920001484 poly(alkylene) Polymers 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000003531 protein hydrolysate Substances 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 102200082402 rs751610198 Human genes 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- FRNOGLGSGLTDKL-UHFFFAOYSA-N thulium atom Chemical compound [Tm] FRNOGLGSGLTDKL-UHFFFAOYSA-N 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- 238000011830 transgenic mouse model Methods 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 238000003146 transient transfection Methods 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- 238000012800 visualization Methods 0.000 description 2
- PCHJSUWPFVWCPO-NJFSPNSNSA-N (199au)gold Chemical compound [199Au] PCHJSUWPFVWCPO-NJFSPNSNSA-N 0.000 description 1
- FLCQLSRLQIPNLM-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-acetylsulfanylacetate Chemical compound CC(=O)SCC(=O)ON1C(=O)CCC1=O FLCQLSRLQIPNLM-UHFFFAOYSA-N 0.000 description 1
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 description 1
- JIRRPAZFOGASCY-ZTNVNUCQSA-N (2r,3s,5s)-5-(6-aminopurin-9-yl)-5-chloro-2-(hydroxymethyl)oxolan-3-ol Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@]1(Cl)C[C@H](O)[C@@H](CO)O1 JIRRPAZFOGASCY-ZTNVNUCQSA-N 0.000 description 1
- GTXSRFUZSLTDFX-HRCADAONSA-N (2s)-n-[(2s)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-4-methyl-2-[[(2s)-2-sulfanyl-4-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)butanoyl]amino]pentanamide Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](S)CCN1C(=O)N(C)C(C)(C)C1=O GTXSRFUZSLTDFX-HRCADAONSA-N 0.000 description 1
- PSWFFKRAVBDQEG-XXTQFKTOSA-N (3s)-3-[[(2s)-6-amino-2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]hexanoyl]amino]-4-[[1-[[(1s)-1-carboxy-2-(4-hydroxyphenyl)ethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)NC(C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PSWFFKRAVBDQEG-XXTQFKTOSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
- 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 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- CJIJXIFQYOPWTF-UHFFFAOYSA-N 7-hydroxycoumarin Natural products O1C(=O)C=CC2=CC(O)=CC=C21 CJIJXIFQYOPWTF-UHFFFAOYSA-N 0.000 description 1
- OXEUETBFKVCRNP-UHFFFAOYSA-N 9-ethyl-3-carbazolamine Chemical compound NC1=CC=C2N(CC)C3=CC=CC=C3C2=C1 OXEUETBFKVCRNP-UHFFFAOYSA-N 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 102000008102 Ankyrins Human genes 0.000 description 1
- 108010049777 Ankyrins Proteins 0.000 description 1
- 108010083359 Antigen Receptors Proteins 0.000 description 1
- 102000006306 Antigen Receptors Human genes 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 102000016904 Armadillo Domain Proteins Human genes 0.000 description 1
- 108010014223 Armadillo Domain Proteins Proteins 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- 238000000035 BCA protein assay Methods 0.000 description 1
- WOVKYSAHUYNSMH-UHFFFAOYSA-N BROMODEOXYURIDINE Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-UHFFFAOYSA-N 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-OIOBTWANSA-N Bromine-77 Chemical compound [77Br] WKBOTKDWSSQWDR-OIOBTWANSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108090000209 Carbonic anhydrases Proteins 0.000 description 1
- 102000003846 Carbonic anhydrases Human genes 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- 102100037579 D-3-phosphoglycerate dehydrogenase Human genes 0.000 description 1
- 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 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 241000289632 Dasypodidae Species 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
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- SHIBSTMRCDJXLN-UHFFFAOYSA-N Digoxigenin Natural products C1CC(C2C(C3(C)CCC(O)CC3CC2)CC2O)(O)C2(C)C1C1=CC(=O)OC1 SHIBSTMRCDJXLN-UHFFFAOYSA-N 0.000 description 1
- BVTJGGGYKAMDBN-UHFFFAOYSA-N Dioxetane Chemical compound C1COO1 BVTJGGGYKAMDBN-UHFFFAOYSA-N 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 102400001047 Endostatin Human genes 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- 241000305071 Enterobacterales Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 102000002090 Fibronectin type III Human genes 0.000 description 1
- 108050009401 Fibronectin type III Proteins 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 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
- 241000287828 Gallus gallus Species 0.000 description 1
- 108010010803 Gelatin 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
- 108010015776 Glucose oxidase Proteins 0.000 description 1
- 239000004366 Glucose oxidase Substances 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 101000998950 Homo sapiens Immunoglobulin heavy variable 1-18 Proteins 0.000 description 1
- 101000998953 Homo sapiens Immunoglobulin heavy variable 1-2 Proteins 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- JJKOTMDDZAJTGQ-DQSJHHFOSA-N Idoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN2CCCC2)=CC=1)/C1=CC=C(I)C=C1 JJKOTMDDZAJTGQ-DQSJHHFOSA-N 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 102100036884 Immunoglobulin heavy variable 1-18 Human genes 0.000 description 1
- 102100036887 Immunoglobulin heavy variable 1-2 Human genes 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 108010030506 Integrin alpha6beta4 Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- ZCYVEMRRCGMTRW-AHCXROLUSA-N Iodine-123 Chemical compound [123I] ZCYVEMRRCGMTRW-AHCXROLUSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- 102000019298 Lipocalin Human genes 0.000 description 1
- 108050006654 Lipocalin Proteins 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 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
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 108010026217 Malate Dehydrogenase Proteins 0.000 description 1
- 241000237852 Mollusca Species 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 101710204212 Neocarzinostatin Proteins 0.000 description 1
- 102000006538 Nitric Oxide Synthase Type I Human genes 0.000 description 1
- 108010008858 Nitric Oxide Synthase Type I Proteins 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920001744 Polyaldehyde Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108091036414 Polyinosinic:polycytidylic acid Proteins 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108700033844 Pseudomonas aeruginosa toxA Proteins 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- 102000014400 SH2 domains Human genes 0.000 description 1
- 108050003452 SH2 domains Proteins 0.000 description 1
- 101150001535 SRC gene Proteins 0.000 description 1
- 101150099493 STAT3 gene Proteins 0.000 description 1
- 229920002305 Schizophyllan Polymers 0.000 description 1
- 241000239226 Scorpiones Species 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- UIRKNQLZZXALBI-MSVGPLKSSA-N Squalamine Chemical compound C([C@@H]1C[C@H]2O)[C@@H](NCCCNCCCCN)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CC[C@H](C(C)C)OS(O)(=O)=O)[C@@]2(C)CC1 UIRKNQLZZXALBI-MSVGPLKSSA-N 0.000 description 1
- UIRKNQLZZXALBI-UHFFFAOYSA-N Squalamine Natural products OC1CC2CC(NCCCNCCCCN)CCC2(C)C2C1C1CCC(C(C)CCC(C(C)C)OS(O)(=O)=O)C1(C)CC2 UIRKNQLZZXALBI-UHFFFAOYSA-N 0.000 description 1
- 108010088160 Staphylococcal Protein A Proteins 0.000 description 1
- 102000002933 Thioredoxin Human genes 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- VWQVUPCCIRVNHF-OUBTZVSYSA-N Yttrium-90 Chemical compound [90Y] VWQVUPCCIRVNHF-OUBTZVSYSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 229960005310 aldesleukin Drugs 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 238000003016 alphascreen Methods 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 230000001548 androgenic effect Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000001130 anti-lysozyme effect Effects 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 229910052787 antimony Inorganic materials 0.000 description 1
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical compound [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- XFILPEOLDIKJHX-QYZOEREBSA-N batimastat Chemical compound C([C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)[C@H](CSC=1SC=CC=1)C(=O)NO)C1=CC=CC=C1 XFILPEOLDIKJHX-QYZOEREBSA-N 0.000 description 1
- 229950001858 batimastat Drugs 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 102000005936 beta-Galactosidase Human genes 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229950004398 broxuridine Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 190000008236 carboplatin Chemical compound 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- ZXFCRFYULUUSDW-OWXODZSWSA-N chembl2104970 Chemical compound C([C@H]1C2)C3=CC=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2CC(O)=C(C(=O)N)C1=O ZXFCRFYULUUSDW-OWXODZSWSA-N 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229950009003 cilengitide Drugs 0.000 description 1
- AMLYAMJWYAIXIA-VWNVYAMZSA-N cilengitide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C(C)C)N(C)C(=O)[C@H]1CC1=CC=CC=C1 AMLYAMJWYAIXIA-VWNVYAMZSA-N 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 238000000749 co-immunoprecipitation Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- RYGMFSIKBFXOCR-AKLPVKDBSA-N copper-67 Chemical compound [67Cu] RYGMFSIKBFXOCR-AKLPVKDBSA-N 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000012866 crystallographic experiment Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960003843 cyproterone Drugs 0.000 description 1
- DUSHUSLJJMDGTE-ZJPMUUANSA-N cyproterone Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DUSHUSLJJMDGTE-ZJPMUUANSA-N 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 150000001945 cysteines Chemical class 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 125000001295 dansyl group Chemical group [H]C1=C([H])C(N(C([H])([H])[H])C([H])([H])[H])=C2C([H])=C([H])C([H])=C(C2=C1[H])S(*)(=O)=O 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960002086 dextran Drugs 0.000 description 1
- 229940041984 dextran 1 Drugs 0.000 description 1
- 229960000633 dextran sulfate Drugs 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- QONQRTHLHBTMGP-UHFFFAOYSA-N digitoxigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C1=CC(=O)OC1 QONQRTHLHBTMGP-UHFFFAOYSA-N 0.000 description 1
- SHIBSTMRCDJXLN-KCZCNTNESA-N digoxigenin Chemical compound C1([C@@H]2[C@@]3([C@@](CC2)(O)[C@H]2[C@@H]([C@@]4(C)CC[C@H](O)C[C@H]4CC2)C[C@H]3O)C)=CC(=O)OC1 SHIBSTMRCDJXLN-KCZCNTNESA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 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 compound 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
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229940011871 estrogen Drugs 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
- 229960005420 etoposide Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 238000002270 exclusion chromatography Methods 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 238000000475 fluorescence cross-correlation spectroscopy Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 238000011990 functional testing Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940116332 glucose oxidase Drugs 0.000 description 1
- 235000019420 glucose oxidase Nutrition 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- LVASCWIMLIKXLA-LSDHHAIUSA-N halofuginone Chemical compound O[C@@H]1CCCN[C@H]1CC(=O)CN1C(=O)C2=CC(Cl)=C(Br)C=C2N=C1 LVASCWIMLIKXLA-LSDHHAIUSA-N 0.000 description 1
- 229950010152 halofuginone Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000002998 immunogenetic effect Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 description 1
- 229950008097 improsulfan Drugs 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- APFVFJFRJDLVQX-AHCXROLUSA-N indium-111 Chemical compound [111In] APFVFJFRJDLVQX-AHCXROLUSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000012482 interaction analysis Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940117681 interleukin-12 Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- XMBWDFGMSWQBCA-BJUDXGSMSA-N iodane Chemical compound [126IH] XMBWDFGMSWQBCA-BJUDXGSMSA-N 0.000 description 1
- XMBWDFGMSWQBCA-LZFNBGRKSA-N iodane Chemical compound [133IH] XMBWDFGMSWQBCA-LZFNBGRKSA-N 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 210000004901 leucine-rich repeat Anatomy 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 238000000504 luminescence detection Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 229950008959 marimastat Drugs 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- QSHDDOUJBYECFT-NJFSPNSNSA-N mercury-203 Chemical compound [203Hg] QSHDDOUJBYECFT-NJFSPNSNSA-N 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 231100000782 microtubule inhibitor Toxicity 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 230000000921 morphogenic effect Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- VIJMMQUAJQEELS-UHFFFAOYSA-N n,n-bis(ethenyl)ethenamine Chemical compound C=CN(C=C)C=C VIJMMQUAJQEELS-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- BSIZUMJRKYHEBR-QGZVFWFLSA-N n-hydroxy-2(r)-[[(4-methoxyphenyl)sulfonyl](3-picolyl)amino]-3-methylbutanamide hydrochloride Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N([C@H](C(C)C)C(=O)NO)CC1=CC=CN=C1 BSIZUMJRKYHEBR-QGZVFWFLSA-N 0.000 description 1
- AEMBWNDIEFEPTH-UHFFFAOYSA-N n-tert-butyl-n-ethylnitrous amide Chemical compound CCN(N=O)C(C)(C)C AEMBWNDIEFEPTH-UHFFFAOYSA-N 0.000 description 1
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- KDLHZDBZIXYQEI-VENIDDJXSA-N palladium-100 Chemical compound [100Pd] KDLHZDBZIXYQEI-VENIDDJXSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 230000003076 paracrine Effects 0.000 description 1
- 229960001218 pegademase Drugs 0.000 description 1
- 108010027841 pegademase bovine Proteins 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- CTRLRINCMYICJO-UHFFFAOYSA-N phenyl azide Chemical group [N-]=[N+]=NC1=CC=CC=C1 CTRLRINCMYICJO-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 108010025221 plasma protein Z Proteins 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108010067988 prolactin-binding protein Proteins 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 239000012562 protein A resin Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 229940051022 radioimmunoconjugate Drugs 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 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
- 108091092562 ribozyme Proteins 0.000 description 1
- 238000009666 routine test Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- KJTLSVCANCCWHF-NJFSPNSNSA-N ruthenium-103 Chemical compound [103Ru] KJTLSVCANCCWHF-NJFSPNSNSA-N 0.000 description 1
- KJTLSVCANCCWHF-RNFDNDRNSA-N ruthenium-105 Chemical compound [105Ru] KJTLSVCANCCWHF-RNFDNDRNSA-N 0.000 description 1
- KJTLSVCANCCWHF-AHCXROLUSA-N ruthenium-97 Chemical compound [97Ru] KJTLSVCANCCWHF-AHCXROLUSA-N 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- SIXSYDAISGFNSX-NJFSPNSNSA-N scandium-47 Chemical compound [47Sc] SIXSYDAISGFNSX-NJFSPNSNSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 108700022137 serine(71)- interleukin-1 beta Proteins 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 229940048086 sodium pyrophosphate Drugs 0.000 description 1
- PUZPDOWCWNUUKD-ULWFUOSBSA-M sodium;fluorine-18(1-) Chemical compound [18F-].[Na+] PUZPDOWCWNUUKD-ULWFUOSBSA-M 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 229950001248 squalamine Drugs 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 238000000547 structure data Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000011806 swiss nude mouse Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 108060008226 thioredoxin Proteins 0.000 description 1
- 229940094937 thioredoxin Drugs 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- FRNOGLGSGLTDKL-YPZZEJLDSA-N thulium-167 Chemical compound [167Tm] FRNOGLGSGLTDKL-YPZZEJLDSA-N 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 230000030968 tissue homeostasis Effects 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000003656 tris buffered saline Substances 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical compound C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 description 1
- HFTAFOQKODTIJY-UHFFFAOYSA-N umbelliferone Natural products Cc1cc2C=CC(=O)Oc2cc1OCC=CC(C)(C)O HFTAFOQKODTIJY-UHFFFAOYSA-N 0.000 description 1
- 229950008737 vadimezan Drugs 0.000 description 1
- XGOYIMQSIKSOBS-UHFFFAOYSA-N vadimezan Chemical compound C1=CC=C2C(=O)C3=CC=C(C)C(C)=C3OC2=C1CC(O)=O XGOYIMQSIKSOBS-UHFFFAOYSA-N 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- 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
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/5748—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving oncogenic proteins
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
- G01N33/57492—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds localized on the membrane of tumor or cancer 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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- 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
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/515—Complete light chain, i.e. VL + CL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/53—Hinge
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/72—Increased effector function due to an Fc-modification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/75—Agonist effect on antigen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/91—Transferases (2.)
- G01N2333/912—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
- G01N2333/91205—Phosphotransferases in general
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oncology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cell Biology (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Mycology (AREA)
- Biotechnology (AREA)
- Food Science & Technology (AREA)
- General Physics & Mathematics (AREA)
- Hospice & Palliative Care (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Pathology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
前記抗体は、それぞれ配列番号1、2および3のアミノ酸配列を有するCDR−H1、CDR−H2およびCDR−H3を含む重鎖と、それぞれ配列番号5、6および7のアミノ酸配列を有するCDR−L1、CDR−L2およびCDR−L3を含む軽鎖とを含んでなり、前記抗体が配列番号56のアミノ酸配列を含むヒンジ領域をさらに含んでなり、
c−Metのリガンド非依存性活性化を特徴とする癌、好ましくはc−Metの過剰発現をさらに特徴とする癌であって、前記c−Metの過剰発現がより好ましくはc−Met遺伝子増幅に起因し、かつ、さらにより好ましくはc−Metリガンド非依存性活性化を生じる癌を有する予防または治療を必要とする患者の予防または治療を目的とする使用のための、モノクローナル抗体またはその二価の機能性断片もしくは誘導体に関する。
配列番号1:GYIFTAYT
配列番号2:IKPNNGLA
配列番号3:ARSEITTEFDY。
CDR−H1は配列番号1のアミノ酸配列を含んでなり、
CDR−H2は配列番号2のアミノ酸配列を含んでなり、
CDR−H3は配列番号3のアミノ酸配列を含んでなる。
配列番号5:ESVDSYANSF
配列番号6:RAS
配列番号7:QQSKEDPLT。
CDR−L1は配列番号5のアミノ酸配列を含んでなり、
CDR−L2は配列番号6のアミノ酸配列を含んでなり、
CDR−L3は配列番号7のアミノ酸配列を含んでなる。
配列番号46:EVQLQQSGPELVKPGASVKISCKTSGYIFTAYTMHWVRQSLGESLDWIGGIKPNNGLANYNQKFKGKATLTVDKSSSTAYMDLRSLTSEDSAVYYCARSEITTEFDYWGQGTALTVSS。
配列番号47:DIVLTQSPASLAVSLGQRATISCRASESVDSYANSFMHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSKEDPLTFGSGTKLEMKR。
配列番号4:QVQLVQSGAEVKKPGASVKVSCKASGYIFTAYTMHWVRQAPGQGLEWMGWIKPNNGLANYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARSEITTEFDYWGQGTLVTVSS。
配列番号8:DIVLTQSPDSLAVSLGERATINCKSSESVDSYANSFMHWYQQKPGQPPKLLIYRASTRESGVPDRFSGSGSRTDFTLTISSLQAEDVAVYYCQQSKEDPLTFGGGTKVEIKR、
配列番号9:DIVMTQSPDSLAVSLGERATINCKSSESVDSYANSFMHWYQQKPGQPPKLLIYRASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKEDPLTFGGGTKVEIKR、
配列番号10:DIVMTQSPDSLAVSLGERATINCKSSESVDSYANSFLHWYQQKPGQPPKLLIYRASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKEDPLTFGGGTKVEIKR。
本発明によれば、本発明の抗体断片は、ペプシンまたはパパインのような酵素による消化および/または化学的還元によるジスルフィド橋の開裂による消化のような方法によって上記のような抗体から出発して得ることができる。もう一つの方法では、本発明に含まれる抗体断片は、同様に当業者に周知の遺伝子組換えの手法によって、または例えばApplied Biosystems社などによって供給されるような自動ペプチド合成装置によるペプチド合成によって得ることができる。
系統発生的保存が良好なこと
周知の三次元分子構成を有する強固な構造(例えば、結晶学またはNMR)
サイズが小さいこと
転写後修飾がないかまたはごく僅かであること
産生、発現および精製が容易なこと。
a) 本発明による抗体、またはその機能性断片もしくは誘導体の1つをコードする核酸、DNAまたはRNA、
b) 配列番号11、配列番号12、配列番号13の配列と、配列番号15、配列番号16および配列番号17の配列とを含んでなる核酸、
c) 配列番号14と、配列番号18、19または20の配列とを含んでなる核酸配列、
d) b)またはc)で定義された核酸の対応するRNA核酸、
e) a)、b)およびc)で定義された核酸の相補性核酸、および
f) 配列番号11〜13および15〜17の配列のCDRの少なくとも1つと高ストリンジェンシー条件下でハイブリダイズすることができる少なくとも18個のヌクレオチドの核酸
から選択されることを特徴とする単離核酸に関する。
本発明による抗体、またはその機能性断片もしくは誘導体の1つをコードする核酸、DNAまたはRNAであって、前記抗体のヒンジ領域をコードする核酸配列が、配列番号29〜35および配列番号73〜87の配列からなる群から選択される配列を含んでなりまたは有するもの
から選択されることを特徴とする単離核酸に関する。
この趣意で、本発明によるヌクレオチド配列は、選択された宿主の自律性の複製ベクターに挿入することができ、または選択された宿主の組込みベクターであることができる。
a) 培地および適当な培養条件での本発明による宿主細胞の培養、および
b) 培地または前記培養細胞から出発して産生した前記抗体、またはそれらの機能性断片の1つの回収
を含んでなることを特徴とする方法である。
a) 生物試料と本発明による抗体、またはその機能性断片もしくは誘導体との接触、および
b) ことによると形成されるc−Met/抗体複合体の証明
を含んでなることを特徴とする、方法に用いることができる。
a) 本発明による抗体、またはその機能性断片もしくは誘導体、
b) 必要に応じて、免疫反応に好都合な媒質の形成のための試薬、
c) 必要に応じて、免疫反応によって産生したc−Met/抗体複合体を証明することができる試薬
を含んでなることを特徴とする。
抗c−Met抗体を生成させるために、8週齢のBALB/cを、CHOの細胞膜上にc−Metを発現するトランスフェクションしたCHO細胞系(20x106個/用量/マウス)で3〜5回皮下免疫し、または最初の免疫には完全Freundアジュバントと、また引き続く免疫には不完全Freundアジュバントと、混合したc−Met細胞外ドメイン融合タンパク質(10〜15μg/用量/マウス)(R&D Systems,Catalog #358MT)またはこの組換えタンパク質の断片を2〜3回皮下に免疫した。マウスにCHO−cMet細胞と組換えタンパク質との両方を投与した混合プロトコールも行った。細胞融合の3日前に、マウスに組換えタンパク質または断片をi.p.またはi.v.で追加免疫した。次いで、マウスの脾臓を回収してSP2/0−Ag14骨髄腫細胞(ATCC)に融合させ、HAT選択を行った。4回の融合を行った。一般に、モノクローナル抗体またはそれらの機能性断片、特にネズミ起源のものの調製には、マニュアル「抗体」(Harlow and Lane,抗体:実験室マニュアル(Antibodies: A Laboratory Manual), Cold Spring Harbor Laboratory, Cold Spring Harbor NY, pp. 726, 1988)に詳細に記載されている手法、またはKohler and Milstein(Nature, 256:495-497, 1975)によって報告されているハイブリドーマの調製手法を参照することができる。
1°)軽鎖可変ドメイン(VL)のヒト化
予備段階として、224G11VLのヌクレオチド配列をIMGTデーターベース(http://imgt.cines.fr)に含まれるネズミの生殖細胞系遺伝子配列と比較した。それぞれ、V領域について99.31%およびJ領域について94.28%の配列同一性を示すネズミIGKV3−5*01およびIGKJ4*01生殖細胞系遺伝子を同定した。これらの高い相同性に関して、対応するマウス生殖細胞系の代わりに224G11VLヌクレオチド配列を用いて、直接ヒト相同性を調査した。
予備段階として、224G11VHのヌクレオチド配列を、IMGTデーターベース(http://imgt.cines.fr)に含まれるネズミの生殖細胞系遺伝子配列と比較した。
ヒンジ領域は、免疫グロブリンの可変ドメインの柔軟性に強力に関与していることは、当業者に周知である(Brekke et al., 1995; Roux et al., 1997を参照)。224G11Mabのキメラ化工程中に、マウス定常ドメインIGHG1をヒト起源の同等なIGHG1部分で置換した。ヒンジ領域のアミノ酸配列は高度に分岐していたので、ヒンジ領域の「ネズミ化(murinization)」を行ってその長さと剛性を保持した。ヒトIGHG2ヒンジ領域は、マウスIGHG1ヒンジの最も近い相同物に対応しているので、この配列も同様に考慮した。マウスIGHG1およびヒトIGHG2ヒンジの部分をヒトIGHG1ヒンジ部分に組込むことによって、一連の7種類のヒンジ配列を構築した(配列番号22〜28)。
キメラ、ヒト化および/または遺伝子工学処理したヒンジ領域を含むすべての上記Mab形態を、一過性トランスフェクションおよびpCEP4発現ベクターを有するHEK293/EBNA系を用いることによって産生した(InVitrogen,米国)。
この機能アッセイにより、MabのみによるまたはHGFの共存におけるc−Metリン酸化状態の変化を観察することができる。
最初のセットの実験では、無関連のマウスIgG1、ヒトIgG1およびヒトIgG2は、いずれのBRETモデルでもHGF誘発BRETシグナルの効果を持たなかった(12回の独立した実験からの典型的実験;図6)。これらのMabを、直ちにコントロールとして引用する。
直接ELISAを開始し、組換えc−Met上での様々なキメラおよびヒト化形態の結合能を決定した。簡単に説明すれば、R&D Systems製の組換え二量体性c−Metを、96穴のImmunlon IIプレート上に1.25μg/mlでコーティングした。4℃で一晩インキュベーションした後、ウェルを0.5%ゼラチン/PBS溶液で飽和した。次いで、プレートを37℃で1時間インキュベーションした後、試験を行う抗体の2倍希釈液を加えた。プレートを更に1時間インキュベーションした後、ネズミの抗体を検出するためのヤギ抗マウスIgGHRPと、キメラおよびヒト化抗体認識のためのヤギ抗ヒトκ軽鎖HRPを加えた。プレートを1時間インキュベーションし、ペルオキシダーゼ基質TMBUptimaを加え、5分後に1MH2SO4で中和した。図11に示した結果は、すべての試験形態はc−Met認識について類似していることを示していた。
ATCCのNCI−H441細胞を、RPMI1640培地(Invitrogen Corporation, Scotland,英国)、10%FCS(Invitrogen Corporation)、1%L−グルタミン(Invitrogen corporation)中で常法により培養した。増殖アッセイのため、細胞を使用の3日前に継代し、プレートに播種する前に増殖のコンフルエント期になるようにした。NCI−H441細胞を、96穴組織培養プレートで200μlの無血清培地(RPMI1640培地+1%L−グルタミン)中で3.75x104細胞/ウェルの密度で播種した。24時間の培養後、試験を行う抗体をNCI−H441に加え、37℃で30分間インキュベーションした後、HGFを400ng/ml(5nM)の最終濃度で更に142時間加えた。それぞれの抗体について試験した用量は、10〜0.0097μg/ml(それぞれのウェルでの最終濃度)の範囲である。この実験において、ネズミIgG1Mabをネズミアイソタイプコントロールとして加え、試験した抗体は下記のものであった:m224G11およびそのヒトIgG1キメラ形態であって、[224G11]chimとして同定されたもの。細胞単独−/+HGFで培養したウェルも包含された。次いで、細胞を、[3H]チミジン(Amersham Biosciences AB, Uppsala,スウェーデン)0.25μCiで7時間および30分間パルス標識した。トリクロロ酢酸不溶性のDNAに取り込まれた[3H]チミジンの大きさを、液体シンチレーションカウンティングによって定量した。結果は、未変換cpmデーターとして表しており、腫瘍細胞に抗c−MetMabを単独で加えたときに起こり得る潜在的な固有アゴニスト活性を一層良好に評価できる。
NCI−H441は、乳頭状肺腺癌に由来し、高レベルc−Metを発現し、c−MetRTKの構成性リン酸化を示す。
ATCCのNCI−H441細胞を、RPMI1640培地(Invitrogen Corporation, Scotland,英国)、10%FCS(Invitrogen Corporation)、1%L−グルタミン(Invitrogen corporation)中で常法により培養した。増殖アッセイのため、細胞を使用の3日前に継代し、プレートに播種する前に増殖のコンフルエント期になるようにした。NCI−H441細胞を、96穴組織培養プレートで200μlの無血清培地(RPMI1640培地+1%L−グルタミン)中で3.75x104細胞/ウェルの密度で播種した。24時間の培養後、試験を行う抗体をNCI−H441に加え、37℃で30分間インキュベーションした後、HGFを400ng/ml(5nM)の最終濃度で更に142時間で加えた。それぞれの抗体について試験した用量は、10〜0.0097μg/ml(それぞれのウェルでの最終濃度)の範囲である。この実験において、ネズミIgG1Mabをネズミアイソタイプコントロールとしておよびアゴニストの負のコントロールとして加えた。試験した抗体は下記のものであった:i)m224G11、ii)それぞれ、[224G11]chim、[224G11][MHchim]、[224G11][MUP9Hchim]、[224G11][MMCHchim]、[224G11][TH7chim]として同定されるそのヒトIgG1キメラ形態、iii)それぞれ、[224G11][Hz1]、[224G11][Hz2]、[224G11][Hz3]と表されるそのヒト化IgG1形態。細胞単独−/+HGFで培養したウェルも包含された。ハイブリドーマ細胞系としてATCCで入手可能なGenetech製の5D5全長(whole)抗体を、完全アゴニストの正のコントロールとして導入し、その後m5D5と命名した。次いで、細胞を、[3H]チミジン(Amersham Biosciences AB, Uppsala,スウェーデン)0.25μCiで7時間および30分間パルス標識した。トリクロロ酢酸不溶性のDNAに取り込まれた[3H]チミジンの大きさを、液体シンチレーションカウンティングによって定量した。結果は、未変換cpmデーターとして表しており、腫瘍細胞に抗c−MetMabを単独で加えたときに起こり得る潜在的な固有アゴニスト活性を一層良好に評価できる。
ATCCのNCI−H441細胞を、RPMI1640培地(Invitrogen Corporation, Scotland,英国)、10%FCS(Invitrogen Corporation)、1%L−グルタミン(Invitrogen corporation)中で常法により培養した。増殖アッセイのため、細胞を使用の3日前に継代し、プレートに播種するに増殖のコンフルエント期になるようにした。NCI−H441細胞を、96穴組織培養プレートで200μlの無血清培地(RPMI1640培地+1%L−グルタミン)中で3.75x104細胞/ウェルの密度で播種した。24時間の培養後、試験を行う抗体をNCI−H441に加え、37℃で30分間インキュベーションした後、HGFを400ng/ml(5nM)の最終濃度で更に142時間で加えた。それぞれの抗体について試験した用量は、10〜0.0097μg/ml(それぞれのウェルでの最終濃度)の範囲である。この実験において、アゴニスト活性についてのネズミIgG1Mabをバックグラウンドの負のコントロールとして加え、試験した抗体は下記のものであった:i)m224G11、ii)それぞれ、[224G11]chim、[224G11][TH7chim]として同定されたそのヒトIgG1キメラ形態、iii)それぞれ、[224G11][TH7Hz1]、[224G11][TH7Hz3]と表されるそのヒト化IgG1形態。細胞単独−/+HGFで培養したウェルも包含された。ハイブリドーマ細胞系としてATCCから入手可能なGenetech製の5D5全長抗体を、完全アゴニストの正のコントロールとして導入し、その後m5D5と命名した。次いで、細胞を、[3H]チミジン(Amersham Biosciences AB, Uppsala,スウェーデン)0.25μCiで7時間および30分間パルス標識した。トリクロロ酢酸不溶性のDNAに取り込まれた[3H]チミジンの大きさを、液体シンチレーションカウンティングによって定量した。結果は、未変換cpmデーターとして表しており、腫瘍細胞に抗c−MetMabを単独で加えたときに起こり得る潜在的な固有アゴニスト活性を一層良好に評価できる。
NCI−H441は、乳頭状肺腺癌由来であり、高レベルのc−Metを発現し、c−MetRTKの構成的リン酸化を明らかにしている。
下記の例では、紛らわしさを回避するため、h224G11という表現は、本発明の抗体のヒト化形態224G11[TH7Hz3]を指す。
c−Met受容体の可溶性シェディング形態は、天然ではヒト腫瘍を異種移植したマウスの血清またはc−Metを発現している腫瘍を有するヒト患者の血清に見られる。更に、DN30Mabのようなc−Metに対する抗体は、インビトロ実験におけるc−Metシェディング誘発因子として記載されている。m224G11がそのような特性を有するかどうかを決定するため、細胞を6穴プレートで、10%FCS培地中に播種した。細胞が80%コンフルエンスに達したときに、培地を除去し、新鮮な完全培地+/−試験を行う化合物を加えた。細胞を、m224G11、アイソタイプコントロールmIgG1またはPBSと共に更に72時間インキュベーションした。PMA(ホルボールミリステートアセテート)を、シェディング誘発因子として導入した。HGFも細胞で試験し、天然に存在するシェディングに対するc−Metリガンドの影響を決定した。次いで、上清を集めて0.2μmフィルターで濾過した後、ELISA試験を用いて、c−Metの可溶性形態をm224G11またはc11E1と同じエピトープを認識しない抗c−Met抗体で捕捉した(図21)。更に、それぞれのウェル由来の細胞をPBSで洗浄し、溶解して、タンパク質濃度を決定した。ELISAのため、224D10をキャプチャー抗体として用い、プレート飽和の後、6穴プレートからの濾過した上清をELISA試験に加えた。モノマー性c−Met形態を、正のコントロールとして用いた。上清をインキュベーションした後、プレートを洗浄して未結合c−Metを除去し、c11E1を用いて224G11Mabによって捕捉されたc−Metを検出した。試験の顕色(revelation)は、HRP接合抗hFcポリクローナル抗体を添加することによって最後に行った。
本発明の上記実験では、5D5などの他の抗体で見られたのとは対照的に、m224G11およびそのヒト化形態h224G11は有意な固有活性腫瘍細胞系を示さないことが明らかになった。この特性を他の細胞系にひろげるため、Hs746T、NCI−H441、Hs578T、NCI−H125、T98G、MDA−MB−231、PC3など様々なレベルのc−Met発現を有する癌細胞系のセットで、ウェスタンブロット分析およびホスホELISA実験を様々な時間に加えた抗体単独で行った。同じ試験は、正常細胞HUVECでも行った。
NCI−H441は、乳頭状肺腺癌由来であり、高レベルのc−Metを発現し、c−MetRTKの構成的リン酸化を示す。
h224G11はIgG1アイソタイプであるので、ADCCはヒトにおけるそのインビボ効果の部分である可能性がある。インビトロでの[51Cr]放出細胞傷害性アッセイは、ターゲット細胞としてHs746TまたはNCI−H441細胞と、ヒト末梢血単核リンパ球から精製したNK細胞を用いて行った。
パラフィン包埋腫瘍IHC染色の手順:冷凍腫瘍の8〜12μM切片を、予め冷却した−20℃のアセトンで直ぐに3分間固定した。次に、スライドを室温で30分間〜1時間冷却した。PBSで2回洗浄した後、内在性ペルオキシダーゼ活性をペルオキシダーゼ遮断試薬(Dako K4007)を用いて5分間遮断した。切片をPBSで洗浄して、アビジン/ビオチン遮断試薬(Dako X0590)中でインキュベーションした直後、非特異的部位をPBS−BSA4%で室温にて30分間飽和した。次いで、スライドを、ビオチン化h224G11(50〜10μg/ml)またはヒトビオチン化IgG1/κ(50〜10μg/ml、結合部位)をネガティブコントロールとして室温にて2時間インキュベーションした。
2種類の胃癌細胞であるHs746T(ATCC)およびMKN45(JCRB)、ならびに肺扁平上皮癌であるEBC−1(JCRB)は、図36A、37Aおよび38AでFACS解析によって示されるように、c−Metを過剰発現する3つの細胞系である。またこれらの細胞系は、c−Metの増幅細胞系として文献に記載されている。後者の点を確認するために、c−Met遺伝子増幅を、ΔΔCt法を用いた定量リアルタイムPCRにより測定した。それぞれ示した細胞系からQIAamp DNA midi kit(Qiagen, Les Ulis, FR)を用いて50ngのゲノムDNAを抽出して用いた。参照遺伝子は、染色体17に位置するDNAトポイソメラーゼIIIアルファであった。c−MET遺伝子に対するプライマーはエクソン14に位置した。両方の遺伝子に対応するプライマーはSmolen et al.(PNAS, 2006, 103: 2316-2321)に記載されており、同様なPCR効率が得られるものである。QPCRプロトコールは、95℃で10分サイクル後、95℃で15秒/95℃で45秒を連続40サイクルからなる。データーは、最初に参照遺伝子で標準化し、その後各細胞系をハプロイドゲノムごとにc−Met遺伝子のシングルコピーを含有するMCG−7細胞で標準化した。図36B、37Bおよび38Bに示される結果は、3つの細胞系が5〜10倍の遺伝子増幅と評価される有意なc−Met増幅を示したことを表している。
この実験は、h224G11が、Hs746T、MKN45およびEBC1の腫瘍増殖を有意に減少することを表しており(図36D、37Dおよび38D)、ヒト化抗体が胃および肺リガンド非依存性細胞系の腫瘍増殖を阻害できることをすることを示す。これらの結果が得られる前は、ヒト化抗体の修飾されたヒンジの存在がどのようにそのc−Metリガンド非依存性化に影響を及ぼすのかは、変更されたヒンジがそのアゴニスト/アンタゴニスト特性にも影響するため、明らかではなかった。
hs746T腫瘍異種移植阻害を生じる反応のより正確な機構を決定するために、3つのh224G11の腹腔内接種の影響を、腫瘍有糸分裂インデックス(Ki67)、アポトーシス(活性化カスパーゼ3)およびc−Met発現について免疫組織化学(IHC)法を用いて評価した。3尾のマウスをそれぞれの状態について分析した。コントロールのものと比較して処理した腫瘍において有意なc−Metのダウンレギュレーションが観察された(それぞれ、図39CおよびD)。図39AおよびBパネルは、アイソタイプコントロールに相当する。さらに、有意なKi67レベルの減少(図39EおよびF)および活性化カスパーゼ3染色の増加(図39EおよびF)が全ての所為した腫瘍においてみられ、これはH224G11が有意に細胞増殖を阻害し、腫瘍内の細胞アポトーシスを誘発できることを示す。
Claims (22)
- c−Met二量体化を阻害することができるモノクローナル抗体またはその二価の機能性断片もしくは誘導体であって、
前記抗体が、それぞれ配列番号1、2および3のアミノ酸配列を有するCDR−H1、CDR−H2およびCDR−H3を含む重鎖と、それぞれ配列番号5、6および7のアミノ酸配列を有するCDR−L1、CDR−L2およびCDR−L3を含む軽鎖とを含んでなり、更に配列番号56のアミノ酸配列を含むヒンジ領域をも含んでなり、
c−Metのリガンド非依存性活性化を特徴とする癌を有する予防または治療を必要とする患者の予防または治療に使用するための、モノクローナル抗体またはその二価の機能性断片もしくは誘導体。 - 前記ヒンジ領域が配列番号57のアミノ酸配列を含んでなる、請求項1に記載の抗体またはその二価の機能性断片もしくは誘導体。
- 前記ヒンジ領域が配列番号21のアミノ酸配列を含んでなる、請求項1に記載の抗体またはその二価の機能性断片もしくは誘導体。
- 前記ヒンジ領域が配列番号22〜28および配列番号58〜72からなる群から選択されるアミノ酸配列を含んでなる、請求項1に記載の抗体またはその二価の機能性断片もしくは誘導体。
- c−Metの過剰発現を特徴とする癌を有する予防または治療を必要とする患者の予防または治療に使用するための、請求項1に記載の抗体またはその二価の機能性断片もしくは誘導体。
- c−Metの遺伝子増殖に起因するc−Metの過剰発現を特徴とする癌を有する予防または治療を必要とする患者の予防または治療に使用するための、請求項1に記載の抗体またはその二価の機能性断片もしくは誘導体。
- c−Metの遺伝子増殖に起因し、かつ、c−Metのリガンド非依存性活性化を生じるc−Metの過剰発現を特徴とする癌を有する予防または治療を必要とする患者の予防または治療に使用するための、請求項6に記載の抗体またはその二価の機能性断片もしくは誘導体。
- 癌が、腎細胞癌および胃癌からなる群から選択される、c−Metの遺伝子増殖に起因するc−Metの過剰発現を特徴とする癌を有する予防または治療を必要とする患者の予防または治療に使用するための、請求項6に記載の抗体またはその二価の機能性断片もしくは誘導体。
- キメラ抗体からなる、請求項1に記載の抗体またはその二価の機能性断片もしくは誘導体。
- ヒト抗体からなる、請求項1に記載の抗体またはその二価の機能性断片もしくは誘導体。
- ヒト化抗体からなる、請求項1に記載の抗体またはその二価の機能性断片もしくは誘導体。
- 配列番号4のアミノ酸配列を含む配列の重鎖可変ドメインと、配列番号8、9または10のアミノ酸配列を含む配列の軽鎖可変ドメインとを含んでなる、請求項11に記載の抗体またはその二価の機能性断片もしくは誘導体。
- 配列番号4のアミノ酸配列を含む配列の重鎖可変ドメインと、配列番号8のアミノ酸配列を含む配列の軽鎖可変ドメインと、配列番号22のアミノ酸配列を含むヒンジ領域とを含んでなる、請求項12に記載の抗体またはその二価の機能性断片もしくは誘導体。
- 配列番号4のアミノ酸配列を含む配列の重鎖可変ドメインと、配列番号9のアミノ酸配列を含む配列の軽鎖可変ドメインと、配列番号22のアミノ酸配列を含むヒンジ領域とを含んでなる、請求項12に記載の抗体またはその二価の機能性断片もしくは誘導体。
- 配列番号4のアミノ酸配列を含む配列の重鎖可変ドメインと、配列番号10のアミノ酸配列を含む配列の軽鎖可変ドメインと、配列番号22のアミノ酸配列を含むヒンジ領域とを含んでなる、請求項12に記載の抗体またはその二価の機能性断片もしくは誘導体。
- 配列番号4のアミノ酸配列を含む配列の重鎖可変ドメインと、配列番号8のアミノ酸配列を含む配列の軽鎖可変ドメインと、配列番号28のアミノ酸配列を含むヒンジ領域とを含んでなる、請求項12に記載の抗体またはその二価の機能性断片もしくは誘導体。
- 配列番号4のアミノ酸配列を含む配列の重鎖可変ドメインと、配列番号9のアミノ酸配列を含む配列の軽鎖可変ドメインと、配列番号28のアミノ酸配列を含むヒンジ領域とを含んでなる、請求項12に記載の抗体またはその二価の機能性断片もしくは誘導体。
- 配列番号4のアミノ酸配列を含む配列の重鎖可変ドメインと、配列番号10のアミノ酸配列を含む配列の軽鎖可変ドメインと、配列番号28のアミノ酸配列を含むヒンジ領域とを含んでなる、請求項12に記載の抗体またはその二価の機能性断片もしくは誘導体。
- 医薬としての、請求項1〜18のいずれか一項に記載の抗体。
- c−Metのリガンド非依存性活性化を特徴とする癌を有する予防または治療を必要とする患者の予防または治療のための組成物であって、
前記組成物は、請求項1〜19のいずれか一項に記載の抗体またはその二価の機能性断片もしくは誘導体からなる化合物を活性成分として含んでなる、組成物。 - 医薬としての、請求項20に記載の組成物。
- c−Metのリガンド非依存性活性化を特徴とする癌を有する予防または治療を必要とする患者の予防または治療のための医薬の調製のための、請求項1〜19のいずれか一項に記載の抗体またはその二価の機能性断片もしくは誘導体、または請求項20または21に記載の組成物の使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/791,681 | 2010-06-01 | ||
US12/791,681 US8545839B2 (en) | 2008-12-02 | 2010-06-01 | Anti-c-Met antibody |
PCT/EP2011/059139 WO2011151412A1 (en) | 2010-06-01 | 2011-06-01 | Novel anti-cmet antibody |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2013533222A true JP2013533222A (ja) | 2013-08-22 |
JP5973998B2 JP5973998B2 (ja) | 2016-08-23 |
Family
ID=44119439
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2013512928A Active JP5973998B2 (ja) | 2010-06-01 | 2011-06-01 | 新規抗cMET抗体 |
Country Status (20)
Country | Link |
---|---|
US (4) | US8545839B2 (ja) |
EP (1) | EP2575879B1 (ja) |
JP (1) | JP5973998B2 (ja) |
KR (1) | KR101838311B1 (ja) |
CN (2) | CN105688209A (ja) |
AU (1) | AU2011260286B2 (ja) |
BR (1) | BR112012030805A2 (ja) |
CA (1) | CA2801264C (ja) |
ES (1) | ES2582038T3 (ja) |
HU (1) | HUE029043T2 (ja) |
IL (1) | IL223366B (ja) |
MA (1) | MA34289B1 (ja) |
MX (1) | MX340101B (ja) |
MY (1) | MY163096A (ja) |
NZ (1) | NZ604056A (ja) |
PL (1) | PL2575879T3 (ja) |
RU (1) | RU2607377C2 (ja) |
TN (1) | TN2012000558A1 (ja) |
UA (1) | UA113388C2 (ja) |
WO (1) | WO2011151412A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013534515A (ja) * | 2010-06-01 | 2013-09-05 | モナシュ ユニバーシティ | プロセシングされていない受容体型チロシンキナーゼc−METに対する抗体 |
Families Citing this family (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR074438A1 (es) * | 2008-12-02 | 2011-01-19 | Pf Medicament | Proceso para la modulacion de la actividad antagonista de un anticuerpo monoclonal |
US9469691B2 (en) | 2008-12-02 | 2016-10-18 | Pierre Fabre Medicament | Anti-cMET antibody |
AR074439A1 (es) | 2008-12-02 | 2011-01-19 | Pf Medicament | Anticuerpo anti-cmet (receptor c-met) |
EP2287197A1 (en) * | 2009-08-21 | 2011-02-23 | Pierre Fabre Medicament | Anti-cMET antibody and its use for the detection and the diagnosis of cancer |
EP2635602B1 (en) | 2010-11-03 | 2016-09-07 | Argen-X Nv | Anti c-met antibodies |
EP2670426B1 (en) | 2011-01-31 | 2017-05-10 | The General Hospital Corporation | Multimodal trail molecules and uses in cellular therapies |
JP6123140B2 (ja) | 2011-09-13 | 2017-05-10 | インテル・コーポレーション | デジタル広告システム |
KR101865223B1 (ko) | 2011-10-05 | 2018-06-08 | 삼성전자주식회사 | 항 c-Met 인간화 항체 및 그의 용도 |
US9926364B2 (en) | 2011-11-03 | 2018-03-27 | Argen-X N.V. | Chimeric human-llama antigens and methods of use |
US20150147274A1 (en) * | 2011-12-02 | 2015-05-28 | Cancer Research Technology Limited | Antibodies against hgf - receptor and uses |
KR101910601B1 (ko) | 2011-12-22 | 2018-10-23 | 삼성전자주식회사 | 면역원성이 제거된 항 c-Met 인간화 항체 및 그의 용도 |
EP2863946A4 (en) * | 2012-06-21 | 2016-04-13 | Sorrento Therapeutics Inc | ANTIGEN-BINDING PROTEINS THAT BIND TO C-MET |
EP2877572B1 (en) | 2012-07-24 | 2018-11-28 | The General Hospital Corporation | Oncolytic virus therapy for resistant tumors |
US9605074B2 (en) * | 2012-08-30 | 2017-03-28 | The General Hospital Corporation | Multifunctional nanobodies for treating cancer |
US9931400B2 (en) | 2012-09-12 | 2018-04-03 | Samsung Electronics Co., Ltd. | Method of combination therapy for prevention or treatment of c-Met or angiogenesis factor induced diseases |
KR101819404B1 (ko) | 2012-10-12 | 2018-02-28 | 메디뮨 리미티드 | 피롤로벤조디아제핀 및 그의 컨주게이트 |
CA3182876A1 (en) | 2012-11-21 | 2014-05-30 | Janssen Biotech, Inc. | Bispecific egfr/c-met antibodies |
US9695228B2 (en) * | 2012-11-21 | 2017-07-04 | Janssen Biotech, Inc. | EGFR and c-Met fibronectin type III domain binding molecules |
JP6444902B2 (ja) | 2013-03-13 | 2018-12-26 | メドイミューン・リミテッドMedImmune Limited | ピロロベンゾジアゼピン及びその結合体 |
KR102049990B1 (ko) * | 2013-03-28 | 2019-12-03 | 삼성전자주식회사 | c-Met 항체 및 VEGF 결합 단편이 연결된 융합 단백질 |
KR102139607B1 (ko) * | 2013-04-01 | 2020-07-30 | 삼성전자주식회사 | 항 c-Met 항체 및 FGFR 저해제를 포함하는 병용 투여용 약학 조성물 |
KR102060540B1 (ko) | 2013-04-03 | 2019-12-31 | 삼성전자주식회사 | 항 c-Met 항체 및 항 Ang2 항체를 포함하는 병용 투여용 약학 조성물 |
WO2015031626A1 (en) * | 2013-08-28 | 2015-03-05 | Abbvie Inc. | Soluble cmet assay |
WO2015057545A2 (en) | 2013-10-14 | 2015-04-23 | Janssen Biotech, Inc. | Cysteine engineered fibronectin type iii domain binding molecules |
US9717715B2 (en) | 2013-11-15 | 2017-08-01 | Samsung Electronics Co., Ltd. | Method of combination therapy using an anti-C-Met antibody |
CN103739672B (zh) * | 2013-12-31 | 2015-06-10 | 威特曼生物科技(南京)有限公司 | 一种聚乙二醇修饰的抑制vegfr2酪氨酸激酶多肽及其应用 |
KR101615619B1 (ko) | 2014-08-07 | 2016-04-26 | 주식회사 파멥신 | c-Met 특이적 인간 항체 및 그 제조방법 |
CN106687141A (zh) | 2014-09-10 | 2017-05-17 | 麦迪穆有限责任公司 | 吡咯并苯并二氮杂卓及其缀合物 |
KR20160068558A (ko) * | 2014-12-05 | 2016-06-15 | 삼성바이오에피스 주식회사 | 마우스 cmv 프로모터를 포함하는 융합 폴리뉴클레오타이드 및 이를 이용한 목적 폴리펩타이드의 생산 방법 |
EP4233909A3 (en) | 2016-05-17 | 2023-09-20 | AbbVie Biotherapeutics Inc. | Anti-cmet antibody drug conjugates and methods for their use |
EP3471750A4 (en) | 2016-06-21 | 2020-02-26 | Janssen Biotech, Inc. | CYSTEINE-MODIFIED TYPE III FIBRONECTIN BINDING MOLECULES |
US20200023072A1 (en) | 2016-10-11 | 2020-01-23 | Medimmune Limited | Antibody-drug conjugates with immune-mediated therapy agents |
TWI782930B (zh) | 2016-11-16 | 2022-11-11 | 美商再生元醫藥公司 | 抗met抗體,結合met之雙特異性抗原結合分子及其使用方法 |
US10597438B2 (en) | 2016-12-14 | 2020-03-24 | Janssen Biotech, Inc. | PD-L1 binding fibronectin type III domains |
WO2018111978A1 (en) | 2016-12-14 | 2018-06-21 | Janssen Biotech, Inc. | Cd137 binding fibronectin type iii domains |
CA3046963A1 (en) | 2016-12-14 | 2018-06-21 | Janssen Biotech, Inc. | Cd8a-binding fibronectin type iii domains |
KR20200042485A (ko) * | 2017-08-09 | 2020-04-23 | 메뤼스 엔.페. | EGFR 및 cMET에 결합하는 항체 |
GB201803892D0 (en) | 2018-03-12 | 2018-04-25 | Ultrahuman Six Ltd | C-met binding agents |
EP3796942A1 (en) | 2018-05-23 | 2021-03-31 | ADC Therapeutics SA | Molecular adjuvant |
JP7482363B2 (ja) * | 2018-08-08 | 2024-05-14 | ドラゴンフライ セラピューティクス, インコーポレイテッド | Nkg2d、cd16及び腫瘍関連抗原に結合するタンパク質 |
AU2020321368A1 (en) * | 2019-07-30 | 2022-03-10 | Mythic Therapeutics, Inc. | Antigen-binding protein constructs and uses thereof |
MX2022002886A (es) | 2019-09-16 | 2022-04-06 | Regeneron Pharma | Proteinas de union met radiomarcadas para la obtencion de imagenes por inmuno-pet. |
US11781138B2 (en) | 2019-10-14 | 2023-10-10 | Aro Biotherapeutics Company | FN3 domain-siRNA conjugates and uses thereof |
WO2021076546A1 (en) | 2019-10-14 | 2021-04-22 | Aro Biotherapeutics Company | Cd71 binding fibronectin type iii domains |
US20230372528A1 (en) | 2020-10-16 | 2023-11-23 | University Of Georgia Research Foundation, Inc. | Glycoconjugates |
WO2022104692A1 (en) * | 2020-11-20 | 2022-05-27 | Bliss Biopharmaceutical (Hangzhou) Co., Ltd. | Engineered antibody, antibody-drug conjugate, and use thereof |
GB202102396D0 (en) | 2021-02-19 | 2021-04-07 | Adc Therapeutics Sa | Molecular adjuvant |
BR112023021325A2 (pt) | 2021-04-14 | 2023-12-19 | Aro Biotherapeutics Company | Domínios de fibronectina tipo iii de ligação a cd71 |
AR125473A1 (es) * | 2021-04-29 | 2023-07-19 | Abbvie Inc | Conjugados de anticuerpo anti-c-met y fármaco |
WO2024153168A2 (en) * | 2023-01-19 | 2024-07-25 | Beigene, Ltd. | Anti-cmet antibodies and methods of use |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080248028A1 (en) * | 2004-03-24 | 2008-10-09 | Xencor, Inc. | Immunoglobulin Variants Outside the Fc Region |
WO2009007427A2 (en) * | 2007-07-12 | 2009-01-15 | Pierre Fabre Medicament | Novel antibodies inhibiting c-met dimerization, and uses thereof |
JP2012510280A (ja) * | 2008-12-02 | 2012-05-10 | ピエール、ファーブル、メディカマン | 新規な抗cMET抗体 |
Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2840250C2 (de) | 1978-09-15 | 1983-01-20 | Siemens AG, 1000 Berlin und 8000 München | Schaltungsanordnung für eine leitungsgespeiste Lautfernsprechstation |
US4424200A (en) | 1979-05-14 | 1984-01-03 | Nuc Med Inc. | Method for radiolabeling proteins with technetium-99m |
US4479930A (en) | 1982-07-26 | 1984-10-30 | Trustees Of The University Of Massachusetts | Amines coupled wth dicyclic dianhydrides capable of being radiolabeled product |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4831175A (en) | 1986-09-05 | 1989-05-16 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Backbone polysubstituted chelates for forming a metal chelate-protein conjugate |
IL162181A (en) | 1988-12-28 | 2006-04-10 | Pdl Biopharma Inc | A method of producing humanized immunoglubulin, and polynucleotides encoding the same |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
GB8924581D0 (en) | 1989-11-01 | 1989-12-20 | Pa Consulting Services | Bleaching of hair |
GB9014932D0 (en) | 1990-07-05 | 1990-08-22 | Celltech Ltd | Recombinant dna product and method |
WO1994004679A1 (en) | 1991-06-14 | 1994-03-03 | Genentech, Inc. | Method for making humanized antibodies |
JPH05244982A (ja) | 1991-12-06 | 1993-09-24 | Sumitomo Chem Co Ltd | 擬人化b−b10 |
US5639641A (en) | 1992-09-09 | 1997-06-17 | Immunogen Inc. | Resurfacing of rodent antibodies |
US5686292A (en) | 1995-06-02 | 1997-11-11 | Genentech, Inc. | Hepatocyte growth factor receptor antagonist antibodies and uses thereof |
US20040208876A1 (en) * | 2003-04-18 | 2004-10-21 | Kim Kyung Jin | Monoclonal antibodies to hepatocyte growth factor |
HN2004000285A (es) | 2003-08-04 | 2006-04-27 | Pfizer Prod Inc | ANTICUERPOS DIRIGIDOS A c-MET |
US20050233960A1 (en) | 2003-12-11 | 2005-10-20 | Genentech, Inc. | Methods and compositions for inhibiting c-met dimerization and activation |
RU2398777C2 (ru) * | 2004-08-05 | 2010-09-10 | Дженентек, Инк. | ГУМАНИЗИРОВАННЫЕ АНТАГОНИСТЫ, НАПРАВЛЕННЫЕ ПРОТИВ c-met |
WO2006043892A1 (en) * | 2004-10-20 | 2006-04-27 | Peas Institut Ab | Assessment of biological activity of hepatocyte growth factor (hgf) |
US8008443B2 (en) | 2005-04-26 | 2011-08-30 | Medimmune, Llc | Modulation of antibody effector function by hinge domain engineering |
EP2388276A3 (en) | 2005-07-18 | 2013-11-27 | Amgen, Inc | Human anti-B7RP1 neutralizing antibodies |
US8652469B2 (en) | 2005-07-28 | 2014-02-18 | Novartis Ag | M-CSF-specific monoclonal antibody and uses thereof |
JP5536445B2 (ja) | 2006-03-30 | 2014-07-02 | ノバルティス アーゲー | c−Metの抗体の組成物およびその使用方法 |
WO2009006520A1 (en) * | 2007-07-03 | 2009-01-08 | Medimmune, Llc | Hinge domain engineering |
EP2143441A1 (en) * | 2008-07-08 | 2010-01-13 | Pierre Fabre Medicament | Combination of a c-Met antagonist and an aminoheteroaryl compound for the treatment of cancer |
WO2010064089A1 (en) | 2008-12-02 | 2010-06-10 | Pierre Fabre Medicament | Novel anti-cmet antibody |
-
2010
- 2010-06-01 US US12/791,681 patent/US8545839B2/en active Active
-
2011
- 2011-01-06 UA UAA201214956A patent/UA113388C2/uk unknown
- 2011-06-01 KR KR1020127031242A patent/KR101838311B1/ko active IP Right Grant
- 2011-06-01 RU RU2012154339A patent/RU2607377C2/ru active
- 2011-06-01 WO PCT/EP2011/059139 patent/WO2011151412A1/en active Application Filing
- 2011-06-01 HU HUE11722828A patent/HUE029043T2/en unknown
- 2011-06-01 AU AU2011260286A patent/AU2011260286B2/en active Active
- 2011-06-01 MX MX2012013989A patent/MX340101B/es active IP Right Grant
- 2011-06-01 NZ NZ604056A patent/NZ604056A/en unknown
- 2011-06-01 CA CA2801264A patent/CA2801264C/en active Active
- 2011-06-01 MY MYPI2012005152A patent/MY163096A/en unknown
- 2011-06-01 CN CN201610125411.2A patent/CN105688209A/zh active Pending
- 2011-06-01 JP JP2013512928A patent/JP5973998B2/ja active Active
- 2011-06-01 ES ES11722828.8T patent/ES2582038T3/es active Active
- 2011-06-01 EP EP11722828.8A patent/EP2575879B1/en active Active
- 2011-06-01 MA MA35420A patent/MA34289B1/fr unknown
- 2011-06-01 BR BR112012030805A patent/BR112012030805A2/pt not_active Application Discontinuation
- 2011-06-01 PL PL11722828.8T patent/PL2575879T3/pl unknown
- 2011-06-01 CN CN201180035181.6A patent/CN103002916B/zh active Active
-
2012
- 2012-11-27 TN TNP2012000558A patent/TN2012000558A1/en unknown
- 2012-11-29 IL IL223366A patent/IL223366B/en active IP Right Grant
-
2013
- 2013-08-29 US US14/013,955 patent/US20140115727A1/en not_active Abandoned
-
2015
- 2015-02-27 US US14/633,553 patent/US20150307613A1/en not_active Abandoned
- 2015-04-02 US US14/677,032 patent/US20160039935A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080248028A1 (en) * | 2004-03-24 | 2008-10-09 | Xencor, Inc. | Immunoglobulin Variants Outside the Fc Region |
WO2009007427A2 (en) * | 2007-07-12 | 2009-01-15 | Pierre Fabre Medicament | Novel antibodies inhibiting c-met dimerization, and uses thereof |
JP2012510280A (ja) * | 2008-12-02 | 2012-05-10 | ピエール、ファーブル、メディカマン | 新規な抗cMET抗体 |
Non-Patent Citations (1)
Title |
---|
MOLECULAR IMMUNOLOGY, vol. 31, no. 15, JPN5013007095, 1994, pages 1201 - 1210, ISSN: 0003106373 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013534515A (ja) * | 2010-06-01 | 2013-09-05 | モナシュ ユニバーシティ | プロセシングされていない受容体型チロシンキナーゼc−METに対する抗体 |
Also Published As
Publication number | Publication date |
---|---|
US20140115727A1 (en) | 2014-04-24 |
US20150307613A1 (en) | 2015-10-29 |
PL2575879T3 (pl) | 2016-10-31 |
RU2607377C2 (ru) | 2017-01-10 |
CA2801264C (en) | 2018-08-21 |
IL223366B (en) | 2018-06-28 |
EP2575879B1 (en) | 2016-04-20 |
HUE029043T2 (en) | 2017-01-30 |
MA34289B1 (fr) | 2013-06-01 |
JP5973998B2 (ja) | 2016-08-23 |
MX2012013989A (es) | 2013-02-26 |
KR101838311B1 (ko) | 2018-03-13 |
NZ604056A (en) | 2014-10-31 |
US20110097262A1 (en) | 2011-04-28 |
WO2011151412A1 (en) | 2011-12-08 |
US8545839B2 (en) | 2013-10-01 |
CN103002916B (zh) | 2016-08-17 |
US20160039935A1 (en) | 2016-02-11 |
ES2582038T3 (es) | 2016-09-08 |
CN103002916A (zh) | 2013-03-27 |
BR112012030805A2 (pt) | 2017-09-19 |
AU2011260286B2 (en) | 2015-11-19 |
UA113388C2 (xx) | 2017-01-25 |
MX340101B (es) | 2016-06-24 |
TN2012000558A1 (en) | 2014-04-01 |
MY163096A (en) | 2017-08-15 |
RU2012154339A (ru) | 2014-07-20 |
AU2011260286A1 (en) | 2013-01-10 |
KR20130086533A (ko) | 2013-08-02 |
CA2801264A1 (en) | 2011-12-08 |
CN105688209A (zh) | 2016-06-22 |
EP2575879A1 (en) | 2013-04-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6309657B2 (ja) | 新規な抗cMET抗体 | |
JP5973998B2 (ja) | 新規抗cMET抗体 | |
JP5889923B2 (ja) | c−METの二量体化を阻害する新規な抗体およびその使用 | |
US20210087278A1 (en) | ANTI-cMET ANTIBODY | |
US20140112911A9 (en) | Novel anti-cmet antibody |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20140520 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20150630 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20150930 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20151030 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20151130 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160104 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20160617 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20160715 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5973998 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |