JP7240680B2 - 癌の診断および治療 - Google Patents
癌の診断および治療 Download PDFInfo
- Publication number
- JP7240680B2 JP7240680B2 JP2020520844A JP2020520844A JP7240680B2 JP 7240680 B2 JP7240680 B2 JP 7240680B2 JP 2020520844 A JP2020520844 A JP 2020520844A JP 2020520844 A JP2020520844 A JP 2020520844A JP 7240680 B2 JP7240680 B2 JP 7240680B2
- Authority
- JP
- Japan
- Prior art keywords
- her2
- expression
- cells
- cancer cells
- rab5
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 206010028980 Neoplasm Diseases 0.000 title claims description 88
- 201000011510 cancer Diseases 0.000 title claims description 77
- 238000011282 treatment Methods 0.000 title claims description 50
- 238000003745 diagnosis Methods 0.000 title description 5
- 230000014509 gene expression Effects 0.000 claims description 274
- 210000004027 cell Anatomy 0.000 claims description 228
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 213
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 213
- 102000028589 Rab4 Human genes 0.000 claims description 89
- 238000000034 method Methods 0.000 claims description 84
- 102100039100 Ras-related protein Rab-5A Human genes 0.000 claims description 83
- 108010032037 rab5 GTP-Binding Proteins Proteins 0.000 claims description 83
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 claims description 73
- 101710113864 Heat shock protein 90 Proteins 0.000 claims description 72
- 239000003814 drug Substances 0.000 claims description 72
- 101150060955 RAB11A gene Proteins 0.000 claims description 67
- 102100022873 Ras-related protein Rab-11A Human genes 0.000 claims description 67
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 claims description 67
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 claims description 67
- 229940079593 drug Drugs 0.000 claims description 56
- 239000000427 antigen Substances 0.000 claims description 53
- 108091007433 antigens Proteins 0.000 claims description 53
- 102000036639 antigens Human genes 0.000 claims description 53
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims description 53
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 49
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 49
- 230000001965 increasing effect Effects 0.000 claims description 38
- 239000002596 immunotoxin Substances 0.000 claims description 34
- 239000000611 antibody drug conjugate Substances 0.000 claims description 33
- 206010006187 Breast cancer Diseases 0.000 claims description 32
- 208000026310 Breast neoplasm Diseases 0.000 claims description 32
- 229940049595 antibody-drug conjugate Drugs 0.000 claims description 31
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 claims description 30
- -1 CD79a Proteins 0.000 claims description 28
- 229940127121 immunoconjugate Drugs 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 24
- 102000025171 antigen binding proteins Human genes 0.000 claims description 23
- 108091000831 antigen binding proteins Proteins 0.000 claims description 23
- 108010044923 rab4 GTP-Binding Proteins Proteins 0.000 claims description 23
- 229960001612 trastuzumab emtansine Drugs 0.000 claims description 22
- 229940051026 immunotoxin Drugs 0.000 claims description 18
- 230000002637 immunotoxin Effects 0.000 claims description 18
- 231100000608 immunotoxin Toxicity 0.000 claims description 18
- 102000001301 EGF receptor Human genes 0.000 claims description 17
- 239000003053 toxin Substances 0.000 claims description 17
- 231100000765 toxin Toxicity 0.000 claims description 17
- 108700012359 toxins Proteins 0.000 claims description 17
- 101100086302 Arabidopsis thaliana RABA1B gene Proteins 0.000 claims description 16
- 108700039148 rab11 Proteins 0.000 claims description 16
- BXTJCSYMGFJEID-XMTADJHZSA-N (2s)-2-[[(2r,3r)-3-[(2s)-1-[(3r,4s,5s)-4-[[(2s)-2-[[(2s)-2-[6-[3-[(2r)-2-amino-2-carboxyethyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]hexanoyl-methylamino]-3-methylbutanoyl]amino]-3-methylbutanoyl]-methylamino]-3-methoxy-5-methylheptanoyl]pyrrolidin-2-yl]-3-met Chemical compound C([C@H](NC(=O)[C@H](C)[C@@H](OC)[C@@H]1CCCN1C(=O)C[C@H]([C@H]([C@@H](C)CC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)CCCCCN1C(C(SC[C@H](N)C(O)=O)CC1=O)=O)C(C)C)OC)C(O)=O)C1=CC=CC=C1 BXTJCSYMGFJEID-XMTADJHZSA-N 0.000 claims description 15
- 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 claims description 10
- 238000000338 in vitro Methods 0.000 claims description 10
- 108060006698 EGF receptor Proteins 0.000 claims description 9
- 206010033128 Ovarian cancer Diseases 0.000 claims description 9
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 9
- 108020004999 messenger RNA Proteins 0.000 claims description 9
- 229950000720 moxetumomab pasudotox Drugs 0.000 claims description 9
- 101100067974 Arabidopsis thaliana POP2 gene Proteins 0.000 claims description 8
- 206010009944 Colon cancer Diseases 0.000 claims description 8
- 101100118549 Homo sapiens EGFR gene Proteins 0.000 claims description 8
- 101100123851 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HER1 gene Proteins 0.000 claims description 8
- 229950008925 depatuxizumab mafodotin Drugs 0.000 claims description 8
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 7
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 7
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 7
- 206010005003 Bladder cancer Diseases 0.000 claims description 7
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 7
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
- 206010027406 Mesothelioma Diseases 0.000 claims description 7
- 208000034578 Multiple myelomas Diseases 0.000 claims description 7
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 7
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 7
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 7
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 7
- 206010060862 Prostate cancer Diseases 0.000 claims description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 7
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 7
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 7
- 238000001574 biopsy Methods 0.000 claims description 7
- 239000008280 blood Substances 0.000 claims description 7
- 210000004369 blood Anatomy 0.000 claims description 7
- 229960000455 brentuximab vedotin Drugs 0.000 claims description 7
- 208000005017 glioblastoma Diseases 0.000 claims description 7
- 229950004101 inotuzumab ozogamicin Drugs 0.000 claims description 7
- 229950003526 lorvotuzumab mertansine Drugs 0.000 claims description 7
- 201000005202 lung cancer Diseases 0.000 claims description 7
- 208000020816 lung neoplasm Diseases 0.000 claims description 7
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 7
- 201000001441 melanoma Diseases 0.000 claims description 7
- 201000002528 pancreatic cancer Diseases 0.000 claims description 7
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 7
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 7
- 206010014733 Endometrial cancer Diseases 0.000 claims description 6
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 6
- 229940127177 HuM195/rGel Drugs 0.000 claims description 6
- 229950000518 labetuzumab Drugs 0.000 claims description 6
- MFZSNESUTRVBQX-XEURHVNRSA-N (2S)-2-amino-6-[4-[[3-[[(2S)-1-[[(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl]oxy]-1-oxopropan-2-yl]-methylamino]-3-oxopropyl]disulfanyl]pentanoylamino]hexanoic acid Chemical compound CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)[C@H](C)N(C)C(=O)CCSSC(C)CCC(=O)NCCCC[C@H](N)C(O)=O)[C@]2(C)O[C@H]2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2 MFZSNESUTRVBQX-XEURHVNRSA-N 0.000 claims description 5
- ZOHXWSHGANNQGO-DSIKUUPMSA-N 1-amino-4-[[5-[[(2S)-1-[[(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl]oxy]-1-oxopropan-2-yl]-methylamino]-2-methyl-5-oxopentan-2-yl]disulfanyl]-1-oxobutane-2-sulfonic acid Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCC(C)(C)SSCCC(C(N)=O)S(O)(=O)=O)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 ZOHXWSHGANNQGO-DSIKUUPMSA-N 0.000 claims description 5
- 102100038080 B-cell receptor CD22 Human genes 0.000 claims description 5
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 5
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 claims description 5
- 102000018651 Epithelial Cell Adhesion Molecule Human genes 0.000 claims description 5
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 claims description 5
- 101150112082 Gpnmb gene Proteins 0.000 claims description 5
- 102100022662 Guanylyl cyclase C Human genes 0.000 claims description 5
- 102100030595 HLA class II histocompatibility antigen gamma chain Human genes 0.000 claims description 5
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 claims description 5
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 5
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 claims description 5
- 101001023230 Homo sapiens Folate receptor alpha Proteins 0.000 claims description 5
- 101000899808 Homo sapiens Guanylyl cyclase C Proteins 0.000 claims description 5
- 101001082627 Homo sapiens HLA class II histocompatibility antigen gamma chain Proteins 0.000 claims description 5
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 claims description 5
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 claims description 5
- 101000576802 Homo sapiens Mesothelin Proteins 0.000 claims description 5
- 101000628547 Homo sapiens Metalloreductase STEAP1 Proteins 0.000 claims description 5
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 claims description 5
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 claims description 5
- 101001077409 Homo sapiens Ras-related protein Rab-5B Proteins 0.000 claims description 5
- 101001077405 Homo sapiens Ras-related protein Rab-5C Proteins 0.000 claims description 5
- 101000946860 Homo sapiens T-cell surface glycoprotein CD3 epsilon chain Proteins 0.000 claims description 5
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 claims description 5
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 claims description 5
- 102100025096 Mesothelin Human genes 0.000 claims description 5
- 102100026712 Metalloreductase STEAP1 Human genes 0.000 claims description 5
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 claims description 5
- 102100035486 Nectin-4 Human genes 0.000 claims description 5
- 101710043865 Nectin-4 Proteins 0.000 claims description 5
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 claims description 5
- 101710160107 Outer membrane protein A Proteins 0.000 claims description 5
- 102100025132 Ras-related protein Rab-5B Human genes 0.000 claims description 5
- 102100025138 Ras-related protein Rab-5C Human genes 0.000 claims description 5
- 102100035794 T-cell surface glycoprotein CD3 epsilon chain Human genes 0.000 claims description 5
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 claims description 5
- 230000003247 decreasing effect Effects 0.000 claims description 5
- 229950004079 denintuzumab mafodotin Drugs 0.000 claims description 5
- 229960004679 doxorubicin Drugs 0.000 claims description 5
- 229950000932 indusatumab vedotin Drugs 0.000 claims description 5
- 108040006849 interleukin-2 receptor activity proteins Proteins 0.000 claims description 5
- 229950009416 polatuzumab vedotin Drugs 0.000 claims description 5
- 208000015347 renal cell adenocarcinoma Diseases 0.000 claims description 5
- 229940127171 LMB-2 Drugs 0.000 claims description 4
- 238000000099 in vitro assay Methods 0.000 claims description 4
- 229950010074 pinatuzumab vedotin Drugs 0.000 claims description 4
- 230000004043 responsiveness Effects 0.000 claims description 4
- 229950000035 mirvetuximab soravtansine Drugs 0.000 claims description 3
- 230000002829 reductive effect Effects 0.000 claims description 3
- 230000001747 exhibiting effect Effects 0.000 claims 1
- 230000035945 sensitivity Effects 0.000 description 90
- 239000000090 biomarker Substances 0.000 description 79
- 108090000623 proteins and genes Proteins 0.000 description 79
- 102000004169 proteins and genes Human genes 0.000 description 75
- 108050007312 Rab4 Proteins 0.000 description 67
- 239000000523 sample Substances 0.000 description 46
- 230000000694 effects Effects 0.000 description 32
- 229960000575 trastuzumab Drugs 0.000 description 29
- 238000012417 linear regression Methods 0.000 description 28
- 238000004458 analytical method Methods 0.000 description 26
- 150000001875 compounds Chemical class 0.000 description 25
- 108091034117 Oligonucleotide Proteins 0.000 description 24
- 150000007523 nucleic acids Chemical class 0.000 description 22
- 102000039446 nucleic acids Human genes 0.000 description 20
- 108020004707 nucleic acids Proteins 0.000 description 20
- 238000001514 detection method Methods 0.000 description 19
- 230000004044 response Effects 0.000 description 19
- 230000003321 amplification Effects 0.000 description 18
- 238000003199 nucleic acid amplification method Methods 0.000 description 18
- 230000002596 correlated effect Effects 0.000 description 17
- 101100402572 Arabidopsis thaliana MS5 gene Proteins 0.000 description 16
- 238000001262 western blot Methods 0.000 description 16
- 230000006870 function Effects 0.000 description 14
- 238000004064 recycling Methods 0.000 description 14
- 230000001988 toxicity Effects 0.000 description 14
- 231100000419 toxicity Toxicity 0.000 description 14
- 230000002121 endocytic effect Effects 0.000 description 13
- 230000032258 transport Effects 0.000 description 13
- 230000003834 intracellular effect Effects 0.000 description 12
- 239000003550 marker Substances 0.000 description 12
- 238000011275 oncology therapy Methods 0.000 description 12
- 230000008685 targeting Effects 0.000 description 11
- 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 10
- 230000012202 endocytosis Effects 0.000 description 10
- 230000003993 interaction Effects 0.000 description 10
- 102000004243 Tubulin Human genes 0.000 description 9
- 108090000704 Tubulin Proteins 0.000 description 9
- 230000001413 cellular effect Effects 0.000 description 9
- 210000001163 endosome Anatomy 0.000 description 9
- 230000007246 mechanism Effects 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- 230000009471 action Effects 0.000 description 8
- 229940125644 antibody drug Drugs 0.000 description 8
- 239000012472 biological sample Substances 0.000 description 8
- 238000010195 expression analysis Methods 0.000 description 8
- 238000000611 regression analysis Methods 0.000 description 8
- 238000002560 therapeutic procedure Methods 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 238000002965 ELISA Methods 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 230000001086 cytosolic effect Effects 0.000 description 7
- 231100000433 cytotoxic Toxicity 0.000 description 7
- 230000001472 cytotoxic effect Effects 0.000 description 7
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 7
- 108060003951 Immunoglobulin Proteins 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- 238000003018 immunoassay Methods 0.000 description 6
- 102000018358 immunoglobulin Human genes 0.000 description 6
- 230000037361 pathway Effects 0.000 description 6
- 102000040430 polynucleotide Human genes 0.000 description 6
- 108091033319 polynucleotide Proteins 0.000 description 6
- 239000002157 polynucleotide Substances 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 238000004393 prognosis Methods 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
- 239000000126 substance Substances 0.000 description 6
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 6
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 5
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 5
- 210000000481 breast Anatomy 0.000 description 5
- 230000000295 complement effect Effects 0.000 description 5
- 210000000172 cytosol Anatomy 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- 108700004714 Gelonium multiflorum GEL Proteins 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 239000013610 patient sample Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 230000005945 translocation Effects 0.000 description 4
- 229940127169 DAB389IL2 Drugs 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000004891 communication Methods 0.000 description 3
- 238000010219 correlation analysis Methods 0.000 description 3
- 238000002790 cross-validation Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003596 drug target Substances 0.000 description 3
- 238000002651 drug therapy Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 229950009672 glembatumumab vedotin Drugs 0.000 description 3
- 229940072221 immunoglobulins Drugs 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 229960002087 pertuzumab Drugs 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 238000012109 statistical procedure Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012549 training Methods 0.000 description 3
- 210000003956 transport vesicle Anatomy 0.000 description 3
- 238000011269 treatment regimen Methods 0.000 description 3
- HPZMWTNATZPBIH-UHFFFAOYSA-N 1-methyladenine Chemical compound CN1C=NC2=NC=NC2=C1N HPZMWTNATZPBIH-UHFFFAOYSA-N 0.000 description 2
- RFLVMTUMFYRZCB-UHFFFAOYSA-N 1-methylguanine Chemical compound O=C1N(C)C(N)=NC2=C1N=CN2 RFLVMTUMFYRZCB-UHFFFAOYSA-N 0.000 description 2
- YSAJFXWTVFGPAX-UHFFFAOYSA-N 2-[(2,4-dioxo-1h-pyrimidin-5-yl)oxy]acetic acid Chemical compound OC(=O)COC1=CNC(=O)NC1=O YSAJFXWTVFGPAX-UHFFFAOYSA-N 0.000 description 2
- FZWGECJQACGGTI-UHFFFAOYSA-N 2-amino-7-methyl-1,7-dihydro-6H-purin-6-one Chemical compound NC1=NC(O)=C2N(C)C=NC2=N1 FZWGECJQACGGTI-UHFFFAOYSA-N 0.000 description 2
- OVONXEQGWXGFJD-UHFFFAOYSA-N 4-sulfanylidene-1h-pyrimidin-2-one Chemical compound SC=1C=CNC(=O)N=1 OVONXEQGWXGFJD-UHFFFAOYSA-N 0.000 description 2
- OIVLITBTBDPEFK-UHFFFAOYSA-N 5,6-dihydrouracil Chemical compound O=C1CCNC(=O)N1 OIVLITBTBDPEFK-UHFFFAOYSA-N 0.000 description 2
- DCPSTSVLRXOYGS-UHFFFAOYSA-N 6-amino-1h-pyrimidine-2-thione Chemical compound NC1=CC=NC(S)=N1 DCPSTSVLRXOYGS-UHFFFAOYSA-N 0.000 description 2
- 206010061818 Disease progression Diseases 0.000 description 2
- 208000017891 HER2 positive breast carcinoma Diseases 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- HYVABZIGRDEKCD-UHFFFAOYSA-N N(6)-dimethylallyladenine Chemical compound CC(C)=CCNC1=NC=NC2=C1N=CN2 HYVABZIGRDEKCD-UHFFFAOYSA-N 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 108010004729 Phycoerythrin Proteins 0.000 description 2
- 101150032328 RAB5A gene Proteins 0.000 description 2
- 108090000829 Ribosome Inactivating Proteins Proteins 0.000 description 2
- 230000009227 antibody-mediated cytotoxicity Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 238000003491 array Methods 0.000 description 2
- 239000012830 cancer therapeutic Substances 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 230000010013 cytotoxic mechanism Effects 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 108010017271 denileukin diftitox Proteins 0.000 description 2
- 229960002923 denileukin diftitox Drugs 0.000 description 2
- 230000005750 disease progression Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 102000015694 estrogen receptors Human genes 0.000 description 2
- 108010038795 estrogen receptors Proteins 0.000 description 2
- 230000028023 exocytosis Effects 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 239000012530 fluid Substances 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
- 230000004927 fusion Effects 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 238000001114 immunoprecipitation Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000008316 intracellular mechanism Effects 0.000 description 2
- 230000010189 intracellular transport Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 230000002132 lysosomal effect Effects 0.000 description 2
- 238000009607 mammography Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229960005558 mertansine Drugs 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 238000001558 permutation test Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 102000003998 progesterone receptors Human genes 0.000 description 2
- 108090000468 progesterone receptors Proteins 0.000 description 2
- 239000000092 prognostic biomarker Substances 0.000 description 2
- 231100000654 protein toxin Toxicity 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229950000143 sacituzumab govitecan Drugs 0.000 description 2
- ULRUOUDIQPERIJ-PQURJYPBSA-N sacituzumab govitecan Chemical compound N([C@@H](CCCCN)C(=O)NC1=CC=C(C=C1)COC(=O)O[C@]1(CC)C(=O)OCC2=C1C=C1N(C2=O)CC2=C(C3=CC(O)=CC=C3N=C21)CC)C(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN(N=N1)C=C1CNC(=O)C(CC1)CCC1CN1C(=O)CC(SC[C@H](N)C(O)=O)C1=O ULRUOUDIQPERIJ-PQURJYPBSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000002626 targeted therapy Methods 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 239000000107 tumor biomarker Substances 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- BNJNAEJASPUJTO-DUOHOMBCSA-N vadastuximab talirine Chemical compound COc1ccc(cc1)C2=CN3[C@@H](C2)C=Nc4cc(OCCCOc5cc6N=C[C@@H]7CC(=CN7C(=O)c6cc5OC)c8ccc(NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CCCCCN9C(=O)C[C@@H](SC[C@H](N)C(=O)O)C9=O)C(C)C)cc8)c(OC)cc4C3=O BNJNAEJASPUJTO-DUOHOMBCSA-N 0.000 description 2
- SATCOUWSAZBIJO-UHFFFAOYSA-N 1-methyladenine Natural products N=C1N(C)C=NC2=C1NC=N2 SATCOUWSAZBIJO-UHFFFAOYSA-N 0.000 description 1
- WJNGQIYEQLPJMN-IOSLPCCCSA-N 1-methylinosine Chemical compound C1=NC=2C(=O)N(C)C=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O WJNGQIYEQLPJMN-IOSLPCCCSA-N 0.000 description 1
- HLYBTPMYFWWNJN-UHFFFAOYSA-N 2-(2,4-dioxo-1h-pyrimidin-5-yl)-2-hydroxyacetic acid Chemical compound OC(=O)C(O)C1=CNC(=O)NC1=O HLYBTPMYFWWNJN-UHFFFAOYSA-N 0.000 description 1
- SGAKLDIYNFXTCK-UHFFFAOYSA-N 2-[(2,4-dioxo-1h-pyrimidin-5-yl)methylamino]acetic acid Chemical compound OC(=O)CNCC1=CNC(=O)NC1=O SGAKLDIYNFXTCK-UHFFFAOYSA-N 0.000 description 1
- GEJVQCKUQZXHFN-UHFFFAOYSA-N 2-[6-(aminomethyl)-4-oxo-2-sulfanylidene-1H-pyrimidin-5-yl]acetic acid Chemical compound C(=O)(O)CC=1C(NC(NC=1CN)=S)=O GEJVQCKUQZXHFN-UHFFFAOYSA-N 0.000 description 1
- XMSMHKMPBNTBOD-UHFFFAOYSA-N 2-dimethylamino-6-hydroxypurine Chemical compound N1C(N(C)C)=NC(=O)C2=C1N=CN2 XMSMHKMPBNTBOD-UHFFFAOYSA-N 0.000 description 1
- SMADWRYCYBUIKH-UHFFFAOYSA-N 2-methyl-7h-purin-6-amine Chemical compound CC1=NC(N)=C2NC=NC2=N1 SMADWRYCYBUIKH-UHFFFAOYSA-N 0.000 description 1
- KOLPWZCZXAMXKS-UHFFFAOYSA-N 3-methylcytosine Chemical compound CN1C(N)=CC=NC1=O KOLPWZCZXAMXKS-UHFFFAOYSA-N 0.000 description 1
- GJAKJCICANKRFD-UHFFFAOYSA-N 4-acetyl-4-amino-1,3-dihydropyrimidin-2-one Chemical compound CC(=O)C1(N)NC(=O)NC=C1 GJAKJCICANKRFD-UHFFFAOYSA-N 0.000 description 1
- MQJSSLBGAQJNER-UHFFFAOYSA-N 5-(methylaminomethyl)-1h-pyrimidine-2,4-dione Chemical compound CNCC1=CNC(=O)NC1=O MQJSSLBGAQJNER-UHFFFAOYSA-N 0.000 description 1
- WPYRHVXCOQLYLY-UHFFFAOYSA-N 5-[(methoxyamino)methyl]-2-sulfanylidene-1h-pyrimidin-4-one Chemical compound CONCC1=CNC(=S)NC1=O WPYRHVXCOQLYLY-UHFFFAOYSA-N 0.000 description 1
- LQLQRFGHAALLLE-UHFFFAOYSA-N 5-bromouracil Chemical compound BrC1=CNC(=O)NC1=O LQLQRFGHAALLLE-UHFFFAOYSA-N 0.000 description 1
- KELXHQACBIUYSE-UHFFFAOYSA-N 5-methoxy-1h-pyrimidine-2,4-dione Chemical compound COC1=CNC(=O)NC1=O KELXHQACBIUYSE-UHFFFAOYSA-N 0.000 description 1
- ZLAQATDNGLKIEV-UHFFFAOYSA-N 5-methyl-2-sulfanylidene-1h-pyrimidin-4-one Chemical compound CC1=CNC(=S)NC1=O ZLAQATDNGLKIEV-UHFFFAOYSA-N 0.000 description 1
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 description 1
- HSPHKCOAUOJLIO-UHFFFAOYSA-N 6-(aziridin-1-ylamino)-1h-pyrimidin-2-one Chemical compound N1C(=O)N=CC=C1NN1CC1 HSPHKCOAUOJLIO-UHFFFAOYSA-N 0.000 description 1
- CKOMXBHMKXXTNW-UHFFFAOYSA-N 6-methyladenine Chemical compound CNC1=NC=NC2=C1N=CN2 CKOMXBHMKXXTNW-UHFFFAOYSA-N 0.000 description 1
- SWJYOKZMYFJUOY-KQYNXXCUSA-N 9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(methylamino)-7h-purin-8-one Chemical compound OC1=NC=2C(NC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O SWJYOKZMYFJUOY-KQYNXXCUSA-N 0.000 description 1
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 244000099147 Ananas comosus Species 0.000 description 1
- 235000007119 Ananas comosus Nutrition 0.000 description 1
- 101001074560 Arabidopsis thaliana Aquaporin PIP1-2 Proteins 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 241001269524 Dura Species 0.000 description 1
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 108050001049 Extracellular proteins Proteins 0.000 description 1
- 229940125646 FDA-approved antibody drug Drugs 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 101150054472 HER2 gene Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 1
- 101000620798 Homo sapiens Ras-related protein Rab-11A Proteins 0.000 description 1
- 101000635799 Homo sapiens Run domain Beclin-1-interacting and cysteine-rich domain-containing protein Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- 238000000342 Monte Carlo simulation Methods 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- 206010028470 Mycoplasma infections Diseases 0.000 description 1
- SGSSKEDGVONRGC-UHFFFAOYSA-N N(2)-methylguanine Chemical compound O=C1NC(NC)=NC2=C1N=CN2 SGSSKEDGVONRGC-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 241000036848 Porzana carolina Species 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102100039099 Ras-related protein Rab-4A Human genes 0.000 description 1
- 102100030852 Run domain Beclin-1-interacting and cysteine-rich domain-containing protein Human genes 0.000 description 1
- 229940119564 Selective estrogen receptor downregulator Drugs 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960001686 afatinib Drugs 0.000 description 1
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 102000004441 bcr-abl Fusion Proteins Human genes 0.000 description 1
- 108010056708 bcr-abl Fusion Proteins Proteins 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 239000010836 blood and blood product Substances 0.000 description 1
- 229940125691 blood product Drugs 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 210000002806 clathrin-coated vesicle Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000009223 counseling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 210000004395 cytoplasmic granule Anatomy 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000002275 effect on microtubule Effects 0.000 description 1
- 230000013003 endocytic recycling Effects 0.000 description 1
- 239000005447 environmental material Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000003114 enzyme-linked immunosorbent spot assay Methods 0.000 description 1
- 108700020302 erbB-2 Genes Proteins 0.000 description 1
- 238000007387 excisional biopsy Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 230000007274 generation of a signal involved in cell-cell signaling Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 230000001744 histochemical effect Effects 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000003365 immunocytochemistry Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000007386 incisional biopsy Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 230000008606 intracellular interaction Effects 0.000 description 1
- 230000006662 intracellular pathway Effects 0.000 description 1
- 230000007728 intracellular signaling mechanism Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000007477 logistic regression Methods 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 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
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- IZAGSTRIDUNNOY-UHFFFAOYSA-N methyl 2-[(2,4-dioxo-1h-pyrimidin-5-yl)oxy]acetate Chemical compound COC(=O)COC1=CNC(=O)NC1=O IZAGSTRIDUNNOY-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229950007243 mirvetuximab Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000002625 monoclonal antibody therapy Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- XJVXMWNLQRTRGH-UHFFFAOYSA-N n-(3-methylbut-3-enyl)-2-methylsulfanyl-7h-purin-6-amine Chemical compound CSC1=NC(NCCC(C)=C)=C2NC=NC2=N1 XJVXMWNLQRTRGH-UHFFFAOYSA-N 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 238000013188 needle biopsy Methods 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 229940124276 oligodeoxyribonucleotide Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000011176 pooling Methods 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000020775 positive regulation of microtubule depolymerization Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 238000002331 protein detection Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 102000016949 rab GTP-Binding Proteins Human genes 0.000 description 1
- 108010014420 rab GTP-Binding Proteins Proteins 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical compound [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 238000012502 risk assessment Methods 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 1
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 1
- 230000009919 sequestration Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- XNZLMZRIGGHITK-VKXBZTRUSA-N soravtansine Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCC(C)(C)SSCC[C@@H](C(O)=O)S(O)(=O)=O)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2.CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCC(C)(C)SSCC[C@H](C(O)=O)S(O)(=O)=O)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 XNZLMZRIGGHITK-VKXBZTRUSA-N 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000012066 statistical methodology Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000009121 systemic therapy Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000007723 transport mechanism Effects 0.000 description 1
- 239000000439 tumor marker Substances 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 230000028973 vesicle-mediated transport Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- JFCFGYGEYRIEBE-YVLHJLIDSA-N wob38vs2ni Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCC(C)(C)S)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 JFCFGYGEYRIEBE-YVLHJLIDSA-N 0.000 description 1
Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57415—Specifically defined cancers of breast
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6817—Toxins
- A61K47/6819—Plant toxins
- A61K47/6825—Ribosomal inhibitory proteins, i.e. RIP-I or RIP-II, e.g. Pap, gelonin or dianthin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
- G01N33/57492—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds localized on the membrane of tumor or cancer cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/77—Internalization into the cell
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/55—Fusion polypeptide containing a fusion with a toxin, e.g. diphteria toxin
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Description
本出願は、その全体が参照により本明細書に組み込まれる、2017年6月23日に出願された米国仮出願第62/524,116号の優先権および利益を主張する。
本発明は癌マーカーを含むがこれに限定されない、癌診断、研究および治療のための組成物および方法に関する。特に、本発明は、癌治療に対する対象の応答を予測するための組成物および方法に関する。
個人用医薬品への注目が増加していることは、癌生物学に関する我々の知識の増加と共に、癌治療におけるバイオマーカーの高い可能性を明らかにしている。異なるバイオマーカーのスペクトルは患者の生存を予測するため、治療効果を評価するため、または疾患の進行をモニターするために、臨床実務に既に組み込まれている(Bailey et al, Discovery medicine,2014,17:101-114)。高コストの標的癌治療薬は、治療から利益を得る可能性が最も高い患者を選択するためのバイオマーカーの開発にとって強力な推進力である。この目的のために、規制当局は、臨床評価中の新しい治療のための予測バイオマーカーの組み込みをますます必要とする(Marton & Weiner,Biomed Res Int. 2013; 2013:891391.)。
本発明は、癌バイオマーカーを利用する治療を含むがこれに限定されない癌治療のための組成物および方法に関する。特に、本発明は、癌治療に対する対象の応答を予測するための組成物および方法に関する。
図1のAは、SK-BR-3、SKOV-3、HCC1954、AU-565、MDA-MB-435およびMDA-MB-231細胞におけるHER2およびγ-チューブリンの発現のウエスタンブロットの結果である。図1のBは、SK-BR-3、SKOV-3、AU-565、HCC1954およびMDA-MB-435の、各薬物による72時間の治療後の相対的生存率(MTT)を示す。T-DM1にはS字曲線適合モデルa/(1+exp(-(x-x0)/b))を用いた。データの値(%)は、3つの独立した実験(トラスツズマブ、エラーバー:SE)の平均、または少なくとも3つの別々の実験(T-DM1およびMH3-B1/rGel、エラーバー:SD)のうち1つの結果を代表して表している。
本発明の理解を容易にするために、いくつかの用語および表現を下記とおり定義する。
本発明は、癌バイオマーカーを利用する治療を含むがこれに限定されない、癌治療のための組成物および方法に関する。特に、本発明は、癌治療に対する対象の反応を予測するための組成物および方法に関する。
以下の実施例は本発明の特定の実施形態を実証し、さらに例示するために提供され、その範囲を限定するものとして解釈されるべきではない。
(材料及び方法)
細胞および培養:
本研究では、乳癌細胞株SK-BR-3、AU-565(CRL-2351)、HCC1954(CRL-2338)およびMDA-MB-453(HTB-131)および卵巣がん細胞株SKOV-3(HTB-77)という5つのHER2発現性ヒト細胞株を用いた。HER2陰性のヒト乳癌細胞株MDA-MB-231を、HER2発現のネガティブコントロールとして使用した。すべての細胞株は、ノルウェー、オスロの癌研究所の生化学部門ノルウェーラジウム病院、オスロ大学病院から提供されたSK-BR-3を除き、アメリカ合衆国培養細胞系統保存機関(American Type Culture Collection)(Manassas、VA、USA)から入手した。時間経過による細胞株の特性の変化を回避するために、全ての細胞株を継代数3~25の間で使用し、細胞をマイコプラズマ感染について常時にチェックした。SK-BR-3およびSKOV-3細胞を、McCoy 5A培地中で、AU-565、HCC1954およびMDA-MB-231細胞をRPMI-1640培地中(両方とも、Sigma-Aldrich, St. Louis、MO、USAから入手)で培養し、一方、MDA-MB-453を、Leibovitz’s L-15培地(Lonza, Verviers, Belgium)中で培養した。全ての培地は、文献19にしたがって補給した。
96ウェルプレート(Nunc、ロスキルデ、デンマーク)に8×103(SK-BR-3)、1.8×103(SKOV-3)、6×103(AU-565)、4×103(HCC1954)または1×104細胞/ウェル(MDA-MB-453)で細胞を播種し、一晩付着させた。次いで、細胞を、72時間、濃度を増加させながらトラスツズマブ(ハーセプチン(登録商標)、ロシュ、バーゼル、スイス)、T-DM1(ado-トラスツズマブエムタンシン、カドサイラ(登録商標)、ジェネンテック、カリフォルニア州サンフランシスコ、米国カリフォルニア州サンフランシスコ)、MH3-B1/rGelまたはrGel(文献13、20に従って発現および精製)とインキュベートし、その後、文献21に従い、MTTアッセイにより細胞生存率を評価した。IC50値をS字曲線から計算した(適合モデル:a/(1+exp(-(x-x0)/b)。
全細胞抽出物を得て、文献19に記載したようにウエスタンブロットにより分析した。タンパク質のブロット転写は、Trans-Blot(登録商標)Turbo(商標)Transfer System(Bio-Rad Laboratories、CA、USA)を用いて行った。細胞タンパク質発現を、Cell Signaling Technology(Danvers, MA, USA)から得たEGFR(#4267)、HER2(#2165)、HER3(#12708)、HSP90(#4877)抗体、BD Biosciences(San Jose, CA, USA)から得たRab5(610281)およびRab11(610656)抗体、ならびにRab4(R5780)抗体(Sigma-Aldrich)を使用して検出した。タンパク質の発現は、抗原(#T6557)(Sigma-Aldrich)によって検出されたγ-チューブリンと相関していた。Supersignal West Dura Extended duration Substrate(Thermo Scientific, Rockford, IL, USA)およびChemiDoc(商標)デンシトメーター(Bio-Rad)を膜上のタンパク質バンドの検出に使用した。ImageLab 4.1(Bio-Radのソフトウェア)を、タンパク質発現の定量のために使用した。各タンパク質の発現を、最高発現細胞株に対して計算した。
細胞株におけるHER2、HER3、EGFR、Rab4、Rab5、Rab11およびHSP90の相対的発現を、1/IC50(T-DM1)またはターゲティング指数(TI)(MH3-B1/rGel)によって測定した2つのHER2標的治療薬に対する細胞株感受性に対してプロットし、線形回帰を評価した。いくつかのタンパク質は、HER2と共にT-DM1またはMH3-B1/rGelに毒性に影響を及ぼし得る。しかしながら、HER2と比較した場合の影響のレベルは変化し得る。ここでは、HER2と線形相関する1/IC50(T-DM1)またはTI(MH3-B1/rGel)によって得られたR2値が他のタンパク質(HER3、EGFR、Rab4、Rab5、Rab11およびHSP90)の相対的発現を回帰に組み込むことによって増加し得るかどうかを計算した。これらの回帰曲線は、以下の式を用いて、HER2と共に各タンパク質について1~0の範囲の寄与係数を減少させて確立した;
正の勾配を有する曲線についてはHER2×(1-(1-タンパク質)×F)、および
負の勾配を有する曲線についてはHER2/(1-(1-タンパク質)×F)であり、ここで、HER2はHER2の相対的発現であり、タンパク質は目的のタンパク質の相対的発現であり、Fは1~0の寄与係数である。
T-DM1およびMH3-B1/rGelの有効性はトラスツズマブ感受性と相関していなかった。HER2陰性として報告されているMDA-MB-231における低発現と比較して、本研究で使用した5つのHER2発現細胞株において、強いHER2発現が立証された(図1のA)(文献22)。HER2を標的としたmAbトラスツズマブおよび細胞内作用性HER2を標的とした治療薬T-DM1およびMH3-B1/rGelの抗増殖効果は、5つのHER2陽性細胞株において確立された(図1のB)。細胞をトラスツズマブ、T-DM1またはMH3-B1/rGelで72時間処理すると、SK-BR-3およびAU-565細胞は3つの治療薬すべてに高感受性であることが明らかになったが、逆に、SKOV-3細胞はトラスツズマブに非応答性であることが見出され、T-DM1およびMH3-B1/rGelに対して低感受性であったことが、それぞれ1.2μg/mLという比較的高いIC50および2.4という低いTI50によって実証された(図1および図2のB)。HCC1954およびMDA-MB-453細胞はいずれもトラスツズマブ治療に対して低感受性から中感受性であることが見出されたが、細胞内作用性HER2標的治療薬に対しては異なる反応を示し、HCC1954細胞はT-DM1およびMH3-B1/rGelの両方に対して高感受性を示したが、MDA-MB-453細胞はこれら2つの薬物に対して低感受性を示した(図1および図2のB)。したがって、トラスツズマブ感受性とT-DM1およびMH3-B1/rGelに対する感受性との間には、5つの細胞株間で明確な関連性は認められなかった(図1および図2のB)。T-DM1およびMH3-B1/rGelは細胞内で明確に異なる作用点を有するが、細胞株の間でこれらの2つの治療薬に対する感受性の間に一貫性が明らかにされ、ここで、2つの治療薬の一方に対する高/低応答は他方に対する同様の高/低応答を予測させるように思われた。
相対的HER2発現×
(1-(1-Rab5発現)×0.3)×
(1-(1-Rab4発現)×0.6)×
(1-(1-相対的HSP90発現)×0.8)/
(1-(1-(1/相対的Rab11発現))×0.4)
バイオマーカー主導の個人用癌治療の分野は、臨床的に承認された標的化抗癌治療剤の数が増加することにつれて急速に成長している。全体として、薬物ベースの個別化された癌治療の効力は、予後、応答および/または耐性を予測するための選択されたバイオマーカーの信頼性に依存する。HER2標的mAbトラスツズマブの開発は、HER2陽性(全乳癌の約20%)に分類される乳癌患者としてのバイオマーカー主導の個別化がん治療の分野で、治療の一環としてトラスツズマブをルーチン投与することに成功した話である(文献26)。他の例としては、イマチニブの使用のための慢性骨髄性白血病(CML)におけるBCR-ABL融合、または大腸癌の治療におけるセツキシマブの使用のためのEGFRおよびRAS野生型発現の評価がある(文献27)。
患者集団:
治療前発現および病理学的完全奏効(pCR)データはT-DM1+ペルツズマブ(TDM1+P)群の52人の患者について利用可能であり、トラスツズマブ制御(TH)群の31人の患者について分析のために利用可能であった。進行した患者、同意を撤回した患者、治療施設を離れた患者、または手術前に非プロトコール療法を受けた患者は、この分析のために非pCRとみなされる。以下の表は、各アーム内のHRサブタイプによるpCR速度を示す;
すべてのI-SPY2サンプルは、Agilentの2つのカスタムアレイ(15746および32627デザイン)のいずれかに分析される。TDM1+Pアーム中の全てのサンプルを32627アレイ上でアッセイし、一方、THアームをプラットフォーム間で分割し、古い15746プラットフォーム上の22サンプルおよび32627アレイ上の9サンプルを用いた。2つの設計にわたるデータを組み合わせるために、15746プラットフォームのプローブアノテーションを更新し(2016年9月)、各プラットフォームについて、複数のプローブによって表される遺伝子がプローブにわたる平均として計算されるように、平均化することによって正規化された発現データを崩壊させた。次に、ComBatアルゴリズムを適用して、プラットフォームバイアスを調整し、2つのプラットフォームからのデータを組み合わせた。この手順は、実験群にかかわらず、最初の880人のI-SPY 2患者の治療前データについて行われた。THおよびTDM1+Pアームからの組み合わされたプラットフォーム調整されたデータは32627および更新された15746アレイ設計のためのアノテーションファイルとともに、この送達に含まれる。
RAB5A、RAB4A、RAB11A、およびHSP90AA1の正規化され、プラットフォーム補正された治療前発現レベルを、最初に、適格バイオマーカー評価(QBE)計画に従って、TDM1+Pに対する応答の特定バイオマーカーとして個別に試験した。
・モデル1A:TDM1+PアームにおけるpCR~バイオマーカー
・モデル1B:THアームにおけるpCR~バイオマーカー
・モデル1C:pCR~治療+バイオマーカー+治療xバイオマーカー
・モデル1D:pCR~治療+バイオマーカー+治療xバイオマーカー+HRステータス
評価されたバイオマーカーのうち、RAB5Aのみが、TDM1+pアーム(尤度比(LR)試験p=0.012)での応答と関連しているが、対照アーム(LR試験p=0.242)では関連していない。
本発明者らはバイオマーカーx処置相互作用のp値を最小化する閾値を同定するために、モンテカルロ2倍交差検定手順を使用した。具体的には100回の反復について、本発明者らは本発明者らの訓練セットとして、治療群とpCR状態とのバランスをとって、症例の半分を無作為に選択した。我々は10パーセンタイルと90パーセンタイルとの間のあらゆる値を、トレーニングセットを「高」対「低」RAB5A発現群に二分するための潜在的閾値として考慮し、一連のロジスティック回帰モデルに適合させて、バイオマーカーx処置相互作用を評価した(モデル1C)。本発明者らはトレーニングセット中の相互作用項についてのLR試験p値を最小にする閾値を選択し、それを使用して試験セットを二分し、試験セット中のバイオマーカーx処置相互作用の有意性を評価した。次に、ロジット方法を用いて100個の試験セットにわたってLRp値結合し、最小結合LR試験p値生じる閾値を選択した。
・モデル2:pCR~HR+RAB5A+治療+HRx処置+RAB5Ax処置
患者をRAB5A-高(>=9.76)群とRAB5A-低(<9.76)群に二分するために同定した最適閾値(9.76)を適用した場合、ベイズ推定pCR確率は、RAB5A-高の患者の対照群の24%に対してTDM1+P群で68%であった。対照的に、推定pCR確率はTDM1+PアームにおけるRAB5A-低サブセットにおいて28%であり、THアームにおいて42%である。比較のために、同じモデルを用いて、HER2+群全体の推定pCR確率は、TDM1+P群で61%、TH群で27%である。ベイズpCR確率曲線を図10に示す。
本実施例は、1-SPY2試験におけるTH-およびT-DM1+P群のHSP90、Rab11a、Rab4AおよびRab5a発現プロファイルと治療成績との相関の評価を示す。1-SPY-2データからのRNA発現プロファイルを、T-トラスツズマブ+化学療法(TH)またはトラスツズマブ-エムタシン+ペルツズマブ+化学療法(TDM1+P)を受けた2つの治療群において、pCRとHSP90、Rab11A、Rab4AおよびRab5aの発現レベルとの間の相関について評価した。T-DM1+Pアームにおいて、pCR0群とpCR1群との間でRab5Aの発現レベルに有意差がある。2つのアームのいずれにおいても、他のタンパク質のいずれについても有意差は見出されなかった。
1 A. de Gramont, S. Watson, L. M. Ellis, J. Rodon, J. Tabernero, A. de Gramont and S. R. Hamilton, Nature reviews. Clinical oncology, 2015, 12, 197-212.
2 D. J. Slamon, W. Godolphin, L. A. Jones, J. A. Holt, S. G. Wong, D. E. Keith, W. J. Levin, S. G. Stuart, J. Udove, A. Ullrich and et al., Science, 1989, 244, 707-712.
3 A. Hernandez-Blanquisett, D. Touya, K. Strasser-Weippl, R. Ruiz, J. St Louis and P. Goss, Breast (Edinburgh, Scotland), 2016, 29, 170-177.
4 M. F. Rimawi, R. Schiff and C. K. Osborne, Annual review of medicine, 2015, 66, 111-128.
5 R. A. Clynes, T. L. Towers, L. G. Presta and J. V. Ravetch, Nature medicine, 2000, 6, 443-446.
6 N. Harbeck, M. W. Beckmann, A. Rody, A. Schneeweiss, V. Muller, T. Fehm, N. Marschner, O. Gluz, I. Schrader, G. Heinrich, M. Untch and C. Jackisch, Breast care (Basel, Switzerland), 2013, 8, 49-55.
7 G. D. Lewis Phillips, G. Li, D. L. Dugger, L. M. Crocker, K. L. Parsons, E. Mai, W. A. Blattler, J. M. Lambert, R. V. Chari, R. J. Lutz, W. L. Wong, F. S. Jacobson, H. Koeppen, R. H. Schwall, S. R. Kenkare-Mitra, S. D. Spencer and M. X. Sliwkowski, Cancer research, 2008, 68, 9280-9290.
8 S. Verma, D. Miles, L. Gianni, I. E. Krop, M. Welslau, J. Baselga, M. Pegram, D. Y. Oh, V. Dieras, E. Guardino, L. Fang, M. W. Lu, S. Olsen and K. Blackwell, The New England journal of medicine, 2012, 367, 1783-1791.
9 J. M. Baron, B. L. Boster and C. M. Barnett, Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners, 2015, 21, 132-142.
10 H. K. Erickson, P. U. Park, W. C. Widdison, Y. V. Kovtun, L. M. Garrett, K. Hoffman, R. J. Lutz, V. S. Goldmacher and W. A. Blattler, Cancer research, 2006, 66, 4426-4433.
11 M. T. Martinez, J. A. Perez-Fidalgo, P. Martin-Martorell, J. M. Cejalvo, V. Pons, B. Bermejo, M. Martin, J. Albanell and A. Lluch, Critical reviews in oncology/hematology, 2016, 97, 96-106.
12 Y. Cao, J. D. Marks, J. W. Marks, L. H. Cheung, S. Kim and M. G. Rosenblum, Cancer Res., 2009, 69, 8987-8995.
13 Y. Cao, J. D. Marks, Q. Huang, S. I. Rudnick, C. Xiong, W. N. Hittelman, X. Wen, J. W. Marks, L. H. Cheung, K. Boland, C. Li, G. P. Adams and M. G. Rosenblum, Mol.Cancer Ther., 2012, 11, 143-153.
14 F. Stirpe, S. Olsnes and A. Pihl, J Biol.Chem., 1980, 255, 6947-6953.
15 M. Ritchie, L. Tchistiakova and N. Scott, mAbs, 2013, 5, 13-21.
16 J. Baselga, G. D. Lewis Phillips, S. Verma, J. Ro, J. Huober, A. E. Guardino, M. K. Samant, S. Olsen, S. L. de Haas and M. D. Pegram, Clinical cancer research : an official journal of the American Association for Cancer Research, 2016, 22, 3755-3763.
17 S. B. Kim, H. Wildiers, I. E. Krop, M. Smitt, R. Yu, S. Lysbet de Haas and A. Gonzalez-Martin, Int J Cancer, 2016, 139, 2336-2342.
18 H. Stenmark, Nature reviews. Molecular cell biology, 2009, 10, 513-525.
19 B. Bull-Hansen, Y. Cao, K. Berg, E. Skarpen, M. G. Rosenblum and A. Weyergang, J.Control Release., 2014, 182C:58-66. doi: 10.1016/j.jconrel.2014.03.014., 58-66.
20 M. G. Rosenblum, W. A. Kohr, K. L. Beattie, W. G. Beattie, W. Marks, P. D. Toman and L. Cheung, J.Interferon Cytokine Res., 1995, 15, 547-555.
21 A. Weyergang, P. K. Selbo and K. Berg, J.Control Release., 2006, 111, 165-173.
22 K. Subik, J. F. Lee, L. Baxter, T. Strzepek, D. Costello, P. Crowley, L. Xing, M. C. Hung, T. Bonfiglio, D. G. Hicks and P. Tang, Breast Cancer (Auckl.). 2010, %20;4:35-41., 35-41.
23 R. L. Dillon, S. Chooniedass, A. Premsukh, G. P. Adams, J. Entwistle, G. C. MacDonald and J. Cizeau, Journal of immunotherapy (Hagerstown, Md. : 1997), 2016, 39, 117-126.
24 M. Zerial and H. McBride, Nature reviews. Molecular cell biology, 2001, 2, 107-117.
25 C. D. Austin, A. M. De Maziere, P. I. Pisacane, S. M. van Dijk, C. Eigenbrot, M. X. Sliwkowski, J. Klumperman and R. H. Scheller, Molecular biology of the cell, 2004, 15, 5268-5282.
26 J. Baselga, E. A. Perez, T. Pienkowski and R. Bell, The oncologist, 2006, 11 Suppl 1, 4-12.
27 J. Baselga, Eur.J.Cancer, 2001, 37 Suppl 4, S16-S22.
28 E. A. Perez, S. A. Hurvitz, L. C. Amler, K. E. Mundt, V. Ng, E. Guardino and L. Gianni, Breast cancer research : BCR, 2014, 16, R50.
29 A. Citri, K. B. Skaria and Y. Yarden, Experimental cell research, 2003, 284, 54-65.
30 B. D. Grant and J. G. Donaldson, Nature reviews. Molecular cell biology, 2009, 10, 597-608.
31 E. Frittoli, A. Palamidessi, P. Marighetti, S. Confalonieri, F. Bianchi, C. Malinverno, G. Mazzarol, G. Viale, I. Martin-Padura, M. Garre, D. Parazzoli, V. Mattei, S. Cortellino, G. Bertalot, P. P. Di Fiore and G. Scita, The Journal of cell biology, 2014, 206, 307-328.
32 V. Bertelsen and E. Stang, Membranes, 2014, 4, 424-446.
33 K. Cortese, M. T. Howes, R. Lundmark, E. Tagliatti, P. Bagnato, A. Petrelli, M. Bono, H. T. McMahon, R. G. Parton and C. Tacchetti, Molecular biology of the cell, 2013, 24, 129-144.
34 S. Takahashi, K. Kubo, S. Waguri, A. Yabashi, H. W. Shin, Y. Katoh and K. Nakayama, Journal of cell science, 2012, 125, 4049-4057.
上記明細書に記載された全ての刊行物、特許、特許出願およびアクセッション番号は、その全体が参照により本明細書に援用される。本発明は、特定の実施形態に関して開示されているが、特許請求の範囲に記載された本発明がそのような特定の実施形態に過度に限定されるべきではないことは、理解されるべきである。実際、本発明に記載された組成物および方法の種々の改変および変形は当業者にとって明らかであり、以下の特許請求の範囲に示した範囲に含まれることが意図される。
Claims (18)
- ヒト癌細胞が、
(a)癌細胞の表面抗原を標的とする免疫複合体であって、該免疫複合体が薬物または毒素に連結または結合されている抗原結合タンパク質である免疫複合体、または
(b)癌細胞の表面抗原を標的とする、薬物または毒素を含まない抗原結合タンパク質に対して応答性があるかどうかを、in vitroで決定するための方法であって、
in vitroでの分析によって、対象から得られた癌細胞におけるRAB5の発現レベルを測定することを含み、
二分しきい値と比較して増加したRAB5の発現レベルが、前記免疫複合体に対する応答性を示し、かつ前記二分しきい値と比較して低下したRAB5の発現レベルが、前記薬物または毒素を含まない抗原結合タンパク質に対する応答性を示す、方法。 - 前記RAB5が、RAB5A、RAB5BおよびRAB5Cからなる群より選択される、請求項1に記載の方法。
- 前記癌細胞における前記RAB5の発現レベルを測定することが、RAB5 mRNAまたはRAB5タンパク質のレベルを測定することを含む、請求項1または2に記載の方法。
- RAB4、RAB11またはHSP90のうちの1つ以上の発現レベルを分析する工程をさらに含む、請求項1~3のいずれか1項に記載の方法。
- 前記癌細胞は、外科腫瘍サンプル、生検サンプルまたは血液サンプルから得られる、請求項1~4のいずれか1項に記載の方法。
- 前記癌細胞は、乳癌細胞、結腸直腸癌細胞、肺癌細胞、前立腺癌細胞、黒色腫細胞、神経膠芽腫細胞、膵癌細胞、腎細胞癌細胞、卵巣癌細胞、膀胱癌細胞、子宮内膜癌細胞、胃腸癌細胞、中皮腫細胞、多発性骨髄腫細胞、急性骨髄性白血病細胞、急性リンパ芽球性白血病細胞および非ホジキンリンパ腫からなる群より選択される、請求項1~5のいずれか1項に記載の方法。
- 前記癌細胞の表面抗原の発現を分析する工程をさらに含む、請求項1~6のいずれか1項に記載の方法。
- 前記表面抗原が、上皮成長因子受容体(HER1)、HER2、HER3およびこれらの組み合わせのうちの少なくとも1つからなる群から選択され、抗体薬物複合体または免疫毒素は、該上皮成長因子受容体(HER1)、HER2およびHER3のうちの1つの標的である、請求項7に記載の方法。
- 前記表面抗原が、HER2である、請求項7または8のいずれか1項に記載の方法。
- 癌細胞を有していると同定されている患者における癌の治療のための方法において使用するための、癌細胞の表面抗原を標的とする免疫複合体を含む組成物であって、前記癌細胞は前記表面抗原を発現し、請求項1に記載のin vitroで分析する方法により分析されたRAB5の発現レベルが、請求項1に記載の二分しきい値と比較して増加し、
前記免疫複合体が、薬物または毒素に連結または結合されている抗原結合タンパク質である、組成物。 - 癌細胞を有していると同定されている患者における癌の治療のための方法において使用するための、癌細胞の表面抗原を標的とする抗原結合タンパク質を含む組成物であって、前記癌細胞は前記表面抗原を発現し、請求項1に記載のin vitroで分析する方法により分析されたRAB5の発現レベルが、請求項1に記載の二分しきい値と比較して低下し、
前記抗原結合タンパク質が、薬物または毒素を含まない、組成物。 - 前記免疫複合体または前記抗原結合タンパク質が、HER2、HER3、EGFR、CD3ε、CD19、CD22、CD25、CD30、CD33、CD56、CEA(CD66e)、CD74、CD79a、CD138、NaPi2b、gpNMB、TROP-2、GUCY2C、Nectin-4、SC-16、STEAP1、FRα、IL-2R、EpCAMおよびMSLNからなる群より選択される細胞表面抗原に結合する、請求項10または11に記載の使用のための組成物。
- 前記免疫複合体が、
(a)トラスツズマブエムタンシン、ブレンツキシマブベドチン、イノツズマブオゾガマイシン、ピナツズマブベドチン、ポラツズマブベドチン、リファスツズマブベドチン、グレンバツズマブベドチン(glembatuzumab vedotin)、コルツキシマブラブタンシン、ロルボツズマブメルタンシン、インダツキシマブラブタンシン、サシツズマブゴビチカン(sacitizumab govitican)、ラベツズマブゴビチカン(labetuzumab
govitican)、ミラツズマブドキソルビシン、インデュサツマブベドチン、バダスツキシマブタリリン、デニンツズマブマホドチン、エンホルツマブベドチン、ロバルピツズマブテシリン、バンドルツズマブベドチン、ミルベツキシマブソラブタンシン、ABT-414、IMGN289およびAMG595からなる群より選択される抗体薬物複合体であるか、または、
(b)MH3-B1/rGel、デニロイキンディフティトックス、モキセツモマブパスドトクス、オポルツズマブモノトキス(oportuzumab monotox)、レジミューン(resimmune)、LMB-2、DT2219ARL、HuM195/rGel、RG7787、MOC31PEおよびD2C7-ITからなる群より選択される免疫毒素である、請求項10または12に記載の使用のための組成物。 - 前記癌細胞が、乳癌細胞、結腸直腸癌細胞、肺癌細胞、前立腺癌細胞、黒色腫細胞、神経膠芽腫細胞、膵癌細胞、腎細胞癌細胞、卵巣癌細胞、膀胱癌細胞、子宮内膜癌細胞、胃腸癌細胞、中皮腫細胞、多発性骨髄腫細胞、急性骨髄性白血病細胞、急性リンパ芽球性白血病細胞および非ホジキンリンパ腫からなる群より選択される、請求項10~13のいずれか1項に記載の使用のための組成物。
- 前記表面抗原が、上皮成長因子受容体(HER1)、HER2、HER3およびこれらの組み合わせのうちの少なくとも1つからなる群から選択され、抗体薬物複合体または免疫毒素は、該表面抗原の標的である、請求項10および12~14のいずれか1項に記載の使用のための組成物。
- 前記表面抗原が、HER2である、請求項15に記載の使用のための組成物。
- 前記抗体薬物複合体または免疫毒素が、トラスツズマブエムタンシン(T-DM1)、ABT-414、IMGN289、AMG595およびAMG595からなる群より選択される、請求項15または16に記載の使用のための組成物。
- 前記免疫毒素がトラスツズマブエムタンシン(T-DM1)である、請求項17に記載の使用のための組成物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2023027235A JP2023065521A (ja) | 2017-06-23 | 2023-02-24 | 癌の診断および治療 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762524116P | 2017-06-23 | 2017-06-23 | |
US62/524,116 | 2017-06-23 | ||
PCT/IB2018/000826 WO2018234872A1 (en) | 2017-06-23 | 2018-06-22 | DIAGNOSIS AND TREATMENT OF CANCER |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023027235A Division JP2023065521A (ja) | 2017-06-23 | 2023-02-24 | 癌の診断および治療 |
Publications (4)
Publication Number | Publication Date |
---|---|
JP2020524720A JP2020524720A (ja) | 2020-08-20 |
JP2020524720A5 JP2020524720A5 (ja) | 2021-08-05 |
JPWO2018234872A5 JPWO2018234872A5 (ja) | 2022-01-31 |
JP7240680B2 true JP7240680B2 (ja) | 2023-03-16 |
Family
ID=63556360
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020520844A Active JP7240680B2 (ja) | 2017-06-23 | 2018-06-22 | 癌の診断および治療 |
JP2023027235A Pending JP2023065521A (ja) | 2017-06-23 | 2023-02-24 | 癌の診断および治療 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023027235A Pending JP2023065521A (ja) | 2017-06-23 | 2023-02-24 | 癌の診断および治療 |
Country Status (8)
Country | Link |
---|---|
US (3) | US11506668B2 (ja) |
EP (1) | EP3642628A1 (ja) |
JP (2) | JP7240680B2 (ja) |
KR (2) | KR102606022B1 (ja) |
CN (1) | CN110998328A (ja) |
AU (1) | AU2018287514A1 (ja) |
CA (1) | CA3068167A1 (ja) |
WO (1) | WO2018234872A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113181373B (zh) * | 2021-05-10 | 2024-03-01 | 深圳安特生物医药科技有限公司 | 一种抗体药物偶联制剂及其制备方法和应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001020022A1 (en) | 1999-09-16 | 2001-03-22 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Assay to detect substances useful for therapy |
US20070020696A1 (en) | 2003-07-10 | 2007-01-25 | Marino Zerial | Appl proteins as rab5 effectors |
US20110044977A1 (en) | 2009-07-31 | 2011-02-24 | Genentech, Inc. | Subcutaneous anti-HER2 antibody formulations and uses thereof |
JP2016527483A (ja) | 2013-06-13 | 2016-09-08 | ユニバーシティ オブ サウス オーストラリアUniversity of South Australia | 前立腺癌を検出する方法 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070128636A1 (en) * | 2005-12-05 | 2007-06-07 | Baker Joffre B | Predictors Of Patient Response To Treatment With EGFR Inhibitors |
WO2009089521A2 (en) * | 2008-01-10 | 2009-07-16 | Nuvera Biosciences, Inc. | Predictors for evaluating response to cancer therapy |
US20110224313A1 (en) * | 2008-06-05 | 2011-09-15 | British Columbia Cancer Agency Branch | Compositions and methods for classifying lung cancer and prognosing lung cancer survival |
MY148542A (en) * | 2009-06-15 | 2013-04-30 | Cancer Res Initiatives Foundation | A method for the assessment of cancer in a biological sample obtained from a subject |
AU2015219495B2 (en) * | 2014-02-21 | 2019-11-21 | Ibc Pharmaceuticals, Inc. | Disease therapy by inducing immune response to Trop-2 expressing cells |
US20170037480A1 (en) | 2014-04-11 | 2017-02-09 | Whitehead Institute For Biomedical Research | Hsf1 in tumor stroma |
CA2999981A1 (en) * | 2015-09-25 | 2017-03-30 | Provista Diagnostics, Inc. | Biomarkers for detection of breast cancer in women with dense breasts |
-
2018
- 2018-06-22 CA CA3068167A patent/CA3068167A1/en active Pending
- 2018-06-22 CN CN201880047828.9A patent/CN110998328A/zh active Pending
- 2018-06-22 WO PCT/IB2018/000826 patent/WO2018234872A1/en unknown
- 2018-06-22 KR KR1020207002243A patent/KR102606022B1/ko active IP Right Grant
- 2018-06-22 US US16/624,654 patent/US11506668B2/en active Active
- 2018-06-22 KR KR1020237039877A patent/KR20230162145A/ko not_active Application Discontinuation
- 2018-06-22 AU AU2018287514A patent/AU2018287514A1/en active Pending
- 2018-06-22 EP EP18768932.8A patent/EP3642628A1/en active Pending
- 2018-06-22 JP JP2020520844A patent/JP7240680B2/ja active Active
-
2022
- 2022-10-14 US US18/046,619 patent/US20230314441A1/en active Pending
- 2022-10-14 US US18/046,606 patent/US20230184777A1/en active Pending
-
2023
- 2023-02-24 JP JP2023027235A patent/JP2023065521A/ja active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001020022A1 (en) | 1999-09-16 | 2001-03-22 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Assay to detect substances useful for therapy |
US20070020696A1 (en) | 2003-07-10 | 2007-01-25 | Marino Zerial | Appl proteins as rab5 effectors |
US20110044977A1 (en) | 2009-07-31 | 2011-02-24 | Genentech, Inc. | Subcutaneous anti-HER2 antibody formulations and uses thereof |
JP2016527483A (ja) | 2013-06-13 | 2016-09-08 | ユニバーシティ オブ サウス オーストラリアUniversity of South Australia | 前立腺癌を検出する方法 |
Non-Patent Citations (4)
Title |
---|
EDLER, E. et al.,Probing the druggability of membrane-bound Rab5 by molecular dynamics simulations,JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY,2017年01月16日,Vol.32, No.1,pp.434-443 |
MENDOZA, P. et al.,Rab5 activation promotes focal adhesion disassembly, migration and invasiveness in tumor cells,Journal of Cell Science,2013年,Vol.126, No.17,pp.3835-3847 |
MILLINO, C. et al.,Gene and MicroRNA Expression Are Predictive of Tumor Response in Rectal Adenocarcinoma Patients Treated With Preoperative Chemoradiotherapy,Journal of Cellular Physiology,2016年05月25日,Vol.232, No.2,pp.426-435 |
ZHAO, Z. et al.,Rab5a overexpression promoting ovarian cancer cell proliferation may be associated with APPL1-related epidermal growth factor signaling pathway,Cancer Science,2010年06月,Vol.101, No.6,pp.1454-1462 |
Also Published As
Publication number | Publication date |
---|---|
US20200182879A1 (en) | 2020-06-11 |
WO2018234872A1 (en) | 2018-12-27 |
KR20230162145A (ko) | 2023-11-28 |
JP2020524720A (ja) | 2020-08-20 |
JP2023065521A (ja) | 2023-05-12 |
CN110998328A (zh) | 2020-04-10 |
CA3068167A1 (en) | 2018-12-27 |
US20230314441A1 (en) | 2023-10-05 |
AU2018287514A1 (en) | 2020-01-16 |
EP3642628A1 (en) | 2020-04-29 |
US20230184777A1 (en) | 2023-06-15 |
US11506668B2 (en) | 2022-11-22 |
KR102606022B1 (ko) | 2023-11-24 |
KR20200042461A (ko) | 2020-04-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Amaria et al. | Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma | |
Scholler et al. | Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma | |
Bianchini et al. | Biomarker analysis of the NeoSphere study: pertuzumab, trastuzumab, and docetaxel versus trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel for the neoadjuvant treatment of HER2-positive breast cancer | |
Tuefferd et al. | HER2 status in ovarian carcinomas: a multicenter GINECO study of 320 patients | |
Lee et al. | HER2 heterogeneity affects trastuzumab responses and survival in patients with HER2-positive metastatic breast cancer | |
JP2021007416A (ja) | 細胞全体でのアッセイおよび方法 | |
Fujii et al. | International harmonization of provisional diagnostic criteria for ERBB2-amplified metastatic colorectal cancer allowing for screening by next-generation sequencing panel | |
Payne et al. | Measurements of EGFR expression on circulating tumor cells are reproducible over time in metastatic breast cancer patients | |
Nistor et al. | Real-time PCR complements immunohistochemistry in the determination of HER-2/neu status in breast cancer | |
JP2023065521A (ja) | 癌の診断および治療 | |
Aoyama et al. | A comparison of HER2/neu gene amplification and its protein overexpression between primary breast cancer and metastatic lymph nodes | |
US20220357329A1 (en) | Predictive liquid markers for cancer immunotherapy | |
McIntyre et al. | Specific and sensitive hydrolysis probe-based real-time PCR detection of epidermal growth factor receptor variant III in oral squamous cell carcinoma | |
Kontani et al. | Clinical usefulness of human epidermal growth factor receptor-2 extracellular domain as a biomarker for monitoring cancer status and predicting the therapeutic efficacy in breast cancer | |
US20230266322A1 (en) | Methods for predicting the risk of recurrence and/or death of patients suffering from a solid cancer after preoperative adjuvant therapy and radical surgery | |
JP2012085556A (ja) | 乳がんの診断方法 | |
JP2012085555A (ja) | 乳がん診断用マーカー | |
JP2012085554A (ja) | 乳がんのサブタイプの判別方法 | |
AU2020288603A1 (en) | Methods for modulating a treatment regimen | |
US20230235408A1 (en) | Methods for predicting the risk of recurrence and/or death of patients suffering from a solid cancer after preoperative adjuvant therapies | |
JP7042753B2 (ja) | 免疫チェックポイント阻害剤の投与対象となる個体の選択方法 | |
KR102326119B1 (ko) | 암의 면역 치료 후 예후 예측용 바이오 마커 | |
US20090233293A1 (en) | Ttk directed diagnostics for neoplastic disease |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210622 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210622 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220121 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220628 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220928 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20230124 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20230224 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7240680 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |