WO2001036472A2 - Compositions and methods for regulating tumor-associated antigen expression - Google Patents
Compositions and methods for regulating tumor-associated antigen expression Download PDFInfo
- Publication number
- WO2001036472A2 WO2001036472A2 PCT/US2000/031511 US0031511W WO0136472A2 WO 2001036472 A2 WO2001036472 A2 WO 2001036472A2 US 0031511 W US0031511 W US 0031511W WO 0136472 A2 WO0136472 A2 WO 0136472A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tumor
- cells
- antigen
- agent
- expression
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 228
- 239000000427 antigen Substances 0.000 title claims abstract description 177
- 108091007433 antigens Proteins 0.000 title claims abstract description 80
- 102000036639 antigens Human genes 0.000 title claims abstract description 80
- 238000000034 method Methods 0.000 title claims abstract description 69
- 230000001105 regulatory effect Effects 0.000 title claims description 12
- 239000000203 mixture Substances 0.000 title abstract description 19
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 169
- 201000001441 melanoma Diseases 0.000 claims abstract description 160
- 108010010995 MART-1 Antigen Proteins 0.000 claims abstract description 131
- 102000016200 MART-1 Antigen Human genes 0.000 claims abstract description 131
- NEHKZPHIKKEMAZ-ZFVKSOIMSA-N (2s)-2-[[(2s,3r)-2-[[(2s)-2-[[(2s,3s)-2-[[2-[[(2s,3s)-2-[[2-[[(2s)-2-[[(2s)-2-azaniumylpropanoyl]amino]propanoyl]amino]acetyl]amino]-3-methylpentanoyl]amino]acetyl]amino]-3-methylpentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-methylb Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O NEHKZPHIKKEMAZ-ZFVKSOIMSA-N 0.000 claims abstract description 18
- 238000011282 treatment Methods 0.000 claims abstract description 12
- 210000004027 cell Anatomy 0.000 claims description 270
- 210000004881 tumor cell Anatomy 0.000 claims description 116
- 101000578784 Homo sapiens Melanoma antigen recognized by T-cells 1 Proteins 0.000 claims description 113
- 102100028389 Melanoma antigen recognized by T-cells 1 Human genes 0.000 claims description 111
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 claims description 97
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 92
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 75
- 229920001184 polypeptide Polymers 0.000 claims description 65
- 239000006228 supernatant Substances 0.000 claims description 48
- 102000004140 Oncostatin M Human genes 0.000 claims description 37
- 108090000630 Oncostatin M Proteins 0.000 claims description 37
- 230000002222 downregulating effect Effects 0.000 claims description 37
- 101150029707 ERBB2 gene Proteins 0.000 claims description 29
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 28
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 28
- 101710091881 GTPase HRas Proteins 0.000 claims description 25
- 102100029974 GTPase HRas Human genes 0.000 claims description 25
- 201000011510 cancer Diseases 0.000 claims description 25
- 230000002401 inhibitory effect Effects 0.000 claims description 19
- 239000012634 fragment Substances 0.000 claims description 17
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 claims description 16
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 claims description 16
- 102000007066 Prostate-Specific Antigen Human genes 0.000 claims description 16
- 108010072866 Prostate-Specific Antigen Proteins 0.000 claims description 16
- 229920002684 Sepharose Polymers 0.000 claims description 16
- 238000004113 cell culture Methods 0.000 claims description 16
- 108010052178 teleocalcin Proteins 0.000 claims description 15
- 102100040283 Peptidyl-prolyl cis-trans isomerase B Human genes 0.000 claims description 14
- 108010048032 cyclophilin B Proteins 0.000 claims description 14
- 230000003828 downregulation Effects 0.000 claims description 14
- 108010044156 peptidyl-prolyl cis-trans isomerase b Proteins 0.000 claims description 14
- 102000010735 Adenomatous polyposis coli protein Human genes 0.000 claims description 13
- 108010038310 Adenomatous polyposis coli protein Proteins 0.000 claims description 13
- 206010009944 Colon cancer Diseases 0.000 claims description 13
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims description 13
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims description 13
- 230000002163 immunogen Effects 0.000 claims description 13
- 102000055046 tissue-factor-pathway inhibitor 2 Human genes 0.000 claims description 12
- 108010016054 tissue-factor-pathway inhibitor 2 Proteins 0.000 claims description 12
- 208000006332 Choriocarcinoma Diseases 0.000 claims description 11
- 238000002955 isolation Methods 0.000 claims description 11
- 101100455063 Caenorhabditis elegans lmp-1 gene Proteins 0.000 claims description 10
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 claims description 10
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 claims description 10
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 claims description 10
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 102000003425 Tyrosinase Human genes 0.000 claims description 9
- 108060008724 Tyrosinase Proteins 0.000 claims description 9
- 230000028993 immune response Effects 0.000 claims description 9
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 8
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 8
- 102000003730 Alpha-catenin Human genes 0.000 claims description 8
- 108090000020 Alpha-catenin Proteins 0.000 claims description 8
- 108060000903 Beta-catenin Proteins 0.000 claims description 8
- 102000015735 Beta-catenin Human genes 0.000 claims description 8
- 206010006187 Breast cancer Diseases 0.000 claims description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims description 8
- 102000000905 Cadherin Human genes 0.000 claims description 8
- 108050007957 Cadherin Proteins 0.000 claims description 8
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 claims description 8
- 101100216227 Dictyostelium discoideum anapc3 gene Proteins 0.000 claims description 8
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 claims description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 8
- 206010033128 Ovarian cancer Diseases 0.000 claims description 8
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 8
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 8
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 8
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 8
- 206010060862 Prostate cancer Diseases 0.000 claims description 8
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 8
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 8
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 8
- 206010057644 Testis cancer Diseases 0.000 claims description 8
- 108010026331 alpha-Fetoproteins Proteins 0.000 claims description 8
- 208000019065 cervical carcinoma Diseases 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 102000054078 gamma Catenin Human genes 0.000 claims description 8
- 108010084448 gamma Catenin Proteins 0.000 claims description 8
- 206010017758 gastric cancer Diseases 0.000 claims description 8
- 208000032839 leukemia Diseases 0.000 claims description 8
- 208000014018 liver neoplasm Diseases 0.000 claims description 8
- 201000005202 lung cancer Diseases 0.000 claims description 8
- 208000020816 lung neoplasm Diseases 0.000 claims description 8
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 8
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 8
- 201000011549 stomach cancer Diseases 0.000 claims description 8
- 201000003120 testicular cancer Diseases 0.000 claims description 8
- 208000017604 Hodgkin disease Diseases 0.000 claims description 7
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 7
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 claims description 7
- 210000004698 lymphocyte Anatomy 0.000 claims description 7
- 238000012216 screening Methods 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 239000012228 culture supernatant Substances 0.000 claims description 6
- 230000037361 pathway Effects 0.000 claims description 6
- -1 RCASl Proteins 0.000 claims description 5
- WEYNBWVKOYCCQT-UHFFFAOYSA-N 1-(3-chloro-4-methylphenyl)-3-{2-[({5-[(dimethylamino)methyl]-2-furyl}methyl)thio]ethyl}urea Chemical compound O1C(CN(C)C)=CC=C1CSCCNC(=O)NC1=CC=C(C)C(Cl)=C1 WEYNBWVKOYCCQT-UHFFFAOYSA-N 0.000 claims description 5
- 102100027241 Adenylyl cyclase-associated protein 1 Human genes 0.000 claims description 5
- 101710137115 Adenylyl cyclase-associated protein 1 Proteins 0.000 claims description 5
- 102100021879 Adenylyl cyclase-associated protein 2 Human genes 0.000 claims description 5
- 101710137132 Adenylyl cyclase-associated protein 2 Proteins 0.000 claims description 5
- 102100035526 B melanoma antigen 1 Human genes 0.000 claims description 5
- 206010005003 Bladder cancer Diseases 0.000 claims description 5
- 201000009030 Carcinoma Diseases 0.000 claims description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 5
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 claims description 5
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 claims description 5
- 108010067770 Endopeptidase K Proteins 0.000 claims description 5
- 208000032612 Glial tumor Diseases 0.000 claims description 5
- 206010018338 Glioma Diseases 0.000 claims description 5
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims description 5
- 101000874316 Homo sapiens B melanoma antigen 1 Proteins 0.000 claims description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims description 5
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 5
- 108010051791 Nuclear Antigens Proteins 0.000 claims description 5
- 102000019040 Nuclear Antigens Human genes 0.000 claims description 5
- 108060006580 PRAME Proteins 0.000 claims description 5
- 102000036673 PRAME Human genes 0.000 claims description 5
- 102100034640 PWWP domain-containing DNA repair factor 3A Human genes 0.000 claims description 5
- 108050007154 PWWP domain-containing DNA repair factor 3A Proteins 0.000 claims description 5
- 206010038389 Renal cancer Diseases 0.000 claims description 5
- 108091008874 T cell receptors Proteins 0.000 claims description 5
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 claims description 5
- 208000000389 T-cell leukemia Diseases 0.000 claims description 5
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 claims description 5
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 5
- 108010006620 fodrin Proteins 0.000 claims description 5
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 5
- 201000010982 kidney cancer Diseases 0.000 claims description 5
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 5
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 4
- 239000013592 cell lysate Substances 0.000 claims description 4
- 230000002708 enhancing effect Effects 0.000 claims description 4
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 claims description 3
- 101100504181 Arabidopsis thaliana GCS1 gene Proteins 0.000 claims 2
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 claims 2
- 102000013529 alpha-Fetoproteins Human genes 0.000 claims 2
- 230000004069 differentiation Effects 0.000 abstract description 2
- 230000000694 effects Effects 0.000 description 38
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 30
- 108090000623 proteins and genes Proteins 0.000 description 27
- 102000004169 proteins and genes Human genes 0.000 description 22
- 239000003112 inhibitor Substances 0.000 description 18
- 238000003556 assay Methods 0.000 description 17
- 102000025850 HLA-A2 Antigen Human genes 0.000 description 12
- 108010074032 HLA-A2 Antigen Proteins 0.000 description 12
- 230000009089 cytolysis Effects 0.000 description 12
- 239000013543 active substance Substances 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- 239000002609 medium Substances 0.000 description 10
- 230000003292 diminished effect Effects 0.000 description 9
- 210000001744 T-lymphocyte Anatomy 0.000 description 8
- 108010050904 Interferons Proteins 0.000 description 7
- 102000014150 Interferons Human genes 0.000 description 7
- 210000002752 melanocyte Anatomy 0.000 description 7
- 230000001743 silencing effect Effects 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 102100023635 Alpha-fetoprotein Human genes 0.000 description 6
- 108010031111 EBV-encoded nuclear antigen 1 Proteins 0.000 description 6
- 102000003886 Glycoproteins Human genes 0.000 description 6
- 108090000288 Glycoproteins Proteins 0.000 description 6
- 201000010208 Seminoma Diseases 0.000 description 6
- 239000011230 binding agent Substances 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 108020004707 nucleic acids Proteins 0.000 description 6
- 102000039446 nucleic acids Human genes 0.000 description 6
- 150000007523 nucleic acids Chemical class 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 206010041823 squamous cell carcinoma Diseases 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- 201000002510 thyroid cancer Diseases 0.000 description 6
- 206010039491 Sarcoma Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000030279 gene silencing Effects 0.000 description 5
- 230000008073 immune recognition Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 230000000670 limiting effect Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 229920005654 Sephadex Polymers 0.000 description 4
- 239000012507 Sephadex™ Substances 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- 238000001574 biopsy Methods 0.000 description 4
- 230000005859 cell recognition Effects 0.000 description 4
- 239000006285 cell suspension Substances 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000003636 conditioned culture medium Substances 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 239000007943 implant Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 208000030507 AIDS Diseases 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000009746 Adult T-Cell Leukemia-Lymphoma Diseases 0.000 description 3
- 206010001413 Adult T-cell lymphoma/leukaemia Diseases 0.000 description 3
- 208000003174 Brain Neoplasms Diseases 0.000 description 3
- 101100045694 Caenorhabditis elegans art-1 gene Proteins 0.000 description 3
- 241000283707 Capra Species 0.000 description 3
- 208000009458 Carcinoma in Situ Diseases 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 206010014733 Endometrial cancer Diseases 0.000 description 3
- 206010014759 Endometrial neoplasm Diseases 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 3
- 108010008177 Fd immunoglobulins Proteins 0.000 description 3
- 201000008808 Fibrosarcoma Diseases 0.000 description 3
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- 208000000172 Medulloblastoma Diseases 0.000 description 3
- 208000003445 Mouth Neoplasms Diseases 0.000 description 3
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 3
- 206010029260 Neuroblastoma Diseases 0.000 description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 3
- 208000015634 Rectal Neoplasms Diseases 0.000 description 3
- 208000000453 Skin Neoplasms Diseases 0.000 description 3
- 206010043276 Teratoma Diseases 0.000 description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 3
- 208000008383 Wilms tumor Diseases 0.000 description 3
- 208000009956 adenocarcinoma Diseases 0.000 description 3
- 230000003305 autocrine Effects 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 201000009036 biliary tract cancer Diseases 0.000 description 3
- 208000020790 biliary tract neoplasm Diseases 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 230000006037 cell lysis Effects 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 125000003636 chemical group Chemical group 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 230000001086 cytosolic effect Effects 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002651 drug therapy Methods 0.000 description 3
- 239000012636 effector Substances 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 201000004101 esophageal cancer Diseases 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 210000004602 germ cell Anatomy 0.000 description 3
- 208000005017 glioblastoma Diseases 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 229940079322 interferon Drugs 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 206010024627 liposarcoma Diseases 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 230000002101 lytic effect Effects 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 208000025113 myeloid leukemia Diseases 0.000 description 3
- 201000008026 nephroblastoma Diseases 0.000 description 3
- 150000002894 organic compounds Chemical class 0.000 description 3
- 201000008968 osteosarcoma Diseases 0.000 description 3
- 230000000644 propagated effect Effects 0.000 description 3
- 206010038038 rectal cancer Diseases 0.000 description 3
- 201000001275 rectum cancer Diseases 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 201000000849 skin cancer Diseases 0.000 description 3
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 3
- 208000017572 squamous cell neoplasm Diseases 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 230000003068 static effect Effects 0.000 description 3
- 210000002536 stromal cell Anatomy 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 208000030829 thyroid gland adenocarcinoma Diseases 0.000 description 3
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 102100022886 ADP-ribosylation factor-like protein 4C Human genes 0.000 description 2
- 108010032595 Antibody Binding Sites Proteins 0.000 description 2
- 208000013165 Bowen disease Diseases 0.000 description 2
- 208000019337 Bowen disease of the skin Diseases 0.000 description 2
- 239000002126 C01EB10 - Adenosine Substances 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
- 238000002965 ELISA Methods 0.000 description 2
- 108010035452 HLA-A1 Antigen Proteins 0.000 description 2
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 2
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 2
- 108010078049 Interferon alpha-2 Proteins 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 102100021747 Leukemia inhibitory factor receptor Human genes 0.000 description 2
- 101710142062 Leukemia inhibitory factor receptor Proteins 0.000 description 2
- 102000000440 Melanoma-associated antigen Human genes 0.000 description 2
- 108050008953 Melanoma-associated antigen Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 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 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 229930182558 Sterol Natural products 0.000 description 2
- SMPZPKRDRQOOHT-UHFFFAOYSA-N acronycine Chemical compound CN1C2=CC=CC=C2C(=O)C2=C1C(C=CC(C)(C)O1)=C1C=C2OC SMPZPKRDRQOOHT-UHFFFAOYSA-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
- 239000004480 active ingredient Substances 0.000 description 2
- 229960005305 adenosine Drugs 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- 238000010170 biological method Methods 0.000 description 2
- 238000012832 cell culture technique Methods 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 210000004748 cultured cell Anatomy 0.000 description 2
- 230000001461 cytolytic effect Effects 0.000 description 2
- 108091009381 deaminase binding proteins Proteins 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000003413 degradative effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001400 expression cloning Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 238000001641 gel filtration chromatography Methods 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 230000003278 mimic effect Effects 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 238000002823 phage display Methods 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000007423 screening assay Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 238000001542 size-exclusion chromatography Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 150000003432 sterols Chemical class 0.000 description 2
- 235000003702 sterols Nutrition 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- PVYJZLYGTZKPJE-UHFFFAOYSA-N streptonigrin Chemical compound C=1C=C2C(=O)C(OC)=C(N)C(=O)C2=NC=1C(C=1N)=NC(C(O)=O)=C(C)C=1C1=CC=C(OC)C(OC)=C1O PVYJZLYGTZKPJE-UHFFFAOYSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- HZSBSRAVNBUZRA-RQDPQJJXSA-J (1r,2r)-cyclohexane-1,2-diamine;tetrachloroplatinum(2+) Chemical compound Cl[Pt+2](Cl)(Cl)Cl.N[C@@H]1CCCC[C@H]1N HZSBSRAVNBUZRA-RQDPQJJXSA-J 0.000 description 1
- MNHVIVWFCMBFCV-AVGNSLFASA-N (2S)-2-[[(2S)-2-[[(4S)-4-amino-4-carboxybutanoyl]amino]-6-diazo-5-oxohexanoyl]amino]-6-diazo-5-oxohexanoic acid Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CCC(=O)C=[N+]=[N-])C(=O)N[C@@H](CCC(=O)C=[N+]=[N-])C(O)=O MNHVIVWFCMBFCV-AVGNSLFASA-N 0.000 description 1
- PAYBYKKERMGTSS-MNCSTQPFSA-N (2r,3r,3as,9ar)-7-fluoro-2-(hydroxymethyl)-6-imino-2,3,3a,9a-tetrahydrofuro[1,2][1,3]oxazolo[3,4-a]pyrimidin-3-ol Chemical compound N=C1C(F)=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 PAYBYKKERMGTSS-MNCSTQPFSA-N 0.000 description 1
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 description 1
- SWXOGPJRIDTIRL-DOUNNPEJSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s)-1-amino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pent Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 SWXOGPJRIDTIRL-DOUNNPEJSA-N 0.000 description 1
- MWWSFMDVAYGXBV-FGBSZODSSA-N (7s,9s)-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.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 MWWSFMDVAYGXBV-FGBSZODSSA-N 0.000 description 1
- RCFNNLSZHVHCEK-YGCMNLPTSA-N (7s,9s)-7-[(2s,4r,6s)-4-amino-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.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[C@H](C)O1 RCFNNLSZHVHCEK-YGCMNLPTSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-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
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- OJRZEKJECRTBPJ-NGAMADIESA-N (z,5s)-5-acetamido-1-diazonio-6-hydroxy-6-oxohex-1-en-2-olate Chemical compound CC(=O)N[C@H](C(O)=O)CC\C([O-])=C\[N+]#N OJRZEKJECRTBPJ-NGAMADIESA-N 0.000 description 1
- FONKWHRXTPJODV-DNQXCXABSA-N 1,3-bis[2-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-3h-pyrrolo[3,2-e]indole-6-carbonyl]-1h-indol-5-yl]urea Chemical compound C1([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C4=CC(O)=C5NC=C(C5=C4[C@H](CCl)C3)C)=C2C=C(O)C2=C1C(C)=CN2 FONKWHRXTPJODV-DNQXCXABSA-N 0.000 description 1
- OUPZKGBUJRBPGC-HLTSFMKQSA-N 1,5-bis[[(2r)-oxiran-2-yl]methyl]-3-[[(2s)-oxiran-2-yl]methyl]-1,3,5-triazinane-2,4,6-trione Chemical compound O=C1N(C[C@H]2OC2)C(=O)N(C[C@H]2OC2)C(=O)N1C[C@H]1CO1 OUPZKGBUJRBPGC-HLTSFMKQSA-N 0.000 description 1
- UOAFGUOASVSLPK-UHFFFAOYSA-N 1-(2-chloroethyl)-3-(2,2-dimethylpropyl)-1-nitrosourea Chemical compound CC(C)(C)CNC(=O)N(N=O)CCCl UOAFGUOASVSLPK-UHFFFAOYSA-N 0.000 description 1
- JQJSFAJISYZPER-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-(2,3-dihydro-1h-inden-5-ylsulfonyl)urea Chemical compound C1=CC(Cl)=CC=C1NC(=O)NS(=O)(=O)C1=CC=C(CCC2)C2=C1 JQJSFAJISYZPER-UHFFFAOYSA-N 0.000 description 1
- SNYUHPPZINRDSG-UHFFFAOYSA-N 1-(oxiran-2-ylmethyl)-4-[1-(oxiran-2-ylmethyl)piperidin-4-yl]piperidine Chemical compound C1CC(C2CCN(CC3OC3)CC2)CCN1CC1CO1 SNYUHPPZINRDSG-UHFFFAOYSA-N 0.000 description 1
- ZKFNOUUKULVDOB-UHFFFAOYSA-N 1-amino-1-phenylmethyl phosphonic acid Chemical compound OP(=O)(O)C(N)C1=CC=CC=C1 ZKFNOUUKULVDOB-UHFFFAOYSA-N 0.000 description 1
- VKDGNNYJFSHYKD-UHFFFAOYSA-N 2,5-diamino-2-(difluoromethyl)pentanoic acid;hydron;chloride Chemical compound Cl.NCCCC(N)(C(F)F)C(O)=O VKDGNNYJFSHYKD-UHFFFAOYSA-N 0.000 description 1
- NJWBUDCAWGTQAS-UHFFFAOYSA-N 2-(chrysen-6-ylmethylamino)-2-methylpropane-1,3-diol;methanesulfonic acid Chemical compound CS(O)(=O)=O.C1=CC=C2C(CNC(CO)(CO)C)=CC3=C(C=CC=C4)C4=CC=C3C2=C1 NJWBUDCAWGTQAS-UHFFFAOYSA-N 0.000 description 1
- QXLQZLBNPTZMRK-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-1-(2,4-dimethylphenyl)prop-2-en-1-one Chemical compound CN(C)CC(=C)C(=O)C1=CC=C(C)C=C1C QXLQZLBNPTZMRK-UHFFFAOYSA-N 0.000 description 1
- KPRFMAZESAKTEJ-UHFFFAOYSA-N 2-[1-amino-4-[2,5-dioxo-4-(1-phenylethyl)pyrrolidin-3-yl]-1-oxobutan-2-yl]-5-carbamoylheptanedioic acid;azane Chemical compound [NH4+].[NH4+].C=1C=CC=CC=1C(C)C1C(CCC(C(CCC(CC([O-])=O)C(N)=O)C([O-])=O)C(N)=O)C(=O)NC1=O KPRFMAZESAKTEJ-UHFFFAOYSA-N 0.000 description 1
- QCXJFISCRQIYID-IAEPZHFASA-N 2-amino-1-n-[(3s,6s,7r,10s,16s)-3-[(2s)-butan-2-yl]-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-10-propan-2-yl-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]-4,6-dimethyl-3-oxo-9-n-[(3s,6s,7r,10s,16s)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propa 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=C2C(C(=O)N[C@@H]3C(=O)N[C@H](C(N4CCC[C@H]4C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]3C)=O)[C@@H](C)CC)=C(N)C(=O)C(C)=C2O2)C2=C(C)C=C1 QCXJFISCRQIYID-IAEPZHFASA-N 0.000 description 1
- DSWLRNLRVBAVFC-UHFFFAOYSA-N 2-methylsulfinyl-1-pyridin-2-ylethanone Chemical compound CS(=O)CC(=O)C1=CC=CC=N1 DSWLRNLRVBAVFC-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-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
- GRLUHXSUZYFZCW-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine;dihydrochloride Chemical compound Cl.Cl.C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 GRLUHXSUZYFZCW-UHFFFAOYSA-N 0.000 description 1
- GTJXPMSTODOYNP-BTKVJIOYSA-N 3-[(e)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 GTJXPMSTODOYNP-BTKVJIOYSA-N 0.000 description 1
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 1
- QNKJFXARIMSDBR-UHFFFAOYSA-N 3-[2-[bis(2-chloroethyl)amino]ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione Chemical compound O=C1N(CCN(CCCl)CCCl)C(=O)NC11CCCCC1 QNKJFXARIMSDBR-UHFFFAOYSA-N 0.000 description 1
- WUIABRMSWOKTOF-OYALTWQYSA-N 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox Chemical compound OS([O-])(=O)=O.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=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OYALTWQYSA-N 0.000 description 1
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 1
- AKJHMTWEGVYYSE-AIRMAKDCSA-N 4-HPR Chemical compound C=1C=C(O)C=CC=1NC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-AIRMAKDCSA-N 0.000 description 1
- PXLPCZJACKUXGP-UHFFFAOYSA-N 5-(3,4-dichlorophenyl)-6-ethylpyrimidine-2,4-diamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C(Cl)=C1 PXLPCZJACKUXGP-UHFFFAOYSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-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
- DQOGWKZQQBYYMW-LQGIGNHCSA-N 5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline-2,4-diamine;(2s,3s,4s,5r,6s)-3,4,5,6-tetrahydroxyoxane-2-carboxylic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O.COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 DQOGWKZQQBYYMW-LQGIGNHCSA-N 0.000 description 1
- OTSZCHORPMQCBZ-UHFFFAOYSA-N 6-[(3-chlorophenyl)-imidazol-1-ylmethyl]-1h-benzimidazole;hydron;chloride Chemical compound Cl.ClC1=CC=CC(C(C=2C=C3NC=NC3=CC=2)N2C=NC=C2)=C1 OTSZCHORPMQCBZ-UHFFFAOYSA-N 0.000 description 1
- KXBCLNRMQPRVTP-UHFFFAOYSA-N 6-amino-1,5-dihydroimidazo[4,5-c]pyridin-4-one Chemical compound O=C1NC(N)=CC2=C1N=CN2 KXBCLNRMQPRVTP-UHFFFAOYSA-N 0.000 description 1
- ZNTIXVYOBQDFFV-UHFFFAOYSA-N 6-amino-1,5-dihydroimidazo[4,5-c]pyridin-4-one;methanesulfonic acid Chemical compound CS(O)(=O)=O.O=C1NC(N)=CC2=C1N=CN2 ZNTIXVYOBQDFFV-UHFFFAOYSA-N 0.000 description 1
- KABRXLINDSPGDF-UHFFFAOYSA-N 7-bromoisoquinoline Chemical compound C1=CN=CC2=CC(Br)=CC=C21 KABRXLINDSPGDF-UHFFFAOYSA-N 0.000 description 1
- LPDLEICKXUVJHW-QJILNLRNSA-N 78nz2pmp25 Chemical compound OS(O)(=O)=O.O([C@]12[C@H](OC(C)=O)[C@]3(CC)C=CCN4CC[C@@]5([C@H]34)[C@H]1N(C)C1=C5C=C(C(=C1)OC)[C@]1(C(=O)OC)C3=C(C4=CC=CC=C4N3)CCN3C[C@H](C1)C[C@@](C3)(O)CC)C(=O)N(CCCl)C2=O LPDLEICKXUVJHW-QJILNLRNSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 101710117290 Aldo-keto reductase family 1 member C4 Proteins 0.000 description 1
- 108091006522 Anion exchangers Proteins 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108700032558 Aspergillus restrictus MITF Proteins 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- CIUUIPMOFZIWIZ-UHFFFAOYSA-N Bropirimine Chemical compound NC1=NC(O)=C(Br)C(C=2C=CC=CC=2)=N1 CIUUIPMOFZIWIZ-UHFFFAOYSA-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
- 0 C*=C(C)C*#[N+][O-] Chemical compound C*=C(C)C*#[N+][O-] 0.000 description 1
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 241001092081 Carpenteria Species 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 102000016950 Chemokine CXCL1 Human genes 0.000 description 1
- 108010014419 Chemokine CXCL1 Proteins 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- PPASFTRHCXASPY-UHFFFAOYSA-N Cl.Cl.NCCCNc1ccc2c3c(nn2CCNCCO)c4c(O)ccc(O)c4C(=O)c13 Chemical compound Cl.Cl.NCCCNc1ccc2c3c(nn2CCNCCO)c4c(O)ccc(O)c4C(=O)c13 PPASFTRHCXASPY-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
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- SPKNARKFCOPTSY-UHFFFAOYSA-N D-asperlin Natural products CC1OC1C1C(OC(C)=O)C=CC(=O)O1 SPKNARKFCOPTSY-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.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 MWWSFMDVAYGXBV-RUELKSSGSA-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
- 241000196324 Embryophyta Species 0.000 description 1
- NBEALWAVEGMZQY-UHFFFAOYSA-N Enpromate Chemical compound C=1C=CC=CC=1C(C#C)(C=1C=CC=CC=1)OC(=O)NC1CCCCC1 NBEALWAVEGMZQY-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 101710178376 Heat shock 70 kDa protein Proteins 0.000 description 1
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 description 1
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 description 1
- 101000690301 Homo sapiens Aldo-keto reductase family 1 member C4 Proteins 0.000 description 1
- 101000935587 Homo sapiens Flavin reductase (NADPH) Proteins 0.000 description 1
- 101000620359 Homo sapiens Melanocyte protein PMEL Proteins 0.000 description 1
- 101000973997 Homo sapiens Nucleosome assembly protein 1-like 4 Proteins 0.000 description 1
- 101000992170 Homo sapiens Oncostatin-M Proteins 0.000 description 1
- 101000947178 Homo sapiens Platelet basic protein Proteins 0.000 description 1
- 101001116548 Homo sapiens Protein CBFA2T1 Proteins 0.000 description 1
- 101001062222 Homo sapiens Receptor-binding cancer antigen expressed on SiSo cells Proteins 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 108010054698 Interferon Alfa-n3 Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102000010781 Interleukin-6 Receptors Human genes 0.000 description 1
- 108010038501 Interleukin-6 Receptors Proteins 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 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
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 102000043129 MHC class I family Human genes 0.000 description 1
- 108091054437 MHC class I family Proteins 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- 102100022430 Melanocyte protein PMEL Human genes 0.000 description 1
- 206010027145 Melanocytic naevus Diseases 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- HRHKSTOGXBBQCB-UHFFFAOYSA-N Mitomycin E Natural products O=C1C(N)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)C3N(C)C3CN12 HRHKSTOGXBBQCB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- USVMJSALORZVDV-SDBHATRESA-N N(6)-(Delta(2)-isopentenyl)adenosine Chemical compound C1=NC=2C(NCC=C(C)C)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O USVMJSALORZVDV-SDBHATRESA-N 0.000 description 1
- LYPFDBRUNKHDGX-SOGSVHMOSA-N N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 Chemical compound N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 LYPFDBRUNKHDGX-SOGSVHMOSA-N 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 208000007256 Nevus Diseases 0.000 description 1
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 description 1
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 102100022396 Nucleosome assembly protein 1-like 4 Human genes 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 101150057744 PDGFA gene Proteins 0.000 description 1
- 101150117945 PDGFB gene Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 108010067902 Peptide Library Proteins 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- XESARGFCSKSFID-UHFFFAOYSA-N Pyrazofurin Natural products OC1=C(C(=O)N)NN=C1C1C(O)C(O)C(CO)O1 XESARGFCSKSFID-UHFFFAOYSA-N 0.000 description 1
- 102100029165 Receptor-binding cancer antigen expressed on SiSo cells Human genes 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 102100030859 Tissue factor Human genes 0.000 description 1
- 102100030951 Tissue factor pathway inhibitor Human genes 0.000 description 1
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 1
- 102000006747 Transforming Growth Factor alpha Human genes 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 1
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 1
- VGQOVCHZGQWAOI-UHFFFAOYSA-N UNPD55612 Natural products N1C(O)C2CC(C=CC(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-UHFFFAOYSA-N 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
- VUPBDWQPEOWRQP-RTUCOMKBSA-N [(2R,3S,4S,5R,6R)-2-[(2R,3S,4S,5S,6S)-2-[(1S,2S)-3-[[(2R,3S)-5-[[(2S,3R)-1-[[2-[4-[4-[[4-amino-6-[3-(4-aminobutylamino)propylamino]-6-oxohexyl]carbamoyl]-1,3-thiazol-2-yl]-1,3-thiazol-2-yl]-1-[(2S,3R,4R,5S,6S)-5-amino-3,4-dihydroxy-6-methyloxan-2-yl]oxy-2-hydroxyethyl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-hydroxy-5-oxopentan-2-yl]amino]-2-[[6-amino-2-[(1S)-3-amino-1-[[(2S)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-1-(1H-imidazol-5-yl)-3-oxopropoxy]-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl] carbamate Chemical compound C[C@@H](O)[C@H](NC(=O)C[C@H](O)[C@@H](C)NC(=O)[C@@H](NC(=O)c1nc(nc(N)c1C)[C@H](CC(N)=O)NC[C@H](N)C(N)=O)[C@H](O[C@@H]1O[C@@H](CO)[C@@H](O)[C@H](O)[C@@H]1O[C@H]1O[C@H](CO)[C@@H](O)[C@H](OC(N)=O)[C@@H]1O)c1cnc[nH]1)C(=O)NC(O[C@@H]1O[C@@H](C)[C@@H](N)[C@@H](O)[C@H]1O)C(O)c1nc(cs1)-c1nc(cs1)C(=O)NCCCC(N)CC(=O)NCCCNCCCCN VUPBDWQPEOWRQP-RTUCOMKBSA-N 0.000 description 1
- SPKNARKFCOPTSY-XWPZMVOTSA-N [(2r,3s)-2-[(2s,3r)-3-methyloxiran-2-yl]-6-oxo-2,3-dihydropyran-3-yl] acetate Chemical compound C[C@H]1O[C@@H]1[C@H]1[C@@H](OC(C)=O)C=CC(=O)O1 SPKNARKFCOPTSY-XWPZMVOTSA-N 0.000 description 1
- IVCRCPJOLWECJU-XQVQQVTHSA-N [(7r,8r,9s,10r,13s,14s,17s)-7,13-dimethyl-3-oxo-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1C[C@]2(C)[C@@H](OC(C)=O)CC[C@H]2[C@@H]2[C@H](C)CC3=CC(=O)CC[C@@H]3[C@H]21 IVCRCPJOLWECJU-XQVQQVTHSA-N 0.000 description 1
- KMLCRELJHYKIIL-UHFFFAOYSA-N [1-(azanidylmethyl)cyclohexyl]methylazanide;platinum(2+);sulfuric acid Chemical compound [Pt+2].OS(O)(=O)=O.[NH-]CC1(C[NH-])CCCCC1 KMLCRELJHYKIIL-UHFFFAOYSA-N 0.000 description 1
- QPWBZVAOCWJTFK-UHFFFAOYSA-L [2-(azanidylmethyl)-3-hydroxy-2-(hydroxymethyl)propyl]azanide;cyclobutane-1,1-dicarboxylate;platinum(4+) Chemical compound [Pt+4].[NH-]CC(C[NH-])(CO)CO.[O-]C(=O)C1(C([O-])=O)CCC1 QPWBZVAOCWJTFK-UHFFFAOYSA-L 0.000 description 1
- ODEDPKNSRBCSDO-UHFFFAOYSA-N [2-(hexadecylsulfanylmethyl)-3-methoxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCSCC(COC)COP([O-])(=O)OCC[N+](C)(C)C ODEDPKNSRBCSDO-UHFFFAOYSA-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
- NAFFDQVVNWTDJD-UHFFFAOYSA-L [4-(azanidylmethyl)oxan-4-yl]methylazanide;cyclobutane-1,1-dicarboxylate;platinum(4+) Chemical compound [Pt+4].[NH-]CC1(C[NH-])CCOCC1.[O-]C(=O)C1(C([O-])=O)CCC1 NAFFDQVVNWTDJD-UHFFFAOYSA-L 0.000 description 1
- JURAJLFHWXNPHG-UHFFFAOYSA-N [acetyl(methylcarbamoyl)amino] n-methylcarbamate Chemical compound CNC(=O)ON(C(C)=O)C(=O)NC JURAJLFHWXNPHG-UHFFFAOYSA-N 0.000 description 1
- RUGAHXUZHWYHNG-NLGNTGLNSA-N acetic acid;(4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5, Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 RUGAHXUZHWYHNG-NLGNTGLNSA-N 0.000 description 1
- IGCAUIJHGNYDKE-UHFFFAOYSA-N acetic acid;1,4-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione Chemical compound CC([O-])=O.CC([O-])=O.O=C1C2=CC=CC=C2C(=O)C2=C1C(NCC[NH2+]CCO)=CC=C2NCC[NH2+]CCO IGCAUIJHGNYDKE-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- QAWIHIJWNYOLBE-OKKQSCSOSA-N acivicin Chemical compound OC(=O)[C@@H](N)[C@@H]1CC(Cl)=NO1 QAWIHIJWNYOLBE-OKKQSCSOSA-N 0.000 description 1
- 229950008427 acivicin Drugs 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 229950000616 acronine Drugs 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
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 229950004955 adozelesin Drugs 0.000 description 1
- BYRVKDUQDLJUBX-JJCDCTGGSA-N adozelesin Chemical compound C1=CC=C2OC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)NC=C5C)=CC2=C1 BYRVKDUQDLJUBX-JJCDCTGGSA-N 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 229960005310 aldesleukin Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229950004821 ambomycin Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 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
- VGQOVCHZGQWAOI-HYUHUPJXSA-N anthramycin Chemical compound N1[C@@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-HYUHUPJXSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- HRXVDDOKERXBEY-UHFFFAOYSA-N azatepa Chemical compound C1CN1P(=O)(N1CC1)N(CC)C1=NN=CS1 HRXVDDOKERXBEY-UHFFFAOYSA-N 0.000 description 1
- 229950004295 azotomycin Drugs 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
- 230000008901 benefit Effects 0.000 description 1
- 229950005567 benzodepa Drugs 0.000 description 1
- MMIMIFULGMZVPO-UHFFFAOYSA-N benzyl 3-bromo-2,6-dinitro-5-phenylmethoxybenzoate Chemical compound [O-][N+](=O)C1=C(C(=O)OCC=2C=CC=CC=2)C([N+](=O)[O-])=C(Br)C=C1OCC1=CC=CC=C1 MMIMIFULGMZVPO-UHFFFAOYSA-N 0.000 description 1
- VFIUCBTYGKMLCM-UHFFFAOYSA-N benzyl n-[bis(aziridin-1-yl)phosphoryl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)NP(=O)(N1CC1)N1CC1 VFIUCBTYGKMLCM-UHFFFAOYSA-N 0.000 description 1
- 102000015736 beta 2-Microglobulin Human genes 0.000 description 1
- 108010081355 beta 2-Microglobulin Proteins 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 229950006844 bizelesin Drugs 0.000 description 1
- 229960004395 bleomycin sulfate Drugs 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- PZOHOALJQOFNTB-UHFFFAOYSA-M brequinar sodium Chemical compound [Na+].N1=C2C=CC(F)=CC2=C(C([O-])=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PZOHOALJQOFNTB-UHFFFAOYSA-M 0.000 description 1
- 229950009494 bropirimine Drugs 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 108700002839 cactinomycin Proteins 0.000 description 1
- 229950009908 cactinomycin Drugs 0.000 description 1
- IVFYLRMMHVYGJH-PVPPCFLZSA-N calusterone Chemical compound C1C[C@]2(C)[C@](O)(C)CC[C@H]2[C@@H]2[C@@H](C)CC3=CC(=O)CC[C@]3(C)[C@H]21 IVFYLRMMHVYGJH-PVPPCFLZSA-N 0.000 description 1
- 229950009823 calusterone Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229950009338 caracemide Drugs 0.000 description 1
- 229950005155 carbetimer Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin 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=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 229950001725 carubicin Drugs 0.000 description 1
- BBZDXMBRAFTCAA-AREMUKBSSA-N carzelesin Chemical compound C1=2NC=C(C)C=2C([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)C3=CC4=CC=C(C=C4O3)N(CC)CC)=C2C=C1OC(=O)NC1=CC=CC=C1 BBZDXMBRAFTCAA-AREMUKBSSA-N 0.000 description 1
- 229950007509 carzelesin Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- OWSKEUBOCMEJMI-KPXOXKRLSA-N chembl2105946 Chemical compound [N-]=[N+]=CC(=O)CC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@H](CCC(=O)C=[N+]=[N-])C(O)=O OWSKEUBOCMEJMI-KPXOXKRLSA-N 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000014564 chemokine production Effects 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 150000001840 cholesterol esters Chemical class 0.000 description 1
- 229950011359 cirolemycin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 238000007821 culture assay Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 238000011266 cytolytic assay Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 238000012303 cytoplasmic staining Methods 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- YCWXIQRLONXJLF-PFFGJIDWSA-N d06307 Chemical compound OS(O)(=O)=O.C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(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.C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(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 YCWXIQRLONXJLF-PFFGJIDWSA-N 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- VPOCYEOOFRNHNL-RQDPQJJXSA-J dexormaplatin Chemical compound Cl[Pt](Cl)(Cl)Cl.N[C@@H]1CCCC[C@H]1N VPOCYEOOFRNHNL-RQDPQJJXSA-J 0.000 description 1
- 229950001640 dexormaplatin Drugs 0.000 description 1
- 229950010621 dezaguanine Drugs 0.000 description 1
- WVYXNIXAMZOZFK-UHFFFAOYSA-N diaziquone Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 description 1
- 229950002389 diaziquone Drugs 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- OTKJDMGTUTTYMP-UHFFFAOYSA-N dihydrosphingosine Natural products CCCCCCCCCCCCCCCC(O)C(N)CO OTKJDMGTUTTYMP-UHFFFAOYSA-N 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- CZLKTMHQYXYHOO-QTNFYWBSSA-L disodium;(2s)-2-[(2-phosphonatoacetyl)amino]butanedioic acid Chemical compound [Na+].[Na+].OC(=O)C[C@@H](C(O)=O)NC(=O)CP([O-])([O-])=O CZLKTMHQYXYHOO-QTNFYWBSSA-L 0.000 description 1
- SVJSWELRJWVPQD-KJWOGLQMSA-L disodium;(2s)-2-[[4-[2-[(6r)-2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl]amino]pentanedioate Chemical compound [Na+].[Na+].C([C@@H]1CC=2C(=O)N=C(NC=2NC1)N)CC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 SVJSWELRJWVPQD-KJWOGLQMSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 229940017825 dromostanolone Drugs 0.000 description 1
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 1
- 229950005133 duazomycin Drugs 0.000 description 1
- 229930192837 duazomycin Natural products 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 1
- 229950006700 edatrexate Drugs 0.000 description 1
- 229960002046 eflornithine hydrochloride Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- MGQRRMONVLMKJL-KWJIQSIXSA-N elsamitrucin Chemical compound O1[C@H](C)[C@H](O)[C@H](OC)[C@@H](N)[C@H]1O[C@@H]1[C@](O)(C)[C@@H](O)[C@@H](C)O[C@H]1OC1=CC=CC2=C(O)C(C(O3)=O)=C4C5=C3C=CC(C)=C5C(=O)OC4=C12 MGQRRMONVLMKJL-KWJIQSIXSA-N 0.000 description 1
- 229950002339 elsamitrucin Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229950010625 enloplatin Drugs 0.000 description 1
- 229950001022 enpromate Drugs 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- 229950004926 epipropidine Drugs 0.000 description 1
- 229960003265 epirubicin hydrochloride Drugs 0.000 description 1
- 229950001426 erbulozole Drugs 0.000 description 1
- KLEPCGBEXOCIGS-QPPBQGQZSA-N erbulozole Chemical compound C1=CC(NC(=O)OCC)=CC=C1SC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C=CC(OC)=CC=2)OC1 KLEPCGBEXOCIGS-QPPBQGQZSA-N 0.000 description 1
- HCZKYJDFEPMADG-UHFFFAOYSA-N erythro-nordihydroguaiaretic acid Natural products C=1C=C(O)C(O)=CC=1CC(C)C(C)CC1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229960001766 estramustine phosphate sodium Drugs 0.000 description 1
- IIUMCNJTGSMNRO-VVSKJQCTSA-L estramustine sodium phosphate Chemical compound [Na+].[Na+].ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 IIUMCNJTGSMNRO-VVSKJQCTSA-L 0.000 description 1
- WCDWBPCFGJXFJZ-UHFFFAOYSA-N etanidazole Chemical compound OCCNC(=O)CN1C=CN=C1[N+]([O-])=O WCDWBPCFGJXFJZ-UHFFFAOYSA-N 0.000 description 1
- 229950006566 etanidazole Drugs 0.000 description 1
- HZQPPNNARUQMJA-IMIWJGOWSA-N ethyl n-[4-[[(2r,4r)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methylsulfanyl]phenyl]carbamate;hydrochloride Chemical compound Cl.C1=CC(NC(=O)OCC)=CC=C1SC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 HZQPPNNARUQMJA-IMIWJGOWSA-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
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229950011548 fadrozole Drugs 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- NMUSYJAQQFHJEW-ARQDHWQXSA-N fazarabine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-ARQDHWQXSA-N 0.000 description 1
- 229950005096 fazarabine Drugs 0.000 description 1
- 229950003662 fenretinide Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000012757 fluorescence staining Methods 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229950005682 flurocitabine Drugs 0.000 description 1
- UXTSQCOOUJTIAC-UHFFFAOYSA-N fosquidone Chemical compound C=1N2CC3=CC=CC=C3C(C)C2=C(C(C2=CC=C3)=O)C=1C(=O)C2=C3OP(O)(=O)OCC1=CC=CC=C1 UXTSQCOOUJTIAC-UHFFFAOYSA-N 0.000 description 1
- 229950005611 fosquidone Drugs 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 229960005144 gemcitabine hydrochloride Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 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
- 238000013537 high throughput screening Methods 0.000 description 1
- 102000043703 human OSM Human genes 0.000 description 1
- 102000054751 human RUNX1T1 Human genes 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- SOCGJDYHNGLZEC-UHFFFAOYSA-N hydron;n-methyl-n-[4-[(7-methyl-3h-imidazo[4,5-f]quinolin-9-yl)amino]phenyl]acetamide;chloride Chemical compound Cl.C1=CC(N(C(C)=O)C)=CC=C1NC1=CC(C)=NC2=CC=C(NC=N3)C3=C12 SOCGJDYHNGLZEC-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 229960001176 idarubicin hydrochloride 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
- 229950006905 ilmofosine Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000007124 immune defense Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229960003521 interferon alfa-2a Drugs 0.000 description 1
- 229960003507 interferon alfa-2b Drugs 0.000 description 1
- 229940109242 interferon alfa-n3 Drugs 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 229950010897 iproplatin Drugs 0.000 description 1
- 229960000779 irinotecan hydrochloride Drugs 0.000 description 1
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.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 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 108010021336 lanreotide Proteins 0.000 description 1
- 229960001739 lanreotide acetate 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
- 210000000265 leukocyte Anatomy 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- KDQAABAKXDWYSZ-SDCRJXSCSA-N leurosidine sulfate Chemical compound OS(O)(=O)=O.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 KDQAABAKXDWYSZ-SDCRJXSCSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 108010013555 lipoprotein-associated coagulation inhibitor Proteins 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- XDMHALQMTPSGEA-UHFFFAOYSA-N losoxantrone hydrochloride Chemical compound Cl.Cl.OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO XDMHALQMTPSGEA-UHFFFAOYSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960003951 masoprocol Drugs 0.000 description 1
- HCZKYJDFEPMADG-TXEJJXNPSA-N masoprocol Chemical compound C([C@H](C)[C@H](C)CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-TXEJJXNPSA-N 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- 229960002868 mechlorethamine hydrochloride Drugs 0.000 description 1
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960003846 melengestrol acetate Drugs 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- LWYJUZBXGAFFLP-OCNCTQISSA-N menogaril Chemical compound O1[C@@]2(C)[C@H](O)[C@@H](N(C)C)[C@H](O)[C@@H]1OC1=C3C(=O)C(C=C4C[C@@](C)(O)C[C@H](C4=C4O)OC)=C4C(=O)C3=C(O)C=C12 LWYJUZBXGAFFLP-OCNCTQISSA-N 0.000 description 1
- 229950002676 menogaril Drugs 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 208000021039 metastatic melanoma Diseases 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- KPQJSSLKKBKWEW-RKDOVGOJSA-N methanesulfonic acid;5-nitro-2-[(2r)-1-[2-[[(2r)-2-(5-nitro-1,3-dioxobenzo[de]isoquinolin-2-yl)propyl]amino]ethylamino]propan-2-yl]benzo[de]isoquinoline-1,3-dione Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.[O-][N+](=O)C1=CC(C(N([C@@H](CNCCNC[C@@H](C)N2C(C=3C=C(C=C4C=CC=C(C=34)C2=O)[N+]([O-])=O)=O)C)C2=O)=O)=C3C2=CC=CC3=C1 KPQJSSLKKBKWEW-RKDOVGOJSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- BKBBTCORRZMASO-ZOWNYOTGSA-M methotrexate monosodium Chemical compound [Na+].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 BKBBTCORRZMASO-ZOWNYOTGSA-M 0.000 description 1
- 229960003058 methotrexate sodium Drugs 0.000 description 1
- HRHKSTOGXBBQCB-VFWICMBZSA-N methylmitomycin Chemical compound O=C1C(N)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N(C)[C@H]3CN12 HRHKSTOGXBBQCB-VFWICMBZSA-N 0.000 description 1
- VQJHOPSWBGJHQS-UHFFFAOYSA-N metoprine, methodichlorophen Chemical compound CC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C(Cl)=C1 VQJHOPSWBGJHQS-UHFFFAOYSA-N 0.000 description 1
- QTFKTBRIGWJQQL-UHFFFAOYSA-N meturedepa Chemical compound C1C(C)(C)N1P(=O)(NC(=O)OCC)N1CC1(C)C QTFKTBRIGWJQQL-UHFFFAOYSA-N 0.000 description 1
- 229950009847 meturedepa Drugs 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 238000012737 microarray-based gene expression Methods 0.000 description 1
- 239000003094 microcapsule Substances 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
- DRCJGCOYHLTVNR-ZUIZSQJWSA-N mitindomide Chemical compound C1=C[C@@H]2[C@@H]3[C@H]4C(=O)NC(=O)[C@H]4[C@@H]3[C@H]1[C@@H]1C(=O)NC(=O)[C@H]21 DRCJGCOYHLTVNR-ZUIZSQJWSA-N 0.000 description 1
- 229950001314 mitindomide Drugs 0.000 description 1
- 229950002137 mitocarcin Drugs 0.000 description 1
- 229950000911 mitogillin Drugs 0.000 description 1
- 108010026677 mitomalcin Proteins 0.000 description 1
- 229950007612 mitomalcin Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229950005715 mitosper Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004169 mitoxantrone hydrochloride Drugs 0.000 description 1
- 238000012243 multiplex automated genomic engineering Methods 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- NKFHKYQGZDAKMX-PPRKPIOESA-N n-[(e)-1-[(2s,4s)-4-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1h-tetracen-2-yl]ethylideneamino]benzamide;hydrochloride Chemical compound Cl.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)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 NKFHKYQGZDAKMX-PPRKPIOESA-N 0.000 description 1
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 1
- WRINSSLBPNLASA-FOCLMDBBSA-N n-methyl-n-[(e)-(n-methylanilino)diazenyl]aniline Chemical compound C=1C=CC=CC=1N(C)\N=N\N(C)C1=CC=CC=C1 WRINSSLBPNLASA-FOCLMDBBSA-N 0.000 description 1
- 239000013642 negative control Substances 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
- 229950006344 nocodazole Drugs 0.000 description 1
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@@]5(C)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 description 1
- 229950009266 nogalamycin Drugs 0.000 description 1
- 238000007899 nucleic acid hybridization Methods 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229950008017 ormaplatin Drugs 0.000 description 1
- 229950000370 oxisuran Drugs 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 229960001744 pegaspargase Drugs 0.000 description 1
- 108010001564 pegaspargase Proteins 0.000 description 1
- 229950006960 peliomycin Drugs 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin 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)NCCCN[C@@H](C)C=1C=CC=CC=1)[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=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- VPAWVRUHMJVRHU-VGDKGRGNSA-N perfosfamide Chemical compound OO[C@@H]1CCO[P@@](=O)(N(CCCl)CCCl)N1 VPAWVRUHMJVRHU-VGDKGRGNSA-N 0.000 description 1
- 229950009351 perfosfamide Drugs 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 description 1
- 229950001100 piposulfan Drugs 0.000 description 1
- XESARGFCSKSFID-FLLFQEBCSA-N pirazofurin Chemical compound OC1=C(C(=O)N)NN=C1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 XESARGFCSKSFID-FLLFQEBCSA-N 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- JKPDEYAOCSQBSZ-OEUJLIAZSA-N plomestane Chemical compound O=C1CC[C@]2(CC#C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKPDEYAOCSQBSZ-OEUJLIAZSA-N 0.000 description 1
- 229950004541 plomestane Drugs 0.000 description 1
- 229940068585 podofilox Drugs 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 229920006149 polyester-amide block copolymer Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 229960004293 porfimer sodium Drugs 0.000 description 1
- 229950004406 porfiromycin Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960001586 procarbazine hydrochloride Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000000734 protein sequencing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000013014 purified material Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- MKSVFGKWZLUTTO-FZFAUISWSA-N puromycin dihydrochloride Chemical compound Cl.Cl.C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO MKSVFGKWZLUTTO-FZFAUISWSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- 102000016914 ras Proteins Human genes 0.000 description 1
- 108010014186 ras Proteins Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000012465 retentate Substances 0.000 description 1
- 229960004356 riboprine Drugs 0.000 description 1
- QXKJWHWUDVQATH-UHFFFAOYSA-N rogletimide Chemical compound C=1C=NC=CC=1C1(CC)CCC(=O)NC1=O QXKJWHWUDVQATH-UHFFFAOYSA-N 0.000 description 1
- 229950005230 rogletimide Drugs 0.000 description 1
- 229950008902 safingol Drugs 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 229950009089 simtrazene Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- XBUIKNRVGYFSHL-IAVQPKKASA-M sodium;[(1e,3r,4r,6r,7z,9z,11e)-3,6,13-trihydroxy-3-methyl-1-[(2r)-6-oxo-2,3-dihydropyran-2-yl]trideca-1,7,9,11-tetraen-4-yl] hydrogen phosphate Chemical compound [Na+].OC/C=C/C=C\C=C/[C@H](O)C[C@@H](OP(O)([O-])=O)[C@@](O)(C)\C=C\[C@H]1CC=CC(=O)O1 XBUIKNRVGYFSHL-IAVQPKKASA-M 0.000 description 1
- MIXCUJKCXRNYFM-UHFFFAOYSA-M sodium;diiodomethanesulfonate;n-propyl-n-[2-(2,4,6-trichlorophenoxy)ethyl]imidazole-1-carboxamide Chemical compound [Na+].[O-]S(=O)(=O)C(I)I.C1=CN=CN1C(=O)N(CCC)CCOC1=C(Cl)C=C(Cl)C=C1Cl MIXCUJKCXRNYFM-UHFFFAOYSA-M 0.000 description 1
- 229950009641 sparsomycin Drugs 0.000 description 1
- XKLZIVIOZDNKEQ-CLQLPEFOSA-N sparsomycin Chemical compound CSC[S@](=O)C[C@H](CO)NC(=O)\C=C\C1=C(C)NC(=O)NC1=O XKLZIVIOZDNKEQ-CLQLPEFOSA-N 0.000 description 1
- XKLZIVIOZDNKEQ-UHFFFAOYSA-N sparsomycin Natural products CSCS(=O)CC(CO)NC(=O)C=CC1=C(C)NC(=O)NC1=O XKLZIVIOZDNKEQ-UHFFFAOYSA-N 0.000 description 1
- OTKJDMGTUTTYMP-ZWKOTPCHSA-N sphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@@H](N)CO OTKJDMGTUTTYMP-ZWKOTPCHSA-N 0.000 description 1
- 229950006050 spiromustine Drugs 0.000 description 1
- 229950004330 spiroplatin Drugs 0.000 description 1
- 239000003381 stabilizer Substances 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
- 229950007841 sulofenur Drugs 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 108700003774 talisomycin Proteins 0.000 description 1
- 229950002687 talisomycin 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
- 229940063683 taxotere Drugs 0.000 description 1
- URLYINUFLXOMHP-HTVVRFAVSA-N tcn-p Chemical compound C=12C3=NC=NC=1N(C)N=C(N)C2=CN3[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O URLYINUFLXOMHP-HTVVRFAVSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- RNVNXVVEDMSRJE-UHFFFAOYSA-N teloxantrone hydrochloride Chemical compound Cl.Cl.OCCNCCN1NC2=C3C(=O)C=CC(=O)C3=C(O)C3=C2C1=CC=C3NCCNC RNVNXVVEDMSRJE-UHFFFAOYSA-N 0.000 description 1
- 229960002197 temoporfin Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229950008703 teroxirone Drugs 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 description 1
- 229950011457 tiamiprine Drugs 0.000 description 1
- 229960003723 tiazofurine Drugs 0.000 description 1
- FVRDYQYEVDDKCR-DBRKOABJSA-N tiazofurine Chemical compound NC(=O)C1=CSC([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=N1 FVRDYQYEVDDKCR-DBRKOABJSA-N 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 229950002376 tirapazamine Drugs 0.000 description 1
- QVMPZNRFXAKISM-UHFFFAOYSA-N tirapazamine Chemical compound C1=CC=C2[N+]([O-])=NC(=N)N(O)C2=C1 QVMPZNRFXAKISM-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 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
- 229960002190 topotecan hydrochloride Drugs 0.000 description 1
- 229960004167 toremifene citrate Drugs 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960000538 trimetrexate glucuronate Drugs 0.000 description 1
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 1
- 229960004824 triptorelin Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- SPDZFJLQFWSJGA-UHFFFAOYSA-N uredepa Chemical compound C1CN1P(=O)(NC(=O)OCC)N1CC1 SPDZFJLQFWSJGA-UHFFFAOYSA-N 0.000 description 1
- 229950006929 uredepa Drugs 0.000 description 1
- 229960002730 vapreotide Drugs 0.000 description 1
- 108700029852 vapreotide Proteins 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.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 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.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=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
- 229960002110 vincristine sulfate Drugs 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
- 229960005212 vindesine sulfate Drugs 0.000 description 1
- BCXOZISMDZTYHW-IFQBWSDRSA-N vinepidine sulfate Chemical compound OS(O)(=O)=O.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=O)C=2)OC)C[C@@H](C2)CC)N2CCC2=C1NC1=CC=CC=C21 BCXOZISMDZTYHW-IFQBWSDRSA-N 0.000 description 1
- 229960002166 vinorelbine tartrate Drugs 0.000 description 1
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[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-IWWDSPBFSA-N 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- DVPVGSLIUJPOCJ-XXRQFBABSA-N x1j761618a Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(=O)CN(C)C)[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.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(=O)CN(C)C)[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 DVPVGSLIUJPOCJ-XXRQFBABSA-N 0.000 description 1
- 229950003017 zeniplatin Drugs 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
-
- 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
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- 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
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/46449—Melanoma antigens
- A61K39/464491—Melan-A/MART
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0693—Tumour cells; Cancer cells
-
- 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
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to methods and compositions for the treatment of tumors.
- the invention relates to methods and agents for the treatment of tumors expressing a tumor-antigen [also known as a tumor-associated antigen (TAA). lineage specific, differentiation, or self -antigen], and more specifically to methods and agents for the treatment of melanomas expressing the Melan- A/M ART- 1 antigen.
- TAA tumor-associated antigen
- the invention also relates to methods for identifying agents that regulate expression of tumor -antigens.
- TIL tumor-infiltrating lymphocytes
- TAA tumor-associated antigens
- TILs show strong in vitro lytic activity which is often directed against targets expressing HLA-A2 and the immunodominant peptide of Melan- A/MART-1 (AAGIGILTV. SEQ ID NO:l) (Kawakami Y. and Rosenberg SA. Int Rev Immunol. 1997. 14: 173-92; Zhai. Y..
- the invention provides methods for identifying agents that modulate expression of tumor-associated antigens in tumor cells.
- the invention also provides agents and pharmaceutical compositions containing such agents that modulate expression of tumor- associated antigens in tumor cells.
- the invention therefore, is particularly useful, inter alia, for treating subjects with autologous. solid tumors having cells that express, or that can be induced to express, tumor-associated antigens.
- One category of materials according to the invention is tumor-antigen expression down-regulating agents. These agents include tumor cell isolates and isolated or substantially purified materials. Another category of materials according to the invention is inhibitors of such agents that down-regulate tumor-antigen expression.
- a malignant melanoma cell isolate that down-regulates Melan- A/MART- 1 expression in malignant melanoma cells when contacted with malignant melanoma cells.
- the cell isolate can be derived from Melan- A MART-1 antigen -expressing and/or -nonexpressing malignant melanoma cells.
- the malignant melanoma cells are low-Melan- A/MART- 1 antigen-expressing cells.
- the cell isolate comprises a polypeptide.
- the cell isolate is a substantially pure polypeptide.
- the substantially pure polypeptide is a polypeptide selected from the group consisting of Oncostatin M.
- the cell isolate is a supernatant, or fraction thereof, of Melan- A/MART- 1 antigen-expressing malignant melanoma cells.
- the cell isolate comprises at least one polypeptide selected from the group consisting of Oncostatin M. Stanniocalcin, and Tissue Factor Pathway
- the malignant melanoma cells express low levels of
- the malignant melanoma cells express high levels of Melan- A/MART- 1 antigen.
- a substantially pure organic agent that down-regulates Melan- A/MART- 1 expression in malignant melanoma cells at effective concentrations.
- the agent is present at effective concentrations in the supernatant of confluent malignant melanoma cells cultured under standard conditions (e.g., flatbed, static culture) for a period of at least one hour.
- the culture conditions include a ratio of 5 x 10 6 cells/ml medium, and the agent is heat sensitive at 80°C, proteinase K sensitive, and binds to and elutes-off blue- and/or red- Sepharose ® (Pharmacia Biotech, Inc., Piscataway, NJ).
- the organic agent is a polypeptide.
- the polypeptide is selected from the group consisting of Oncostatin M. Stanniocalcin, and Tissue Factor Pathway Inhibitor-2.
- the malignant melanoma cells express low levels of Melan- A/MART- 1 antigen. In further embodiments. the malignant melanoma cells express high levels of Melan- A/MART- 1 antigen.
- an isolated organic agent that binds selectively to a malignant melanoma cell isolate that down-regulates Melan- A/MART- 1 expression in malignant melanoma cells, and inhibits down-regulation of Melan- A/MART- 1 expression in malignant melanoma cells.
- the malignant melanoma cell isolate comprises at least one polypeptide.
- the malignant melanoma cell isolate is a substantially pure polypeptide.
- the substantially pure polypeptide is a polypeptide selected from the group consisting of Oncostatin M, Stanniocalcin. and Tissue Factor Pathway Inhibitor-2.
- the isolated binding organic agent is a polypeptide.
- the polypeptide when the isolated binding organic agent is a polypeptide, can be an antibody or an antibody fragment selected from the group consisting of a Fab fragment, a F(ab) fragment, or a fragment including a CDR3 region selective for the polypeptide.
- the antibody or fragment thereof may be chimeric or humanized.
- the antibody can be selected from the group consisting of an anti-Oncostatin-M antibody, an anti-Stanniocalcin antibody. and an anti-Tissue Factor Pathway Inhibitor-2 antibody.
- an isolated binding organic agent which binds selectively to a substantially pure organic agent that down-regulates Melan- A/MART- 1 expression in malignant melanoma cells, and inhibits down-regulation of
- the substantially pure organic agent comprises at least one polypeptide having Melan- A/MART- 1 expression down-regulating properties in malignant melanoma cells.
- the substantially pure organic agent is a substantially pure polypeptide.
- the substantially pure polypeptide is a polypeptide selected from the group consisting of Oncostatin M, Stanniocalcin. and Tissue Factor Pathway Inhibitor-2.
- the isolated binding organic agent is a polypeptide. In yet further embodiments, when the isolated binding organic agent is a polypeptide.
- the polypeptide can be an antibody or an antibody fragment selected from the group consisting of a Fab fragment, a F(ab) fragment, or a fragment including a CDR3 region selective for the polypeptide.
- the antibody or fragment thereof may be chimeric or humanized.
- the antibody can be selected from the group consisting of an anti-Oncostatin-M antibody, an anti- Stanniocalcin antibody, and an anti-Tissue Factor Pathway Inhibitor-2 antibody.
- a pharmaceutical composition includes an isolated binding organic agent which binds selectively to a substantially pure organic agent that down-regulates Melan- A/M ART- 1 expression in malignant melanoma cells.
- the isolated binding organic agent that binds selectively the substantially pure organic agent inhibits such down-regulation, and is present in an effective amount to inhibit such down-regulation.
- the composition also includes a pharmaceutically acceptable carrier.
- a pharmaceutical composition includes an isolated binding organic agent which binds selectively a malignant melanoma cell isolate that down-regulates Melan- A/MART- 1 expression in malignant melanoma cells.
- the isolated binding organic agent that binds selectively the malignant melanoma cell isolate inhibits such down-regulation, and is present in an effective amount to inhibit such down-regulation.
- the composition also includes a pharmaceutically acceptable carrier.
- the invention in another aspect provides a method for isolating a tumor cell-derived tumor-antigen expression down-regulating agent.
- the method involves (a) preparing a culture of tumor cells that have down-regulated tumor-antigen expression, (b) isolating a supernatant or cell isolate suspected of containing a tumor-antigen expression down-regulating agent from the culture of step (a), (c) fractionating the supernatant or cell isolate into a plurality of fractions, (d) contacting a fraction from the plurality of fractions with a tumor-antigen expressing tumor cell, (e) measuring tumor-antigen expression on the tumor-antigen expressing cell, and (f) determining whether tumor-antigen expression on the tumor cell is down-regulated as a result of such contacting, for example, by comparison to a control.
- the origin of the tumor cells may be of: biliary tract cancer; brain cancer, including glioblastomas and medulloblastomas; breast cancer; cervical carcinoma; choriocarcinoma: colon cancer; endometrial cancer: esophageal cancer; gastric cancer; hematological neoplasms, including acute lymphocytic and myelogenous leukemia: multiple myeloma: AIDS associated leukemias and adult T-cell leukemia lymphoma; intraepithelial neoplasms, including Bowen's disease and Page s disease; liver cancer: lung cancer; lymphomas.
- neuroblastomas oral cancer, including squamous cell carcinoma; ovarian cancer, including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells: pancreas cancer; prostate cancer; rectal cancer: sarcomas, including leiomyosarcoma, rhabdomyosarcoma. liposarcoma, fibrosarcoma and osteosarcoma; skin cancer, including melanoma. Kaposi ' s sarcoma, basocellular cancer and squamous cell cancer: testicular cancer, including germinal tumors (seminoma.
- the tumor- antigen can be Melan-A/MART-1.
- Dipeptidyl peptidase IV (DPPIV). adenosine deaminase- binding protein (ADAbp), cyclophilin b, Colorectal associated antigen (CRC)— C017- 1A/GA733.
- Carcinoembryonic Antigen CEA and its immunogenic epitopes CAP-1 and CAP-2, etv6, amll.
- PSA Prostate Specific Antigen
- PSMA prostate-specific membrane antigen
- T-cell receptor/CD3-zeta chain MAGE-family of tumor antigens, GAGE- 1.2, BAGE, RAGE. GnT-V, MUM-1.
- CDK4 tyrosinase. p53. MUC family, HER2/neu, p21ras. RCAS1 , ⁇ -fetoprotein. E-cadherin.
- the fraction from the plurality of fractions can be undiluted or concentrated.
- cancers or tumors escaping immune recognition and tumor-antigens associated with such tumors include acute lymphoblastic leukemia (etv6; amll; cyclophilin b), glioma (E-cadherin: ⁇ -catenin: ⁇ -catenin; ⁇ -catenin; pl20ctn), bladder cancer
- p21ras billiary cancer
- breast cancer MUC family; HER2/neu: c-erbB-2
- cervical carcinoma p53; p21ras
- colon carcinoma p21ras: HER2/neu: c-erbB-2; MUC family
- colorectal cancer Colorectal associated antigen (CRC)— C017-1A/GA733; APC
- CEA choriocarcinoma
- CEA epithelial cell-cancer
- gastric cancer HER2/neu; c- erbB-2; ga733 glycoprotein
- hepatocellular cancer ⁇ -fetoprotein
- hodgkins lymphoma hepatocellular cancer
- lymphoid cell-derived leukemia EBNA-1
- lung cancer CEA: MAGE-3: NY-ESO-1). lymphoid cell-derived leukemia
- cyclophilin b myeloma (MUC family; p21ras), non-small cell lung carcinoma (HER2/neu; c-erbB-2).
- nasopharyngeal cancer lmp-1 : EBNA-1
- ovarian cancer cancer MUC family; HER2/neu; c-erbB-2).
- prostate cancer Prostate Specific Antigen (PSA) and its immunogenic epitopes PSA-1.
- PSA-2. and PSA-3 PSMA: HER2/neu; c-erbB-2), pancreatic cancer (p21ras; MUC family; HER2/neu; c-erbB-2; ga733 glycoprotein).
- HER2/neu c-erbB-2
- testicular cancer NY-ESO-1.
- T cell leukemia HTLV-1 epitopes
- melanoma Melan- A/MART- 1 ; cdc27; MAGE-3: p21ras: gpl00 Pmel 117 ).
- the invention in a further aspect provides a method of screening for tumor-antigen expression modulating agents.
- the method involves (a) contacting an agent suspected of being a tumor antigen expression modulating agent with a tumor-antigen expressing tumor cell, (b) measuring tumor-antigen expression of the tumor cell, and (c) determining whether tumor-antigen expression on the tumor cell is modulated as a result of such contacting, for example, by comparison to a control. Both up-modulating and down-modulating agents can be identified. Tumor cells and tumor-antigens expressed by the tumor cells are as described above.
- the agent suspected of being a tumor-antigen expression modulating agent is an agent present in a tumor cell-culture supernatant, tumor cell eluate, or tumor cell lysate.
- a method for isolating an agent that up-regulates tumor-antigen expression.
- the method includes (a) providing a tumor- antigen expression down-regulating agent which may be isolated according to any of the foregoing methods of the invention, (b) preparing a culture of tumor cells, wherein the tumor cells may be identical to those used in the isolation of the tumor-antigen expression down- regulating agent of (a), (c) contacting the isolated tumor-antigen expression down-regulating agent of (a) and a putative inhibitory agent of the isolated tumor-antigen expression down- regulating agent of (a) with the culture cells of (b), (d) determining tumor-antigen expression in the culture cells, and (e) comparing the tumor-antigen expression determined in (d) with a control.
- Tumor cells and tumor-antigens expressed by the tumor cells are as described above.
- the tumor cells are melanoma cells and the tumor-antigen is Melan- A/MART-1.
- the control tumor-antigen expression is determined in the presence of an agent of (a) and in absence of the putative inhibitory agent of (a).
- a method is provided for enhancing a melanoma-specific immune response in a subject with melanoma.
- the method involves administering to a subject in need of such treatment an isolated binding organic agent which binds selectively to: (i) a substantially pure organic agent, or (ii) a malignant melanoma cell isolate, either of which down-regulates Melan-A/MART-1 expression in malignant melanoma cells when contacted with malignant melanoma cells, in an amount effective to inhibit down- regulation of Melan-A/MART-1 expression in malignant melanoma cells and enhance a melanoma-specific immune response in the subject.
- the isolated binding organic agent is at least one polypeptide.
- the polypeptide is selected from the group consisting of Oncostatin M. Stanniocalcin. and Tissue Factor Pathway Inhibitor-2.
- the method further comprises co-administering to the subject an anti-tumor agent other than the agents of the invention.
- methods for preparing medicaments useful in enhancing a melanoma-specific immune response in a subject with melanoma are also provided.
- Figure 1 shows graphs depicting Melan-A/MART-1 expression on different melanoma tumor lines and the differences culture density has on such expression: Fig. IA on MU-tumor; Fig. IB on MA-tumor; Fig.lC on MO-tumor: Fig. ID control, HLA-I expression on MU-tumor; Fig. IE control. HLA-A2 expression on MU-tumor.
- Figure 2 shows graphs depicting the effect of MART- 1 /Melan- A expression on target cell recognition and lysis by TIL;
- Fig. 2A shows MU-TIL lysis of autologous MU-tumor;
- Fig. 2B shows MU-TIL lysis of Melan- A/MART- 1 -negative targets;
- Fig. 2C shows anti-HLA- A2-specif ⁇ c lysis of targets.
- SEQ ID NO:l is the immunodominant amino acid sequence of the Melan-A/MART-1 peptide.
- SEQ ID NO:2 is a melanocyte lineage-derived peptide for Tyrosinase.
- SEQ ID NO:3 is a melanocyte lineage-derived peptide for Tyrosinase.
- SEQ ID NO:4 is a melanocyte lineage-derived peptide for MAGE-3.
- agents and pharmaceutical compositions containing such agents that modulate expression of tumor-associated antigens in tumor cells can be used, inter alia, in vivo or in vitro, for the purpose of inhibiting growth of a tumor having cells expressing tumor-associated antigens, and in a variety of screening assays in order to identify additional agents that modulate expression of tumor-associated antigens in tumor cells.
- TAA down-modulation is mediated through an agent secreted by the tumor cells (i.e.. autocrine secretion/down-modulation).
- autocrine secretion/down-modulation an agent secreted by the tumor cells
- Down-modulating (down-regulating), refers to inhibition of tumor- antigen (or TAA) expression.
- Inhibition of tumor-antigen expression refers to inhibiting (i.e., reducing to a detectable extent) expression/presentation of the specific antigen intracellularly and/or at the surface of a tumor cell.
- Such inhibition of tumor-antigen expression can be directly determined by detecting a decrease in the level of mRNA for the gene encoding the antigen, or the level of peptide expression of the tumor-antigen, using any suitable means known to the art, such as nucleic acid hybridization or, preferably, antibody detection methods, respectively (see Examples).
- Inhibition of tumor-antigen expression can also be determined indirectly, for example, by detecting a change in tumor-cell lysis ability by TILs that specifically recognize the tumor-antigen.
- the present invention relates in one aspect to a malignant melanoma cell isolate with Melan-A/MART-1 expression down-regulating activity. Therefore, in one important embodiment, the malignant melanoma cell isolate is useful in screening for binding agents that inhibit its activity. Inhibition of the isolate's activity is desirable in melanomas, where the proliferating cells secrete the isolate and down-modulate expression of the Melan-A/MART-1 antigen, to escape immune recognition, and continue to grow and expand.
- isolated means separated from the environment of the cells, such as a supernatant, a lysate. a fraction thereof, etc.
- isolated means separated from its native environment and present in sufficient quantity to permit its identification or use according to the invention. "Isolated” , when referring to a protein or polypeptide. means, for example: (i) selectively produced by expression cloning, or
- Isolated proteins or polypeptides may. but need not be. substantially pure. Because an isolated protein may be admixed with a pharmaceutically acceptable carrier in a pharmaceutical preparation, the protein may comprise only a small percentage by weight of the preparation. The protein is nonetheless isolated in that it has been separated from many of the substances with which it may be associated in living systems, i.e. isolated from certain other proteins.
- the agent that down-regulates Melan-A/MART-1 expression in malignant melanoma cells when contacted with malignant melanoma cells is a substantially pure, native, biological, organic agent.
- the agent is heat sensitive at 80°C. proteinase K sensitive, and binds to and elutes-off blue- and/or Red Sepharose®.
- the substantially pure organic agent is at least one polypeptide.
- the at least one polypeptide with Melan-A/MART-1 expression down-regulating properties in malignant melanoma cells has a molecular weight between about 20kD and about 30 kD, and preferably at about 25kD.
- the agent that down-regulates Melan-A/MART-1 expression in malignant melanoma cells when contacted with malignant melanoma cells is at least one. at least two. or at least three polypeptides. each polypeptide selected from the group consisting of Oncostatin M, Stanniocalcin, and Tissue Factor Pathway Inhibitor-2.
- Oncostatin M is the subject of United States patent 5.618.715 to Shoyab et al., which is expressly incorporated herein by reference.
- Stanniocalcin is the subject of United States patents 5.994,301, 5,877,290, and 5,837,498, and of WO 952441 1. all of which are expressly incorporated herein by reference.
- Tissue Factor Pathway Inhibitor-2 is the subject of United States patents 5,849.875, 5,773,251, 5.576.294. 5.466.783. 5.106.833. and 4.966.852. all of which are expressly inco ⁇ orated herein by reference.
- the malignant melanoma cell isolate can be obtained from a non-homogenous proteinaceous solution such as a cell culture supernatant or cell homogenate.
- Malignant melanoma cells can be isolated from a subject using a tumor biopsy, by disaggregating the biopsy sample, and forming cell suspensions.
- These malignant melanoma cell suspensions can be cultured according to standard cell culture techniques. In small scale, the cultures can be contained in culture plates, flasks, and dishes. In important embodiments, under standard culture conditions (e.g., on typical culture plates, flasks, and dishes that are 'static' -i.e. nonperfused), the culture conditions include a ratio of 5 x 10 6 cells/ml of medium. In larger
- the cultures can be contained in roller bottles, spinner flasks (i.e. 'nonstatic " ) and other large scale culture vessels such as fermenters. Culturing in a three-dimensional, porous, solid matrices, as well as constant perfusion of media conditions may also be used.
- the malignant melanoma cell isolate can be obtained from the supernatants of the above-described cell cultures, although the entire culture can be in homogenized and subjected to the steps described below for isolation of a malignant melanoma cell isolate that down-regulates Melan-A/MART-1 expression in malignant melanoma cells when contacted with malignant melanoma cells.
- the supernatant is removed by aspiration or by centrifugation of the cell culture to remove the cells.
- the cultures can also be filtered to remove cells and cell debris.
- the collected can be obtained from the supernatants of the above-described cell cultures, although the entire culture can be in homogenized and subjected to the steps described below for isolation of a malignant melanoma cell isolate that down-regulates Melan-A/MART-1 expression in malignant melanoma cells when contacted with malignant melanoma cells.
- the supernatant is removed by aspiration or by centrifugation of
- 15 supernatant is (in its entirety) the malignant melanoma cell isolate.
- the malignant melanoma cell supernatant can be fractionated according to standard chromatographic procedures to facilitate further isolation of the desired agent.
- standard chromatographic procedures include, but are not limited to, size-exclusion chromatography, FPLC. HPLC, gel filtration chromatography, ion-exchange 0 chromatography, hydrophobic chromatography, immune-affinity chromatography, electrophoresis. etc.
- the fractions of malignant melanoma cell isolate-containing supernatant then are used to down-regulate Melan-A/MART-1 expression in malignant melanoma cells when contacted with malignant melanoma cells.
- the down-regulating 5 activity of the fraction can be measured as described above, or according to the assays described in greater detail in the Examples. Other suitable methods will be known to one of ordinary skill in the art and can be employed using routine experimentation.
- the fractions which are positive for the malignant melanoma cell isolate can be subjected to additional rounds of screening using the foregoing methodology.
- the purity of o the fraction can be assessed after each round of culture stimulation by subjecting an aliquot of the fraction to SDS-PAGE or other analytical methods for visualizing the mixture of constituents in the fraction.
- the nature of the malignant melanoma cell isolate as a protein, nucleic acid, lipid, carbohydrate etc.. can be confirmed at any time by treating an aliquot of a positive fraction with non-specific degradative enzymes for the foregoing classes of molecules and testing the treated fraction in the same assays detailed above.
- the malignant melanoma cell isolate can then be further purified for the active down- regulating agent, if desired, using immunological and molecular biological methods (see, e.g. Molecular Cloning: A Laboratory Manual J. Sambrook, et al.. eds.. Second Edition. Cold Spring Harbor Laboratory Press. Cold Spring Harbor, New York, 1989. or Current Protocols in Molecular Biology, F.M. Ausubel. et al., eds.. John Wiley & Sons. Inc., New York).
- a fraction positive for one active agent e.g., the agent that is heat sensitive at 80°C, proteinase K sensitive, binds to and elutes-off blue-Sepharose®.
- the fraction can be subjected to SDS-PAGE, transferred to a membrane such as polyvinylidene fluoride by electroblotting, and N-terminal amino sequence determined by Edman degradation, mass spectroscopy, etc.
- a membrane such as polyvinylidene fluoride by electroblotting, and N-terminal amino sequence determined by Edman degradation, mass spectroscopy, etc.
- Any sequence information can be used to screen databases for homology to existing proteins and also to generate degenerate nucleic acids useful for screening a cDNA library by standard methods such as colony hybridization or polymerase chain reaction.
- the positive fraction can be used to generate antibodies which recognize the malignant melanoma cell isolate.
- Such antibodies can then be used in expression cloning protocols, Western blots, and other techniques useful in isolation of the malignant melanoma cell isolate.
- any cDNA libraries, expression libraries, etc.. are preferably created from malignant melanoma cells.
- the malignant melanoma cell isolate comprises at least one, at least two. or at least three polypeptides. each polypeptide selected from the group consisting of Oncostatin M, Stanniocalcin. and Tissue Factor Pathway Inhibitor-2.
- the invention also makes it possible to isolate agents which bind to the malignant melanoma cell isolate as disclosed herein, including antibodies and cellular binding partners of the malignant melanoma cell isolate, such as receptors or ligands.
- the malignant melanoma cell isolate or active agent with down-regulating activity is substantially pure, it can be used, for example, to generate polyclonal or monoclonal antibodies according to standard methods (see e.g., Harlow and Lane. eds.. Antibodies: A Laboratory Manual Cold Spring Harbor Press. Cold Spring Harbor. NY, 1988)
- the organic agents which bind to the active agent in the malignant melanoma cell isolate can be used, for example, in screening assays to detect the presence or absence of the active agent in the malignant melanoma cell isolate and complexes of the active agents and their respective binding partners, and in purification protocols to isolate the active agent in the malignant melanoma cell isolate.
- the binding organic agents also can be used to block the effects of the agent down-regulating TAA expression in malignant melanoma cells.
- the invention therefore, embraces organic binding agents which, for example, can be antibodies or fragments of antibodies having the ability to selectively bind the active agent(s) in malignant melanoma cell isolates and inhibit the Melan-A/MART-1 expression down- modulating properties of the agent(s) in the isolate.
- the organic binding agents are peptides.
- the peptide binding agents bind selectively to the ⁇ 25kD polypeptide with Melan-A/MART-1 expression down- modulating activity and inhibit down-modulation of Melan-A/MART-1 expression in malignant melanoma cells, thereby allowing TILs and other cells of the immune system to recognize the malignant melanoma cells as foreign leading to their elimination.
- the organic binding peptides can be antibodies, including polyclonal and monoclonal antibodies, prepared according to conventional methodology.
- the organic binding peptides are antibodies that bind to one or more polypeptides. each polypeptide selected from the group consisting of Oncostatin M, Stanniocalcin. and Tissue Factor Pathway Inhibitor-2.
- Anti-Oncostatin-M antibodies are known in the art. and include Mouse and Goat anti- human Oncostatin M from Research Diagnostics. Flanders. NJ.
- Anti-stanniocalcin antibodies and methods of preparing such antibodies are known in the art, some of which are described in detail in United States patent 5.877.290 to Olsen.
- Anti-Tissue Factor Pathway Inhibitor antibodies are also known in the art. and include sheep anti-human Tissue Factor Pathway Inhibitor antibodies from Enzyme Research Laboratories. South Bend, IN.
- an antibody from which the pFc' region has been enzymatically cleaved, or which has been produced without the pFc * region designated an F(ab') fragment
- an antibody from which the Fc region has been enzymatically cleaved, or which has been produced without the Fc region designated an Fab fragment
- Fab fragments consist of a covalently bound antibody light chain and a portion of the antibody heavy chain denoted Fd.
- the Fd fragments are the major determinant of antibody specificity (a single Fd fragment may be associated with up to ten different light chains without altering antibody specificity) and Fd fragments retain epitope-binding ability in isolation.
- CDRs complementarity determining regions
- FRs framework regions
- CDRl through CDR3 complementarity determining regions
- the present invention also provides for F(ab') 2 , Fab, Fv and Fd fragments: chimeric antibodies in which the Fc and/or FR and/or CDRl and/or CDR2 and/or light chain CDR3 regions have been replaced by homologous human or non-human sequences: chimeric F(ab " ) 2 fragment antibodies in which the FR and/or CDRl and/or CDR2 and/or light chain CDR3 regions have been replaced by homologous human or non-human sequences: chimeric Fab fragment antibodies in which the FR and/or CDRl and/or CDR2 and/or light chain CDR3 regions have been replaced by homologous human or non-human sequences: and chimeric Fd fragment antibodies in which the FR and or CDRl and/or CDR2 regions have been replaced by homologous human or non-human sequences.
- the present invention also includes so-called single chain antibodies.
- the invention involves polypeptides of numerous size and type that bind specifically to the active agent in the malignant melanoma cell isolate, and complexes of both the active agent in the malignant melanoma cell isolate and its binding partners.
- These specifically binding polypeptides may be derived also from sources other than antibody technology.
- polypeptide binding agents can be provided by degenerate peptide libraries which can be readily prepared in solution, in immobilized form or as phage display libraries.
- Combinatorial libraries also can be synthesized of peptides containing one or
- Libraries further can be synthesized of peptides and non-peptide synthetic moieties.
- antibodies and other binding molecules may be used for example to identify tissues expressing protein or to purify protein.
- Antibodies also may be coupled to specific diagnostic labeling agents for imaging of cells and tissues that express the
- the agent which is a tumor-antigen expression down-regulating agent is an agent present in a tumor cell culture supernatant, tumor cell eluate. and/or tumor cell lysate.
- the tumor cell may be of a cancer or tumor type thought to escape immune recognition.
- cancers or tumors may be of the folowing origin: biliary tract cancer; brain cancer, including
- glioblastomas and medulloblastomas breast cancer; cervical carcinoma: choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric cancer: hematological neoplasms, including acute lymphocytic and myelogenous leukemia; multiple myeloma; AIDS associated leukemias and adult T-cell leukemia lymphoma: intraepithelial neoplasms, including Bowen's disease and Paget ' s disease; liver cancer; lung cancer: lymphomas,
- 2o including Hodgkin's disease and lymphocytic lymphomas; neuroblastomas; oral cancer, including squamous cell carcinoma: ovarian cancer, including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells: pancreas cancer; prostate cancer; rectal cancer: sarcomas, including leiomvosarcoma, rhabdomyosarcoma. liposarcoma. fibrosarcoma and osteosarcoma; skin cancer, including melanoma, Kaposi's sarcoma, basocellular cancer
- tumor-antigen can be Melan- A/MART-1.
- Dipeptidyl peptidase IV (DPPIV), adenosine deaminase-binding protein in (ADAbp), cyclophilin b, Colorectal associated antigen (CRC)-C017-1A/GA733, Carcinoembryonic Antigen (CEA) and its immunogenic epitopes CAP-1 and CAP-2. etv6, amll.
- Prostate Specific Antigen (PSA) and its immunogenic epitopes PSA-1. PSA-2, and PSA-3.
- PSMA prostate-specific membrane antigen
- T-cell receptor/CD3-zeta chain MAGE- family of tumor antigens. GAGE- 1.2. BAGE, RAGE. GnT-N, MUM-1. CDK4.
- the fraction from the plurality of fractions can be undiluted or concentrated.
- cancers or tumors escaping immune recognition and tumor- antigens associated with such tumors include acute lymphoblastic leukemia (etv6; amll ; cyclophilin b), glioma (E-cadherin; ⁇ -catenin; ⁇ -catenin; ⁇ -catenin: pl20ctn), bladder cancer (p21ras), billiary cancer (p21ras), breast cancer (MUC family;
- HER2/neu c-erbB-2
- testicular cancer NY-ESO-1
- T cell leukemia HTLV- 1 epitopes
- melanoma Melan-A/MART-1 ; cdc27; MAGE-3; p21ras; gpl00 Pmel 1 17 .
- a subject is a human, non-human primate, cow. horse, pig. sheep, goat, dog, cat or rodent. In all embodiments, human subjects are preferred.
- the isolated Melan-A/MART- 1 expression down- modulation inhibitors of the invention are administered in therapeutically effective amounts.
- a therapeutically effective amount means that amount necessary to delay the onset
- a therapeutically effective amount will vary with the subject ' s age. condition, and sex. as well as the nature and extent of the disease in the subject, all of which can be determined by one of ordinary skill in the art.
- the dosage may be adjusted by the individual physician or veterinarian, particularly in the event of any complication.
- a therapeutically effective amount typically varies from 0.01 mg/kg to about 1000 mg/kg. preferably from about
- the therapeutically effective amount of the isolated Melan-A/MART-1 expression down-modulation inhibitors of the invention is that amount effective to inhibit Melan- A/MART-1 antigen expression down-modulation, and can be determined using, for example, standard tests known in the art.
- a direct way to measure tumor-antigen (e.g., Melan-A/MART-1) expression the tumor cell (e.g.. melanoma) is to use antibodies specific for the tumor-antigen and a number of immunocyto- and immunohisto- chemical protocols well known in the art.
- Antibodies specific for the Melan-A/MART-1 antigen for example, are fully described in U.S. Patent 5,674,749 to Chen et al, entitled: "Monoclonal antibodies which bind to tumor rejection antigen precursor Melan-A. and uses thereof.
- the isolated Melan-A/MART-1 expression down-modulation inhibitors of the invention may be co-administered with an anti-cancer agent other than an agent of the invention (e.g., other than an isolated Melan-A/MART-1 expression down-modulation inhibitor), that can act cooperatively, additively or synergistically with an agent of the invention, for treating or preventing cancers that express (and. it is believed, through autocrine secretions down-modulate) tumor-antigens.
- co-administered means administered substantially simultaneously with another agent (e.g., in different or same compositions/formulations).
- a Melan- A/MART-1 expression down-modulation inhibitor of the invention is administered to the subject close enough in time with the administration of the other agent (e.g., an anti-cancer agent) whereby the two agents may exert an additive or even synergistic effect to upregulate Melan-A/MART-1 expression and inhibit growth and/or proliferation of the cancer.
- the other agent e.g., an anti-cancer agent
- Anti-cancer agents other than agents of the invention include, but are not limited to: Acivicin: Aclarubicin: Acodazole Hydrochloride; Acronine; Adozelesin; Aldesleukin: Altretamine; Ambomycin; Ametantrone Acetate: Aminoglutethimide: Amsacrine: Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine: Azetepa: Azotomycin: Batimastat; Benzodepa: Bicalutamide; Bisantrene Hydrochloride: Bisnafide Dimesylate: Bizelesin; Bleomycin Sulfate: Brequinar Sodium: Bropirimine; Busulfan: Cactinomycin; Calusterone; Caracemide; Carbetimer; Carboplatin: Carmustine: Carubicin Hydrochloride; Carzelesin; Cedefmgol: Chlorambucil; Cirolemycin
- Enpromate Epipropidine; Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride;
- Etoprine Fadrozole Hydrochloride
- Fazarabine Fenretinide: Floxuridine
- Interferon Alfa-2a Interferon Alfa-2b; Interferon Alfa-nl ; Interferon Alfa-n3: Interferon Beta-I a; Interferon Gamma-I b: Iproplatin: Irinotecan Hydrochloride: Lanreotide Acetate; Letrozole: Leuprolide Acetate: Liarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride; Masoprocol: Maytansine; Mechlorethamine Hydrochloride; Megestrol Acetate: Melengestrol Acetate: Melphalan: Menogaril: Mercaptopurine; Methotrexate: Methotrexate Sodium; Metoprine: Meturedepa; Mitindomide; Mitocarcin; Mitocromin: Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochloride: Mycophenolic Acid; Nocodazole
- the above-described drug therapies are well known to those of ordinary skill in the art and are administered by modes known to those of skill in the art.
- the drug therapies are administered in amounts which are effective to achieve the physiological goals in combination with the isolated Melan-A/MART-1 expression down-modulation inhibitors of the invention.
- An isolated Melan-A/MART-1 expression down-modulation inhibitor tumor-antigen
- TAA TAA expression upregulating molecule
- a pharmaceutical composition may include the isolated Melan-A/MART-1 expression down- modulation inhibitor in combination with any standard physiologically and/or pharmaceutically acceptable carriers which are known in the art.
- the compositions can be sterile and contain a therapeutically effective amount of the isolated Melan-A/MART-1 expression down-modulation inhibitor in a unit of weight or volume suitable for administration to a patient.
- pharmaceutically-acceptable carrier as used herein means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration into a human or other animal.
- carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
- the components of the pharmaceutical compositions also are capable of being co-mingled with the molecules of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.
- Pharmaceutically acceptable further means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism.
- the characteristics of the carrier will depend on the route of administration.
- Physiologically and pharmaceutically acceptable carriers include diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials which are well known in the art.
- a variety of administration routes are available. The particular mode selected will depend, of course, upon the particular drug selected, the severity of the condition being treated, and the dosage required for therapeutic efficacy.
- the methods of the invention may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects.
- modes of administration include oral, rectal, topical, nasal, intradermal. or parenteral routes.
- parenteral includes subcutaneous, intravenous, intramuscular, or infusion. Intravenous or intramuscular routes are not particularly suitable for long-term therapy and prophylaxis. They could, however, be preferred in emergency situations. Oral administration will be preferred for prophylactic treatment because of the convenience to the patient as well as the dosing schedule.
- compositions suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the isolated Melan-A/MART-1 expression down-modulation inhibitor, which is preferably isotonic with the blood of the recipient.
- This aqueous preparation may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation also may be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1.3-butane diol.
- the acceptable vehicles and solvents that may be employed are water. Ringer ' s solution, and isotonic sodium chloride solution. In addition.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or di-glycerides.
- fatty acids such as oleic acid may be used in the preparation of injectables.
- Carrier formulations suitable for oral, subcutaneous, intravenous, intramuscular, etc. administrations can be found in Remington's Pharmaceutical Sciences. Mack Publishing Co.. Easton, PA.
- compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy. All methods include the step of bringing the isolated Melan-A/MART-1 expression down-modulation inhibitor into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the isolated Melan-A/MART-1 expression down-modulation inhibitor into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
- compositions suitable for oral administration may be presented as discrete units, such as capsules, tablets, lozenges, each containing a predetermined amount of the isolated Melan- A/MART- 1 expression down-modulation inhibitor.
- Other compositions include suspensions in aqueous liquids or non-aqueous liquids such as a syrup, elixir or an emulsion.
- Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the isolated Melan- A/MART-1 expression down-modulation inhibitors described above, increasing convenience to the subject and the physician.
- Many types of release delivery systems are available and known to those of ordinary skill in the art. They include the above-described polymeric systems, as well as polymer base systems such as poly(lactide-glycolide). copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules of the foregoing polymers containing drugs are described in. for example. U.S. Patent 5.075.109.
- Delivery systems also include non-polymer systems that are: lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono- di- and tri-glycerides: hydrogel release systems; sylastic systems: peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants: and the like.
- lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono- di- and tri-glycerides
- hydrogel release systems sylastic systems: peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants: and the like.
- Specific examples include, but are not limited to: (a) erosional systems in which the isolated Melan-A/MART-1 expression down-modulation inhibitor is contained in a form within a matrix such as those described in U.S. Patent Nos. 4,452,775.
- pump-based hardware delivery systems can be used, some of which are adapted for implantation.
- Long-term sustained release means that the implant is constructed and arranged to delivery therapeutic levels of the active ingredient for at least 30 days, and preferably 60 days.
- Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.
- the invention also embraces methods for isolating tumor cell-derived tumor-antigen expression down-regulating agents.
- a method according to this aspect of the invention typically involves: (a) preparing a culture of tumor cells that have down-regulated tumor- antigen expression, (b) isolating a supernatant or cell isolate suspected of containing a tumor- antigen expression down-regulating agent from the culture of tumor cells that have down- regulated tumor-antigen expression, (c) fractionating the supernatant or cell isolate into a plurality of fractions, (d) contacting a fraction from the plurality of fractions with a tumor- antigen expressing tumor cell, (e) measuring tumor-antigen expression on the tumor-antigen expressing cell, and (f) determining whether tumor-antigen expression on the tumor cell is down-regulated as a result of such contacting, for example, by comparison to a control.
- the tumor-antigen expressing cells contacted in step (d) with the supernatants (cell isolates, or fractions thereof) of the cultures of tumor cells that have down-regulated tumor- antigen expression cells of step (a), are of the same origin (i.e.. patient/tissue/cell line source) with the tumor cells that have down-regulated tumor-antigen expression cells of step (a), the only difference being that the tumor-antigen expressing cells still express the tumor-antigen.
- the origin of the tumor cells may be of: biliary tract cancer; brain cancer, including glioblastomas and medulloblastomas: breast cancer; cervical carcinoma; choriocarcinoma: colon cancer; endometrial cancer: esophageal cancer; gastric cancer; hematological neoplasms, including acute lymphocytic and myelogenous leukemia: multiple myeloma; AIDS associated leukemias and adult T-cell leukemia lymphoma: intraepithelial neoplasms, including Bowen ' s disease and Paget ' s disease: liver cancer: lung cancer: lymphomas.
- Hodgkin ' s disease and lymphocytic lymphomas neuroblastomas
- oral cancer including squamous cell carcinoma
- ovarian cancer including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells
- pancreas cancer prostate cancer
- rectal cancer sarcomas, including leiomvosarcoma. rhabdomyosarcoma. liposarcoma. fibrosarcoma and osteosarcoma
- skin cancer including melanoma, Kaposi ' s sarcoma, basocellular cancer and squamous cell cancer
- testicular cancer including germinal tumors (seminoma.
- the tumor- antigen can be Melan-A/MART-1, Dipeptidyl peptidase IV (DPPIV), adenosine deaminase- binding protein (ADAbp), cyclophilin b, Colorectal associated antigen (CRC)— C017- 1A/GA733.
- DPPIV Dipeptidyl peptidase IV
- ADAbp adenosine deaminase- binding protein
- CRC Colorectal associated antigen
- PSA Prostate Specific Antigen
- PSMA prostate-specific membrane antigen
- T-cell receptor/CD3-zeta chain MAGE-family of tumor antigens. GAGE- 1.2. BAGE. RAGE. GnT-V. MUM-1, CDK4. tyrosinase. p53, MUC family, HER2/neu, p21ras, RCASl, ⁇ -fetoprotein. E-cadherin. ⁇ - catenin, ⁇ -catenin and ⁇ -catenin, pl20ctn. gpl00 Pmel 117 , PRAME, NY-ESO-1, cdc27.
- the fraction from the plurality of fractions can be undiluted or concentrated.
- cancers or tumors escaping immune recognition and tumor- antigens associated with such tumors include acute lymphoblastic leukemia (etv ⁇ : amll: cyclophilin b), glioma (E-cadherin; ⁇ -catenin; ⁇ -catenin: ⁇ -catenin; pl20ctn).
- bladder cancer p21ras
- billiary cancer p21ras
- breast cancer MUC family: HER2/neu: c-erbB-2).
- cervical carcinoma p53; p21ras).
- colon carcinoma p21ras: HER2/neu: c-erbB-2; MUC family
- colorectal cancer Colorectal associated antigen (CRC)— CO 17- 1A/GA733; APC
- CEA choriocarcinoma
- CEA epithelial cell-cancer
- gastric cancer HER2/neu; c-erbB-2; ga733 glycoprotein
- ⁇ -fetoprotein hepatocellular cancer
- hodgkins lymphoma lmp-1 ; EBNA-1).
- lung cancer CEA; MAGE-3; NY-ESO-1). lymphoid cell-derived leukemia (cyclophilin b), myeloma (MUC family; p21ras).
- non-small cell lung carcinoma HER2/neu: c-erbB-2
- nasopharyngeal cancer lmp-1 : EBNA-1.
- ovarian cancer cancer MUC family: HER2/neu; c-erbB-2).
- prostate cancer Prostate Specific Antigen (PSA) and its immunogenic epitopes PSA-1.
- pancreatic cancer p21ras; MUC family: HER2/neu; c-erbB-2; ga733 glycoprotein).
- renal HER2/neu: c-erbB-2
- testicular cancer NY-ESO-1).
- T cell leukemia HTLV-1 epitopes).
- the fraction from the plurality of fractions can be undiluted or concentrated.
- the tumor cell isolate can be obtained from a non-homogenous proteinaceous solution such as a cell culture supernatant or a cell homogenate.
- Tumor cells can be isolated from a subject using a tumor biopsy, by disaggregating the biopsy sample, and forming cell suspensions. These tumor cell suspensions can be cultured according to standard cell culture techniques. In small scale, the cultures can be contained in culture plates, flasks, and dishes.
- a ratio of 5 x 10 cells/ml of medium is typically sufficient to yield an active agent according to the invention, enough so that its effects could be demonstrated.
- the foregoing "typical" ratio of cells/ml of medium can of course vary according to the cell type, the stage of the tumor, etc., and a person of ordinary skill in the art can easily determine the optimal culture conditions on a per individual cell type basis utilizing routine experimentation. Such conditions will also vary when larger scale cell cultures are employed (e.g., use of roller bottles, spinner flasks, fermenters, three-dimensional, porous, solid matrices, as well as constant perfusion of media conditions).
- the tumor cell isolate can be obtained from the supernatants of the above-described cell cultures [i.e.. of the cultured cells of step (a)], although the entire culture can be homogenized and subjected to the steps described below for isolation of a tumor cell isolate that down-regulates tumor-antigen expression when contacted with tumor cells that express a tumor antigen.
- the supernatant is removed by aspiration or by centrifugation of the cell culture to remove the cells.
- the cultures can also be filtered to remove cells and cell debris.
- the collected supernatant is (in its entirety) the tumor cell isolate.
- the tumor cell supernatant can be fractionated according to standard chromatographic procedures to facilitate further isolation of the desired agent.
- the fractions of tumor cell isolate-containing supernatant then are used to down-regulate tumor-antigen expression in tumor cells when contacted with the tumor cells.
- the down-regulating activity of the fraction can be measured according to assays described elsewhere herein. Other suitable methods will be known to one of ordinary skill in the art and can be employed using routine experimentation.
- Typical controls include identically isolated and cultured cells, with the exception that the supernatant medium in the control cultures is removed at regular intervals during the culture period (e.g. every 2-6 hours), being replaced with fresh culture medium. This media change effectively eliminates any down-regulatory effects a control-tumor cell isolate may exert on the control-tumor cell tumor-antigen expression.
- the fractions which are positive for the tumor cell isolate can be subjected to additional rounds of screening using the foregoing methodology.
- the purity of the fraction can be assessed after each round of culture stimulation by subjecting an aliquot of the fraction to SDS-PAGE or other analytical methods for visualizing the mixture of constituents in the fraction.
- the nature of the tumor cell isolate as a protein, nucleic acid, lipid. carbohydrate etc. can be confirmed at any time by treating an aliquot of a positive fraction with nonspecific degradative enzymes for the foregoing classes of molecules and testing the treated fraction in the same assays detailed above.
- the tumor cell isolate can then be further purified for the active down-regulating agent, if desired, using immunological and molecular biological methods (.see, e.g.
- the invention in a further aspect provides a method of screening for tumor-antigen expression modulating agents.
- the method involves (a) contacting an agent suspected of being a tumor antigen expression modulating agent with a tumor-antigen expressing tumor cell, (b) measuring tumor-antigen expression of the tumor cell, and (c) determining whether tumor-antigen expression on the tumor cell is modulated as a result of such contacting, for example, by comparison to a control. Both up-modulating and down-modulating agents can be identified using such methods.
- Tumor cells and tumor-antigens expressed by the tumor cells are as described above.
- the agent suspected of being a tumor- antigen expression modulating agent is an agent present in a tumor cell-culture supernatant. tumor cell eluate. or tumor cell lysate.
- a method for isolating an agent that up-regulates tumor-antigen expression.
- the method involves (a) providing a tumor- antigen expression down-regulating agent which may be isolated according to any of the foregoing methods of the invention, (b) preparing a culture of tumor cells, wherein the tumor cells may be identical (as to the patient/tissue/cell line source) to those used in the isolation of the tumor-antigen expression down-regulating agent which may be isolated according to any of the foregoing methods of the invention, (c) contacting the isolated tumor-antigen expression down-regulating agent and its putative inhibitory agent with the culture cells of step (b), (d) determining tumor-antigen expression in the culture cells, and (e) comparing the tumor- antigen expression determined in (d) with a control.
- Tumor cells and tumor-antigens expressed by the tumor cells are as described above.
- the tumor cells are melanoma cells and the tumor-antigen is Melan-A/MART-1.
- the control tumor-antigen expression is determined in the presence of an agent of (a) and in absence of the putative inhibitory agent of (a). Controls typically include cultures similar to the foregoing control cultures described earlier.
- the method involves contacting the isolated tumor-antigen expression down-regulating agent and its putative inhibitory agent with a culture of tumor cells, wherein the tumor cells may be identical (as to the patient/tissue/cell line source) to those used in the isolation of the tumor-antigen expression down-regulating agent.
- a plurality of cultures are run in parallel, each culture containing different concentrations of the putative inhibitory agent in order to obtain a different level of tumor- antigen expression.
- one of these concentrations serves as a negative control, i.e.. at zero concentration of agent or at a concentration of agent below the limits of assay detection.
- Putative inhibitory agents encompass numerous chemical classes, although typically they are organic compounds.
- the putative inhibitory agents are small organic compounds, i.e.. those having a molecular weight of more than 50 yet less than about 2500. preferably less than about 1000 and. more preferably, less than about 500.
- Putative inhibitory agents comprise functional chemical groups necessary for structural interactions with polypeptides and/or nucleic acids, and typically include at least an amine. carbonyl, hydroxyl or carboxyl group, preferably at least two of the functional chemical groups and more preferably at least three of the functional chemical groups.
- the putative inhibitory agents can comprise cyclic carbon or heterocyclic structure and/or aromatic or polyaromatic structures substituted with one or more of the above-identified functional groups. Putative inhibitory agents also can be biomolecules such as peptides.
- the putative inhibitory agents are polypeptides that bind the isolated tumor-antigen expression down-regulating agent (e.g.. antibodies).
- the agent is a nucleic acid
- the agent typically is a DNA or RNA molecule, although modified nucleic acids as defined herein are also contemplated.
- Putative inhibitory agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides, synthetic organic combinatorial libraries, phage display libraries of random peptides, and the like. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural and synthetically produced libraries and compounds can be readily be modified through conventional chemical, physical, and biochemical means. Further, known pharmacological agents may be subjected to directed or random chemical modifications such as acylation. alkylation. esterification. amidification. etc. to produce structural analogs of the agents.
- reagents also can be included in the culture media. These include reagents such as neutral proteins (e.g., albumin), etc., which may be used to facilitate optimal protein-protein and/or protein-nucleic acid binding. Such a reagent may also reduce nonspecific or background interactions of the reaction components. Other reagents that improve the efficiency of the culture assay such as protease inhibitors, nuclease inhibitors, antimicrobial agents, and the like may also be used, provided that the reagents do not adversely affect the growth of the cells in the culture.
- neutral proteins e.g., albumin
- Other reagents that improve the efficiency of the culture assay such as protease inhibitors, nuclease inhibitors, antimicrobial agents, and the like may also be used, provided that the reagents do not adversely affect the growth of the cells in the culture.
- incubation temperature typically is between 4°C and 40°C.
- Incubation times preferably are minimized to facilitate rapid, high throughput screening, and typically are between 0.1 and 10 hours.
- tumor-antigen expression down- regulating agent and its putative inhibitory agent are added to the tumor cell culture and after further incubation at cell culture conditions (typically between 1 and 48 hours), tumor-antigen expression is detected by any convenient method available to the user, supra.
- TIL Tumor and Tumor Infiltrating Lymphocytes
- TIL tumor infiltrating lymphocytes
- MU, MO, MA and EW were obtained from cutaneous metastatic melanoma deposits and some (MU, MO and MA), were previously described (Pandolfi F, et al., Clin. Exp. Immunol 1994, 95:141-7; Pandolfi F, et al., Cancer Res, 1991, 51:3164-3170).
- MU, MO and MA cutaneous metastatic melanoma deposits and some (MU, MO and MA)
- Pandolfi F et al., Clin. Exp. Immunol 1994, 95:141-7
- Pandolfi F et al., Cancer Res, 1991, 51:3164-3170.
- MU-X were obtained by culture of MU tumor cells at high density (>5xl0 cells/ml) for several days prior to immunoselection with anti-Melan- A/MART-1 specific TIL.
- Conditioned medium from melanoma tumor lines were generated by culturing cells at
- TIL were assayed for the ability to lyse melanoma target cells in 4 hour Cr-release assays as previously described (Hishii M, et al., Proc. Natl. Acad Sci USA. 1997, 94:1378- 1383).
- the melanoma target cells with high constitutive expression of Melan-A/MART-1 were generated by low density culture (1-2 x 10 /ml) were compared with respect to their susceptibility to cytolysis with the same cells cultured for 3 to 6 days in the presence of conditioned medium from the Melan-A/MART-1 negative variant, MU-X. to derive target cells with low Melan-A/MART-1 expression.
- EBV- transformed B lymphocyte targets EBV-3 (HLA-A1. B8. DR3). EBV-19 (HLA-A2. B18. 51
- TIL Tumor Infiltrating T Lymphocytes
- the IL-2 responding TIL propagated from patient MU were over 98% CD3+, CD8+, (CD4-) T cells expressing the ⁇ TCR. As previously reported (Pandolfi F. et al., Clin. Exp.
- Tumour target lysis is shown a follows: ⁇ 10% specific lysis: -; 10-20%: + : 20-40%: ++ ;
- MU-9 which lysed autologous melanoma targets could not be recovered from the freezer for testing for fine specificity with the melanoma peptides. although its TCR was identical to MU- 1 15, indicating that MU-9 was also likely to be Melan-A/MART-1 peptide specific. As noted, clones MU-45, MU-63 and MU-79 were identical to one another as determined by TCR gene is sequencing.
- the diminution of expression of the Melan-A/MART-1 antigen 5 correlated with reduced susceptibility of the target cells to lysis by HLA-A2-restricted, Melan- A/MART-1 -specific CTL.
- the level of Melan-A/MART-1 antigen expression by tumor cells diminished, while levels of HLA-A2 cell surface expression did not decrease, the T cell recognition of these targets decreased.
- the target cells were pulsed with the Melan-A/MART-1 peptide (AAGIGILTV. SEQ ID NO:l) (Chen Y, et al.. Proc Natl Acad 0 Sci USA, 1996. 93:5915-5919; Mattei. S.. et al..
- the Melan-A/MART-1 silencing activity could be heat inactivated by treatment of the supernatants at 80°C for 60 minutes. A similar treatment at 60°C did not influence the activity. o To define this silencing activity in more detail, an assessment of cytokine and chemokine production by tumor cells which lacked Melan-A/MART-1 protein expression was performed. These Melan-A/MART-1 silencing supernatants were found to contain several known cytokines. but they lacked TNF ⁇ . which has been demonstrated to have a partial down- regulatory activity directed at the Melan-A/MART-1 promoter (Butterfield. L. H., et al.. Gene, 5 1997. 191:129-34).
- Material purified by binding and elution from Red Sepharose, followed by binding and elution to Con-A-Sepharose, can be size fractionated on G-50 Sephadex. with the activity centering at approximately 25kD.
- the "activity” parallels the appearance of a "band” on polyacrylamide gel electrophoresis of material fractionated on G-50 Sephadex.
- tryptic digest sequence analysis (performed at Harvard MicroChemistry, Cambridge, MA) showed the presence of sequences corresponding to at least 7 different human proteins. Some of these proteins include Oncostatin-M (OSM), stanniocalcin (STC), and tissue factor pathway inhibitor-2 (TFPI-2).
- OSM Oncostatin-M
- STC stanniocalcin
- TFPI-2 tissue factor pathway inhibitor-2
- Recombinant Oncostatin-M shows "antigen-silencing" activity when tested on the human melanoma cell line, "MU-89" (James T. Kurnick. Massachusetts General Hospital).
- OSM Oncostatin-M
- MU-89 human melanoma cell line
- recombinant OSM causes down-modulation of Melan-A/MART-1 expression comparable to that of "active" supernatants isolated from human melanoma cell lines, such as the EW tumor cell line (James T. Kurnick. Massachusetts General Hospital).
- the down modulation of Melan-A/MART-1 on the MU-89 cell line minimal to undetectable.
- a commercially available polyclonal antibody (Research Diagnostics, Flanders, NJ) to OSM can block the activity of the recombinant OSM.
- the same polyclonal antibody can block the activity of the most purified fraction of EW-supernatant which had been purified by Red Sepharose binding and elution. followed by binding to and elution from Con-A— Sepharose, and fractionation on G-50 Sephadex. to isolate material of approximately 25kD.
- the same polyclonal anti-OSM antibody which blocks recombinant OSM and "purified" fractions from EW-supernatant can only partially (approximately 50%) block the unfractionated EW- supernatant.
- OSM-depleted EW-supernatant fluid (produced by passage over an anti-OSM immuno-affmity column ) is still active in down-modulating
- EW-supernatants (as determined by quantitative ELISA) is approximately 1 ng/ml. yet the antigen-silencing activity of this material is equivalent of recombinant OSM at a dose of
- Oncostatin-M a known cytokine, with well-characterized structure, and several known functions, is capable of mediating antigen-silencing in the melanoma system we have investigated, however, an additional molecule or molecules produced by melanoma cells are also able to manifest antigen silencing.
- Antibodies to the receptor for Oncostatin-M reported to neutralize the OSM activity in other assay systems, do not block the antigen silencing activity of either purified, recombinant OSM or of the EW-supernatant.
- the gpl 30 molecule is reported to be a shared chain in the OSM receptor, the
- Oncostatin-M. and other molecules capable of manifesting antigen-silencing activity may act through additional receptors. including, but not limited to. oncostatin-M binding receptor molecules.
- Oncostatin-M is produced by at least one melanoma cell line (EW), (detectable protein was demonstrated by ELISA), and mRNA transcripts can be isolated from several melanoma cell lines. Melanomas and melanocytes have nto been previously known to express oncostatin-
- Antigen-silencing activity can be demonstrated from many different melanoma cell lines, including Melan-A/MART-1 negative cell lines, and from PMA-stimulated U937, a pro-monocytic leukemic cell line which can be shown to produce Oncostatin-M.
- Oncostatin-M can be used at several fold the dose needed to manifest antigen-silencing (use up to lOOng/ml) without causing significant cellular toxicity, but EW supernatants contain significant toxic activities. even in partially purified fractions, indicating that additional factors are influencing the cellular viability and phenotype.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Microbiology (AREA)
- Zoology (AREA)
- Cell Biology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Hematology (AREA)
- Biotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Toxicology (AREA)
- Biophysics (AREA)
- Oncology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Wood Science & Technology (AREA)
- Urology & Nephrology (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Pathology (AREA)
- Physics & Mathematics (AREA)
- Food Science & Technology (AREA)
- Analytical Chemistry (AREA)
- General Engineering & Computer Science (AREA)
- General Physics & Mathematics (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002388517A CA2388517A1 (en) | 1999-11-16 | 2000-11-15 | Compositions and methods for regulating tumor-associated antigen expression |
JP2001538961A JP2003515535A (en) | 1999-11-16 | 2000-11-15 | Compositions and methods for modulating tumor-associated antigen expression |
AU20432/01A AU2043201A (en) | 1999-11-16 | 2000-11-15 | Compositions and methods for regulating tumor-associated antigen expression |
EP00983714A EP1232178A2 (en) | 1999-11-16 | 2000-11-15 | Compositions and methods for regulating tumor-associated antigen expression |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16580699P | 1999-11-16 | 1999-11-16 | |
US60/165,806 | 1999-11-16 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2001036472A2 true WO2001036472A2 (en) | 2001-05-25 |
WO2001036472A3 WO2001036472A3 (en) | 2002-01-10 |
Family
ID=22600560
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/NL2000/000835 WO2001036461A2 (en) | 1999-11-16 | 2000-11-15 | Compositions and methods for regulating tumor-associated antigen expression |
PCT/US2000/031508 WO2001035903A2 (en) | 1999-11-16 | 2000-11-15 | Compositions and methods for regulating tumor-associated antigen expression |
PCT/US2000/031511 WO2001036472A2 (en) | 1999-11-16 | 2000-11-15 | Compositions and methods for regulating tumor-associated antigen expression |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/NL2000/000835 WO2001036461A2 (en) | 1999-11-16 | 2000-11-15 | Compositions and methods for regulating tumor-associated antigen expression |
PCT/US2000/031508 WO2001035903A2 (en) | 1999-11-16 | 2000-11-15 | Compositions and methods for regulating tumor-associated antigen expression |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1232178A2 (en) |
JP (1) | JP2003515535A (en) |
AU (3) | AU2236201A (en) |
CA (1) | CA2388517A1 (en) |
WO (3) | WO2001036461A2 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9018167B2 (en) | 2010-03-19 | 2015-04-28 | Baxter International Inc. | TFPI inhibitors and methods of use |
US20170196973A1 (en) * | 2013-09-05 | 2017-07-13 | Boise State University | Oncostatin m (osm) antagonists for preventing cancer metastasis and il-6 related disorders |
US9777051B2 (en) | 2008-12-19 | 2017-10-03 | Baxalta GmbH | TFPI inhibitors and methods of use |
US9873720B2 (en) | 2008-12-19 | 2018-01-23 | Baxalta GmbH | TFPI inhibitors and methods of use |
US10697966B2 (en) | 2002-08-01 | 2020-06-30 | Ventana Medical Systems, Inc. | Method for detecting cervical dysplasia |
US11633457B2 (en) | 2019-04-11 | 2023-04-25 | Boise State University | Pharmaceutical compositions comprising oncostatin m (OSM) antagonist derivatives and methods of use |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE476652T1 (en) * | 2005-06-23 | 2010-08-15 | Siemens Healthcare Diagnostics | QUANTITATIVE ASSAY FOR RAS P21 IN BODY FLUID |
WO2009069668A1 (en) * | 2007-11-28 | 2009-06-04 | National University Corporation Nagoya University | Agent for increasing the expression of malignant melanoma antigen, and use thereof |
EP2971045B1 (en) | 2013-03-13 | 2019-06-19 | Health Research, Inc. | Compositions and methods for use of recombinant t cell receptors for direct recognition of tumor antigen |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0450472A1 (en) * | 1990-03-29 | 1991-10-09 | Oncogen Limited Partnership | Monoclonal antibodies that inhibit growth of kaposi's sarcoma |
EP0451612A1 (en) * | 1990-03-29 | 1991-10-16 | Bristol-Myers Squibb Company | Anti-oncostatin M monoclonal antibodies |
US5618715A (en) * | 1985-12-20 | 1997-04-08 | Oncogen Limited Partnership | Oncostatin M and novel compositions having anti-neoplastic activity |
WO1998038310A1 (en) * | 1997-02-28 | 1998-09-03 | Incyte Pharmaceuticals, Inc. | A tm4sf human tumor-associated antigen |
-
2000
- 2000-11-15 CA CA002388517A patent/CA2388517A1/en not_active Abandoned
- 2000-11-15 WO PCT/NL2000/000835 patent/WO2001036461A2/en active Application Filing
- 2000-11-15 WO PCT/US2000/031508 patent/WO2001035903A2/en not_active Application Discontinuation
- 2000-11-15 WO PCT/US2000/031511 patent/WO2001036472A2/en not_active Application Discontinuation
- 2000-11-15 AU AU22362/01A patent/AU2236201A/en not_active Abandoned
- 2000-11-15 AU AU20432/01A patent/AU2043201A/en not_active Abandoned
- 2000-11-15 JP JP2001538961A patent/JP2003515535A/en not_active Withdrawn
- 2000-11-15 EP EP00983714A patent/EP1232178A2/en not_active Withdrawn
- 2000-11-15 AU AU16157/01A patent/AU1615701A/en not_active Withdrawn
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5618715A (en) * | 1985-12-20 | 1997-04-08 | Oncogen Limited Partnership | Oncostatin M and novel compositions having anti-neoplastic activity |
EP0450472A1 (en) * | 1990-03-29 | 1991-10-09 | Oncogen Limited Partnership | Monoclonal antibodies that inhibit growth of kaposi's sarcoma |
EP0451612A1 (en) * | 1990-03-29 | 1991-10-16 | Bristol-Myers Squibb Company | Anti-oncostatin M monoclonal antibodies |
WO1998038310A1 (en) * | 1997-02-28 | 1998-09-03 | Incyte Pharmaceuticals, Inc. | A tm4sf human tumor-associated antigen |
Non-Patent Citations (5)
Title |
---|
JONES D M ET AL: "Expression of oncostatin M in benign and malignant melanocytic lesions." MODERN PATHOLOGY, vol. 12, no. 1, January 1999 (1999-01), page 58A XP001002408 Annual Meeting of the United States and Canadian Academy of Pathology; San Francisco, California; 20-26 March 1999 * |
RAMIREZ-MONTAGUT T ET AL: "Melanoma antigen recognition by tumour-infiltrating T lymphocytes (TIL): Effect of differential expression of Melan-A/MART-1." CLINICAL AND EXPERIMENTAL IMMUNOLOGY, vol. 119, no. 1, January 2000 (2000-01), pages 11-18, XP001002497 * |
RAO C N ET AL: "Prokaryotic expression, purification, and reconstitution of biological activities (antiprotease, antitumor, and heparin-binding) for tissue factor pathway inhibitor-2." BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 276, no. 3, 5 October 2000 (2000-10-05), pages 1286-1294, XP002168970 * |
VANGSTED A J: "Serological tumor markers for small cell lung cancer and their therapeutic implications." ACTA PATHOLOGICA ET IMMUNOLOGICA SCANDINAVICA (APMIS), vol. 102, no. 8, 1994, pages 561-580, XP001002432 * |
ZARLING J M ET AL: "Oncostatin M: A growth regulator produced by differentiated histiocytic lymphoma cells" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES, vol. 83, no. 24, December 1986 (1986-12), pages 9739-9743, XP002168969 * |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10697966B2 (en) | 2002-08-01 | 2020-06-30 | Ventana Medical Systems, Inc. | Method for detecting cervical dysplasia |
US9777051B2 (en) | 2008-12-19 | 2017-10-03 | Baxalta GmbH | TFPI inhibitors and methods of use |
US9873720B2 (en) | 2008-12-19 | 2018-01-23 | Baxalta GmbH | TFPI inhibitors and methods of use |
US11001613B2 (en) | 2008-12-19 | 2021-05-11 | Takeda Pharmaceutical Company Limited | TFPI inhibitors and methods of use |
US9018167B2 (en) | 2010-03-19 | 2015-04-28 | Baxter International Inc. | TFPI inhibitors and methods of use |
US9556230B2 (en) | 2010-03-19 | 2017-01-31 | Baxalta GmbH | TFPI inhibitors and methods of use |
US10201586B2 (en) | 2010-03-19 | 2019-02-12 | Baxalta GmbH | TFPI inhibitors and methods of use |
US11793855B2 (en) | 2010-03-19 | 2023-10-24 | Takeda Pharmaceutical Company Limited | TFPI inhibitors and methods of use |
US10800816B2 (en) | 2012-03-21 | 2020-10-13 | Baxalta GmbH | TFPI inhibitors and methods of use |
US20170196973A1 (en) * | 2013-09-05 | 2017-07-13 | Boise State University | Oncostatin m (osm) antagonists for preventing cancer metastasis and il-6 related disorders |
US10286070B2 (en) * | 2013-09-05 | 2019-05-14 | Boise State University | Oncostatin M (OSM) antagonists for preventing cancer metastasis and IL-6 related disorders |
US11633457B2 (en) | 2019-04-11 | 2023-04-25 | Boise State University | Pharmaceutical compositions comprising oncostatin m (OSM) antagonist derivatives and methods of use |
Also Published As
Publication number | Publication date |
---|---|
WO2001036472A3 (en) | 2002-01-10 |
AU1615701A (en) | 2001-05-30 |
EP1232178A2 (en) | 2002-08-21 |
AU2043201A (en) | 2001-05-30 |
WO2001036461A3 (en) | 2002-01-17 |
AU2236201A (en) | 2001-05-30 |
CA2388517A1 (en) | 2001-05-25 |
WO2001036461A2 (en) | 2001-05-25 |
JP2003515535A (en) | 2003-05-07 |
WO2001035903A2 (en) | 2001-05-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110545883B (en) | Humanized antigen binding domains directed against CD19 and methods of use thereof | |
KR102012113B1 (en) | Anti-pd-1 antibodies and methods of use thereof | |
Parolini et al. | X-linked lymphoproliferative disease: 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus–infected cells | |
CN107206025A (en) | The method and composition treated for adoptive cellular | |
EP0625051A1 (en) | Hepatic growth factor receptor | |
US11925662B2 (en) | Compositions and methods of enhancing anti-tumor response using hybrid neutrophils | |
March et al. | Identification and functional characterization of the hepatic stellate cell CD38 cell surface molecule | |
CN107250160A (en) | (CCR4) antibody of humanization CC-chemokine receptor 4 and its application method | |
RU2598719C2 (en) | Drugs for treating diseases | |
Muik et al. | DuoBody-CD40x4-1BB induces dendritic-cell maturation and enhances T-cell activation through conditional CD40 and 4-1BB agonist activity | |
US20230172980A1 (en) | Chimeric Antigen Receptor, Construction Method Therefor and Application Thereof | |
Chen et al. | Programmed cell death protein-1/programmed death-ligand 1 blockade enhances the antitumor efficacy of adoptive cell therapy against non-small cell lung cancer | |
EP1232178A2 (en) | Compositions and methods for regulating tumor-associated antigen expression | |
CN111040036B (en) | anti-GPC 3 monoclonal antibody, immune effector cell modified by same and application thereof | |
EP4137519A1 (en) | Fusion protein comprising ifn-gamma and anti-erbb antibody for the treatment of cancers | |
EP1712563A1 (en) | Method of isolating monocytes | |
AU2003222221A1 (en) | Map-kinase inhibitors as regulators of tumour-associated antigen expression | |
Kotani et al. | Expression of functional Fas antigen on adult T-cell leukemia | |
CN115925945A (en) | anti-TIGIT humanized antibody or antigen binding fragment thereof and application thereof | |
EP4314253A2 (en) | Methods and compositions for t-cell coculture potency assays and use with cell therapy products | |
JP2023519644A (en) | SSEA-4 binding members | |
US20220106402A1 (en) | Antibody | |
WO2024120484A1 (en) | Antibodies against edil3 and methods of use thereof | |
Shukla et al. | Targeting of palpable B16-F10 melanoma tumors with polyclonal antibodies on white blood cells | |
KR20240038028A (en) | Antigen binding protein that specifically binds to CT45 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2388517 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 2001 538961 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2000983714 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2000983714 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2000983714 Country of ref document: EP |