JP2021519771A - 腫瘍を処置する方法 - Google Patents
腫瘍を処置する方法 Download PDFInfo
- Publication number
- JP2021519771A JP2021519771A JP2020552752A JP2020552752A JP2021519771A JP 2021519771 A JP2021519771 A JP 2021519771A JP 2020552752 A JP2020552752 A JP 2020552752A JP 2020552752 A JP2020552752 A JP 2020552752A JP 2021519771 A JP2021519771 A JP 2021519771A
- Authority
- JP
- Japan
- Prior art keywords
- antibody
- mutations
- tumor
- tmb
- weeks
- 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.)
- Pending
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 336
- 230000035772 mutation Effects 0.000 claims abstract description 243
- 229940045513 CTLA4 antagonist Drugs 0.000 claims abstract description 105
- 239000000427 antigen Substances 0.000 claims abstract description 68
- 108091007433 antigens Proteins 0.000 claims abstract description 67
- 102000036639 antigens Human genes 0.000 claims abstract description 67
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims abstract description 64
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims abstract description 64
- 238000012163 sequencing technique Methods 0.000 claims abstract description 21
- 238000010362 genome editing Methods 0.000 claims abstract description 15
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 15
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 15
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 15
- 206010064571 Gene mutation Diseases 0.000 claims abstract description 12
- 108090000623 proteins and genes Proteins 0.000 claims description 220
- -1 PDFBRA Proteins 0.000 claims description 127
- 238000003556 assay Methods 0.000 claims description 85
- 230000037396 body weight Effects 0.000 claims description 72
- 210000004027 cell Anatomy 0.000 claims description 56
- 102100040678 Programmed cell death protein 1 Human genes 0.000 claims description 55
- 101710089372 Programmed cell death protein 1 Proteins 0.000 claims description 51
- 239000000203 mixture Substances 0.000 claims description 44
- 102000008203 CTLA-4 Antigen Human genes 0.000 claims description 36
- 108010021064 CTLA-4 Antigen Proteins 0.000 claims description 36
- 238000011282 treatment Methods 0.000 claims description 30
- 206010069754 Acquired gene mutation Diseases 0.000 claims description 23
- 239000012472 biological sample Substances 0.000 claims description 23
- 230000037439 somatic mutation Effects 0.000 claims description 23
- 102100025684 APC membrane recruitment protein 1 Human genes 0.000 claims description 20
- 102100033071 Histone acetyltransferase KAT6A Human genes 0.000 claims description 20
- 101000944179 Homo sapiens Histone acetyltransferase KAT6A Proteins 0.000 claims description 20
- 102100027755 Histone-lysine N-methyltransferase 2C Human genes 0.000 claims description 19
- 101001008892 Homo sapiens Histone-lysine N-methyltransferase 2C Proteins 0.000 claims description 19
- 102100027161 BRCA2-interacting transcriptional repressor EMSY Human genes 0.000 claims description 18
- 101001057996 Homo sapiens BRCA2-interacting transcriptional repressor EMSY Proteins 0.000 claims description 18
- 230000000694 effects Effects 0.000 claims description 17
- 102100028650 Glucose-induced degradation protein 4 homolog Human genes 0.000 claims description 15
- 102100022103 Histone-lysine N-methyltransferase 2A Human genes 0.000 claims description 15
- 101001058369 Homo sapiens Glucose-induced degradation protein 4 homolog Proteins 0.000 claims description 15
- 101001045846 Homo sapiens Histone-lysine N-methyltransferase 2A Proteins 0.000 claims description 15
- 101000585703 Homo sapiens Protein L-Myc Proteins 0.000 claims description 15
- 102100030128 Protein L-Myc Human genes 0.000 claims description 15
- 239000003446 ligand Substances 0.000 claims description 14
- 238000006467 substitution reaction Methods 0.000 claims description 12
- 101001008894 Homo sapiens Histone-lysine N-methyltransferase 2D Proteins 0.000 claims description 11
- 238000012217 deletion Methods 0.000 claims description 11
- 230000037430 deletion Effects 0.000 claims description 11
- 238000003780 insertion Methods 0.000 claims description 11
- 230000037431 insertion Effects 0.000 claims description 11
- 230000004048 modification Effects 0.000 claims description 11
- 238000012986 modification Methods 0.000 claims description 11
- 102000005962 receptors Human genes 0.000 claims description 11
- 108020003175 receptors Proteins 0.000 claims description 11
- 101710146195 APC membrane recruitment protein 1 Proteins 0.000 claims description 10
- 102100023266 Dual specificity mitogen-activated protein kinase kinase 2 Human genes 0.000 claims description 10
- 101000719162 Homo sapiens APC membrane recruitment protein 1 Proteins 0.000 claims description 10
- 238000007482 whole exome sequencing Methods 0.000 claims description 10
- 102100021147 DNA mismatch repair protein Msh6 Human genes 0.000 claims description 9
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 claims description 9
- 101001134036 Homo sapiens DNA mismatch repair protein Msh2 Proteins 0.000 claims description 9
- 101000968658 Homo sapiens DNA mismatch repair protein Msh6 Proteins 0.000 claims description 9
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 9
- 108010068353 MAP Kinase Kinase 2 Proteins 0.000 claims description 9
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 9
- 108700020463 BRCA1 Proteins 0.000 claims description 8
- 101150072950 BRCA1 gene Proteins 0.000 claims description 8
- 102100025401 Breast cancer type 1 susceptibility protein Human genes 0.000 claims description 8
- 108091007854 Cdh1/Fizzy-related Proteins 0.000 claims description 8
- 102000038594 Cdh1/Fizzy-related Human genes 0.000 claims description 8
- 102100024185 G1/S-specific cyclin-D2 Human genes 0.000 claims description 8
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 claims description 8
- 102100038970 Histone-lysine N-methyltransferase EZH2 Human genes 0.000 claims description 8
- 101000980741 Homo sapiens G1/S-specific cyclin-D2 Proteins 0.000 claims description 8
- 101000882127 Homo sapiens Histone-lysine N-methyltransferase EZH2 Proteins 0.000 claims description 8
- 101001117312 Homo sapiens Programmed cell death 1 ligand 2 Proteins 0.000 claims description 8
- 101000971404 Homo sapiens Protein kinase C iota type Proteins 0.000 claims description 8
- 108010068342 MAP Kinase Kinase 1 Proteins 0.000 claims description 8
- 108010018650 MEF2 Transcription Factors Proteins 0.000 claims description 8
- 102100038895 Myc proto-oncogene protein Human genes 0.000 claims description 8
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 claims description 8
- 102100024952 Protein CBFA2T1 Human genes 0.000 claims description 8
- 102100021557 Protein kinase C iota type Human genes 0.000 claims description 8
- 238000001574 biopsy Methods 0.000 claims description 8
- 230000008707 rearrangement Effects 0.000 claims description 8
- 102100037263 3-phosphoinositide-dependent protein kinase 1 Human genes 0.000 claims description 7
- 102100028908 Cullin-3 Human genes 0.000 claims description 7
- 102100034157 DNA mismatch repair protein Msh2 Human genes 0.000 claims description 7
- 102100037799 DNA-binding protein Ikaros Human genes 0.000 claims description 7
- 102100022204 DNA-dependent protein kinase catalytic subunit Human genes 0.000 claims description 7
- 102100028072 Fibroblast growth factor 4 Human genes 0.000 claims description 7
- 102100027768 Histone-lysine N-methyltransferase 2D Human genes 0.000 claims description 7
- 102100039489 Histone-lysine N-methyltransferase, H3 lysine-79 specific Human genes 0.000 claims description 7
- 101000600756 Homo sapiens 3-phosphoinositide-dependent protein kinase 1 Proteins 0.000 claims description 7
- 101000916238 Homo sapiens Cullin-3 Proteins 0.000 claims description 7
- 101000599038 Homo sapiens DNA-binding protein Ikaros Proteins 0.000 claims description 7
- 101000619536 Homo sapiens DNA-dependent protein kinase catalytic subunit Proteins 0.000 claims description 7
- 101001060274 Homo sapiens Fibroblast growth factor 4 Proteins 0.000 claims description 7
- 101001045848 Homo sapiens Histone-lysine N-methyltransferase 2B Proteins 0.000 claims description 7
- 101000963360 Homo sapiens Histone-lysine N-methyltransferase, H3 lysine-79 specific Proteins 0.000 claims description 7
- 101000595751 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform Proteins 0.000 claims description 7
- 102000046961 MRE11 Homologue Human genes 0.000 claims description 7
- 108700019589 MRE11 Homologue Proteins 0.000 claims description 7
- 229910015837 MSH2 Inorganic materials 0.000 claims description 7
- 108010074346 Mismatch Repair Endonuclease PMS2 Proteins 0.000 claims description 7
- 108010026664 MutL Protein Homolog 1 Proteins 0.000 claims description 7
- 102000013609 MutL Protein Homolog 1 Human genes 0.000 claims description 7
- 108010029755 Notch1 Receptor Proteins 0.000 claims description 7
- 102100036052 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform Human genes 0.000 claims description 7
- 101150071637 mre11 gene Proteins 0.000 claims description 7
- 102100039082 3 beta-hydroxysteroid dehydrogenase/Delta 5->4-isomerase type 1 Human genes 0.000 claims description 6
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 claims description 6
- 102100034580 AT-rich interactive domain-containing protein 1A Human genes 0.000 claims description 6
- 102100023157 AT-rich interactive domain-containing protein 2 Human genes 0.000 claims description 6
- 102000000872 ATM Human genes 0.000 claims description 6
- 102100035886 Adenine DNA glycosylase Human genes 0.000 claims description 6
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 claims description 6
- 102100024439 Adhesion G protein-coupled receptor A2 Human genes 0.000 claims description 6
- 108010004586 Ataxia Telangiectasia Mutated Proteins Proteins 0.000 claims description 6
- 102000004000 Aurora Kinase A Human genes 0.000 claims description 6
- 108090000461 Aurora Kinase A Proteins 0.000 claims description 6
- 102100027205 B-cell antigen receptor complex-associated protein alpha chain Human genes 0.000 claims description 6
- 102100027203 B-cell antigen receptor complex-associated protein beta chain Human genes 0.000 claims description 6
- 101700002522 BARD1 Proteins 0.000 claims description 6
- 102100021247 BCL-6 corepressor Human genes 0.000 claims description 6
- 102100021256 BCL-6 corepressor-like protein 1 Human genes 0.000 claims description 6
- 102100035080 BDNF/NT-3 growth factors receptor Human genes 0.000 claims description 6
- 102100028048 BRCA1-associated RING domain protein 1 Human genes 0.000 claims description 6
- 102100026596 Bcl-2-like protein 1 Human genes 0.000 claims description 6
- 102100023932 Bcl-2-like protein 2 Human genes 0.000 claims description 6
- 101150008012 Bcl2l1 gene Proteins 0.000 claims description 6
- 101001042041 Bos taurus Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial Proteins 0.000 claims description 6
- 108010014064 CCCTC-Binding Factor Proteins 0.000 claims description 6
- 102100021975 CREB-binding protein Human genes 0.000 claims description 6
- 102100024965 Caspase recruitment domain-containing protein 11 Human genes 0.000 claims description 6
- 102100028003 Catenin alpha-1 Human genes 0.000 claims description 6
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 claims description 6
- 102100031265 Chromodomain-helicase-DNA-binding protein 2 Human genes 0.000 claims description 6
- 108010060313 Core Binding Factor beta Subunit Proteins 0.000 claims description 6
- 102000008147 Core Binding Factor beta Subunit Human genes 0.000 claims description 6
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 claims description 6
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 claims description 6
- 108010009392 Cyclin-Dependent Kinase Inhibitor p16 Proteins 0.000 claims description 6
- 108010016788 Cyclin-Dependent Kinase Inhibitor p21 Proteins 0.000 claims description 6
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 claims description 6
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 claims description 6
- 102100033270 Cyclin-dependent kinase inhibitor 1 Human genes 0.000 claims description 6
- 108010076010 Cystathionine beta-lyase Proteins 0.000 claims description 6
- 102100038497 Cytokine receptor-like factor 2 Human genes 0.000 claims description 6
- 101150077031 DAXX gene Proteins 0.000 claims description 6
- 102100039116 DNA repair protein RAD50 Human genes 0.000 claims description 6
- 102100028559 Death domain-associated protein 6 Human genes 0.000 claims description 6
- 102100038912 E3 SUMO-protein ligase RanBP2 Human genes 0.000 claims description 6
- 102100035813 E3 ubiquitin-protein ligase CBL Human genes 0.000 claims description 6
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 claims description 6
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 claims description 6
- 102100022207 E3 ubiquitin-protein ligase parkin Human genes 0.000 claims description 6
- 101150016325 EPHA3 gene Proteins 0.000 claims description 6
- 102100039563 ETS translocation variant 1 Human genes 0.000 claims description 6
- 102100039578 ETS translocation variant 4 Human genes 0.000 claims description 6
- 102100039577 ETS translocation variant 5 Human genes 0.000 claims description 6
- 102100023387 Endoribonuclease Dicer Human genes 0.000 claims description 6
- 102100031785 Endothelial transcription factor GATA-2 Human genes 0.000 claims description 6
- 102100030324 Ephrin type-A receptor 3 Human genes 0.000 claims description 6
- 102100021606 Ephrin type-A receptor 7 Human genes 0.000 claims description 6
- 102100030779 Ephrin type-B receptor 1 Human genes 0.000 claims description 6
- 102100029095 Exportin-1 Human genes 0.000 claims description 6
- 108010022012 Fanconi Anemia Complementation Group F protein Proteins 0.000 claims description 6
- 108010033305 Fanconi Anemia Complementation Group G protein Proteins 0.000 claims description 6
- 108700026162 Fanconi Anemia Complementation Group L protein Proteins 0.000 claims description 6
- 108010067741 Fanconi Anemia Complementation Group N protein Proteins 0.000 claims description 6
- 102100028412 Fibroblast growth factor 10 Human genes 0.000 claims description 6
- 102100035292 Fibroblast growth factor 14 Human genes 0.000 claims description 6
- 102100031734 Fibroblast growth factor 19 Human genes 0.000 claims description 6
- 102100024802 Fibroblast growth factor 23 Human genes 0.000 claims description 6
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 claims description 6
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 claims description 6
- 102100029974 GTPase HRas Human genes 0.000 claims description 6
- 102100025334 Guanine nucleotide-binding protein G(q) subunit alpha Human genes 0.000 claims description 6
- 102100036738 Guanine nucleotide-binding protein subunit alpha-11 Human genes 0.000 claims description 6
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 claims description 6
- 102100039236 Histone H3.3 Human genes 0.000 claims description 6
- 102100027893 Homeobox protein Nkx-2.1 Human genes 0.000 claims description 6
- 101000744065 Homo sapiens 3 beta-hydroxysteroid dehydrogenase/Delta 5->4-isomerase type 1 Proteins 0.000 claims description 6
- 101000779641 Homo sapiens ALK tyrosine kinase receptor Proteins 0.000 claims description 6
- 101000924266 Homo sapiens AT-rich interactive domain-containing protein 1A Proteins 0.000 claims description 6
- 101000685261 Homo sapiens AT-rich interactive domain-containing protein 2 Proteins 0.000 claims description 6
- 101001000351 Homo sapiens Adenine DNA glycosylase Proteins 0.000 claims description 6
- 101000924577 Homo sapiens Adenomatous polyposis coli protein Proteins 0.000 claims description 6
- 101000833358 Homo sapiens Adhesion G protein-coupled receptor A2 Proteins 0.000 claims description 6
- 101000914489 Homo sapiens B-cell antigen receptor complex-associated protein alpha chain Proteins 0.000 claims description 6
- 101000914491 Homo sapiens B-cell antigen receptor complex-associated protein beta chain Proteins 0.000 claims description 6
- 101000894688 Homo sapiens BCL-6 corepressor-like protein 1 Proteins 0.000 claims description 6
- 101100165236 Homo sapiens BCOR gene Proteins 0.000 claims description 6
- 101000596896 Homo sapiens BDNF/NT-3 growth factors receptor Proteins 0.000 claims description 6
- 101000904691 Homo sapiens Bcl-2-like protein 2 Proteins 0.000 claims description 6
- 101000896987 Homo sapiens CREB-binding protein Proteins 0.000 claims description 6
- 101000761179 Homo sapiens Caspase recruitment domain-containing protein 11 Proteins 0.000 claims description 6
- 101000859063 Homo sapiens Catenin alpha-1 Proteins 0.000 claims description 6
- 101000777079 Homo sapiens Chromodomain-helicase-DNA-binding protein 2 Proteins 0.000 claims description 6
- 101000956427 Homo sapiens Cytokine receptor-like factor 2 Proteins 0.000 claims description 6
- 101000743929 Homo sapiens DNA repair protein RAD50 Proteins 0.000 claims description 6
- 101000880945 Homo sapiens Down syndrome cell adhesion molecule Proteins 0.000 claims description 6
- 101000619542 Homo sapiens E3 ubiquitin-protein ligase parkin Proteins 0.000 claims description 6
- 101000813729 Homo sapiens ETS translocation variant 1 Proteins 0.000 claims description 6
- 101000813747 Homo sapiens ETS translocation variant 4 Proteins 0.000 claims description 6
- 101000813745 Homo sapiens ETS translocation variant 5 Proteins 0.000 claims description 6
- 101000907904 Homo sapiens Endoribonuclease Dicer Proteins 0.000 claims description 6
- 101001066265 Homo sapiens Endothelial transcription factor GATA-2 Proteins 0.000 claims description 6
- 101000967216 Homo sapiens Eosinophil cationic protein Proteins 0.000 claims description 6
- 101000898708 Homo sapiens Ephrin type-A receptor 7 Proteins 0.000 claims description 6
- 101001064150 Homo sapiens Ephrin type-B receptor 1 Proteins 0.000 claims description 6
- 101100119754 Homo sapiens FANCL gene Proteins 0.000 claims description 6
- 101000917237 Homo sapiens Fibroblast growth factor 10 Proteins 0.000 claims description 6
- 101000878181 Homo sapiens Fibroblast growth factor 14 Proteins 0.000 claims description 6
- 101000846394 Homo sapiens Fibroblast growth factor 19 Proteins 0.000 claims description 6
- 101001051973 Homo sapiens Fibroblast growth factor 23 Proteins 0.000 claims description 6
- 101000584633 Homo sapiens GTPase HRas Proteins 0.000 claims description 6
- 101000857888 Homo sapiens Guanine nucleotide-binding protein G(q) subunit alpha Proteins 0.000 claims description 6
- 101001072407 Homo sapiens Guanine nucleotide-binding protein subunit alpha-11 Proteins 0.000 claims description 6
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 claims description 6
- 101000898034 Homo sapiens Hepatocyte growth factor Proteins 0.000 claims description 6
- 101000596894 Homo sapiens High affinity nerve growth factor receptor Proteins 0.000 claims description 6
- 101000632178 Homo sapiens Homeobox protein Nkx-2.1 Proteins 0.000 claims description 6
- 101100508538 Homo sapiens IKBKE gene Proteins 0.000 claims description 6
- 101001034652 Homo sapiens Insulin-like growth factor 1 receptor Proteins 0.000 claims description 6
- 101001076292 Homo sapiens Insulin-like growth factor II Proteins 0.000 claims description 6
- 101001011393 Homo sapiens Interferon regulatory factor 2 Proteins 0.000 claims description 6
- 101001011441 Homo sapiens Interferon regulatory factor 4 Proteins 0.000 claims description 6
- 101001076408 Homo sapiens Interleukin-6 Proteins 0.000 claims description 6
- 101000960234 Homo sapiens Isocitrate dehydrogenase [NADP] cytoplasmic Proteins 0.000 claims description 6
- 101001008854 Homo sapiens Kelch-like protein 6 Proteins 0.000 claims description 6
- 101001008857 Homo sapiens Kelch-like protein 7 Proteins 0.000 claims description 6
- 101000971879 Homo sapiens Kell blood group glycoprotein Proteins 0.000 claims description 6
- 101001038435 Homo sapiens Leucine-zipper-like transcriptional regulator 1 Proteins 0.000 claims description 6
- 101000984620 Homo sapiens Low-density lipoprotein receptor-related protein 1B Proteins 0.000 claims description 6
- 101001088892 Homo sapiens Lysine-specific demethylase 5A Proteins 0.000 claims description 6
- 101001088887 Homo sapiens Lysine-specific demethylase 5C Proteins 0.000 claims description 6
- 101000653374 Homo sapiens Methylcytosine dioxygenase TET2 Proteins 0.000 claims description 6
- 101001007909 Homo sapiens Nuclear pore complex protein Nup93 Proteins 0.000 claims description 6
- 101000741978 Homo sapiens Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein Proteins 0.000 claims description 6
- 101001120097 Homo sapiens Phosphatidylinositol 3-kinase regulatory subunit beta Proteins 0.000 claims description 6
- 101000605639 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 claims description 6
- 101000721645 Homo sapiens Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta Proteins 0.000 claims description 6
- 101000933601 Homo sapiens Protein BTG1 Proteins 0.000 claims description 6
- 101000883014 Homo sapiens Protein capicua homolog Proteins 0.000 claims description 6
- 101000601770 Homo sapiens Protein polybromo-1 Proteins 0.000 claims description 6
- 101000824318 Homo sapiens Protocadherin Fat 1 Proteins 0.000 claims description 6
- 101000779418 Homo sapiens RAC-alpha serine/threonine-protein kinase Proteins 0.000 claims description 6
- 101000798007 Homo sapiens RAC-gamma serine/threonine-protein kinase Proteins 0.000 claims description 6
- 101000712530 Homo sapiens RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 claims description 6
- 101000687474 Homo sapiens Rhombotin-1 Proteins 0.000 claims description 6
- 101000771237 Homo sapiens Serine/threonine-protein kinase A-Raf Proteins 0.000 claims description 6
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 claims description 6
- 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 claims description 6
- 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 claims description 6
- 101000783404 Homo sapiens Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform Proteins 0.000 claims description 6
- 101000651890 Homo sapiens Slit homolog 2 protein Proteins 0.000 claims description 6
- 101000651893 Homo sapiens Slit homolog 3 protein Proteins 0.000 claims description 6
- 101000868152 Homo sapiens Son of sevenless homolog 1 Proteins 0.000 claims description 6
- 101000707567 Homo sapiens Splicing factor 3B subunit 1 Proteins 0.000 claims description 6
- 101000808799 Homo sapiens Splicing factor U2AF 35 kDa subunit Proteins 0.000 claims description 6
- 101000951145 Homo sapiens Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial Proteins 0.000 claims description 6
- 101000685323 Homo sapiens Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial Proteins 0.000 claims description 6
- 101000874160 Homo sapiens Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial Proteins 0.000 claims description 6
- 101000628885 Homo sapiens Suppressor of fused homolog Proteins 0.000 claims description 6
- 101000617808 Homo sapiens Synphilin-1 Proteins 0.000 claims description 6
- 101000666775 Homo sapiens T-box transcription factor TBX3 Proteins 0.000 claims description 6
- 101000819111 Homo sapiens Trans-acting T-cell-specific transcription factor GATA-3 Proteins 0.000 claims description 6
- 101000813738 Homo sapiens Transcription factor ETV6 Proteins 0.000 claims description 6
- 101000819074 Homo sapiens Transcription factor GATA-4 Proteins 0.000 claims description 6
- 101000819088 Homo sapiens Transcription factor GATA-6 Proteins 0.000 claims description 6
- 101000664703 Homo sapiens Transcription factor SOX-10 Proteins 0.000 claims description 6
- 101000711846 Homo sapiens Transcription factor SOX-9 Proteins 0.000 claims description 6
- 101000596093 Homo sapiens Transcription initiation factor TFIID subunit 1 Proteins 0.000 claims description 6
- 101000638154 Homo sapiens Transmembrane protease serine 2 Proteins 0.000 claims description 6
- 101000795659 Homo sapiens Tuberin Proteins 0.000 claims description 6
- 101000823316 Homo sapiens Tyrosine-protein kinase ABL1 Proteins 0.000 claims description 6
- 101000823271 Homo sapiens Tyrosine-protein kinase ABL2 Proteins 0.000 claims description 6
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 claims description 6
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 claims description 6
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 claims description 6
- 101001054878 Homo sapiens Tyrosine-protein kinase Lyn Proteins 0.000 claims description 6
- 101000808011 Homo sapiens Vascular endothelial growth factor A Proteins 0.000 claims description 6
- 101000782132 Homo sapiens Zinc finger protein 217 Proteins 0.000 claims description 6
- 101001026573 Homo sapiens cAMP-dependent protein kinase type I-alpha regulatory subunit Proteins 0.000 claims description 6
- 102100021857 Inhibitor of nuclear factor kappa-B kinase subunit epsilon Human genes 0.000 claims description 6
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 claims description 6
- 102100025947 Insulin-like growth factor II Human genes 0.000 claims description 6
- 102100029838 Interferon regulatory factor 2 Human genes 0.000 claims description 6
- 102100030126 Interferon regulatory factor 4 Human genes 0.000 claims description 6
- 102100039905 Isocitrate dehydrogenase [NADP] cytoplasmic Human genes 0.000 claims description 6
- 102100027789 Kelch-like protein 7 Human genes 0.000 claims description 6
- 102100021447 Kell blood group glycoprotein Human genes 0.000 claims description 6
- 102100040274 Leucine-zipper-like transcriptional regulator 1 Human genes 0.000 claims description 6
- 102100027121 Low-density lipoprotein receptor-related protein 1B Human genes 0.000 claims description 6
- 102100033246 Lysine-specific demethylase 5A Human genes 0.000 claims description 6
- 102100033249 Lysine-specific demethylase 5C Human genes 0.000 claims description 6
- 102100030803 Methylcytosine dioxygenase TET2 Human genes 0.000 claims description 6
- 108010071382 NF-E2-Related Factor 2 Proteins 0.000 claims description 6
- 102000007530 Neurofibromin 1 Human genes 0.000 claims description 6
- 108010085793 Neurofibromin 1 Proteins 0.000 claims description 6
- 108010029751 Notch2 Receptor Proteins 0.000 claims description 6
- 108010029756 Notch3 Receptor Proteins 0.000 claims description 6
- 102100031701 Nuclear factor erythroid 2-related factor 2 Human genes 0.000 claims description 6
- 102100027585 Nuclear pore complex protein Nup93 Human genes 0.000 claims description 6
- 102100040884 Partner and localizer of BRCA2 Human genes 0.000 claims description 6
- 102100038633 Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein Human genes 0.000 claims description 6
- 102100026177 Phosphatidylinositol 3-kinase regulatory subunit beta Human genes 0.000 claims description 6
- 102100038332 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Human genes 0.000 claims description 6
- 102100025059 Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta Human genes 0.000 claims description 6
- 108010051742 Platelet-Derived Growth Factor beta Receptor Proteins 0.000 claims description 6
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 claims description 6
- 102100026036 Protein BTG1 Human genes 0.000 claims description 6
- 102100038777 Protein capicua homolog Human genes 0.000 claims description 6
- 102100037516 Protein polybromo-1 Human genes 0.000 claims description 6
- 102100022095 Protocadherin Fat 1 Human genes 0.000 claims description 6
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 claims description 6
- 102100032314 RAC-gamma serine/threonine-protein kinase Human genes 0.000 claims description 6
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 claims description 6
- 102100024869 Rhombotin-1 Human genes 0.000 claims description 6
- 108700028341 SMARCB1 Proteins 0.000 claims description 6
- 101150008214 SMARCB1 gene Proteins 0.000 claims description 6
- 108060006706 SRC Proteins 0.000 claims description 6
- 102000001332 SRC Human genes 0.000 claims description 6
- 108010017324 STAT3 Transcription Factor Proteins 0.000 claims description 6
- 108010019992 STAT4 Transcription Factor Proteins 0.000 claims description 6
- 102000005886 STAT4 Transcription Factor Human genes 0.000 claims description 6
- 102100025746 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 Human genes 0.000 claims description 6
- 101100485284 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CRM1 gene Proteins 0.000 claims description 6
- 102100029437 Serine/threonine-protein kinase A-Raf Human genes 0.000 claims description 6
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 claims description 6
- 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 claims description 6
- 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 claims description 6
- 102100036122 Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform Human genes 0.000 claims description 6
- 102100024040 Signal transducer and activator of transcription 3 Human genes 0.000 claims description 6
- 102100027340 Slit homolog 2 protein Human genes 0.000 claims description 6
- 102100031711 Splicing factor 3B subunit 1 Human genes 0.000 claims description 6
- 102100038501 Splicing factor U2AF 35 kDa subunit Human genes 0.000 claims description 6
- 102100038014 Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial Human genes 0.000 claims description 6
- 102100023155 Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial Human genes 0.000 claims description 6
- 102100035726 Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial Human genes 0.000 claims description 6
- 102100026939 Suppressor of fused homolog Human genes 0.000 claims description 6
- 102100021997 Synphilin-1 Human genes 0.000 claims description 6
- 102100038409 T-box transcription factor TBX3 Human genes 0.000 claims description 6
- 102100033455 TGF-beta receptor type-2 Human genes 0.000 claims description 6
- 102100021386 Trans-acting T-cell-specific transcription factor GATA-3 Human genes 0.000 claims description 6
- 102100039580 Transcription factor ETV6 Human genes 0.000 claims description 6
- 102100021380 Transcription factor GATA-4 Human genes 0.000 claims description 6
- 102100021382 Transcription factor GATA-6 Human genes 0.000 claims description 6
- 102100038808 Transcription factor SOX-10 Human genes 0.000 claims description 6
- 102100034204 Transcription factor SOX-9 Human genes 0.000 claims description 6
- 102100035222 Transcription initiation factor TFIID subunit 1 Human genes 0.000 claims description 6
- 102100027671 Transcriptional repressor CTCF Human genes 0.000 claims description 6
- 108010082684 Transforming Growth Factor-beta Type II Receptor Proteins 0.000 claims description 6
- 102100031989 Transmembrane protease serine 2 Human genes 0.000 claims description 6
- 102100031638 Tuberin Human genes 0.000 claims description 6
- 102100022596 Tyrosine-protein kinase ABL1 Human genes 0.000 claims description 6
- 102100022651 Tyrosine-protein kinase ABL2 Human genes 0.000 claims description 6
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 claims description 6
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 claims description 6
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 claims description 6
- 102100026857 Tyrosine-protein kinase Lyn Human genes 0.000 claims description 6
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 claims description 6
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 claims description 6
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 6
- 101150094313 XPO1 gene Proteins 0.000 claims description 6
- 102100036595 Zinc finger protein 217 Human genes 0.000 claims description 6
- 108700000711 bcl-X Proteins 0.000 claims description 6
- 210000004369 blood Anatomy 0.000 claims description 6
- 239000008280 blood Substances 0.000 claims description 6
- 102100037490 cAMP-dependent protein kinase type I-alpha regulatory subunit Human genes 0.000 claims description 6
- 108700002148 exportin 1 Proteins 0.000 claims description 6
- 238000011528 liquid biopsy Methods 0.000 claims description 6
- 108010062219 ran-binding protein 2 Proteins 0.000 claims description 6
- 108010057210 telomerase RNA Proteins 0.000 claims description 6
- 102100038776 ADP-ribosylation factor-related protein 1 Human genes 0.000 claims description 5
- 108700020462 BRCA2 Proteins 0.000 claims description 5
- 102100035631 Bloom syndrome protein Human genes 0.000 claims description 5
- 108091009167 Bloom syndrome protein Proteins 0.000 claims description 5
- 101150008921 Brca2 gene Proteins 0.000 claims description 5
- 102100025175 Cellular communication network factor 6 Human genes 0.000 claims description 5
- 102100038214 Chromodomain-helicase-DNA-binding protein 4 Human genes 0.000 claims description 5
- 208000005443 Circulating Neoplastic Cells Diseases 0.000 claims description 5
- 102100035595 Cohesin subunit SA-2 Human genes 0.000 claims description 5
- 108010058546 Cyclin D1 Proteins 0.000 claims description 5
- 102100038111 Cyclin-dependent kinase 12 Human genes 0.000 claims description 5
- 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 claims description 5
- 102100024829 DNA polymerase delta catalytic subunit Human genes 0.000 claims description 5
- 102100033587 DNA topoisomerase 2-alpha Human genes 0.000 claims description 5
- 108010086291 Deubiquitinating Enzyme CYLD Proteins 0.000 claims description 5
- 102100038595 Estrogen receptor Human genes 0.000 claims description 5
- 102000009095 Fanconi Anemia Complementation Group A protein Human genes 0.000 claims description 5
- 108010087740 Fanconi Anemia Complementation Group A protein Proteins 0.000 claims description 5
- 108010077898 Fanconi Anemia Complementation Group E protein Proteins 0.000 claims description 5
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 claims description 5
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 claims description 5
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 claims description 5
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 claims description 5
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 claims description 5
- 102100027909 Folliculin Human genes 0.000 claims description 5
- 102100028122 Forkhead box protein P1 Human genes 0.000 claims description 5
- 102100024165 G1/S-specific cyclin-D1 Human genes 0.000 claims description 5
- 102100039788 GTPase NRas Human genes 0.000 claims description 5
- 101001077417 Gallus gallus Potassium voltage-gated channel subfamily H member 6 Proteins 0.000 claims description 5
- 102100029458 Glutamate receptor ionotropic, NMDA 2A Human genes 0.000 claims description 5
- 102100031561 Hamartin Human genes 0.000 claims description 5
- 102100022057 Hepatocyte nuclear factor 1-alpha Human genes 0.000 claims description 5
- 101000809413 Homo sapiens ADP-ribosylation factor-related protein 1 Proteins 0.000 claims description 5
- 101000934310 Homo sapiens Cellular communication network factor 6 Proteins 0.000 claims description 5
- 101000883749 Homo sapiens Chromodomain-helicase-DNA-binding protein 4 Proteins 0.000 claims description 5
- 101000642968 Homo sapiens Cohesin subunit SA-2 Proteins 0.000 claims description 5
- 101000884345 Homo sapiens Cyclin-dependent kinase 12 Proteins 0.000 claims description 5
- 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 claims description 5
- 101000909198 Homo sapiens DNA polymerase delta catalytic subunit Proteins 0.000 claims description 5
- 101001095815 Homo sapiens E3 ubiquitin-protein ligase RING2 Proteins 0.000 claims description 5
- 101000882584 Homo sapiens Estrogen receptor Proteins 0.000 claims description 5
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 claims description 5
- 101001060703 Homo sapiens Folliculin Proteins 0.000 claims description 5
- 101001059893 Homo sapiens Forkhead box protein P1 Proteins 0.000 claims description 5
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 claims description 5
- 101001125242 Homo sapiens Glutamate receptor ionotropic, NMDA 2A Proteins 0.000 claims description 5
- 101000795643 Homo sapiens Hamartin Proteins 0.000 claims description 5
- 101001045751 Homo sapiens Hepatocyte nuclear factor 1-alpha Proteins 0.000 claims description 5
- 101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 claims description 5
- 101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 claims description 5
- 101001057193 Homo sapiens Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 Proteins 0.000 claims description 5
- 101001032848 Homo sapiens Metabotropic glutamate receptor 3 Proteins 0.000 claims description 5
- 101000961071 Homo sapiens NF-kappa-B inhibitor alpha Proteins 0.000 claims description 5
- 101001120056 Homo sapiens Phosphatidylinositol 3-kinase regulatory subunit alpha Proteins 0.000 claims description 5
- 101001100767 Homo sapiens Protein quaking Proteins 0.000 claims description 5
- 101000686031 Homo sapiens Proto-oncogene tyrosine-protein kinase ROS Proteins 0.000 claims description 5
- 101100087590 Homo sapiens RICTOR gene Proteins 0.000 claims description 5
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 claims description 5
- 101000742859 Homo sapiens Retinoblastoma-associated protein Proteins 0.000 claims description 5
- 101000702545 Homo sapiens Transcription activator BRG1 Proteins 0.000 claims description 5
- 101000687905 Homo sapiens Transcription factor SOX-2 Proteins 0.000 claims description 5
- 101001010792 Homo sapiens Transcriptional regulator ERG Proteins 0.000 claims description 5
- 101000648507 Homo sapiens Tumor necrosis factor receptor superfamily member 14 Proteins 0.000 claims description 5
- 101000864342 Homo sapiens Tyrosine-protein kinase BTK Proteins 0.000 claims description 5
- 101000740048 Homo sapiens Ubiquitin carboxyl-terminal hydrolase BAP1 Proteins 0.000 claims description 5
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 claims description 5
- 101000723661 Homo sapiens Zinc finger protein 703 Proteins 0.000 claims description 5
- 101001117146 Homo sapiens [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial Proteins 0.000 claims description 5
- 102100026539 Induced myeloid leukemia cell differentiation protein Mcl-1 Human genes 0.000 claims description 5
- 102100027004 Inhibin beta A chain Human genes 0.000 claims description 5
- 101000740049 Latilactobacillus curvatus Bioactive peptide 1 Proteins 0.000 claims description 5
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 claims description 5
- 102100038352 Metabotropic glutamate receptor 3 Human genes 0.000 claims description 5
- 108010050345 Microphthalmia-Associated Transcription Factor Proteins 0.000 claims description 5
- 102100030157 Microphthalmia-associated transcription factor Human genes 0.000 claims description 5
- 102100039337 NF-kappa-B inhibitor alpha Human genes 0.000 claims description 5
- 102100029166 NT-3 growth factor receptor Human genes 0.000 claims description 5
- 102100024894 PR domain zinc finger protein 1 Human genes 0.000 claims description 5
- 108010065129 Patched-1 Receptor Proteins 0.000 claims description 5
- 102000012850 Patched-1 Receptor Human genes 0.000 claims description 5
- 102100026169 Phosphatidylinositol 3-kinase regulatory subunit alpha Human genes 0.000 claims description 5
- 108010009975 Positive Regulatory Domain I-Binding Factor 1 Proteins 0.000 claims description 5
- 102100022807 Potassium voltage-gated channel subfamily H member 2 Human genes 0.000 claims description 5
- 102100038669 Protein quaking Human genes 0.000 claims description 5
- 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 claims description 5
- 108700019586 Rapamycin-Insensitive Companion of mTOR Proteins 0.000 claims description 5
- 102000046941 Rapamycin-Insensitive Companion of mTOR Human genes 0.000 claims description 5
- 102100022122 Ras-related C3 botulinum toxin substrate 1 Human genes 0.000 claims description 5
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 claims description 5
- 108010029031 Regulatory-Associated Protein of mTOR Proteins 0.000 claims description 5
- 102100040969 Regulatory-associated protein of mTOR Human genes 0.000 claims description 5
- 102100038042 Retinoblastoma-associated protein Human genes 0.000 claims description 5
- 102100037608 Spectrin alpha chain, erythrocytic 1 Human genes 0.000 claims description 5
- 102100031027 Transcription activator BRG1 Human genes 0.000 claims description 5
- 102100024270 Transcription factor SOX-2 Human genes 0.000 claims description 5
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 claims description 5
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 claims description 5
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 claims description 5
- 102100024250 Ubiquitin carboxyl-terminal hydrolase CYLD Human genes 0.000 claims description 5
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 claims description 5
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 claims description 5
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 claims description 5
- 102000040856 WT1 Human genes 0.000 claims description 5
- 108700020467 WT1 Proteins 0.000 claims description 5
- 101150084041 WT1 gene Proteins 0.000 claims description 5
- 102100028376 Zinc finger protein 703 Human genes 0.000 claims description 5
- 238000012268 genome sequencing Methods 0.000 claims description 5
- 108010019691 inhibin beta A subunit Proteins 0.000 claims description 5
- 210000002381 plasma Anatomy 0.000 claims description 5
- 108010062302 rac1 GTP Binding Protein Proteins 0.000 claims description 5
- 210000002966 serum Anatomy 0.000 claims description 5
- 108010064892 trkC Receptor Proteins 0.000 claims description 5
- CDKIEBFIMCSCBB-UHFFFAOYSA-N 1-(6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)-3-(1-methyl-2-phenylpyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one;hydrochloride Chemical compound Cl.C1C=2C=C(OC)C(OC)=CC=2CCN1C(=O)C=CC(C1=CC=CN=C1N1C)=C1C1=CC=CC=C1 CDKIEBFIMCSCBB-UHFFFAOYSA-N 0.000 claims description 4
- 102100032306 Aurora kinase B Human genes 0.000 claims description 4
- 102100035682 Axin-1 Human genes 0.000 claims description 4
- 102100021631 B-cell lymphoma 6 protein Human genes 0.000 claims description 4
- 108091005625 BRD4 Proteins 0.000 claims description 4
- 102100026008 Breakpoint cluster region protein Human genes 0.000 claims description 4
- 102100029895 Bromodomain-containing protein 4 Human genes 0.000 claims description 4
- 102100034808 CCAAT/enhancer-binding protein alpha Human genes 0.000 claims description 4
- 108010043471 Core Binding Factor Alpha 2 Subunit Proteins 0.000 claims description 4
- 102100029375 Crk-like protein Human genes 0.000 claims description 4
- 102000009512 Cyclin-Dependent Kinase Inhibitor p15 Human genes 0.000 claims description 4
- 108010009356 Cyclin-Dependent Kinase Inhibitor p15 Proteins 0.000 claims description 4
- 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 claims description 4
- 102100026245 E3 ubiquitin-protein ligase RNF43 Human genes 0.000 claims description 4
- 102000018825 Fanconi Anemia Complementation Group C protein Human genes 0.000 claims description 4
- 108010027673 Fanconi Anemia Complementation Group C protein Proteins 0.000 claims description 4
- 102000013601 Fanconi Anemia Complementation Group D2 protein Human genes 0.000 claims description 4
- 108010026653 Fanconi Anemia Complementation Group D2 protein Proteins 0.000 claims description 4
- 102000010634 Fanconi Anemia Complementation Group E protein Human genes 0.000 claims description 4
- 102000012216 Fanconi Anemia Complementation Group F protein Human genes 0.000 claims description 4
- 102000052930 Fanconi Anemia Complementation Group L protein Human genes 0.000 claims description 4
- 102100028043 Fibroblast growth factor 3 Human genes 0.000 claims description 4
- 102100021066 Fibroblast growth factor receptor substrate 2 Human genes 0.000 claims description 4
- 102100037858 G1/S-specific cyclin-E1 Human genes 0.000 claims description 4
- 102000017691 GABRA6 Human genes 0.000 claims description 4
- 102100030708 GTPase KRas Human genes 0.000 claims description 4
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 claims description 4
- 102100038104 Glycogen synthase kinase-3 beta Human genes 0.000 claims description 4
- 108091059596 H3F3A Proteins 0.000 claims description 4
- 102100038885 Histone acetyltransferase p300 Human genes 0.000 claims description 4
- 101000798306 Homo sapiens Aurora kinase B Proteins 0.000 claims description 4
- 101000874566 Homo sapiens Axin-1 Proteins 0.000 claims description 4
- 101000971234 Homo sapiens B-cell lymphoma 6 protein Proteins 0.000 claims description 4
- 101000933320 Homo sapiens Breakpoint cluster region protein Proteins 0.000 claims description 4
- 101000945515 Homo sapiens CCAAT/enhancer-binding protein alpha Proteins 0.000 claims description 4
- 101000919315 Homo sapiens Crk-like protein Proteins 0.000 claims description 4
- 101001115395 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 4 Proteins 0.000 claims description 4
- 101000692702 Homo sapiens E3 ubiquitin-protein ligase RNF43 Proteins 0.000 claims description 4
- 101001060280 Homo sapiens Fibroblast growth factor 3 Proteins 0.000 claims description 4
- 101000818410 Homo sapiens Fibroblast growth factor receptor substrate 2 Proteins 0.000 claims description 4
- 101000738568 Homo sapiens G1/S-specific cyclin-E1 Proteins 0.000 claims description 4
- 101001001400 Homo sapiens Gamma-aminobutyric acid receptor subunit alpha-6 Proteins 0.000 claims description 4
- 101000882390 Homo sapiens Histone acetyltransferase p300 Proteins 0.000 claims description 4
- 101000614988 Homo sapiens Mediator of RNA polymerase II transcription subunit 12 Proteins 0.000 claims description 4
- 101000595741 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform Proteins 0.000 claims description 4
- 101001125574 Homo sapiens Prostasin Proteins 0.000 claims description 4
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 claims description 4
- 101000580092 Homo sapiens RNA-binding protein 10 Proteins 0.000 claims description 4
- 101100078258 Homo sapiens RUNX1T1 gene Proteins 0.000 claims description 4
- 101001112293 Homo sapiens Retinoic acid receptor alpha Proteins 0.000 claims description 4
- 101000881267 Homo sapiens Spectrin alpha chain, erythrocytic 1 Proteins 0.000 claims description 4
- 101000799466 Homo sapiens Thrombopoietin receptor Proteins 0.000 claims description 4
- 101000636213 Homo sapiens Transcriptional activator Myb Proteins 0.000 claims description 4
- 101000807561 Homo sapiens Tyrosine-protein kinase receptor UFO Proteins 0.000 claims description 4
- 101001087416 Homo sapiens Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 claims description 4
- 108010075654 MAP Kinase Kinase Kinase 1 Proteins 0.000 claims description 4
- 108700012912 MYCN Proteins 0.000 claims description 4
- 101150022024 MYCN gene Proteins 0.000 claims description 4
- 101150053046 MYD88 gene Proteins 0.000 claims description 4
- 102100021070 Mediator of RNA polymerase II transcription subunit 12 Human genes 0.000 claims description 4
- 102100033115 Mitogen-activated protein kinase kinase kinase 1 Human genes 0.000 claims description 4
- 102100025751 Mothers against decapentaplegic homolog 2 Human genes 0.000 claims description 4
- 101710143123 Mothers against decapentaplegic homolog 2 Proteins 0.000 claims description 4
- 102100025748 Mothers against decapentaplegic homolog 3 Human genes 0.000 claims description 4
- 101710143111 Mothers against decapentaplegic homolog 3 Proteins 0.000 claims description 4
- 102100025725 Mothers against decapentaplegic homolog 4 Human genes 0.000 claims description 4
- 101710143112 Mothers against decapentaplegic homolog 4 Proteins 0.000 claims description 4
- 102100024134 Myeloid differentiation primary response protein MyD88 Human genes 0.000 claims description 4
- 108700026495 N-Myc Proto-Oncogene Proteins 0.000 claims description 4
- 102100030124 N-myc proto-oncogene protein Human genes 0.000 claims description 4
- 102100036061 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform Human genes 0.000 claims description 4
- 102100029500 Prostasin Human genes 0.000 claims description 4
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 claims description 4
- 102100027514 RNA-binding protein 10 Human genes 0.000 claims description 4
- 108700040655 RUNX1 Translocation Partner 1 Proteins 0.000 claims description 4
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 claims description 4
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 claims description 4
- 102100023606 Retinoic acid receptor alpha Human genes 0.000 claims description 4
- 102100025373 Runt-related transcription factor 1 Human genes 0.000 claims description 4
- 102100034196 Thrombopoietin receptor Human genes 0.000 claims description 4
- 102100030780 Transcriptional activator Myb Human genes 0.000 claims description 4
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 claims description 4
- 102000015098 Tumor Suppressor Protein p53 Human genes 0.000 claims description 4
- 102100037236 Tyrosine-protein kinase receptor UFO Human genes 0.000 claims description 4
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 claims description 4
- 102000009503 Cyclin-Dependent Kinase Inhibitor p18 Human genes 0.000 claims description 3
- 108010009367 Cyclin-Dependent Kinase Inhibitor p18 Proteins 0.000 claims description 3
- 102000007122 Fanconi Anemia Complementation Group G protein Human genes 0.000 claims description 3
- 102100036118 Far upstream element-binding protein 1 Human genes 0.000 claims description 3
- 102100028075 Fibroblast growth factor 6 Human genes 0.000 claims description 3
- 101000930770 Homo sapiens Far upstream element-binding protein 1 Proteins 0.000 claims description 3
- 101001060265 Homo sapiens Fibroblast growth factor 6 Proteins 0.000 claims description 3
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 claims description 3
- 102100032746 Actin-histidine N-methyltransferase Human genes 0.000 claims description 2
- 101000654703 Homo sapiens Actin-histidine N-methyltransferase Proteins 0.000 claims description 2
- 101001043809 Homo sapiens Interleukin-7 receptor subunit alpha Proteins 0.000 claims description 2
- 102100021593 Interleukin-7 receptor subunit alpha Human genes 0.000 claims description 2
- 229940124647 MEK inhibitor Drugs 0.000 claims 2
- 102000052609 BRCA2 Human genes 0.000 claims 1
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 claims 1
- 101710146529 Dual specificity mitogen-activated protein kinase kinase 2 Proteins 0.000 claims 1
- 102100037964 E3 ubiquitin-protein ligase RING2 Human genes 0.000 claims 1
- 102100029525 F-box only protein 7 Human genes 0.000 claims 1
- 102100021064 Fibroblast growth factor receptor substrate 3 Human genes 0.000 claims 1
- 102100021866 Hepatocyte growth factor Human genes 0.000 claims 1
- 101000917536 Homo sapiens F-box only protein 7 Proteins 0.000 claims 1
- 101000818396 Homo sapiens Fibroblast growth factor receptor substrate 3 Proteins 0.000 claims 1
- 102000055120 MEF2 Transcription Factors Human genes 0.000 claims 1
- 102000008071 Mismatch Repair Endonuclease PMS2 Human genes 0.000 claims 1
- 102000001759 Notch1 Receptor Human genes 0.000 claims 1
- 102000001756 Notch2 Receptor Human genes 0.000 claims 1
- 102000001760 Notch3 Receptor Human genes 0.000 claims 1
- 101100127690 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) FAA2 gene Proteins 0.000 claims 1
- 102100033254 Tumor suppressor ARF Human genes 0.000 claims 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 178
- 230000000392 somatic effect Effects 0.000 abstract 1
- 229960003301 nivolumab Drugs 0.000 description 60
- 210000001519 tissue Anatomy 0.000 description 53
- 201000011510 cancer Diseases 0.000 description 50
- 230000014509 gene expression Effects 0.000 description 50
- 229960005386 ipilimumab Drugs 0.000 description 34
- 239000000523 sample Substances 0.000 description 30
- 208000032818 Microsatellite Instability Diseases 0.000 description 28
- 108020004414 DNA Proteins 0.000 description 26
- 238000002512 chemotherapy Methods 0.000 description 26
- 239000003814 drug Substances 0.000 description 26
- 230000004083 survival effect Effects 0.000 description 26
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 23
- 238000002648 combination therapy Methods 0.000 description 23
- 230000004044 response Effects 0.000 description 23
- 229960003852 atezolizumab Drugs 0.000 description 22
- 229950002916 avelumab Drugs 0.000 description 22
- 229950009791 durvalumab Drugs 0.000 description 22
- 210000004602 germ cell Anatomy 0.000 description 22
- 238000012360 testing method Methods 0.000 description 22
- 102000004127 Cytokines Human genes 0.000 description 21
- 108090000695 Cytokines Proteins 0.000 description 21
- 102100034535 Histone H3.1 Human genes 0.000 description 20
- 101001067844 Homo sapiens Histone H3.1 Proteins 0.000 description 20
- 210000001744 T-lymphocyte Anatomy 0.000 description 20
- 201000010099 disease Diseases 0.000 description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 20
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 19
- 102000048362 human PDCD1 Human genes 0.000 description 19
- 210000000987 immune system Anatomy 0.000 description 19
- 229940079593 drug Drugs 0.000 description 18
- 229960002621 pembrolizumab Drugs 0.000 description 18
- 238000004458 analytical method Methods 0.000 description 17
- 102000048776 human CD274 Human genes 0.000 description 17
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 15
- 108010002350 Interleukin-2 Proteins 0.000 description 15
- 102000000588 Interleukin-2 Human genes 0.000 description 15
- 102000043321 human CTLA4 Human genes 0.000 description 15
- 238000003364 immunohistochemistry Methods 0.000 description 14
- 238000005259 measurement Methods 0.000 description 14
- 229950007217 tremelimumab Drugs 0.000 description 14
- 239000002202 Polyethylene glycol Substances 0.000 description 13
- 239000012634 fragment Substances 0.000 description 13
- 238000007481 next generation sequencing Methods 0.000 description 13
- 229920001223 polyethylene glycol Polymers 0.000 description 13
- 230000028993 immune response Effects 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 230000008859 change Effects 0.000 description 11
- 238000009169 immunotherapy Methods 0.000 description 10
- 210000004881 tumor cell Anatomy 0.000 description 10
- 108060003951 Immunoglobulin Proteins 0.000 description 9
- 230000008901 benefit Effects 0.000 description 9
- 102000018358 immunoglobulin Human genes 0.000 description 9
- 230000003993 interaction Effects 0.000 description 9
- 230000033607 mismatch repair Effects 0.000 description 9
- 238000007799 mixed lymphocyte reaction assay Methods 0.000 description 9
- 229920000642 polymer Polymers 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 description 8
- 102100026879 Interleukin-2 receptor subunit beta Human genes 0.000 description 8
- 102100040403 Tumor necrosis factor receptor superfamily member 6 Human genes 0.000 description 8
- 239000000556 agonist Substances 0.000 description 8
- 125000003275 alpha amino acid group Chemical group 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 8
- 238000011161 development Methods 0.000 description 8
- 230000018109 developmental process Effects 0.000 description 8
- 230000037442 genomic alteration Effects 0.000 description 8
- 239000002773 nucleotide Substances 0.000 description 8
- 125000003729 nucleotide group Chemical group 0.000 description 8
- 229920001184 polypeptide Polymers 0.000 description 8
- 102000004196 processed proteins & peptides Human genes 0.000 description 8
- 238000010186 staining Methods 0.000 description 8
- 238000012070 whole genome sequencing analysis Methods 0.000 description 8
- 108091026890 Coding region Proteins 0.000 description 7
- 101001030211 Homo sapiens Myc proto-oncogene protein Proteins 0.000 description 7
- 108091092195 Intron Proteins 0.000 description 7
- 108091092878 Microsatellite Proteins 0.000 description 7
- 102100032929 Son of sevenless homolog 1 Human genes 0.000 description 7
- 230000002068 genetic effect Effects 0.000 description 7
- 239000002955 immunomodulating agent Substances 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 241000894007 species Species 0.000 description 7
- 102000001301 EGF receptor Human genes 0.000 description 6
- 108060006698 EGF receptor Proteins 0.000 description 6
- 102100039849 Histone H2A type 1 Human genes 0.000 description 6
- 102100022102 Histone-lysine N-methyltransferase 2B Human genes 0.000 description 6
- 101000824278 Homo sapiens Acyl-[acyl-carrier-protein] hydrolase Proteins 0.000 description 6
- 101001035431 Homo sapiens Histone H2A type 1 Proteins 0.000 description 6
- 101000596772 Homo sapiens Transcription factor 7-like 1 Proteins 0.000 description 6
- 102100037480 Mismatch repair endonuclease PMS2 Human genes 0.000 description 6
- 102100023181 Neurogenic locus notch homolog protein 1 Human genes 0.000 description 6
- 102100035097 Transcription factor 7-like 1 Human genes 0.000 description 6
- 238000002405 diagnostic procedure Methods 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 230000004927 fusion Effects 0.000 description 6
- 238000003384 imaging method Methods 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 210000002540 macrophage Anatomy 0.000 description 6
- 231100000150 mutagenicity / genotoxicity testing Toxicity 0.000 description 6
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 5
- 102100024458 Cyclin-dependent kinase inhibitor 2A Human genes 0.000 description 5
- 108700024394 Exon Proteins 0.000 description 5
- 101000954986 Homo sapiens Merlin Proteins 0.000 description 5
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 5
- 102100037106 Merlin Human genes 0.000 description 5
- 102100021149 Myocyte-specific enhancer factor 2B Human genes 0.000 description 5
- 102100025246 Neurogenic locus notch homolog protein 2 Human genes 0.000 description 5
- 102100025247 Neurogenic locus notch homolog protein 3 Human genes 0.000 description 5
- 230000006044 T cell activation Effects 0.000 description 5
- 102100023931 Transcriptional regulator ATRX Human genes 0.000 description 5
- 230000033228 biological regulation Effects 0.000 description 5
- 239000012636 effector Substances 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- 230000028327 secretion Effects 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 102100025399 Breast cancer type 2 susceptibility protein Human genes 0.000 description 4
- 101710098191 C-4 methylsterol oxidase ERG25 Proteins 0.000 description 4
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 4
- 102100036448 Endothelial PAS domain-containing protein 1 Human genes 0.000 description 4
- 101710105178 F-box/WD repeat-containing protein 7 Proteins 0.000 description 4
- 102100028138 F-box/WD repeat-containing protein 7 Human genes 0.000 description 4
- 102100032610 Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas Human genes 0.000 description 4
- 102100033636 Histone H3.2 Human genes 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 101001014590 Homo sapiens Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas Proteins 0.000 description 4
- 101001014594 Homo sapiens Guanine nucleotide-binding protein G(s) subunit alpha isoforms short Proteins 0.000 description 4
- 101000871895 Homo sapiens Histone H3.2 Proteins 0.000 description 4
- 101001014610 Homo sapiens Neuroendocrine secretory protein 55 Proteins 0.000 description 4
- 101000616502 Homo sapiens Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1 Proteins 0.000 description 4
- 101000728236 Homo sapiens Polycomb group protein ASXL1 Proteins 0.000 description 4
- 101001126582 Homo sapiens Post-GPI attachment to proteins factor 3 Proteins 0.000 description 4
- 101000797903 Homo sapiens Protein ALEX Proteins 0.000 description 4
- 101001091984 Homo sapiens Rho GTPase-activating protein 26 Proteins 0.000 description 4
- 101001026870 Homo sapiens Serine/threonine-protein kinase D1 Proteins 0.000 description 4
- 101000913761 Homo sapiens Serine/threonine-protein kinase ICK Proteins 0.000 description 4
- 101000628562 Homo sapiens Serine/threonine-protein kinase STK11 Proteins 0.000 description 4
- 101000934888 Homo sapiens Succinate dehydrogenase cytochrome b560 subunit, mitochondrial Proteins 0.000 description 4
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 4
- 101000666429 Homo sapiens Terminal nucleotidyltransferase 5C Proteins 0.000 description 4
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 4
- 101000666382 Homo sapiens Transcription factor E2-alpha Proteins 0.000 description 4
- 101000723740 Homo sapiens Zinc finger protein 24 Proteins 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 102100027240 Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 Human genes 0.000 description 4
- 108700020796 Oncogene Proteins 0.000 description 4
- 102100021797 Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1 Human genes 0.000 description 4
- 102100029799 Polycomb group protein ASXL1 Human genes 0.000 description 4
- 102100035744 Rho GTPase-activating protein 26 Human genes 0.000 description 4
- 102100037310 Serine/threonine-protein kinase D1 Human genes 0.000 description 4
- 102100026621 Serine/threonine-protein kinase ICK Human genes 0.000 description 4
- 102100026715 Serine/threonine-protein kinase STK11 Human genes 0.000 description 4
- 102000013380 Smoothened Receptor Human genes 0.000 description 4
- 101710090597 Smoothened homolog Proteins 0.000 description 4
- 101150045565 Socs1 gene Proteins 0.000 description 4
- 102100025393 Succinate dehydrogenase cytochrome b560 subunit, mitochondrial Human genes 0.000 description 4
- 108700027336 Suppressor of Cytokine Signaling 1 Proteins 0.000 description 4
- 102100024779 Suppressor of cytokine signaling 1 Human genes 0.000 description 4
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 4
- 102100038305 Terminal nucleotidyltransferase 5C Human genes 0.000 description 4
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 4
- 102100028365 Zinc finger protein 24 Human genes 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 230000006023 anti-tumor response Effects 0.000 description 4
- 239000000090 biomarker Substances 0.000 description 4
- 210000003162 effector t lymphocyte Anatomy 0.000 description 4
- 108010018033 endothelial PAS domain-containing protein 1 Proteins 0.000 description 4
- 230000002708 enhancing effect Effects 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 230000000869 mutational effect Effects 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 230000000391 smoking effect Effects 0.000 description 4
- 102100034134 Activin receptor type-1B Human genes 0.000 description 3
- 102100021886 Activin receptor type-2A Human genes 0.000 description 3
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 3
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 3
- 102100022983 B-cell lymphoma/leukemia 11B Human genes 0.000 description 3
- 108091012583 BCL2 Proteins 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 108020004705 Codon Proteins 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- 102000000577 Cyclin-Dependent Kinase Inhibitor p27 Human genes 0.000 description 3
- 108010016777 Cyclin-Dependent Kinase Inhibitor p27 Proteins 0.000 description 3
- 102100036279 DNA (cytosine-5)-methyltransferase 1 Human genes 0.000 description 3
- 102100024812 DNA (cytosine-5)-methyltransferase 3A Human genes 0.000 description 3
- 108010024491 DNA Methyltransferase 3A Proteins 0.000 description 3
- 102100033991 E3 ubiquitin-protein ligase DTX1 Human genes 0.000 description 3
- 238000012286 ELISA Assay Methods 0.000 description 3
- 102100031856 ERBB receptor feedback inhibitor 1 Human genes 0.000 description 3
- 102100029234 Histone-lysine N-methyltransferase NSD2 Human genes 0.000 description 3
- 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 description 3
- 101000799189 Homo sapiens Activin receptor type-1B Proteins 0.000 description 3
- 101000970954 Homo sapiens Activin receptor type-2A Proteins 0.000 description 3
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 3
- 101001017463 Homo sapiens E3 ubiquitin-protein ligase DTX1 Proteins 0.000 description 3
- 101000920812 Homo sapiens ERBB receptor feedback inhibitor 1 Proteins 0.000 description 3
- 101000634048 Homo sapiens Histone-lysine N-methyltransferase NSD2 Proteins 0.000 description 3
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 description 3
- 101001053339 Homo sapiens Inositol polyphosphate 4-phosphatase type II Proteins 0.000 description 3
- 101001077600 Homo sapiens Insulin receptor substrate 2 Proteins 0.000 description 3
- 101000582631 Homo sapiens Menin Proteins 0.000 description 3
- 101000738901 Homo sapiens PMS1 protein homolog 1 Proteins 0.000 description 3
- 101000613490 Homo sapiens Paired box protein Pax-3 Proteins 0.000 description 3
- 101000601724 Homo sapiens Paired box protein Pax-5 Proteins 0.000 description 3
- 101000945735 Homo sapiens Parafibromin Proteins 0.000 description 3
- 101001126417 Homo sapiens Platelet-derived growth factor receptor alpha Proteins 0.000 description 3
- 101000927796 Homo sapiens Rho guanine nucleotide exchange factor 7 Proteins 0.000 description 3
- 101000854388 Homo sapiens Ribonuclease 3 Proteins 0.000 description 3
- 101000987315 Homo sapiens Serine/threonine-protein kinase PAK 3 Proteins 0.000 description 3
- 101000642268 Homo sapiens Speckle-type POZ protein Proteins 0.000 description 3
- 101000772267 Homo sapiens Thyrotropin receptor Proteins 0.000 description 3
- 101000788773 Homo sapiens Zinc finger and BTB domain-containing protein 2 Proteins 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 102100024366 Inositol polyphosphate 4-phosphatase type II Human genes 0.000 description 3
- 102100025092 Insulin receptor substrate 2 Human genes 0.000 description 3
- 108090000484 Kelch-Like ECH-Associated Protein 1 Proteins 0.000 description 3
- 102000004034 Kelch-Like ECH-Associated Protein 1 Human genes 0.000 description 3
- 102000017274 MDM4 Human genes 0.000 description 3
- 108050005300 MDM4 Proteins 0.000 description 3
- 102100030550 Menin Human genes 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- 101150097381 Mtor gene Proteins 0.000 description 3
- 102000043276 Oncogene Human genes 0.000 description 3
- 108700026244 Open Reading Frames Proteins 0.000 description 3
- 102100037482 PMS1 protein homolog 1 Human genes 0.000 description 3
- 102100040891 Paired box protein Pax-3 Human genes 0.000 description 3
- 102100037504 Paired box protein Pax-5 Human genes 0.000 description 3
- 102100034743 Parafibromin Human genes 0.000 description 3
- 102100030485 Platelet-derived growth factor receptor alpha Human genes 0.000 description 3
- 102000001195 RAD51 Human genes 0.000 description 3
- 238000010240 RT-PCR analysis Methods 0.000 description 3
- 108010068097 Rad51 Recombinase Proteins 0.000 description 3
- 102100027911 Serine/threonine-protein kinase PAK 3 Human genes 0.000 description 3
- 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 3
- 102100036422 Speckle-type POZ protein Human genes 0.000 description 3
- 102100029337 Thyrotropin receptor Human genes 0.000 description 3
- 108010047933 Tumor Necrosis Factor alpha-Induced Protein 3 Proteins 0.000 description 3
- 102100024596 Tumor necrosis factor alpha-induced protein 3 Human genes 0.000 description 3
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 3
- 108700042462 X-linked Nuclear Proteins 0.000 description 3
- 108010016200 Zinc Finger Protein GLI1 Proteins 0.000 description 3
- 102100025350 Zinc finger and BTB domain-containing protein 2 Human genes 0.000 description 3
- 102100035535 Zinc finger protein GLI1 Human genes 0.000 description 3
- 230000005875 antibody response Effects 0.000 description 3
- 238000003782 apoptosis assay Methods 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 238000002619 cancer immunotherapy Methods 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- CLBIEZBAENPDFY-HNXGFDTJSA-N dinophysistoxin 1 Chemical compound C([C@H](O1)[C@H](C)/C=C/[C@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)[C@@H](O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(O3)[C@@H](CCCO4)C)C)O2)C(C)=C[C@]21O[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]2O CLBIEZBAENPDFY-HNXGFDTJSA-N 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 210000000981 epithelium Anatomy 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 229940072221 immunoglobulins Drugs 0.000 description 3
- 229940121354 immunomodulator Drugs 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 238000011503 in vivo imaging Methods 0.000 description 3
- 210000004969 inflammatory cell Anatomy 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 101150061338 mmr gene Proteins 0.000 description 3
- 229960005079 pemetrexed Drugs 0.000 description 3
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-L pemetrexed(2-) Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-L 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000005522 programmed cell death Effects 0.000 description 3
- 238000000159 protein binding assay Methods 0.000 description 3
- 230000004043 responsiveness Effects 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 238000011269 treatment regimen Methods 0.000 description 3
- 102100026205 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 Human genes 0.000 description 2
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 2
- 102100034571 AT-rich interactive domain-containing protein 1B Human genes 0.000 description 2
- 102100030835 AT-rich interactive domain-containing protein 5B Human genes 0.000 description 2
- 102100033391 ATP-dependent RNA helicase DDX3X Human genes 0.000 description 2
- 101150020330 ATRX gene Proteins 0.000 description 2
- 102100034111 Activin receptor type-1 Human genes 0.000 description 2
- 102100036793 Adhesion G protein-coupled receptor L3 Human genes 0.000 description 2
- 102100027211 Albumin Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102100030346 Antigen peptide transporter 1 Human genes 0.000 description 2
- 102100030343 Antigen peptide transporter 2 Human genes 0.000 description 2
- 101100404726 Arabidopsis thaliana NHX7 gene Proteins 0.000 description 2
- 102100027971 Arachidonate 12-lipoxygenase, 12R-type Human genes 0.000 description 2
- 108700024832 B-Cell CLL-Lymphoma 10 Proteins 0.000 description 2
- 102100021630 B-cell CLL/lymphoma 7 protein family member A Human genes 0.000 description 2
- 102100037598 B-cell lymphoma/leukemia 10 Human genes 0.000 description 2
- 101150074953 BCL10 gene Proteins 0.000 description 2
- 102100024641 BRCA1-A complex subunit Abraxas 1 Human genes 0.000 description 2
- 102100035647 BRISC and BRCA1-A complex member 1 Human genes 0.000 description 2
- 108700003785 Baculoviral IAP Repeat-Containing 3 Proteins 0.000 description 2
- 102100021662 Baculoviral IAP repeat-containing protein 3 Human genes 0.000 description 2
- 108010040168 Bcl-2-Like Protein 11 Proteins 0.000 description 2
- 102000001765 Bcl-2-Like Protein 11 Human genes 0.000 description 2
- 102100021573 Bcl-2-binding component 3, isoforms 3/4 Human genes 0.000 description 2
- 101150104237 Birc3 gene Proteins 0.000 description 2
- 102100025423 Bone morphogenetic protein receptor type-1A Human genes 0.000 description 2
- 101000964894 Bos taurus 14-3-3 protein zeta/delta Proteins 0.000 description 2
- 101800001415 Bri23 peptide Proteins 0.000 description 2
- 102400000107 C-terminal peptide Human genes 0.000 description 2
- 101800000655 C-terminal peptide Proteins 0.000 description 2
- 102100038078 CD276 antigen Human genes 0.000 description 2
- 108010045374 CD36 Antigens Proteins 0.000 description 2
- 102000053028 CD36 Antigens Human genes 0.000 description 2
- 102100025221 CD70 antigen Human genes 0.000 description 2
- 102000015367 CRBN Human genes 0.000 description 2
- 102100040775 CREB-regulated transcription coactivator 1 Human genes 0.000 description 2
- 102100040807 CUB and sushi domain-containing protein 3 Human genes 0.000 description 2
- 102100024155 Cadherin-11 Human genes 0.000 description 2
- 102100036364 Cadherin-2 Human genes 0.000 description 2
- 102100029761 Cadherin-5 Human genes 0.000 description 2
- 101001110283 Canis lupus familiaris Ras-related C3 botulinum toxin substrate 1 Proteins 0.000 description 2
- 102100026548 Caspase-8 Human genes 0.000 description 2
- 102100028914 Catenin beta-1 Human genes 0.000 description 2
- 102100037182 Cation-independent mannose-6-phosphate receptor Human genes 0.000 description 2
- 102000011068 Cdc42 Human genes 0.000 description 2
- 102100026772 Cell cycle control protein 50A Human genes 0.000 description 2
- 102100031634 Cold shock domain-containing protein E1 Human genes 0.000 description 2
- 102100033601 Collagen alpha-1(I) chain Human genes 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 102100026359 Cyclic AMP-responsive element-binding protein 1 Human genes 0.000 description 2
- 102100034501 Cyclin-dependent kinases regulatory subunit 1 Human genes 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- 101150016994 Cysltr2 gene Proteins 0.000 description 2
- 102100033539 Cysteinyl leukotriene receptor 2 Human genes 0.000 description 2
- 108010026925 Cytochrome P-450 CYP2C19 Proteins 0.000 description 2
- 108010001237 Cytochrome P-450 CYP2D6 Proteins 0.000 description 2
- 102100029363 Cytochrome P450 2C19 Human genes 0.000 description 2
- 102100021704 Cytochrome P450 2D6 Human genes 0.000 description 2
- 102100026982 DCN1-like protein 1 Human genes 0.000 description 2
- 108010009540 DNA (Cytosine-5-)-Methyltransferase 1 Proteins 0.000 description 2
- 102100024810 DNA (cytosine-5)-methyltransferase 3B Human genes 0.000 description 2
- 101710123222 DNA (cytosine-5)-methyltransferase 3B Proteins 0.000 description 2
- 102100029145 DNA damage-inducible transcript 3 protein Human genes 0.000 description 2
- 102100031866 DNA excision repair protein ERCC-5 Human genes 0.000 description 2
- 108010035476 DNA excision repair protein ERCC-5 Proteins 0.000 description 2
- 102100037700 DNA mismatch repair protein Msh3 Human genes 0.000 description 2
- 102100029094 DNA repair endonuclease XPF Human genes 0.000 description 2
- 102100033934 DNA repair protein RAD51 homolog 2 Human genes 0.000 description 2
- 102100034484 DNA repair protein RAD51 homolog 3 Human genes 0.000 description 2
- 102100034483 DNA repair protein RAD51 homolog 4 Human genes 0.000 description 2
- 102100027830 DNA repair protein XRCC2 Human genes 0.000 description 2
- 102100022474 DNA repair protein complementing XP-A cells Human genes 0.000 description 2
- 102100022477 DNA repair protein complementing XP-C cells Human genes 0.000 description 2
- 102100039436 DNA-binding protein inhibitor ID-3 Human genes 0.000 description 2
- 102100022334 Dihydropyrimidine dehydrogenase [NADP(+)] Human genes 0.000 description 2
- 102100029721 DnaJ homolog subfamily B member 1 Human genes 0.000 description 2
- 102100029952 Double-strand-break repair protein rad21 homolog Human genes 0.000 description 2
- 108010044191 Dynamin II Proteins 0.000 description 2
- 102100021238 Dynamin-2 Human genes 0.000 description 2
- 102100032249 Dystonin Human genes 0.000 description 2
- 102100038913 E1A-binding protein p400 Human genes 0.000 description 2
- 102100022183 E3 ubiquitin-protein ligase MIB1 Human genes 0.000 description 2
- 102100024816 E3 ubiquitin-protein ligase TRAF7 Human genes 0.000 description 2
- 102100037024 E3 ubiquitin-protein ligase XIAP Human genes 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000012804 EPCAM Human genes 0.000 description 2
- 101150084967 EPCAM gene Proteins 0.000 description 2
- 102100035079 ETS-related transcription factor Elf-3 Human genes 0.000 description 2
- 102100027100 Echinoderm microtubule-associated protein-like 4 Human genes 0.000 description 2
- 102100034241 Elongator complex protein 2 Human genes 0.000 description 2
- 101710167764 Elongator complex protein 2 Proteins 0.000 description 2
- 102100037114 Elongin-C Human genes 0.000 description 2
- 108010055323 EphB4 Receptor Proteins 0.000 description 2
- 101150025643 Epha5 gene Proteins 0.000 description 2
- 102100021605 Ephrin type-A receptor 5 Human genes 0.000 description 2
- 102100031983 Ephrin type-B receptor 4 Human genes 0.000 description 2
- 102100032031 Epidermal growth factor-like protein 7 Human genes 0.000 description 2
- 102100036725 Epithelial discoidin domain-containing receptor 1 Human genes 0.000 description 2
- 101710131668 Epithelial discoidin domain-containing receptor 1 Proteins 0.000 description 2
- 102100031690 Erythroid transcription factor Human genes 0.000 description 2
- 102000005233 Eukaryotic Initiation Factor-4E Human genes 0.000 description 2
- 108060002636 Eukaryotic Initiation Factor-4E Proteins 0.000 description 2
- 102100022462 Eukaryotic initiation factor 4A-II Human genes 0.000 description 2
- 102100039408 Eukaryotic translation initiation factor 1A, X-chromosomal Human genes 0.000 description 2
- 102100026063 Exosome complex component MTR3 Human genes 0.000 description 2
- 102100024359 Exosome complex exonuclease RRP44 Human genes 0.000 description 2
- 102100029074 Exostosin-2 Human genes 0.000 description 2
- 102100038578 F-box only protein 11 Human genes 0.000 description 2
- 102100024516 F-box only protein 5 Human genes 0.000 description 2
- 102100026353 F-box-like/WD repeat-containing protein TBL1XR1 Human genes 0.000 description 2
- 101710191461 F420-dependent glucose-6-phosphate dehydrogenase Proteins 0.000 description 2
- 102100027279 FAS-associated factor 1 Human genes 0.000 description 2
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 description 2
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 2
- 102100028417 Fibroblast growth factor 12 Human genes 0.000 description 2
- 102100035290 Fibroblast growth factor 13 Human genes 0.000 description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 2
- 102100037665 Fibroblast growth factor 9 Human genes 0.000 description 2
- 102100032596 Fibrocystin Human genes 0.000 description 2
- 102100024058 Flap endonuclease GEN homolog 1 Human genes 0.000 description 2
- 108010010285 Forkhead Box Protein L2 Proteins 0.000 description 2
- 102100035137 Forkhead box protein L2 Human genes 0.000 description 2
- 102100027579 Forkhead box protein P4 Human genes 0.000 description 2
- 102100022148 G protein pathway suppressor 2 Human genes 0.000 description 2
- 102100022951 Gamma-secretase subunit APH-1A Human genes 0.000 description 2
- 102100031885 General transcription and DNA repair factor IIH helicase subunit XPB Human genes 0.000 description 2
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 2
- 108091010837 Glial cell line-derived neurotrophic factor Proteins 0.000 description 2
- 102000034615 Glial cell line-derived neurotrophic factor Human genes 0.000 description 2
- 102100035172 Glucose-6-phosphate 1-dehydrogenase Human genes 0.000 description 2
- 101710155861 Glucose-6-phosphate 1-dehydrogenase Proteins 0.000 description 2
- 101710174622 Glucose-6-phosphate 1-dehydrogenase, chloroplastic Proteins 0.000 description 2
- 101710137456 Glucose-6-phosphate 1-dehydrogenase, cytoplasmic isoform Proteins 0.000 description 2
- 244000060234 Gmelina philippensis Species 0.000 description 2
- 102100039622 Granulocyte colony-stimulating factor receptor Human genes 0.000 description 2
- 102100038367 Gremlin-1 Human genes 0.000 description 2
- 102100036733 Guanine nucleotide-binding protein subunit alpha-12 Human genes 0.000 description 2
- 102100036703 Guanine nucleotide-binding protein subunit alpha-13 Human genes 0.000 description 2
- 102100028972 HLA class I histocompatibility antigen, A alpha chain Human genes 0.000 description 2
- 102100028976 HLA class I histocompatibility antigen, B alpha chain Human genes 0.000 description 2
- 108010075704 HLA-A Antigens Proteins 0.000 description 2
- 108010058607 HLA-B Antigens Proteins 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 102100039855 Histone H1.2 Human genes 0.000 description 2
- 102100027368 Histone H1.3 Human genes 0.000 description 2
- 102100027369 Histone H1.4 Human genes 0.000 description 2
- 102100039265 Histone H2A type 1-C Human genes 0.000 description 2
- 102100030690 Histone H2B type 1-C/E/F/G/I Human genes 0.000 description 2
- 102100030689 Histone H2B type 1-D Human genes 0.000 description 2
- 102100030649 Histone H2B type 1-J Human genes 0.000 description 2
- 102100021639 Histone H2B type 1-K Human genes 0.000 description 2
- 102100021544 Histone H2B type 1-O Human genes 0.000 description 2
- 102100034536 Histone H3.1t Human genes 0.000 description 2
- 102100038736 Histone H3.3C Human genes 0.000 description 2
- 102100033070 Histone acetyltransferase KAT6B Human genes 0.000 description 2
- 102100039996 Histone deacetylase 1 Human genes 0.000 description 2
- 102100021454 Histone deacetylase 4 Human genes 0.000 description 2
- 102100038719 Histone deacetylase 7 Human genes 0.000 description 2
- 102100025210 Histone-arginine methyltransferase CARM1 Human genes 0.000 description 2
- 102100032804 Histone-lysine N-methyltransferase SMYD3 Human genes 0.000 description 2
- 102100029239 Histone-lysine N-methyltransferase, H3 lysine-36 specific Human genes 0.000 description 2
- 102100021088 Homeobox protein Hox-B13 Human genes 0.000 description 2
- 102100028092 Homeobox protein Nkx-3.1 Human genes 0.000 description 2
- 101000691599 Homo sapiens 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 Proteins 0.000 description 2
- 101000627872 Homo sapiens 72 kDa type IV collagenase Proteins 0.000 description 2
- 101000924255 Homo sapiens AT-rich interactive domain-containing protein 1B Proteins 0.000 description 2
- 101000792947 Homo sapiens AT-rich interactive domain-containing protein 5B Proteins 0.000 description 2
- 101000870662 Homo sapiens ATP-dependent RNA helicase DDX3X Proteins 0.000 description 2
- 101000756632 Homo sapiens Actin, cytoplasmic 1 Proteins 0.000 description 2
- 101000799140 Homo sapiens Activin receptor type-1 Proteins 0.000 description 2
- 101000928176 Homo sapiens Adhesion G protein-coupled receptor L3 Proteins 0.000 description 2
- 101000578469 Homo sapiens Arachidonate 12-lipoxygenase, 12R-type Proteins 0.000 description 2
- 101000785776 Homo sapiens Artemin Proteins 0.000 description 2
- 101000971230 Homo sapiens B-cell CLL/lymphoma 7 protein family member A Proteins 0.000 description 2
- 101000903697 Homo sapiens B-cell lymphoma/leukemia 11B Proteins 0.000 description 2
- 101000760704 Homo sapiens BRCA1-A complex subunit Abraxas 1 Proteins 0.000 description 2
- 101000874547 Homo sapiens BRISC and BRCA1-A complex member 1 Proteins 0.000 description 2
- 101000971203 Homo sapiens Bcl-2-binding component 3, isoforms 1/2 Proteins 0.000 description 2
- 101000971209 Homo sapiens Bcl-2-binding component 3, isoforms 3/4 Proteins 0.000 description 2
- 101000934638 Homo sapiens Bone morphogenetic protein receptor type-1A Proteins 0.000 description 2
- 101000884279 Homo sapiens CD276 antigen Proteins 0.000 description 2
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 description 2
- 101100382122 Homo sapiens CIITA gene Proteins 0.000 description 2
- 101000891939 Homo sapiens CREB-regulated transcription coactivator 1 Proteins 0.000 description 2
- 101000892045 Homo sapiens CUB and sushi domain-containing protein 3 Proteins 0.000 description 2
- 101000762236 Homo sapiens Cadherin-11 Proteins 0.000 description 2
- 101000714537 Homo sapiens Cadherin-2 Proteins 0.000 description 2
- 101000899459 Homo sapiens Cadherin-20 Proteins 0.000 description 2
- 101000794587 Homo sapiens Cadherin-5 Proteins 0.000 description 2
- 101000855412 Homo sapiens Carbamoyl-phosphate synthase [ammonia], mitochondrial Proteins 0.000 description 2
- 101000983528 Homo sapiens Caspase-8 Proteins 0.000 description 2
- 101000916173 Homo sapiens Catenin beta-1 Proteins 0.000 description 2
- 101001028831 Homo sapiens Cation-independent mannose-6-phosphate receptor Proteins 0.000 description 2
- 101000910814 Homo sapiens Cell cycle control protein 50A Proteins 0.000 description 2
- 101000940535 Homo sapiens Cold shock domain-containing protein E1 Proteins 0.000 description 2
- 101000855516 Homo sapiens Cyclic AMP-responsive element-binding protein 1 Proteins 0.000 description 2
- 101000710200 Homo sapiens Cyclin-dependent kinases regulatory subunit 1 Proteins 0.000 description 2
- 101000911746 Homo sapiens DCN1-like protein 1 Proteins 0.000 description 2
- 101001027762 Homo sapiens DNA mismatch repair protein Msh3 Proteins 0.000 description 2
- 101000712511 Homo sapiens DNA repair and recombination protein RAD54-like Proteins 0.000 description 2
- 101001132271 Homo sapiens DNA repair protein RAD51 homolog 3 Proteins 0.000 description 2
- 101001132266 Homo sapiens DNA repair protein RAD51 homolog 4 Proteins 0.000 description 2
- 101000649306 Homo sapiens DNA repair protein XRCC2 Proteins 0.000 description 2
- 101000618531 Homo sapiens DNA repair protein complementing XP-A cells Proteins 0.000 description 2
- 101000618535 Homo sapiens DNA repair protein complementing XP-C cells Proteins 0.000 description 2
- 101001036287 Homo sapiens DNA-binding protein inhibitor ID-3 Proteins 0.000 description 2
- 101000902632 Homo sapiens Dihydropyrimidine dehydrogenase [NADP(+)] Proteins 0.000 description 2
- 101000866018 Homo sapiens DnaJ homolog subfamily B member 1 Proteins 0.000 description 2
- 101000584942 Homo sapiens Double-strand-break repair protein rad21 homolog Proteins 0.000 description 2
- 101001016186 Homo sapiens Dystonin Proteins 0.000 description 2
- 101000882371 Homo sapiens E1A-binding protein p400 Proteins 0.000 description 2
- 101000973503 Homo sapiens E3 ubiquitin-protein ligase MIB1 Proteins 0.000 description 2
- 101000830899 Homo sapiens E3 ubiquitin-protein ligase TRAF7 Proteins 0.000 description 2
- 101000877379 Homo sapiens ETS-related transcription factor Elf-3 Proteins 0.000 description 2
- 101001057929 Homo sapiens Echinoderm microtubule-associated protein-like 4 Proteins 0.000 description 2
- 101000881731 Homo sapiens Elongin-C Proteins 0.000 description 2
- 101000921195 Homo sapiens Epidermal growth factor-like protein 7 Proteins 0.000 description 2
- 101001066268 Homo sapiens Erythroid transcription factor Proteins 0.000 description 2
- 101001044475 Homo sapiens Eukaryotic initiation factor 4A-II Proteins 0.000 description 2
- 101001036349 Homo sapiens Eukaryotic translation initiation factor 1A, X-chromosomal Proteins 0.000 description 2
- 101001055984 Homo sapiens Exosome complex component MTR3 Proteins 0.000 description 2
- 101000627103 Homo sapiens Exosome complex exonuclease RRP44 Proteins 0.000 description 2
- 101000918275 Homo sapiens Exostosin-2 Proteins 0.000 description 2
- 101001030683 Homo sapiens F-box only protein 11 Proteins 0.000 description 2
- 101000824114 Homo sapiens F-box only protein 31 Proteins 0.000 description 2
- 101001052797 Homo sapiens F-box only protein 5 Proteins 0.000 description 2
- 101000835675 Homo sapiens F-box-like/WD repeat-containing protein TBL1XR1 Proteins 0.000 description 2
- 101000914654 Homo sapiens FAS-associated factor 1 Proteins 0.000 description 2
- 101000917234 Homo sapiens Fibroblast growth factor 12 Proteins 0.000 description 2
- 101001027380 Homo sapiens Fibroblast growth factor 9 Proteins 0.000 description 2
- 101000730595 Homo sapiens Fibrocystin Proteins 0.000 description 2
- 101000833646 Homo sapiens Flap endonuclease GEN homolog 1 Proteins 0.000 description 2
- 101000861403 Homo sapiens Forkhead box protein P4 Proteins 0.000 description 2
- 101000900320 Homo sapiens G protein pathway suppressor 2 Proteins 0.000 description 2
- 101000757496 Homo sapiens Gamma-secretase subunit APH-1A Proteins 0.000 description 2
- 101000920748 Homo sapiens General transcription and DNA repair factor IIH helicase subunit XPB Proteins 0.000 description 2
- 101000746364 Homo sapiens Granulocyte colony-stimulating factor receptor Proteins 0.000 description 2
- 101001032872 Homo sapiens Gremlin-1 Proteins 0.000 description 2
- 101001072398 Homo sapiens Guanine nucleotide-binding protein subunit alpha-12 Proteins 0.000 description 2
- 101001072481 Homo sapiens Guanine nucleotide-binding protein subunit alpha-13 Proteins 0.000 description 2
- 101001066435 Homo sapiens Hepatocyte growth factor-like protein Proteins 0.000 description 2
- 101001035375 Homo sapiens Histone H1.2 Proteins 0.000 description 2
- 101001009450 Homo sapiens Histone H1.3 Proteins 0.000 description 2
- 101001009443 Homo sapiens Histone H1.4 Proteins 0.000 description 2
- 101001036109 Homo sapiens Histone H2A type 1-C Proteins 0.000 description 2
- 101001084682 Homo sapiens Histone H2B type 1-C/E/F/G/I Proteins 0.000 description 2
- 101001084684 Homo sapiens Histone H2B type 1-D Proteins 0.000 description 2
- 101001084678 Homo sapiens Histone H2B type 1-J Proteins 0.000 description 2
- 101000898898 Homo sapiens Histone H2B type 1-K Proteins 0.000 description 2
- 101000898881 Homo sapiens Histone H2B type 1-O Proteins 0.000 description 2
- 101001067850 Homo sapiens Histone H3.1t Proteins 0.000 description 2
- 101001035966 Homo sapiens Histone H3.3 Proteins 0.000 description 2
- 101001031505 Homo sapiens Histone H3.3C Proteins 0.000 description 2
- 101000944174 Homo sapiens Histone acetyltransferase KAT6B Proteins 0.000 description 2
- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 description 2
- 101000899259 Homo sapiens Histone deacetylase 4 Proteins 0.000 description 2
- 101001032113 Homo sapiens Histone deacetylase 7 Proteins 0.000 description 2
- 101001028782 Homo sapiens Histone-lysine N-methyltransferase EZH1 Proteins 0.000 description 2
- 101000708574 Homo sapiens Histone-lysine N-methyltransferase SMYD3 Proteins 0.000 description 2
- 101000634050 Homo sapiens Histone-lysine N-methyltransferase, H3 lysine-36 specific Proteins 0.000 description 2
- 101001041145 Homo sapiens Homeobox protein Hox-B13 Proteins 0.000 description 2
- 101000578249 Homo sapiens Homeobox protein Nkx-3.1 Proteins 0.000 description 2
- 101000843810 Homo sapiens Hydroxycarboxylic acid receptor 1 Proteins 0.000 description 2
- 101001046870 Homo sapiens Hypoxia-inducible factor 1-alpha Proteins 0.000 description 2
- 101001019455 Homo sapiens ICOS ligand Proteins 0.000 description 2
- 101000852815 Homo sapiens Insulin receptor Proteins 0.000 description 2
- 101001077604 Homo sapiens Insulin receptor substrate 1 Proteins 0.000 description 2
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 2
- 101001015004 Homo sapiens Integrin beta-3 Proteins 0.000 description 2
- 101001001420 Homo sapiens Interferon gamma receptor 1 Proteins 0.000 description 2
- 101000598002 Homo sapiens Interferon regulatory factor 1 Proteins 0.000 description 2
- 101001032345 Homo sapiens Interferon regulatory factor 8 Proteins 0.000 description 2
- 101000599886 Homo sapiens Isocitrate dehydrogenase [NADP], mitochondrial Proteins 0.000 description 2
- 101001050559 Homo sapiens Kinesin-1 heavy chain Proteins 0.000 description 2
- 101000590482 Homo sapiens Kinetochore protein Nuf2 Proteins 0.000 description 2
- 101001139134 Homo sapiens Krueppel-like factor 4 Proteins 0.000 description 2
- 101001139126 Homo sapiens Krueppel-like factor 6 Proteins 0.000 description 2
- 101000703761 Homo sapiens Leucine-rich repeat protein SHOC-2 Proteins 0.000 description 2
- 101001003687 Homo sapiens Lipoma-preferred partner Proteins 0.000 description 2
- 101001063392 Homo sapiens Lymphocyte function-associated antigen 3 Proteins 0.000 description 2
- 101000972291 Homo sapiens Lymphoid enhancer-binding factor 1 Proteins 0.000 description 2
- 101001025967 Homo sapiens Lysine-specific demethylase 6A Proteins 0.000 description 2
- 101000972918 Homo sapiens MAX gene-associated protein Proteins 0.000 description 2
- 101001106413 Homo sapiens Macrophage-stimulating protein receptor Proteins 0.000 description 2
- 101001052076 Homo sapiens Maltase-glucoamylase Proteins 0.000 description 2
- 101001005667 Homo sapiens Mastermind-like protein 2 Proteins 0.000 description 2
- 101000581326 Homo sapiens Mediator of DNA damage checkpoint protein 1 Proteins 0.000 description 2
- 101001005728 Homo sapiens Melanoma-associated antigen 1 Proteins 0.000 description 2
- 101001057158 Homo sapiens Melanoma-associated antigen D1 Proteins 0.000 description 2
- 101000578932 Homo sapiens Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 Proteins 0.000 description 2
- 101001027295 Homo sapiens Metabotropic glutamate receptor 8 Proteins 0.000 description 2
- 101001013648 Homo sapiens Methionine synthase Proteins 0.000 description 2
- 101001116314 Homo sapiens Methionine synthase reductase Proteins 0.000 description 2
- 101000653360 Homo sapiens Methylcytosine dioxygenase TET1 Proteins 0.000 description 2
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 2
- 101001052490 Homo sapiens Mitogen-activated protein kinase 3 Proteins 0.000 description 2
- 101000950695 Homo sapiens Mitogen-activated protein kinase 8 Proteins 0.000 description 2
- 101001055097 Homo sapiens Mitogen-activated protein kinase kinase kinase 6 Proteins 0.000 description 2
- 101001055092 Homo sapiens Mitogen-activated protein kinase kinase kinase 7 Proteins 0.000 description 2
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 2
- 101000589016 Homo sapiens Myomegalin Proteins 0.000 description 2
- 101001000104 Homo sapiens Myosin-11 Proteins 0.000 description 2
- 101001030232 Homo sapiens Myosin-9 Proteins 0.000 description 2
- 101000983292 Homo sapiens N-fatty-acyl-amino acid synthase/hydrolase PM20D1 Proteins 0.000 description 2
- 101001008816 Homo sapiens N-lysine methyltransferase KMT5A Proteins 0.000 description 2
- 101001109463 Homo sapiens NACHT, LRR and PYD domains-containing protein 1 Proteins 0.000 description 2
- 101000624947 Homo sapiens Nesprin-1 Proteins 0.000 description 2
- 101000973623 Homo sapiens Neuronal growth regulator 1 Proteins 0.000 description 2
- 101000981336 Homo sapiens Nibrin Proteins 0.000 description 2
- 101000578062 Homo sapiens Nicastrin Proteins 0.000 description 2
- 101000979497 Homo sapiens Ninein Proteins 0.000 description 2
- 101000844245 Homo sapiens Non-receptor tyrosine-protein kinase TYK2 Proteins 0.000 description 2
- 101000598160 Homo sapiens Nuclear mitotic apparatus protein 1 Proteins 0.000 description 2
- 101000996563 Homo sapiens Nuclear pore complex protein Nup214 Proteins 0.000 description 2
- 101000602926 Homo sapiens Nuclear receptor coactivator 1 Proteins 0.000 description 2
- 101000602930 Homo sapiens Nuclear receptor coactivator 2 Proteins 0.000 description 2
- 101000974356 Homo sapiens Nuclear receptor coactivator 3 Proteins 0.000 description 2
- 101000974343 Homo sapiens Nuclear receptor coactivator 4 Proteins 0.000 description 2
- 101000974340 Homo sapiens Nuclear receptor corepressor 1 Proteins 0.000 description 2
- 101000582254 Homo sapiens Nuclear receptor corepressor 2 Proteins 0.000 description 2
- 101001109719 Homo sapiens Nucleophosmin Proteins 0.000 description 2
- 101001125032 Homo sapiens Nucleotide-binding oligomerization domain-containing protein 1 Proteins 0.000 description 2
- 101000986810 Homo sapiens P2Y purinoceptor 8 Proteins 0.000 description 2
- 101000613563 Homo sapiens PAS domain-containing serine/threonine-protein kinase Proteins 0.000 description 2
- 101000736088 Homo sapiens PC4 and SFRS1-interacting protein Proteins 0.000 description 2
- 101000692980 Homo sapiens PHD finger protein 6 Proteins 0.000 description 2
- 101001094700 Homo sapiens POU domain, class 5, transcription factor 1 Proteins 0.000 description 2
- 101001123298 Homo sapiens PR domain zinc finger protein 14 Proteins 0.000 description 2
- 101000601661 Homo sapiens Paired box protein Pax-7 Proteins 0.000 description 2
- 101000692768 Homo sapiens Paired mesoderm homeobox protein 2B Proteins 0.000 description 2
- 101000579484 Homo sapiens Period circadian protein homolog 1 Proteins 0.000 description 2
- 101000741790 Homo sapiens Peroxisome proliferator-activated receptor gamma Proteins 0.000 description 2
- 101000688606 Homo sapiens Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 Proteins 0.000 description 2
- 101000721646 Homo sapiens Phosphatidylinositol 3-kinase C2 domain-containing subunit gamma Proteins 0.000 description 2
- 101000605630 Homo sapiens Phosphatidylinositol 3-kinase catalytic subunit type 3 Proteins 0.000 description 2
- 101000595746 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform Proteins 0.000 description 2
- 101000692259 Homo sapiens Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 Proteins 0.000 description 2
- 101001113440 Homo sapiens Poly [ADP-ribose] polymerase 2 Proteins 0.000 description 2
- 101000735354 Homo sapiens Poly(rC)-binding protein 1 Proteins 0.000 description 2
- 101000866766 Homo sapiens Polycomb protein EED Proteins 0.000 description 2
- 101000584499 Homo sapiens Polycomb protein SUZ12 Proteins 0.000 description 2
- 101000808592 Homo sapiens Probable ubiquitin carboxyl-terminal hydrolase FAF-X Proteins 0.000 description 2
- 101000741885 Homo sapiens Protection of telomeres protein 1 Proteins 0.000 description 2
- 101000718497 Homo sapiens Protein AF-10 Proteins 0.000 description 2
- 101000933604 Homo sapiens Protein BTG2 Proteins 0.000 description 2
- 101000876829 Homo sapiens Protein C-ets-1 Proteins 0.000 description 2
- 101000912957 Homo sapiens Protein DEK Proteins 0.000 description 2
- 101000866633 Homo sapiens Protein Hook homolog 3 Proteins 0.000 description 2
- 101001056567 Homo sapiens Protein Jumonji Proteins 0.000 description 2
- 101000573199 Homo sapiens Protein PML Proteins 0.000 description 2
- 101000849321 Homo sapiens Protein RRP5 homolog Proteins 0.000 description 2
- 101000880769 Homo sapiens Protein SSX1 Proteins 0.000 description 2
- 101000780643 Homo sapiens Protein argonaute-2 Proteins 0.000 description 2
- 101000941994 Homo sapiens Protein cereblon Proteins 0.000 description 2
- 101000735456 Homo sapiens Protein mono-ADP-ribosyltransferase PARP3 Proteins 0.000 description 2
- 101000735473 Homo sapiens Protein mono-ADP-ribosyltransferase TIPARP Proteins 0.000 description 2
- 101000742054 Homo sapiens Protein phosphatase 1D Proteins 0.000 description 2
- 101000609959 Homo sapiens Protein piccolo Proteins 0.000 description 2
- 101000666144 Homo sapiens Protein-glutamine gamma-glutamyltransferase Z Proteins 0.000 description 2
- 101000602015 Homo sapiens Protocadherin gamma-B4 Proteins 0.000 description 2
- 101000728107 Homo sapiens Putative Polycomb group protein ASXL2 Proteins 0.000 description 2
- 101000798015 Homo sapiens RAC-beta serine/threonine-protein kinase Proteins 0.000 description 2
- 101000591115 Homo sapiens RNA-binding protein Musashi homolog 1 Proteins 0.000 description 2
- 101000591128 Homo sapiens RNA-binding protein Musashi homolog 2 Proteins 0.000 description 2
- 101001130509 Homo sapiens Ras GTPase-activating protein 1 Proteins 0.000 description 2
- 101001110313 Homo sapiens Ras-related C3 botulinum toxin substrate 2 Proteins 0.000 description 2
- 101000686227 Homo sapiens Ras-related protein R-Ras2 Proteins 0.000 description 2
- 101000591211 Homo sapiens Receptor-type tyrosine-protein phosphatase O Proteins 0.000 description 2
- 101000591240 Homo sapiens Receptor-type tyrosine-protein phosphatase S Proteins 0.000 description 2
- 101000694802 Homo sapiens Receptor-type tyrosine-protein phosphatase T Proteins 0.000 description 2
- 101000695838 Homo sapiens Receptor-type tyrosine-protein phosphatase U Proteins 0.000 description 2
- 101000606537 Homo sapiens Receptor-type tyrosine-protein phosphatase delta Proteins 0.000 description 2
- 101000579423 Homo sapiens Regulator of nonsense transcripts 1 Proteins 0.000 description 2
- 101000654718 Homo sapiens SET-binding protein Proteins 0.000 description 2
- 101000616523 Homo sapiens SH2B adapter protein 3 Proteins 0.000 description 2
- 101000687737 Homo sapiens SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 Proteins 0.000 description 2
- 101000587430 Homo sapiens Serine/arginine-rich splicing factor 2 Proteins 0.000 description 2
- 101000628575 Homo sapiens Serine/threonine-protein kinase 19 Proteins 0.000 description 2
- 101000701405 Homo sapiens Serine/threonine-protein kinase 36 Proteins 0.000 description 2
- 101000880431 Homo sapiens Serine/threonine-protein kinase 4 Proteins 0.000 description 2
- 101000880461 Homo sapiens Serine/threonine-protein kinase 40 Proteins 0.000 description 2
- 101001047637 Homo sapiens Serine/threonine-protein kinase LATS2 Proteins 0.000 description 2
- 101001059443 Homo sapiens Serine/threonine-protein kinase MARK1 Proteins 0.000 description 2
- 101000987295 Homo sapiens Serine/threonine-protein kinase PAK 5 Proteins 0.000 description 2
- 101000864800 Homo sapiens Serine/threonine-protein kinase Sgk1 Proteins 0.000 description 2
- 101000802948 Homo sapiens Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform Proteins 0.000 description 2
- 101001123140 Homo sapiens Serine/threonine-protein phosphatase 4 regulatory subunit 2 Proteins 0.000 description 2
- 101000620662 Homo sapiens Serine/threonine-protein phosphatase 6 catalytic subunit Proteins 0.000 description 2
- 101000836394 Homo sapiens Sestrin-1 Proteins 0.000 description 2
- 101000739905 Homo sapiens Sestrin-2 Proteins 0.000 description 2
- 101000739911 Homo sapiens Sestrin-3 Proteins 0.000 description 2
- 101000664956 Homo sapiens Single-strand selective monofunctional uracil DNA glycosylase Proteins 0.000 description 2
- 101000658071 Homo sapiens Splicing factor U2AF 65 kDa subunit Proteins 0.000 description 2
- 101000881230 Homo sapiens Sprouty-related, EVH1 domain-containing protein 1 Proteins 0.000 description 2
- 101000896517 Homo sapiens Steroid 17-alpha-hydroxylase/17,20 lyase Proteins 0.000 description 2
- 101000861263 Homo sapiens Steroid 21-hydroxylase Proteins 0.000 description 2
- 101000616115 Homo sapiens Stress-associated endoplasmic reticulum protein 2 Proteins 0.000 description 2
- 101000633429 Homo sapiens Structural maintenance of chromosomes protein 1A Proteins 0.000 description 2
- 101000708766 Homo sapiens Structural maintenance of chromosomes protein 3 Proteins 0.000 description 2
- 101000687808 Homo sapiens Suppressor of cytokine signaling 2 Proteins 0.000 description 2
- 101000891113 Homo sapiens T-cell acute lymphocytic leukemia protein 1 Proteins 0.000 description 2
- 101000800488 Homo sapiens T-cell leukemia homeobox protein 1 Proteins 0.000 description 2
- 101000837401 Homo sapiens T-cell leukemia/lymphoma protein 1A Proteins 0.000 description 2
- 101000652747 Homo sapiens Target of rapamycin complex 2 subunit MAPKAP1 Proteins 0.000 description 2
- 101000637850 Homo sapiens Tolloid-like protein 2 Proteins 0.000 description 2
- 101001041525 Homo sapiens Transcription factor 12 Proteins 0.000 description 2
- 101000837845 Homo sapiens Transcription factor E3 Proteins 0.000 description 2
- 101000962461 Homo sapiens Transcription factor Maf Proteins 0.000 description 2
- 101000979190 Homo sapiens Transcription factor MafB Proteins 0.000 description 2
- 101000825086 Homo sapiens Transcription factor SOX-11 Proteins 0.000 description 2
- 101000652324 Homo sapiens Transcription factor SOX-17 Proteins 0.000 description 2
- 101000596092 Homo sapiens Transcription initiation factor TFIID subunit 1-like Proteins 0.000 description 2
- 101001051166 Homo sapiens Transcriptional activator MN1 Proteins 0.000 description 2
- 101000775102 Homo sapiens Transcriptional coactivator YAP1 Proteins 0.000 description 2
- 101000835093 Homo sapiens Transferrin receptor protein 1 Proteins 0.000 description 2
- 101000637950 Homo sapiens Transmembrane protein 127 Proteins 0.000 description 2
- 101000762128 Homo sapiens Tumor suppressor candidate 3 Proteins 0.000 description 2
- 101001047681 Homo sapiens Tyrosine-protein kinase Lck Proteins 0.000 description 2
- 101000604583 Homo sapiens Tyrosine-protein kinase SYK Proteins 0.000 description 2
- 101000820294 Homo sapiens Tyrosine-protein kinase Yes Proteins 0.000 description 2
- 101000606129 Homo sapiens Tyrosine-protein kinase receptor TYRO3 Proteins 0.000 description 2
- 101001138544 Homo sapiens UMP-CMP kinase Proteins 0.000 description 2
- 101000955999 Homo sapiens V-set domain-containing T-cell activation inhibitor 1 Proteins 0.000 description 2
- 101000650069 Homo sapiens WD repeat-containing protein 90 Proteins 0.000 description 2
- 101000650162 Homo sapiens WW domain-containing transcription regulator protein 1 Proteins 0.000 description 2
- 101000666295 Homo sapiens X-box-binding protein 1 Proteins 0.000 description 2
- 101000759453 Homo sapiens YY1-associated protein 1 Proteins 0.000 description 2
- 101000788739 Homo sapiens Zinc finger MYM-type protein 3 Proteins 0.000 description 2
- 101000744900 Homo sapiens Zinc finger homeobox protein 3 Proteins 0.000 description 2
- 101000964718 Homo sapiens Zinc finger protein 384 Proteins 0.000 description 2
- 101000785690 Homo sapiens Zinc finger protein 521 Proteins 0.000 description 2
- 101000599037 Homo sapiens Zinc finger protein Helios Proteins 0.000 description 2
- 101000691578 Homo sapiens Zinc finger protein PLAG1 Proteins 0.000 description 2
- 102100030642 Hydroxycarboxylic acid receptor 1 Human genes 0.000 description 2
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 2
- 102100022875 Hypoxia-inducible factor 1-alpha Human genes 0.000 description 2
- 102000001284 I-kappa-B kinase Human genes 0.000 description 2
- 108060006678 I-kappa-B kinase Proteins 0.000 description 2
- 102100034980 ICOS ligand Human genes 0.000 description 2
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 2
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 2
- 102100036721 Insulin receptor Human genes 0.000 description 2
- 102100025087 Insulin receptor substrate 1 Human genes 0.000 description 2
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 2
- 102100032999 Integrin beta-3 Human genes 0.000 description 2
- 102100035678 Interferon gamma receptor 1 Human genes 0.000 description 2
- 102100036981 Interferon regulatory factor 1 Human genes 0.000 description 2
- 102100038069 Interferon regulatory factor 8 Human genes 0.000 description 2
- 108010017411 Interleukin-21 Receptors Proteins 0.000 description 2
- 102100030699 Interleukin-21 receptor Human genes 0.000 description 2
- 102100037845 Isocitrate dehydrogenase [NADP], mitochondrial Human genes 0.000 description 2
- 102100031819 Kappa-type opioid receptor Human genes 0.000 description 2
- 102220516431 Kidney-associated antigen 1_R1A_mutation Human genes 0.000 description 2
- 102100023422 Kinesin-1 heavy chain Human genes 0.000 description 2
- 102100032431 Kinetochore protein Nuf2 Human genes 0.000 description 2
- 102100020677 Krueppel-like factor 4 Human genes 0.000 description 2
- 102100020679 Krueppel-like factor 6 Human genes 0.000 description 2
- 108010020246 Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Proteins 0.000 description 2
- 102100031956 Leucine-rich repeat protein SHOC-2 Human genes 0.000 description 2
- 102100032693 Leucine-rich repeat serine/threonine-protein kinase 2 Human genes 0.000 description 2
- 102100026358 Lipoma-preferred partner Human genes 0.000 description 2
- 102100030984 Lymphocyte function-associated antigen 3 Human genes 0.000 description 2
- 102100022699 Lymphoid enhancer-binding factor 1 Human genes 0.000 description 2
- 102100037462 Lysine-specific demethylase 6A Human genes 0.000 description 2
- 101150113681 MALT1 gene Proteins 0.000 description 2
- 102100022621 MAX gene-associated protein Human genes 0.000 description 2
- 102100026371 MHC class II transactivator Human genes 0.000 description 2
- 108700002010 MHC class II transactivator Proteins 0.000 description 2
- 102100021435 Macrophage-stimulating protein receptor Human genes 0.000 description 2
- 102100025130 Mastermind-like protein 2 Human genes 0.000 description 2
- 102100027643 Mediator of DNA damage checkpoint protein 1 Human genes 0.000 description 2
- 102100025050 Melanoma-associated antigen 1 Human genes 0.000 description 2
- 102100027247 Melanoma-associated antigen D1 Human genes 0.000 description 2
- 108010023335 Member 2 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 2
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 2
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 2
- 102100028328 Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 Human genes 0.000 description 2
- 102100037636 Metabotropic glutamate receptor 8 Human genes 0.000 description 2
- 102100026261 Metalloproteinase inhibitor 3 Human genes 0.000 description 2
- 101710196500 Metallothionein-1A Proteins 0.000 description 2
- 102100031551 Methionine synthase Human genes 0.000 description 2
- 102100024614 Methionine synthase reductase Human genes 0.000 description 2
- 102100030819 Methylcytosine dioxygenase TET1 Human genes 0.000 description 2
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 2
- 102100024192 Mitogen-activated protein kinase 3 Human genes 0.000 description 2
- 102100037808 Mitogen-activated protein kinase 8 Human genes 0.000 description 2
- 102100026889 Mitogen-activated protein kinase kinase kinase 6 Human genes 0.000 description 2
- 102100026888 Mitogen-activated protein kinase kinase kinase 7 Human genes 0.000 description 2
- 102000014962 Monocyte Chemoattractant Proteins Human genes 0.000 description 2
- 108010064136 Monocyte Chemoattractant Proteins Proteins 0.000 description 2
- 102100034256 Mucin-1 Human genes 0.000 description 2
- 108700026676 Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Proteins 0.000 description 2
- 102100038732 Mucosa-associated lymphoid tissue lymphoma translocation protein 1 Human genes 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 102100039229 Myocyte-specific enhancer factor 2C Human genes 0.000 description 2
- 102100032966 Myomegalin Human genes 0.000 description 2
- 102100036639 Myosin-11 Human genes 0.000 description 2
- 102100038938 Myosin-9 Human genes 0.000 description 2
- 102100027445 N-acetylserotonin O-methyltransferase-like protein Human genes 0.000 description 2
- 101710111485 N-acetylserotonin O-methyltransferase-like protein Proteins 0.000 description 2
- 102100026873 N-fatty-acyl-amino acid synthase/hydrolase PM20D1 Human genes 0.000 description 2
- 102100027771 N-lysine methyltransferase KMT5A Human genes 0.000 description 2
- 102100022698 NACHT, LRR and PYD domains-containing protein 1 Human genes 0.000 description 2
- 101000783469 Naja kaouthia Tryptophan-containing weak neurotoxin Proteins 0.000 description 2
- 102100023306 Nesprin-1 Human genes 0.000 description 2
- 102100022223 Neuronal growth regulator 1 Human genes 0.000 description 2
- 101100355599 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) mus-11 gene Proteins 0.000 description 2
- 102100024403 Nibrin Human genes 0.000 description 2
- 102100028056 Nicastrin Human genes 0.000 description 2
- 102100023121 Ninein Human genes 0.000 description 2
- 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 2
- 108020004485 Nonsense Codon Proteins 0.000 description 2
- 102100036961 Nuclear mitotic apparatus protein 1 Human genes 0.000 description 2
- 102100033819 Nuclear pore complex protein Nup214 Human genes 0.000 description 2
- 102100025372 Nuclear pore complex protein Nup98-Nup96 Human genes 0.000 description 2
- 102100037223 Nuclear receptor coactivator 1 Human genes 0.000 description 2
- 102100037226 Nuclear receptor coactivator 2 Human genes 0.000 description 2
- 102100022883 Nuclear receptor coactivator 3 Human genes 0.000 description 2
- 102100022927 Nuclear receptor coactivator 4 Human genes 0.000 description 2
- 102100022935 Nuclear receptor corepressor 1 Human genes 0.000 description 2
- 102100030569 Nuclear receptor corepressor 2 Human genes 0.000 description 2
- 102100022678 Nucleophosmin Human genes 0.000 description 2
- 102100029424 Nucleotide-binding oligomerization domain-containing protein 1 Human genes 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 102100028069 P2Y purinoceptor 8 Human genes 0.000 description 2
- 101700056750 PAK1 Proteins 0.000 description 2
- 102100040902 PAS domain-containing serine/threonine-protein kinase Human genes 0.000 description 2
- 102100036220 PC4 and SFRS1-interacting protein Human genes 0.000 description 2
- 238000012879 PET imaging Methods 0.000 description 2
- 102100026365 PHD finger protein 6 Human genes 0.000 description 2
- 102100035423 POU domain, class 5, transcription factor 1 Human genes 0.000 description 2
- 102100028974 PR domain zinc finger protein 14 Human genes 0.000 description 2
- 102100037503 Paired box protein Pax-7 Human genes 0.000 description 2
- 102100026354 Paired mesoderm homeobox protein 2B Human genes 0.000 description 2
- 102100028293 Period circadian protein homolog 1 Human genes 0.000 description 2
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 2
- 102100024242 Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 Human genes 0.000 description 2
- 102100025063 Phosphatidylinositol 3-kinase C2 domain-containing subunit gamma Human genes 0.000 description 2
- 102100038329 Phosphatidylinositol 3-kinase catalytic subunit type 3 Human genes 0.000 description 2
- 102100036056 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform Human genes 0.000 description 2
- 102100026066 Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 Human genes 0.000 description 2
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 2
- 102100023652 Poly [ADP-ribose] polymerase 2 Human genes 0.000 description 2
- 102100034960 Poly(rC)-binding protein 1 Human genes 0.000 description 2
- 102100031338 Polycomb protein EED Human genes 0.000 description 2
- 102100030702 Polycomb protein SUZ12 Human genes 0.000 description 2
- 102100030423 Post-GPI attachment to proteins factor 3 Human genes 0.000 description 2
- 102100038603 Probable ubiquitin carboxyl-terminal hydrolase FAF-X Human genes 0.000 description 2
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 2
- 102100038745 Protection of telomeres protein 1 Human genes 0.000 description 2
- 102100026286 Protein AF-10 Human genes 0.000 description 2
- 102100026034 Protein BTG2 Human genes 0.000 description 2
- 102100035251 Protein C-ets-1 Human genes 0.000 description 2
- 102100026113 Protein DEK Human genes 0.000 description 2
- 102100031717 Protein Hook homolog 3 Human genes 0.000 description 2
- 102100025733 Protein Jumonji Human genes 0.000 description 2
- 102100026375 Protein PML Human genes 0.000 description 2
- 102100033976 Protein RRP5 homolog Human genes 0.000 description 2
- 102100037687 Protein SSX1 Human genes 0.000 description 2
- 102100034207 Protein argonaute-2 Human genes 0.000 description 2
- 102100034935 Protein mono-ADP-ribosyltransferase PARP3 Human genes 0.000 description 2
- 102100034905 Protein mono-ADP-ribosyltransferase TIPARP Human genes 0.000 description 2
- 102100038675 Protein phosphatase 1D Human genes 0.000 description 2
- 102100039154 Protein piccolo Human genes 0.000 description 2
- 102100038100 Protein-glutamine gamma-glutamyltransferase Z Human genes 0.000 description 2
- 102100037554 Protocadherin gamma-B4 Human genes 0.000 description 2
- 102100029750 Putative Polycomb group protein ASXL2 Human genes 0.000 description 2
- 102100032315 RAC-beta serine/threonine-protein kinase Human genes 0.000 description 2
- 101710018890 RAD51B Proteins 0.000 description 2
- 101150006234 RAD52 gene Proteins 0.000 description 2
- 102000004229 RNA-binding protein EWS Human genes 0.000 description 2
- 108090000740 RNA-binding protein EWS Proteins 0.000 description 2
- 102100034026 RNA-binding protein Musashi homolog 1 Human genes 0.000 description 2
- 102100034027 RNA-binding protein Musashi homolog 2 Human genes 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- 108050007316 Rab35 Proteins 0.000 description 2
- 102000028593 Rab35 Human genes 0.000 description 2
- 102000053062 Rad52 DNA Repair and Recombination Human genes 0.000 description 2
- 108700031762 Rad52 DNA Repair and Recombination Proteins 0.000 description 2
- 102100023320 Ral guanine nucleotide dissociation stimulator Human genes 0.000 description 2
- 101150015043 Ralgds gene Proteins 0.000 description 2
- 102100031426 Ras GTPase-activating protein 1 Human genes 0.000 description 2
- 102100022129 Ras-related C3 botulinum toxin substrate 2 Human genes 0.000 description 2
- 102100025003 Ras-related protein R-Ras2 Human genes 0.000 description 2
- 101000613608 Rattus norvegicus Monocyte to macrophage differentiation factor Proteins 0.000 description 2
- 101000832669 Rattus norvegicus Probable alcohol sulfotransferase Proteins 0.000 description 2
- 108010038036 Receptor Activator of Nuclear Factor-kappa B Proteins 0.000 description 2
- 102100034102 Receptor-type tyrosine-protein phosphatase S Human genes 0.000 description 2
- 102100028645 Receptor-type tyrosine-protein phosphatase T Human genes 0.000 description 2
- 102100028516 Receptor-type tyrosine-protein phosphatase U Human genes 0.000 description 2
- 102100039666 Receptor-type tyrosine-protein phosphatase delta Human genes 0.000 description 2
- 102100028287 Regulator of nonsense transcripts 1 Human genes 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 101001030849 Rhinella marina Mesotocin receptor Proteins 0.000 description 2
- 102100034187 S-methyl-5'-thioadenosine phosphorylase Human genes 0.000 description 2
- 101710136206 S-methyl-5'-thioadenosine phosphorylase Proteins 0.000 description 2
- 102100032741 SET-binding protein Human genes 0.000 description 2
- 102100021778 SH2B adapter protein 3 Human genes 0.000 description 2
- 108700022176 SOS1 Proteins 0.000 description 2
- 101150058731 STAT5A gene Proteins 0.000 description 2
- 101150063267 STAT5B gene Proteins 0.000 description 2
- 108010011005 STAT6 Transcription Factor Proteins 0.000 description 2
- 102100024777 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 Human genes 0.000 description 2
- 101100379220 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) API2 gene Proteins 0.000 description 2
- 101100189632 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) PTC6 gene Proteins 0.000 description 2
- 101100197320 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) RPL35A gene Proteins 0.000 description 2
- 101000702553 Schistosoma mansoni Antigen Sm21.7 Proteins 0.000 description 2
- 101000714192 Schistosoma mansoni Tegument antigen Proteins 0.000 description 2
- 102100029666 Serine/arginine-rich splicing factor 2 Human genes 0.000 description 2
- 102100026757 Serine/threonine-protein kinase 19 Human genes 0.000 description 2
- 102100030513 Serine/threonine-protein kinase 36 Human genes 0.000 description 2
- 102100037629 Serine/threonine-protein kinase 4 Human genes 0.000 description 2
- 102100037627 Serine/threonine-protein kinase 40 Human genes 0.000 description 2
- 102100024043 Serine/threonine-protein kinase LATS2 Human genes 0.000 description 2
- 102100028921 Serine/threonine-protein kinase MARK1 Human genes 0.000 description 2
- 102100027910 Serine/threonine-protein kinase PAK 1 Human genes 0.000 description 2
- 102100027941 Serine/threonine-protein kinase PAK 5 Human genes 0.000 description 2
- 102100030070 Serine/threonine-protein kinase Sgk1 Human genes 0.000 description 2
- 102100035728 Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform Human genes 0.000 description 2
- 102100028619 Serine/threonine-protein phosphatase 4 regulatory subunit 2 Human genes 0.000 description 2
- 102100022345 Serine/threonine-protein phosphatase 6 catalytic subunit Human genes 0.000 description 2
- 102100027288 Sestrin-1 Human genes 0.000 description 2
- 102100037576 Sestrin-2 Human genes 0.000 description 2
- 102100037575 Sestrin-3 Human genes 0.000 description 2
- 108091019659 Shq1 Proteins 0.000 description 2
- 102000034099 Shq1 Human genes 0.000 description 2
- 102100024481 Signal transducer and activator of transcription 5A Human genes 0.000 description 2
- 102100024474 Signal transducer and activator of transcription 5B Human genes 0.000 description 2
- 102100023980 Signal transducer and activator of transcription 6 Human genes 0.000 description 2
- 108010011033 Signaling Lymphocytic Activation Molecule Associated Protein Proteins 0.000 description 2
- 102000013970 Signaling Lymphocytic Activation Molecule Associated Protein Human genes 0.000 description 2
- 102100038661 Single-strand selective monofunctional uracil DNA glycosylase Human genes 0.000 description 2
- 101150043341 Socs3 gene Proteins 0.000 description 2
- 101100193542 Solanum demissum R1A gene Proteins 0.000 description 2
- 101150100839 Sos1 gene Proteins 0.000 description 2
- 102100035040 Splicing factor U2AF 65 kDa subunit Human genes 0.000 description 2
- 102100037614 Sprouty-related, EVH1 domain-containing protein 1 Human genes 0.000 description 2
- 102100021719 Steroid 17-alpha-hydroxylase/17,20 lyase Human genes 0.000 description 2
- 102100021814 Stress-associated endoplasmic reticulum protein 2 Human genes 0.000 description 2
- 102100029538 Structural maintenance of chromosomes protein 1A Human genes 0.000 description 2
- 102100032723 Structural maintenance of chromosomes protein 3 Human genes 0.000 description 2
- 102100031715 Succinate dehydrogenase assembly factor 2, mitochondrial Human genes 0.000 description 2
- 108050007461 Succinate dehydrogenase assembly factor 2, mitochondrial Proteins 0.000 description 2
- 108700027337 Suppressor of Cytokine Signaling 3 Proteins 0.000 description 2
- 102100024784 Suppressor of cytokine signaling 2 Human genes 0.000 description 2
- 102100024283 Suppressor of cytokine signaling 3 Human genes 0.000 description 2
- 101000987219 Sus scrofa Pregnancy-associated glycoprotein 1 Proteins 0.000 description 2
- 102100040365 T-cell acute lymphocytic leukemia protein 1 Human genes 0.000 description 2
- 102100033111 T-cell leukemia homeobox protein 1 Human genes 0.000 description 2
- 102100028676 T-cell leukemia/lymphoma protein 1A Human genes 0.000 description 2
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 2
- 101150057140 TACSTD1 gene Proteins 0.000 description 2
- 102100033456 TGF-beta receptor type-1 Human genes 0.000 description 2
- 108090000925 TNF receptor-associated factor 2 Proteins 0.000 description 2
- 102000004399 TNF receptor-associated factor 3 Human genes 0.000 description 2
- 108090000922 TNF receptor-associated factor 3 Proteins 0.000 description 2
- 102000003718 TNF receptor-associated factor 5 Human genes 0.000 description 2
- 108090000001 TNF receptor-associated factor 5 Proteins 0.000 description 2
- 102100034779 TRAF family member-associated NF-kappa-B activator Human genes 0.000 description 2
- 101800000849 Tachykinin-associated peptide 2 Proteins 0.000 description 2
- 102100030904 Target of rapamycin complex 2 subunit MAPKAP1 Human genes 0.000 description 2
- 108010031429 Tissue Inhibitor of Metalloproteinase-3 Proteins 0.000 description 2
- 102100031997 Tolloid-like protein 2 Human genes 0.000 description 2
- 108010057666 Transcription Factor CHOP Proteins 0.000 description 2
- 102100021123 Transcription factor 12 Human genes 0.000 description 2
- 102100028507 Transcription factor E3 Human genes 0.000 description 2
- 102100039189 Transcription factor Maf Human genes 0.000 description 2
- 102100023234 Transcription factor MafB Human genes 0.000 description 2
- 102100022415 Transcription factor SOX-11 Human genes 0.000 description 2
- 102100030243 Transcription factor SOX-17 Human genes 0.000 description 2
- 102100035238 Transcription initiation factor TFIID subunit 1-like Human genes 0.000 description 2
- 102100024592 Transcriptional activator MN1 Human genes 0.000 description 2
- 102100031873 Transcriptional coactivator YAP1 Human genes 0.000 description 2
- 102100026144 Transferrin receptor protein 1 Human genes 0.000 description 2
- 108010011702 Transforming Growth Factor-beta Type I Receptor Proteins 0.000 description 2
- 102100032072 Transmembrane protein 127 Human genes 0.000 description 2
- 102000000504 Tumor Suppressor p53-Binding Protein 1 Human genes 0.000 description 2
- 108010041385 Tumor Suppressor p53-Binding Protein 1 Proteins 0.000 description 2
- 102100028787 Tumor necrosis factor receptor superfamily member 11A Human genes 0.000 description 2
- 102100027881 Tumor protein 63 Human genes 0.000 description 2
- 101710140697 Tumor protein 63 Proteins 0.000 description 2
- 102100024248 Tumor suppressor candidate 3 Human genes 0.000 description 2
- 102100024036 Tyrosine-protein kinase Lck Human genes 0.000 description 2
- 102100022356 Tyrosine-protein kinase Mer Human genes 0.000 description 2
- 102100038183 Tyrosine-protein kinase SYK Human genes 0.000 description 2
- 102100021788 Tyrosine-protein kinase Yes Human genes 0.000 description 2
- 102100039127 Tyrosine-protein kinase receptor TYRO3 Human genes 0.000 description 2
- 102100029152 UDP-glucuronosyltransferase 1A1 Human genes 0.000 description 2
- 101710205316 UDP-glucuronosyltransferase 1A1 Proteins 0.000 description 2
- 102100020797 UMP-CMP kinase Human genes 0.000 description 2
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 description 2
- 102100028209 WD repeat-containing protein 90 Human genes 0.000 description 2
- 102100027548 WW domain-containing transcription regulator protein 1 Human genes 0.000 description 2
- 108700031544 X-Linked Inhibitor of Apoptosis Proteins 0.000 description 2
- 102100038151 X-box-binding protein 1 Human genes 0.000 description 2
- 102100023267 YY1-associated protein 1 Human genes 0.000 description 2
- 102100025417 Zinc finger MYM-type protein 3 Human genes 0.000 description 2
- 102100039966 Zinc finger homeobox protein 3 Human genes 0.000 description 2
- 102100040731 Zinc finger protein 384 Human genes 0.000 description 2
- 102100026302 Zinc finger protein 521 Human genes 0.000 description 2
- 102100037796 Zinc finger protein Helios Human genes 0.000 description 2
- 102100026200 Zinc finger protein PLAG1 Human genes 0.000 description 2
- 210000005006 adaptive immune system Anatomy 0.000 description 2
- 108010029483 alpha 1 Chain Collagen Type I Proteins 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 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 2
- 230000037429 base substitution Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 108010018804 c-Mer Tyrosine Kinase Proteins 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 108010051348 cdc42 GTP-Binding Protein Proteins 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 108010030886 coactivator-associated arginine methyltransferase 1 Proteins 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 230000009918 complex formation Effects 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 230000009429 distress Effects 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 230000037437 driver mutation Effects 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 238000005516 engineering process 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
- 229960005277 gemcitabine Drugs 0.000 description 2
- 230000004077 genetic alteration Effects 0.000 description 2
- 231100000118 genetic alteration Toxicity 0.000 description 2
- 238000012252 genetic analysis Methods 0.000 description 2
- 230000005745 host immune response Effects 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 229940050526 hydroxyethylstarch Drugs 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 108091008042 inhibitory receptors Proteins 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 238000009115 maintenance therapy Methods 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 210000003071 memory t lymphocyte Anatomy 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000037434 nonsense mutation Effects 0.000 description 2
- 108010054452 nuclear pore complex protein 98 Proteins 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 102000054765 polymorphisms of proteins Human genes 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 102000003998 progesterone receptors Human genes 0.000 description 2
- 108090000468 progesterone receptors Proteins 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 238000010188 recombinant method Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000007480 sanger sequencing Methods 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 2
- 229940066453 tecentriq Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 230000005851 tumor immunogenicity Effects 0.000 description 2
- 108010073629 xeroderma pigmentosum group F protein Proteins 0.000 description 2
- 108020001588 κ-opioid receptors Proteins 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- 102100026210 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 Human genes 0.000 description 1
- 102100027962 2-5A-dependent ribonuclease Human genes 0.000 description 1
- 101150106899 28 gene Proteins 0.000 description 1
- 102100027399 A disintegrin and metalloproteinase with thrombospondin motifs 2 Human genes 0.000 description 1
- 108091005662 ADAMTS2 Proteins 0.000 description 1
- 102100024379 AF4/FMR2 family member 1 Human genes 0.000 description 1
- 102100024387 AF4/FMR2 family member 3 Human genes 0.000 description 1
- 102100038507 AT-rich interactive domain-containing protein 3B Human genes 0.000 description 1
- 102100027447 ATP-dependent DNA helicase Q1 Human genes 0.000 description 1
- 102100027452 ATP-dependent DNA helicase Q4 Human genes 0.000 description 1
- 102100036409 Activated CDC42 kinase 1 Human genes 0.000 description 1
- 102100034614 Ankyrin repeat domain-containing protein 11 Human genes 0.000 description 1
- 101100058320 Arabidopsis thaliana BHLH12 gene Proteins 0.000 description 1
- 101100168911 Arabidopsis thaliana CUL4 gene Proteins 0.000 description 1
- 101100086324 Arabidopsis thaliana RABB1B gene Proteins 0.000 description 1
- 208000034048 Asymptomatic disease Diseases 0.000 description 1
- 102100026630 Aurora kinase C Human genes 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 102100037674 Bis(5'-adenosyl)-triphosphatase Human genes 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- 102000015347 COP1 Human genes 0.000 description 1
- 108060001826 COP1 Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 1
- 102000001326 Chemokine CCL4 Human genes 0.000 description 1
- 108010055165 Chemokine CCL4 Proteins 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 108010078239 Chemokine CX3CL1 Proteins 0.000 description 1
- 102000011022 Chorionic Gonadotropin Human genes 0.000 description 1
- 108010062540 Chorionic Gonadotropin Proteins 0.000 description 1
- 102100021898 Cyclin-Q Human genes 0.000 description 1
- 101100459256 Cyprinus carpio myca gene Proteins 0.000 description 1
- 102100028712 Cytosolic purine 5'-nucleotidase Human genes 0.000 description 1
- 238000007400 DNA extraction Methods 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 102100024607 DNA topoisomerase 1 Human genes 0.000 description 1
- 101100168913 Dictyostelium discoideum culD gene Proteins 0.000 description 1
- 101100226017 Dictyostelium discoideum repD gene Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 101150105460 ERCC2 gene Proteins 0.000 description 1
- 102100021710 Endonuclease III-like protein 1 Human genes 0.000 description 1
- 102100040438 Epithelial cell-transforming sequence 2 oncogene-like Human genes 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 102100030667 Eukaryotic peptide chain release factor subunit 1 Human genes 0.000 description 1
- 102100029055 Exostosin-1 Human genes 0.000 description 1
- 102100036144 FLYWCH-type zinc finger-containing protein 1 Human genes 0.000 description 1
- 101150106966 FOXO1 gene Proteins 0.000 description 1
- 102100034553 Fanconi anemia group J protein Human genes 0.000 description 1
- 102100028073 Fibroblast growth factor 5 Human genes 0.000 description 1
- 102100020871 Forkhead box protein G1 Human genes 0.000 description 1
- 101710087964 Forkhead box protein G1 Proteins 0.000 description 1
- 102100020997 Fractalkine Human genes 0.000 description 1
- 102100030334 Friend leukemia integration 1 transcription factor Human genes 0.000 description 1
- 102100039825 G protein-regulated inducer of neurite outgrowth 2 Human genes 0.000 description 1
- 102100037859 G1/S-specific cyclin-D3 Human genes 0.000 description 1
- 102100027541 GTP-binding protein Rheb Human genes 0.000 description 1
- 102100035184 General transcription and DNA repair factor IIH helicase subunit XPD Human genes 0.000 description 1
- 208000031448 Genomic Instability Diseases 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 102100029283 Hepatocyte nuclear factor 3-alpha Human genes 0.000 description 1
- 102100029235 Histone-lysine N-methyltransferase NSD3 Human genes 0.000 description 1
- 101000691589 Homo sapiens 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 Proteins 0.000 description 1
- 101001080057 Homo sapiens 2-5A-dependent ribonuclease Proteins 0.000 description 1
- 101000833180 Homo sapiens AF4/FMR2 family member 1 Proteins 0.000 description 1
- 101000833166 Homo sapiens AF4/FMR2 family member 3 Proteins 0.000 description 1
- 101000808906 Homo sapiens AT-rich interactive domain-containing protein 3B Proteins 0.000 description 1
- 101000580659 Homo sapiens ATP-dependent DNA helicase Q1 Proteins 0.000 description 1
- 101000580577 Homo sapiens ATP-dependent DNA helicase Q4 Proteins 0.000 description 1
- 101000928956 Homo sapiens Activated CDC42 kinase 1 Proteins 0.000 description 1
- 101000924476 Homo sapiens Ankyrin repeat domain-containing protein 11 Proteins 0.000 description 1
- 101000765862 Homo sapiens Aurora kinase C Proteins 0.000 description 1
- 101100166600 Homo sapiens CD28 gene Proteins 0.000 description 1
- 101000897449 Homo sapiens Cyclin-Q Proteins 0.000 description 1
- 101000915162 Homo sapiens Cytosolic purine 5'-nucleotidase Proteins 0.000 description 1
- 101000931098 Homo sapiens DNA (cytosine-5)-methyltransferase 1 Proteins 0.000 description 1
- 101000830681 Homo sapiens DNA topoisomerase 1 Proteins 0.000 description 1
- 101000938776 Homo sapiens ETS domain-containing transcription factor ERF Proteins 0.000 description 1
- 101000970385 Homo sapiens Endonuclease III-like protein 1 Proteins 0.000 description 1
- 101000817241 Homo sapiens Epithelial cell-transforming sequence 2 oncogene-like Proteins 0.000 description 1
- 101000938790 Homo sapiens Eukaryotic peptide chain release factor subunit 1 Proteins 0.000 description 1
- 101000918311 Homo sapiens Exostosin-1 Proteins 0.000 description 1
- 101000930684 Homo sapiens FLYWCH-type zinc finger-containing protein 1 Proteins 0.000 description 1
- 101000848171 Homo sapiens Fanconi anemia group J protein Proteins 0.000 description 1
- 101001060267 Homo sapiens Fibroblast growth factor 5 Proteins 0.000 description 1
- 101001062996 Homo sapiens Friend leukemia integration 1 transcription factor Proteins 0.000 description 1
- 101001034045 Homo sapiens G protein-regulated inducer of neurite outgrowth 2 Proteins 0.000 description 1
- 101000738559 Homo sapiens G1/S-specific cyclin-D3 Proteins 0.000 description 1
- 101000574654 Homo sapiens GTP-binding protein Rit1 Proteins 0.000 description 1
- 101001062353 Homo sapiens Hepatocyte nuclear factor 3-alpha Proteins 0.000 description 1
- 101000634046 Homo sapiens Histone-lysine N-methyltransferase NSD3 Proteins 0.000 description 1
- 101001042104 Homo sapiens Inducible T-cell costimulator Proteins 0.000 description 1
- 101001001418 Homo sapiens Inhibitor of growth protein 4 Proteins 0.000 description 1
- 101001053362 Homo sapiens Inositol polyphosphate-4-phosphatase type I A Proteins 0.000 description 1
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 1
- 101000599056 Homo sapiens Interleukin-6 receptor subunit beta Proteins 0.000 description 1
- 101001042362 Homo sapiens Leukemia inhibitory factor receptor Proteins 0.000 description 1
- 101000614013 Homo sapiens Lysine-specific demethylase 2B Proteins 0.000 description 1
- 101001088893 Homo sapiens Lysine-specific demethylase 4C Proteins 0.000 description 1
- 101001059429 Homo sapiens MAP/microtubule affinity-regulating kinase 3 Proteins 0.000 description 1
- 101001059427 Homo sapiens MAP/microtubule affinity-regulating kinase 4 Proteins 0.000 description 1
- 101000576894 Homo sapiens Macrophage mannose receptor 1 Proteins 0.000 description 1
- 101001005609 Homo sapiens Mitogen-activated protein kinase kinase kinase 13 Proteins 0.000 description 1
- 101001005550 Homo sapiens Mitogen-activated protein kinase kinase kinase 14 Proteins 0.000 description 1
- 101001055085 Homo sapiens Mitogen-activated protein kinase kinase kinase 9 Proteins 0.000 description 1
- 101001023043 Homo sapiens Myoblast determination protein 1 Proteins 0.000 description 1
- 101000613577 Homo sapiens Paired box protein Pax-2 Proteins 0.000 description 1
- 101000601664 Homo sapiens Paired box protein Pax-8 Proteins 0.000 description 1
- 101000702560 Homo sapiens Probable global transcription activator SNF2L1 Proteins 0.000 description 1
- 101000945496 Homo sapiens Proliferation marker protein Ki-67 Proteins 0.000 description 1
- 101000738940 Homo sapiens Proline-rich nuclear receptor coactivator 1 Proteins 0.000 description 1
- 101000959489 Homo sapiens Protein AF-9 Proteins 0.000 description 1
- 101000893493 Homo sapiens Protein flightless-1 homolog Proteins 0.000 description 1
- 101000727821 Homo sapiens RING1 and YY1-binding protein Proteins 0.000 description 1
- 101000686231 Homo sapiens Ras-related GTP-binding protein C Proteins 0.000 description 1
- 101000686246 Homo sapiens Ras-related protein R-Ras Proteins 0.000 description 1
- 101000666634 Homo sapiens Rho-related GTP-binding protein RhoH Proteins 0.000 description 1
- 101000945093 Homo sapiens Ribosomal protein S6 kinase alpha-4 Proteins 0.000 description 1
- 101001051706 Homo sapiens Ribosomal protein S6 kinase beta-1 Proteins 0.000 description 1
- 101001051714 Homo sapiens Ribosomal protein S6 kinase beta-2 Proteins 0.000 description 1
- 101000631899 Homo sapiens Ribosome maturation protein SBDS Proteins 0.000 description 1
- 101100478277 Homo sapiens SPTA1 gene Proteins 0.000 description 1
- 101000632056 Homo sapiens Septin-9 Proteins 0.000 description 1
- 101000695043 Homo sapiens Serine/threonine-protein kinase BRSK1 Proteins 0.000 description 1
- 101001047642 Homo sapiens Serine/threonine-protein kinase LATS1 Proteins 0.000 description 1
- 101000693262 Homo sapiens Sphingosine 1-phosphate receptor 2 Proteins 0.000 description 1
- 101000641015 Homo sapiens Sterile alpha motif domain-containing protein 9 Proteins 0.000 description 1
- 101000702606 Homo sapiens Structure-specific endonuclease subunit SLX4 Proteins 0.000 description 1
- 101000796673 Homo sapiens Transformation/transcription domain-associated protein Proteins 0.000 description 1
- 101000658084 Homo sapiens U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit-related protein 2 Proteins 0.000 description 1
- 101001030255 Homo sapiens Unconventional myosin-XVIIIa Proteins 0.000 description 1
- 101000915606 Homo sapiens Zinc finger protein 781 Proteins 0.000 description 1
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 1
- 108091008028 Immune checkpoint receptors Proteins 0.000 description 1
- 102000037978 Immune checkpoint receptors Human genes 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 102100035677 Inhibitor of growth protein 4 Human genes 0.000 description 1
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 1
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 1
- 102100024367 Inositol polyphosphate-4-phosphatase type I A Human genes 0.000 description 1
- 102100025390 Integrin beta-2 Human genes 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108090000177 Interleukin-11 Proteins 0.000 description 1
- 108090000176 Interleukin-13 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 102100037795 Interleukin-6 receptor subunit beta Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 1
- 102100021747 Leukemia inhibitory factor receptor Human genes 0.000 description 1
- 102100040584 Lysine-specific demethylase 2B Human genes 0.000 description 1
- 102100033230 Lysine-specific demethylase 4C Human genes 0.000 description 1
- 108010009254 Lysosomal-Associated Membrane Protein 1 Proteins 0.000 description 1
- 102100035133 Lysosome-associated membrane glycoprotein 1 Human genes 0.000 description 1
- 102100028920 MAP/microtubule affinity-regulating kinase 3 Human genes 0.000 description 1
- 102100028913 MAP/microtubule affinity-regulating kinase 4 Human genes 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
- 102100025184 Mitogen-activated protein kinase kinase kinase 13 Human genes 0.000 description 1
- 102100025211 Mitogen-activated protein kinase kinase kinase 14 Human genes 0.000 description 1
- 102100026909 Mitogen-activated protein kinase kinase kinase 9 Human genes 0.000 description 1
- 101100490437 Mus musculus Acvrl1 gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000008300 Mutant Proteins Human genes 0.000 description 1
- 108010021466 Mutant Proteins Proteins 0.000 description 1
- 102100035077 Myoblast determination protein 1 Human genes 0.000 description 1
- 102100022437 Myotonin-protein kinase Human genes 0.000 description 1
- 102000001753 Notch4 Receptor Human genes 0.000 description 1
- 108010029741 Notch4 Receptor Proteins 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 1
- 102100040852 Paired box protein Pax-2 Human genes 0.000 description 1
- 102100037502 Paired box protein Pax-8 Human genes 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 102100032543 Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN Human genes 0.000 description 1
- 208000006994 Precancerous Conditions Diseases 0.000 description 1
- 102100031031 Probable global transcription activator SNF2L1 Human genes 0.000 description 1
- 102100034836 Proliferation marker protein Ki-67 Human genes 0.000 description 1
- 102100037394 Proline-rich nuclear receptor coactivator 1 Human genes 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102100039686 Protein AF-9 Human genes 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 241001510071 Pyrrhocoridae Species 0.000 description 1
- 101150020518 RHEB gene Proteins 0.000 description 1
- 101150111584 RHOA gene Proteins 0.000 description 1
- 102100029760 RING1 and YY1-binding protein Human genes 0.000 description 1
- 102100025009 Ras-related GTP-binding protein C Human genes 0.000 description 1
- 102100024683 Ras-related protein R-Ras Human genes 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102100038338 Rho-related GTP-binding protein RhoH Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 102100033644 Ribosomal protein S6 kinase alpha-4 Human genes 0.000 description 1
- 102100024908 Ribosomal protein S6 kinase beta-1 Human genes 0.000 description 1
- 102100024917 Ribosomal protein S6 kinase beta-2 Human genes 0.000 description 1
- 102100028750 Ribosome maturation protein SBDS Human genes 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 101100168914 Schizosaccharomyces pombe (strain 972 / ATCC 24843) pcu4 gene Proteins 0.000 description 1
- 101100153534 Schizosaccharomyces pombe (strain 972 / ATCC 24843) tnr3 gene Proteins 0.000 description 1
- 102100028024 Septin-9 Human genes 0.000 description 1
- 102100028623 Serine/threonine-protein kinase BRSK1 Human genes 0.000 description 1
- 102100024031 Serine/threonine-protein kinase LATS1 Human genes 0.000 description 1
- 101100459257 Solanum lycopersicum MYC1 gene Proteins 0.000 description 1
- 102100025749 Sphingosine 1-phosphate receptor 2 Human genes 0.000 description 1
- 102100034291 Sterile alpha motif domain-containing protein 9 Human genes 0.000 description 1
- 102100031003 Structure-specific endonuclease subunit SLX4 Human genes 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 210000000447 Th1 cell Anatomy 0.000 description 1
- 102100032762 Transformation/transcription domain-associated protein 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
- 102100022387 Transforming protein RhoA Human genes 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 102100021657 Tyrosine-protein phosphatase non-receptor type 6 Human genes 0.000 description 1
- 101710128901 Tyrosine-protein phosphatase non-receptor type 6 Proteins 0.000 description 1
- 102100035036 U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit-related protein 2 Human genes 0.000 description 1
- 102100038932 Unconventional myosin-XVIIIa Human genes 0.000 description 1
- 108020004417 Untranslated RNA Proteins 0.000 description 1
- 102000039634 Untranslated RNA Human genes 0.000 description 1
- 101100459258 Xenopus laevis myc-a gene Proteins 0.000 description 1
- 108700031763 Xeroderma Pigmentosum Group D Proteins 0.000 description 1
- 102100028582 Zinc finger protein 781 Human genes 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 201000005179 adrenal carcinoma Diseases 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 208000037844 advanced solid tumor Diseases 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000009464 antigen specific memory response Effects 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000005975 antitumor immune response Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000003766 bioinformatics method Methods 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000029918 bioluminescence Effects 0.000 description 1
- 238000005415 bioluminescence Methods 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 108010005713 bis(5'-adenosyl)triphosphatase Proteins 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 238000013276 bronchoscopy Methods 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000000739 chaotic effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000000222 eosinocyte Anatomy 0.000 description 1
- 230000008995 epigenetic change Effects 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000001808 exosome Anatomy 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000012224 gene deletion Methods 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 230000008826 genomic mutation Effects 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 238000012165 high-throughput sequencing Methods 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 229940084986 human chorionic gonadotropin Drugs 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000000899 immune system response Effects 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000014828 interferon-gamma production Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960005558 mertansine Drugs 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 108091027963 non-coding RNA Proteins 0.000 description 1
- 102000042567 non-coding RNA Human genes 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000007842 plasma-based assay Methods 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000002708 random mutagenesis Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000013077 scoring method Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229940121497 sintilimab Drugs 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229950007213 spartalizumab Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000017572 squamous cell neoplasm Diseases 0.000 description 1
- 210000004085 squamous epithelial cell Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 229950007123 tislelizumab Drugs 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940121514 toripalimab Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229940055760 yervoy Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour 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
- A61K2039/507—Comprising a combination of two or more separate 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
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Abstract
Description
本発明は、非小細胞肺癌(NSCLC)に由来する腫瘍に罹患している対象を免疫療法を用いて処置する方法を提供する。
ヒト癌は多数の遺伝的および後成的変化を保有し、免疫系により認識可能となる可能性のあるネオ抗原を産生する(Sjoblom et al., Science (2006) 314(5797):268-274)。TおよびBリンパ球からなる適応免疫系は、広い能力および多様な腫瘍抗原に応答するための精巧な特異性を備えた強力な抗癌能を有する。さらに、免疫系は、相当な柔軟性および記憶成分を示す。適応免疫系の全ての特質の利用の成功は、全ての癌処置モダリティの中で、免疫療法を独特のものとする。
本発明の特定の面は、非小細胞肺癌(NSCLC)由来の腫瘍に罹患している対象を処置するための方法であって、治療的有効量の(a)プログラム細胞死−1(PD−1)受容体に特異的に結合し、PD−1活性を阻害する抗体またはその抗原結合部分(“抗PD−1抗体”)またはプログラム細胞死−リガンド1(PD−L1)に特異的に結合し、PD−1活性を阻害する抗体もしくはその抗原結合部分(“抗PD−L1抗体”)および(b)細胞傷害性Tリンパ球抗原−4(CTLA−4)に特異的に結合する抗体もしくはその抗原結合部分(“抗CTLA−4抗体”)を対象に投与することを含み、ここで、該腫瘍が、検査された遺伝子の1メガベースあたり少なくとも約10個の変異の腫瘍遺伝子変異量(TMB)状態を有する、方法を提供する。ある態様において、該方法は、投与前に対象から得られた生物学的サンプルのTMB状態を測定することをさらに含む。
E1.非小細胞肺癌(NSCLC)に由来する腫瘍に罹患している対象の処置のための、治療的有効量の、(a)プログラム細胞死−1(PD−1)受容体に特異的に結合し、PD−1活性を阻害する抗体もしくはその抗原結合部分(“抗PD−1抗体”)またはプログラム細胞死−リガンド1(PD−L1)に特異的に結合し、PD−1活性を阻害する抗体もしくはその抗原結合部分(“抗PD−L1抗体”)、および(b)細胞傷害性Tリンパ球抗原−4(CTLA−4)に特異的に結合する抗体もしくはその抗原結合部分(“抗CTLA−4抗体”)を対象に投与することを含む方法であって、ここで、該腫瘍が、検査された遺伝子の1メガベースあたり少なくとも約10個の変異の腫瘍遺伝子変異量(TMB)状態を有する、方法。
本発明は、非小細胞肺癌(NSCLC)由来の腫瘍に罹患している対象を処置する方法であって、該対象に(a)抗PD−1抗体または抗PD−L1抗体および(b)抗CLTA−4抗体を含む併用療法剤を投与することを含む方法を提供し、ここで、該腫瘍は、高い腫瘍遺伝子変異量(TMB)状態を有する。特定の態様において、腫瘍は、検査された遺伝子の1メガベースあたり少なくとも約10個の変異のTMBを有する。
本明細書の記載がより容易に理解され得るように、いくつかの用語を最初に定義する。本明細書で特に別の定義が明記されている場合を除いて、本明細書で用いるとき、以下の用語はそれぞれ、以下に記載の意味を有するものとする。さらなる定義が、本明細書を通して記載される。
本発明の特定の面は、高TMB状態を有するNSCLC由来の腫瘍に罹患している対象の処置方法であって、対象に治療的有効量の(a)抗PD−1抗体または抗PD−L1抗体および(b)抗CTLA−4抗体を投与することを含む、方法に関する。本発明の他の面は、NSCLC由来の腫瘍に罹患しており、(a)抗PD−1抗体または抗PD−L1抗体および(b)抗CTLA−4抗体の併用療法に適する、対象を同定する方法であって、該対象の生物学的サンプルのTMB状態を測定することを含む方法に関し、ここで、TMB状態とは、検査されたゲノムの1メガベースあたり少なくとも約10個の変異を含み、該対象が、併用療法に適すると同定されている。本発明は、腫瘍免疫原性がTMBおよび/またはネオ抗原量に直接関連しているという事実に基づく。
FOUNDATIONONE(登録商標)アッセイは、これに限定されないが、肺癌、結腸癌および乳癌の固形腫瘍、黒色腫および卵巣癌を含む固形腫瘍のための網羅的ゲノムプロファイリングアッセイである。FOUNDATIONONE(登録商標)アッセイは、ゲノム改変(塩基置換、挿入および欠失、コピー数変化および再配列)を同定し、ゲノム特性(例えば、TMBおよびマイクロサテライト不安定性)を選択するためのハイブリッドキャプチャー次世代シークエンシング法を用いる。該アッセイは、315個の癌関連遺伝子の全コード領域、および28個の遺伝子に由来する選択されたイントロンを含む、322個のユニークな遺伝子を網羅する。FOUNDATIONONE(登録商標)アッセイ遺伝子の完全リストを、表2および3に示す。2018年3月16日に最終アクセスしたFoundationMedicine.comで利用可能なFOUNDATIONONE:Technical Specifications、Foundation Medicine、Inc.(引用によりその全体を本明細書に包含させる)を参照のこと。
一態様において、TMBは、EXODX(登録商標)固形腫瘍アッセイを用いて測定される。EXODX(登録商標)固形腫瘍アッセイは、癌経路における実用的な変異を検出するexoRNAおよびcfDNAに基づくアッセイである。EXODX(登録商標)固形腫瘍アッセイは、組織サンプルを必要としない血漿に基づくアッセイである。EXODX(登録商標)固形腫瘍アッセイは、26個の遺伝子および1000個の変異を網羅する。EXODX(登録商標)固形腫瘍アッセイで網羅される特定の遺伝子を表4に示す。2019年3月25日に最終アクセスしたexosomedx.comで利用可能な血漿に基づく固形腫瘍変異パネル液体生検(Plasma-Based Solid Tumor Mutation Panel Liquid Biopsy)(Exosome Diagnostics, Inc.)を参照のこと。
ある態様において、TMB状態は、Guardant360アッセイを用いて決定される。Guardant360アッセイは、少なくとも73個の遺伝子(表5)、23個のインデル(表6)、18個のCNV(表7)および6個の融合遺伝子(表8)の変異を測定する。2019年3月25日に最終アクセスしたGuardantHealth.comを参照のこと。
ある態様において、TMBは、TruSight腫瘍170アッセイ(ILLUMINA)を用いて決定される。前記TruSight腫瘍170アッセイは、DNAおよびRNAを同時に解析する一般的な固形腫瘍に関連する170個の遺伝子を網羅する次世代シークエンシングアッセイである。前記TruSight腫瘍170アッセイは、融合、スプライス変異体、挿入/欠失、単一ヌクレオチド変異型(SNV)および増幅を評価する。前記TruSight腫瘍170アッセイ遺伝子リストを、表12から14に示す。
FOUNDATIONONE(登録商標) CDX(商標)(“F1CDx”)は、ホルマリンで固定されたパラフィン包埋(FFPE)腫瘍組織試料から単離されたDNAを用いて、324個の遺伝子および選択された遺伝子再配列、ならびにゲノム特性(マイクロサテライト不安定性(MSI)および腫瘍遺伝子変異量(TMB)を含む)における置換、挿入および欠失の変化(インデル)、およびコピー数変化(CNA)の検出のための次世代シークエンシングに基づくインビトロ診断装置である。F1CDxは、NSCLC、黒色腫、乳癌、結腸直腸癌および卵巣癌を含むいくつかの腫瘍への適用について米国食品医薬品局(FDA)に認可されている。
ある態様において、TMB状態は、MSK−IMPACT(商標)アッセイを用いて評価される。MSK−IMPACT(商標)アッセイは、468個の遺伝子の変異状態を解析するために次世代シークエンシングを用いる。標的遺伝子は、ILLUMINA HISEQ(商標)装置で捕捉され、配列決定される。MSK−IMPACT(商標)アッセイは、固形悪性腫瘍の体細胞変異およびマイクロサテライト不安定性の検出について米国FDAに認可されている。MSK−IMPACT(商標)アッセイによって分析される468個の遺伝子の全リストを、表14に示す。accessdata.fda.govで2017年11月15日に利用可能なEvaluation of Automatic Class III Designation for MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets): Decision Summary(米国食品医薬品局)を参照のこと。
ある態様において、TMBは、NEOGENICS(登録商標)NEOTYOPE(商標)アッセイを用いて決定される。ある態様において、TMBは、NEOTYPE(商標)ディスカバリープロファイルを用いて決定される。ある態様において、TMBは、NEOTYPE固形腫瘍プロファイルを用いて決定される。NEOGENICSアッセイは、配列決定されたDNAの1メガベースあたりの非同義DNAコード配列の変化の数を測定する。
ある態様において、TMBは、THERMOFISHER SCIENTIFIC(登録商標)ONCOMINE(商標)腫瘍変異アッセイを用いて決定される。ある態様において、TMBは、THERMOFISHER SCIENTIFIC(登録商標)ION TORRENT(商標)ONCOMINE(商標)腫瘍変異アッセイを用いて決定される。ION TORRENT(商標)ONCOMINE(商標)腫瘍変異アッセイは、腫瘍変異量を決定するために体細胞変異を定量化する標的化NGSアッセイである。該アッセイは、1.7MbのDNAを網羅する。THERMOFISHER SCIENTIFIC(登録商標) ION TORRENT(商標) ONCOMINE(商標) 腫瘍変異アッセイにより分析される408個の遺伝子の完全なリストを、表15に示す(Iontorrent、Oncomine Tumor Mutation Load Assay Flyer参照、assets.thermofisher.com/TFS-Assets/CSD/Flyers/ oncomine-tumor-mutation-load-assay-flyer.pdfで利用可能、最終訪問日2019年3月25日)。
ある態様において、TMBは、NOVOGENE(商標)NOVOPM(商標)アッセイを用いて決定される。ある態様において、TMBは、NOVOGENE(商標)NOVOPM(商標)癌パネルアッセイを用いて決定される。NOVOGENE(商標)NOVOPM癌パネルアッセイは、548個の遺伝子の全コード領域および21個の遺伝子のイントロン(約1.5MbのDNAを表す)を解析し、全米総合癌情報ネットワーク(NCCN)ガイドラインおよび医学文献による固形腫瘍の診断および/または処置に適する網羅的NGS癌パネルである。該アッセイは、SNV、インデル(InDel)、融合およびコピー数変異(CNV)のゲノム異常を検出する。
ある態様において、TMBは、CARIS(登録商標)ライフサイエンスから供されるTMBアッセイを用いて決定される。ある態様において、TMBは、PESONALIS(登録商標)ACE ImmunoIDアッセイを用いて決定される。ある態様において、TMBは、PGDX(登録商標)CANCERXOME(商標)−Rアッセイを用いて決定される。
MLLT10、MMP2、MN1、MTC、MTOT、MTR、MTRR、MUC1、MY8、MYH11、MYH9、NCOA1、NCOA2、NCOA4、NFK81、NFK82、NIN、NLRP1、NUMA1、NUP214、P8RM1、P8X1、PAX−、PAX3、PAX8、PAXS、PDE4DIP、PDGF8、PER1、PGAP3、PHOX28、PIK3C28、PKHD1、PLAG1、PLCG1、PLEKHGS、PML、POU5F1、PSIP1、PTGS2、RADSO、RALGDS、RHOH、RNASEL、RNF2、RNF213、RPS6KA2、RRM1、SAMD9、SBDS、SMUG1、SOHO、SOX11、SSX1、STK36、SYNE1、T8X22、TAF1L、TAL1、TCF12、TCF7L1、TFE3、TGF8R2、TGM7、TH8S1、TIMP3、TLR4、TLX1、TNK2、TPR、TRIM24、TRIM33、TRIP11、TRRAP、U8R5、UGT1A1、USP9X、WAS、WRN、XP01、XPA、XPC、ZNF384、ZNF521およびそれらの組み合わせからなる群より選択される1以上の遺伝子を含む。
、MLL3、MLLT10、MMP2、MN1、MTC、MTOT、MTR、MTRR、MUC1、MY8、MYH11、MYH9、NCOA1、NCOA2、NCOA4、NFK81、NFK82、NIN、NLRP1、NUMA1、NUP214、P8RM1、P8X1、PAX−、PAX3、PAX8、PAXS、PDE4DIP、PDGF8、PER1、PGAP3、PHOX28、PIK3C28、PKHD1、PLAG1、PLCG1、PLEKHGS、PML、POU5F1、PSIP1、PTGS2、RADSO、RALGDS、RHOH、RNASEL、RNF2、RNF213、RPS6KA2、RRM1、SAMD9、SBDS、SMUG1、SOHO、SOX11、SSX1、STK36、SYNE1、T8X22、TAF1L、TAL1、TCF12、TCF7L1、TFE3、TGF8R2、TGM7、TH8S1、TIMP3、TLR4、TLX1、TNK2、TPR、TRIM24、TRIM33、TRIP11、TRRAP、U8R5、UGT1A1、USP9X、WAS、WRN、XP01、XPA、XPC、ZNF384、ZNF521およびそれらの組み合わせからなる群より選択される少なくとも約20、少なくとも約30、少なくとも約40、少なくとも約50、少なくとも約60、少なくとも約70、少なくとも約80、少なくとも約90、少なくとも約100、少なくとも約110、少なくとも約120、少なくとも約130、少なくとも約140、少なくとも約150、少なくとも約160、少なくとも約170、少なくとも約180、少なくとも約190、少なくとも約200、少なくとも約210、少なくとも約220、少なくとも約230、少なくとも約240、少なくとも約250、少なくとも約260、少なくとも約270、少なくとも約280、少なくとも約290、または少なくとも約300個の遺伝子を含む。
約70個の変異/腫瘍、少なくとも約75個の変異/腫瘍、少なくとも約80個の変異/腫瘍、少なくとも約85個の変異/腫瘍、少なくとも約90個の変異/腫瘍、少なくとも約95個の変異/腫瘍、少なくとも約100個の変異/腫瘍、少なくとも約105個の変異/腫瘍、少なくとも約110個の変異/腫瘍、少なくとも約115個の変異/腫瘍、または少なくとも約120個の変異/腫瘍を有する場合、高TMB状態を有する。ある態様において、腫瘍は、少なくとも約125個の変異/腫瘍、少なくとも約150個の変異/腫瘍、少なくとも約175個の変異/腫瘍、少なくとも約200個の変異/腫瘍、少なくとも約225個の変異/腫瘍、少なくとも約250個の変異/腫瘍、少なくとも約275個の変異/腫瘍、少なくとも約300個の変異/腫瘍、少なくとも約350個の変異/腫瘍、少なくとも約400個の変異/腫瘍、または少なくとも約500個の変異/腫瘍を有する場合、高TMB状態を有する。特定の一態様において、腫瘍は、少なくとも約100個の変異/腫瘍を有する場合、高TMB状態を有する。
TMB状態は、(a)抗PD−1抗体または抗PD−L1抗体、および(b)抗CTLA−4抗体を含む併用療法に対する腫瘍の応答を予測する手段として、単独で、または他の因子と組み合わせて用いることができる。ある態様において、腫瘍のTMB状態のみが、(a)抗PD−1抗体または抗PD−L1抗体および(b)抗CTLA−4抗体を含む併用療法に応答する可能性が高い腫瘍を有する患者を同定するために用いられる。他の態様において、PD−L1状態およびTMB状態を用いて、(a)抗PD−1抗体または抗PD−L1抗体および(b)抗CTLA−4抗体を含む併用療法に応答する可能性が高い腫瘍を有する患者を特定する。特定の態様において、腫瘍は、1%未満のPD−L1発現を有し、例えば、腫瘍細胞の1%未満がPD−L1を発現する。特定の態様において、対象は、高いTMB状態(≧10変異(mut)/Mb)および1%未満の腫瘍PD−L1発現レベルを有する。
組織スコア=[(%腫瘍x1(低強度))+(%腫瘍x2(中間強度))+(%腫瘍x3(高強度)]。
TMB状態は、(a)抗PD−1抗体または抗PD−L1抗体および(b)抗CLTA−4抗体の併用療法に対するNSCLCに由来する腫瘍の応答性を予測するための手段として、単独で、または他の因子、例えばMSI状態と組み合わせて用いることができる。一態様において、MSI状態はTMB状態の一部である。他の態様において、MSI状態は、TMB状態とは別に測定される。
本発明は、有効量の(a)抗PD−1抗体または抗PD−L1抗体および(b)抗CLTA−4抗体を対象に投与することを含む、NSCLCに由来する腫瘍に罹患している対象を処置する方法に関し、ここで、該腫瘍は高TMB状態を有する。特定の態様において、腫瘍は、1メガベースあたり少なくとも約10個の変異のTMB状態を有する。ある態様において、この方法は、投与前に対象から得られた生物学的サンプルのTMB状態を測定することをさらに含む。
本発明の特定の面は、(a)抗PD−1抗体または抗PD−L1抗体および(b)抗CLTA−4抗体を対象に投与することを含む、NSCLCに由来する腫瘍に罹患している対象を処置する方法に関し、ここで、腫瘍は高TMB状態、例えば、検査された遺伝子の1メガベースあたり少なくとも約10個の変異のTMBを有する。該方法は、対象から得られた生物学的サンプルのTMB状態を測定することをさらに含む。さらに、本発明は、例えば、検査された遺伝子の1メガベースあたり少なくとも約10個の変異の高TMBの測定に基づき、そのような治療に適すると同定された対象に(a)抗PD−1抗体または抗PD−L1抗体および(b)抗CLTA−4抗体を投与することを企図する。
当技術分野で既知の抗PD−1抗体は、本明細書に記載の組成物および方法において用いることができる。高い親和性でPD−1に特異的に結合する種々のヒトモノクローナル抗体は、米国特許第8,008,449号に記載されている。米国特許第8,008,449号に記載の抗PD−1ヒト抗体は、以下の特徴の1以上を示すことが証明されている:(a)Biacoreバイオセンサーシステムを用いる表面プラズモン共鳴によって決定される、1×10−7Mまたはそれ以下のKDでヒトPD−1に結合する;(b)ヒトCD28、CTLA−4またはICOSに実質的に結合しない;(c)混合リンパ球反応(MLR)アッセイにおいてT細胞の増殖を増加させる;(d)MLRアッセイにおいてインターフェロン−γの産生を増加させる;(e)MLRアッセイにおいてIL−2分泌を増加させる;(f)ヒトPD−1およびカニクイザルPD−1に結合する;(g)PD−1に対するPD−L1および/またはPD−L2の結合を阻害する;(h)抗原特異的記憶応答を刺激する;(i)抗体応答を刺激する;および(j)インビボでの腫瘍細胞の増殖を阻害する。本発明に用いられ得る抗PD−1抗体には、ヒトPD−1に特異的に結合し、前記特徴のうちの少なくとも1つ、ある態様において、少なくとも5つを示すモノクローナル抗体が含まれる。
特定の態様において、抗PD−L1抗体は、本明細書に記載の方法のいずれかにおいて抗PD−1抗体の代わりに用いられる。当技術分野で知られている抗PD−L1抗体は、本発明の組成物および方法で用いられ得る。本発明の組成物および方法に有用な抗PD−L1抗体の例には、米国特許第9,580,507号に記載の抗体が含まれる。米国特許第9,580,507号に記載の抗PD−L1ヒトモノクローナル抗体は、以下の特徴の1以上を示すことが示されている:(a)Biacoreバイオセンサーシステムを用いて表面プラズモン共鳴によって測定される、1x10−7Mまたはそれ以下のKDでヒトPD−L1に結合する;(b)混合リンパ球反応(MLR)アッセイにおいてT細胞の増殖を増加させる;(c)MLRアッセイにおいてインターフェロン−γ産生を増加させる;(d)MLRアッセイにおいてIL−2分泌を増加させる;(e)抗体応答を刺激する;および(f)T細胞エフェクター細胞および/または樹状細胞におけるT調節性細胞の効果を逆転させる。本発明に用いられ得る抗PD−L1抗体には、ヒトPD−L1に特異的に結合し、前記特徴のうちの少なくとも1つ、ある態様において、少なくとも5つを示す、モノクローナル抗体が含まれる。
当技術分野で知られている抗CTLA−4抗体は、本発明の組成物および方法に用いられ得る。本明細書に記載の抗CTLA−4抗体は、CTLA−4とヒトB7受容体との相互作用を破壊するように、ヒトCTLA−4に結合する。CTLA−4とB7の相互作用は、CTLA−4受容体を担持するT細胞の不活性化につながるシグナルを伝達するため、相互作用の破壊は、かかるT細胞の活性化を効果的に誘導、増強または延長し、それにより免疫反応を誘導、増強または延長する。
ある態様において、本発明の方法は、(a)抗PD−1抗体または抗PD−L1抗体、(b)抗CTLA−4抗体、および(c)サイトカインを投与することを含む、NSCLCに由来する腫瘍に罹患している対象を処置することを含み、ここで、該腫瘍は高TMB状態を有し、例えば、該腫瘍は、検査した遺伝子の1メガベースあたり少なくとも約10個の変異のTMB状態を有する。サイトカインは、当技術分野で知られているサイトカイン類またはその変異体であり得る。ある態様において、サイトカインは、インターロイキン−2(IL−2)、IL−1β、IL−6、TNF−α、RANTES、単球化学誘引物質タンパク質(MCP−1)、単球炎症性タンパク質(MIP−1αおよびMIP−1β)、IL−8、リンホタクチン、フラクタルカイン、IL−1、IL−4、IL−10、IL−11、IL−13、LIF、インターフェロン−α、TGF−βおよびそれらの組み合わせからなる群より選択される。ある態様において、サイトカインは、CD122アゴニストである。特定の態様において、サイトカインは、IL−2またはその変異体を含む。
特定の態様において、抗PD−1抗体、抗PD−L1抗体および/または抗CTLA−4抗体は、治療的有効量で投与される。ある態様において、この方法は、治療的有効量の抗PD−1抗体および抗CTLA−4抗体を投与することを含む。他の態様において、この方法は、治療的有効量の抗PD−L1抗体および抗CTLA−4抗体を投与することを含む。本明細書に記載の抗PD−1抗体、抗PD−L1抗体または抗CTLA−4抗体はいずれも、本発明の方法に使用できる。特定の態様において、抗PD−1抗体は、ニボルマブを含む。ある態様において、抗PD−1抗体は、ペンブロリズマブを含む。ある態様において、抗PD−L1抗体はアテゾリズマブを含む。ある態様において、抗PD−L1抗体はデュルバルマブを含む。ある態様において、抗PD−L1抗体はアベルマブを含む。ある態様において、抗CTLA−4抗体はイピリムマブを含む。ある態様において、抗CTLA−4抗体は、イピリムマブおよびトレメリムマブを含む。
NSCLCは、米国および世界中で、乳癌、結腸癌および前立腺癌を合わせた数を超える、癌による死亡の主要な原因である。米国において、肺および気管支の新たな症例が228,190例診断され、この疾患のために約159,480名が死亡している(Siegel et al. (2014) CA Cancer J Clin 64(1):9−29)。患者の大多数(約78%)は、進行性/再発性または転移性と診断される。肺癌から副腎への転移が一般的であり、転移患者の約33%がそのような転移を有する。NSCLC療法は、徐々に改善されたOSを示しているが、有益度はプラトーに達している(末期患者の平均OSは、ちょうど1年である)。これらの対象のほぼ全てにおいて第1選択療法(1L therapy)後に進行が起こり、5年生存率は、難治性群で僅か3.6%である。2005年から2009年の間、米国における肺癌の相対的5年生存率は、15.9%であった(NCCNガイドライン(登録商標)、バージョン3.2014−非小細胞肺癌、www.nccn.org/professionals/physician_gls/pdf/nscl.pdfで利用可能、最終アクセス2014年5月14日)。
本発明の特定の面において、対象は、NSCLCに由来する腫瘍の処置のための少なくとも1つの先行療法を受けている。少なくとも1つの先行療法は、NSCLCまたはそれに由来する腫瘍の処置のための当技術分野で知られている任意の治療であり得る。特に、少なくとも1つの先行療法は、NSCLCの処置のための標準治療であり得る。
本発明の特定の面は、高いTMB状態を有する腫瘍に罹患している対象を処置するための方法であって、該対象に免疫療法剤を投与することを含む方法に関し、ここで、免疫療法剤は抗LAG−3抗体またはその抗原結合部分を含む。該方法は、対象から得られた生物学的サンプルのTMB状態を測定することをさらに含んでいてよい。さらに、本発明は、例えば、高TMBの測定に基づいて、抗LAG−3抗体またはその抗原結合部分を、そのような治療に適していると同定された対象に投与することを企図する。
本発明の特定の面は、高いTMB状態を有する腫瘍に罹患している対象を処置するための方法であって、該対象に免疫療法剤を投与することを含む方法に関し、ここで、免疫療法剤は抗CD137抗体またはその抗原結合部分を含む。該方法は、対象から得られた生物学的サンプルのTMB状態を測定することをさらに含んでいてよい。さらに、本発明は、例えば、高TMBの測定に基づいて、抗CD137抗体またはその抗原結合部分を、そのような治療に適していると同定された対象に投与することを企図する。
号に記載の抗体(例えば、53A2)である。ある態様において、抗CD137抗体は、米国特許第6,210,669号に記載の抗体(例えば、1D8、3B8または3E1)である。ある態様において、抗体は、ファイザー社のPF−05082566(PF-2566)である。他の態様において、本発明に有用な抗CD137抗体は、本明細書に記載の抗CD137抗体と交差競合する。ある態様において、抗CD137抗体は、本明細書に記載の抗CD137抗体と同じエピトープに結合する。他の愛用において、本発明において有用な抗CD137抗体は、本明細書に記載の抗CD137抗体の6つのCDRを含む。
本発明の特定の面は、高いTMB状態を有する腫瘍に罹患している対象を処置するための方法であって、該対象に免疫療法剤を投与することを含む方法に関し、ここで、該免疫療法剤は抗KIR抗体またはその抗原結合部分を含む。この方法は、対象から得られた生物学的サンプルのTMB状態を測定することをさらに含む。さらに、本発明は、例えば、高TMBの測定に基づいて、抗KIR抗体またはその抗原結合部分を、そのような治療に適していると同定された対象に投与することを企図する。
本発明の特定の面は、高いTMB状態を有する腫瘍に罹患している対象を処置するための方法であって、該対象に免疫療法剤を投与することを含む方法に関し、ここで、該免疫療法剤は抗GITR抗体またはその抗原結合部分を含む。この方法は、対象から得られた生物学的サンプルのTMB状態を測定することをさらに含む。さらに、本発明は、例えば、高TMBの測定に基づいて、抗GITR抗体またはその抗原結合部分を、そのような治療に適していると同定された対象に投与することを企図する。
AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPYTFGQGTKLEIK (配列番号2); または
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGFHWVRQAPGKGLEWVAVIWYAGSNKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGQLDYYYYYVMDVWGQGTTVTVSS (配列番号3)、および
DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPYTFGQGTKLEIK (配列番号4); または
VQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYAGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGRIAVAFYYSMDVWGQGTTVTVSS (配列番号5)、および
DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPYTFGQGTKLEIK (配列番号6)。
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGSMVRGDYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (配列番号7)、および
AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (配列番号8)、または
qvqlvesgggvvqpgrslrlscaasgftfssygmhwvrqapgkglewvaviwyegsnkyyadsvkgrftisrdnskntlylqmnslraedtavyycarggsmvrgdyyygmdvwgqgttvtvssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkrvepkscdkthtcppcpapeaegapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpssiektiskakgqprepqvytlppsreemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg (配列番号9)、および
AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (配列番号10)。
ある態様において、免疫療法は、抗TGFβ抗体を含む。特定の態様において、抗TGFβ抗体は、国際公開第WO/2009/073533に記載の抗TGFβ抗体である。
本発明の治療剤は、組成物、例えば、抗体および/またはサイトカインおよび薬学的に許容される担体を含む医薬組成物に構成され得る。本明細書で用いる“薬学的に許容される担体”には、生理学的に適合する任意のおよび全ての溶媒、分散媒、コーティング剤、抗菌剤および抗真菌剤、等張剤および吸収遅延剤などが含まれる。好ましくは、抗体を含む組成物のための担体は、静脈内、筋肉内、皮下、非経腸、脊髄または上皮投与(例えば、注射または点滴による投与)に適するが、一方、抗体および/またはサイトカインを含む組成物のための担体は、非経腸投与、例えば経口投与に適する。ある態様において、皮下注射は、Halozyme Therapeutics社のENHANZE(登録商標)薬物送達技術(引用によりその内容全体を本明細書に包含させる米国特許第7,767,429号を参照のこと)に基づく。ENHANZE(登録商標)は、組換えヒトヒアルロニダーゼ酵素(rHuPH20)との抗体の共製剤を用い、これは、細胞外マトリックスにより皮下に送達され得る生物学的製剤および薬剤の量に関する従来の制限を取り除く(米国特許第7,767,429号を参照のこと)。本発明の医薬組成物は、1以上の薬学的に許容される塩、抗酸化剤、水性および非水性担体、ならびに/または防腐剤、湿潤剤、乳化剤および分散剤などのアジュバントを含み得る。従って、ある態様において、本発明の医薬組成物は、組換えヒトヒアルロニダーゼ酵素、例えばrHuPH20をさらに含み得る。
治療用途のための(a)抗PD−1抗体または抗PD−L1抗体および(b)抗CLTA−4抗体を含むキットもまた、本発明の範囲内である。キットは、一般的に、キットの内容物の意図された使用を示すラベルおよび使用説明書を含む。ラベルという用語には、キットに添付されているまたは含まれる、あるいはそれ以外の方法でキットに包含される、文書または記録された資料が含まれる。従って、本発明は、NSCLCに由来する腫瘍に罹患している対象の処置のためのキットを提供し、該キットには、(a)体重1kg当たり0.1〜10mgの範囲の投与量の抗PD−1抗体または体重1kg当たり0.1〜20mgの範囲の投与量の抗PD−L1抗体;(b)体重1kg当たり0.1〜10mgの範囲の投与量の抗CTLA−4抗体;(c)本明細書に記載の方法における、(a)抗PD−1抗体または抗PD−L1抗体および(b)抗CTLA−4抗体の使用のための指示書、が含まれる。ある態様において、本発明は、NSCLCに由来する腫瘍に罹患している対象を処置するためのキットを提供し、該キットには、(a)200mg〜800mgの投与量範囲の抗PD−1抗体または200mg〜1800mgの投与量範囲の抗PD−L1抗体;(b)10mg〜800mgの投与量範囲の抗CTLA−4抗体;(c)本明細書に記載の方法における、(a)抗PD−1抗体または抗PD−L1抗体および(b)抗CTLA−4抗体の使用のための指示書、が含まれる。
実施例1:非小細胞肺癌の高腫瘍変異負荷におけるニボルマブ+イピリムマブの併用
ニボルマブ+イピリムマブは、第1相NSCLC治験において有望な有効性を示し、腫瘍遺伝子変異量(TMB)が可能性のある有益なバイオマーカーとして浮上している。本治験は、バイオマーカーで選択されたNSCLC集団における、第1選択薬(first-line)ニボルマブおよびニボルマブをベースとした併用剤の非盲検マルチパートの第3相臨床治験である。本発明者らは、高TMB(1メガベース当たり10個以上の変異)の患者における、ニボルマブ+イピリムマブ併用療法と化学療法との無増悪生存期間(PFS)の主要(co-primary)エンドポイントに関するパート1の結果を報告する。本治験は、PD−L1選択患者における全生存期間の主要エンドポイントについても継続される。
登録前6月以内に得られた新鮮なまたは保存された(archival)腫瘍バイオプシー標本(患者が何らかの全身抗がん療法を受けていない場合)を、抗PD−L1抗体(28−8抗体)を用いて中央検査部でPD−L1の検査を行った(Hanna, N., et al. J Oncol Pract 13:832-7 (2017))。
本治験は、異なる患者集団を対象に、異なるニボルマブをベースとしたレジメンと化学療法とを比較評価するために設計されたマルチパートの第3相治験である。腫瘍PD−L1発現率が1%以上の患者および1%未満の患者を、16カ月間、同一施設で同時に登録した(図2)。PD−L1発現率が1%以上の患者を、腫瘍組織(扁平上皮型 対 非扁平上皮型NSCLC)により(i)2週間毎にニボルマブ3mg/kgと、6週間毎にイピリムマブ1mg/kgを投与する群、(ii)組織学的根拠に基づくプラチナ製剤を3週間毎に最大4サイクルまで投与する群、または(iii)ニボルマブ240mgを2週間毎に投与する群に、無作為に層別化した(1:1:1)。PD−L1発現率が1%未満の患者を、腫瘍組織により(i)2週間毎にニボルマブ3mg/kgと、6週間毎にイピリムマブ1mg/kgを投与する群、(ii)組織学的根拠に基づくプラチナ製剤を3週間毎に最大4サイクルまで投与する群、または(iii)ニボルマブ360mgと組織学的根拠に基づくプラチナ製剤を3週間毎に最大4サイクルまで投与する群投与する群に、無作為に層別化した(1:1:1)。4サイクルの化学療法またはニボルマブによる化学療法後に安定した疾患、または奏効している非扁平上皮NSCLC患者は、ペメトレキセドまたはペメトレキセドとニボルマブを併用した維持療法を継続できた。すべての治療を、疾患の進行、許容できない毒性、またはプロトコール毎の完了まで継続した(免疫療法の場合は2年まで)。治験内の治療群間の入れ替え(クロスオーバー)は許容されなかった。
TMBを、324の遺伝子および選択的遺伝子再配列における置換、挿入および欠失(indels)、およびコピー数の変化を検出するために次世代シークエンシングを採用した、検証済みアッセイFOUNDATIONONE(登録商標) CDX(商標)を用いて、保存されたまたは新鮮なホルマリン固定パラフィン包埋腫瘍サンプルにおいて評価した(Ettinger, D.S., et al. J Natl Compr Canc Netw, 15:504-35 (2017))。独立した報告が、全エクソームシークエンシング(WES)から推定されたTMBと、標的化次世代シークエンシング(NGS)から推定されたTMBとの間の一致を実証している。Szustakowski J., et al. Evaluation of tumor mutation burden as a biomarker for immune checkpoint inihibitor efficacy: A calibration study of whole exome sequencing with FoundationOne(登録商標). Presented at the American Association for Caner Research 2018 Annual Meeting; 2018; Chicago, Illinois; Zehir A, et al. Nat Med 2017;23:703-713; Rizvi H., et al., J Clin Oncol 2018;36:633-41参照。TMBを、以前に定義された方法に従って計算した。Reck, M., et al., N Engl J Med, 375:1823-33 (2016)。要約すると、TMBは、検査したゲノムの1メガベースあたりの体細胞、コーディング、塩基置換および短いインデルの数として定義された。同義変異を含む標的遺伝子のコーディング領域におけるすべての塩基置換およびインデル(indels)は、COSMICによる発癌性ドライバー事象ならびにdbSNPおよびExACデータベースに従った生殖細胞の状態の両方について、Foundation Medicine臨床コホートでまとめられた稀な生殖細胞事象のプライベートデータベースに加えて、フィルタリングされた。SGZ(体細胞−生殖細胞−接合度)ツールを用いた生殖細胞の状態の計算上の評価に基づく追加のフィルタリングも行われた。Aguiar, P.N., et al., ESMO Open, 2:e000200 (2017)。
本治験のパート1では、2つの主要エンドポイントが設定された。1つ目の主要エンドポイントは、TMBを選択した患者集団において、ニボルマブ+イピリムマブ 対 化学療法による盲検化された独立した中央評価により評価された無増悪生存期間(PFS)であった。これまでの知見(Ramalingam SS, et al. Tumor mutation burden(TMB)as a biomarker for clinical benefit from dual immune checkpoint blockade with nivolumab (nivo) + ipilimumab (ipi) in first-line (1L) non-small cell lung cancer (NSCLC): identification of TMB cutoff from CheckMate 568. Presented at the American Association for Cancer Research 2018 Annual Meeting; 2018; Chicago, Illinois.)に基づき、主要エンドポイントの予め計画された解析のために、≧10個の変異/Mbの予め定義されたTMBカットオフが選択された。2つ目の主要エンドポイントは、PD−L1で選択された患者集団におけるニボルマブ+イピリムマブ 対 化学療法による全生存期間(OS)であった。
無作為化されたすべての患者(PD−L1発現の有無にかかわらず)において、ニボルマブ+イピリムマブ 対 化学療法でPFSが改善し(ハザード比[HR]、0.83;95%、0.72〜0.96)、1年PFS率は31% 対 17%であった。PFS中央値は、ニボルマブ+イピリムマブで4.9ヵ月(95%CI、4.1〜5.6)、化学療法で5.5ヵ月(95%CI、4.6〜5.6)であった。ニボルマブ+イピリムマブ 対 化学療法でも同様の利益がTMB評価対象患者で認められ(HR、0.82;95%CI、0.68〜0.99)、1年PFS率は32% 対 15%であった。PFS中央値はそれぞれ、4.9ヵ月(95%CI、3.7〜5.7)および5.5ヵ月(95%CI、4.6〜5.6)であった。図4Aおよび4Bを参照のこと。
高TMB(≧10変異/Mb)患者における主要エンドポイントの解析は、ニボルマブ+イピリムマブ 対 化学療法でPFSの有意な改善を示し(HR、0.58;97.5%CI、0.41〜0.81;P=0.0002)、1年PFS率は43% 対 13%(化学療法)であり、PFS中央値はそれぞれ7.2カ月(95%CI、5.5〜13.2)および5.5カ月(95%CI、4.4〜5.8)であった。図4A参照。TMB≧10変異/Mbの患者におけるPFSの予めに指定された多変量解析において、ベースラインPD−L1発現レベル(≧1%、<1%)、性別、腫瘍組織学(扁平上皮、非扁平上皮)およびECOG PS(0、≧1)を調整したニボルマブ+イピリムマブ 対 化学療法の治療効果は、一次PFS解析と一致していた(HR、0.57;95%CI、0.40〜0.80、多変量CoxモデルP=0.0002)。TMB<10変異/Mbの患者では、ニボルマブ+イピリムマブ 対 化学療法でPFSの改善は観察されなかった(HR、1.07;95%CI、0.84〜1.35);PFS中央値は、ニボルマブ+イピリムマブで3.2ヵ月(95%CI、2.7〜4.3)、化学療法で5.5ヵ月(95%CI、4.3〜5.6)であった。図5参照。
PD−L1状態別のサブグループ解析では、PD−L1発現量が1%以上の患者と1%未満の患者では、ニボルマブ+イピリムマブの併用で化学療法と比較してPFSが改善したことが示された。図6Aおよび6B参照。扁平上皮および非扁平上皮腫瘍組織型の両方の患者において、ニボルマブ+イピリムマブの併用は化学療法と比較して改善されたPFSが認められた。図6Cおよび6D参照。TMB≧10変異/Mbを有する患者の大部分の他のサブグループにおいて、ニボルマブ+イピリムマブの併用で化学療法と比較してPFSが改善された。図6E参照。
治験の副次エンドポイントは、TMB≧13変異/MbおよびPD−L1発現率1%以上の患者(PD−L1発現率1%未満の患者はニボルマブ投与を受ける資格がない)におけるニボルマブ(n=79)と化学療法(n=71)の有効性であった。この患者群では、ニボルマブによるPFSの改善は認められなかった(HR、0.95;97.5%CI、0.61、1.48;P=0.7776)。PFS中央値はニボルマブで4.2ヵ月(95%CI、2.7〜8.3)、化学療法で5.6ヵ月(95%CI、4.5〜7.0)であった。図7参照。
ニボルマブ処置またはニボルマブ+イピリムマブ併用処置は、治験責任医師により評価された臨床的有用性を有し、処置に忍容性が継続している場合には、進行後も継続して投与することが認められた。患者は、治験薬処置中止後、3ヵ月ごとに対面または電話での連絡により、全生存期間を追跡された。
本発明者らは、PD−L1発現が1%未満の患者における、化学療法に対するニボルマブ+イピリムマブ併用およびニボルマブ+化学療法の有効性および安全性を主要エンドポイントとした実施例1の第3相治験の結果を報告する。最近の研究では、化学療法に抗PD−(L)1療法を追加することで、化学療法単独に比べて結果が改善することが示されている。しかし、PD−L1発現が1%未満の非扁平上皮NSCLC患者(PFS HR:0.75および0.77)では、あまり有益性がなかったことが観察された。
ニボルマブ+化学療法を受けた腫瘍PD−L1発現が1%未満の患者では、1年無増悪生存率(PFS)が26%であったのに対し、化学療法単独の患者では1年PFS率は14%であった(図9A)。ニボルマブ+化学療法で処置された患者の奏効率は、化学療法単独で処置された患者では23.1%であったのに対して、36.7%であった(図9B)。ニボルマブ+化学療法で処置された患者の奏効期間(DOR)は、化学療法単独で処置された患者で約24%であったのに対し、1年では約28%であった(図9C)。さらに、ニボルマブ+イピリムマブで処置された患者のORRは約25.1%であり、DOR中央値は約17.97ヵ月であった(95%CI:12.2、NR)(データ示さず)。
処置関連有害事象(TRAE)を、表25および図11にまとめる。ニボルマブ+化学療法群では処置関連死が4例、ニボルマブ+イピリムマブ群では処置関連死が3例、化学療法群では処置関連死が6例であった。化学療法群における処置関連の有害事象は、ニボルマブ+化学療法群と同様であり、以前の報告と一致していた(図11)。
Claims (15)
- 非小細胞肺癌(NSCLC)に由来する腫瘍に罹患している対象の処置において、細胞傷害性Tリンパ球抗原−4(CTLA−4)に特異的に結合する抗体もしくはその抗原結合部分(“抗CTLA−4抗体”)と併用するための、プログラム細胞死−1(PD−1)受容体に特異的に結合し、PD−1活性を阻害する抗体もしくはその抗原結合部分(“抗PD−1抗体”)またはプログラム細胞死−リガンド1(PD−L1)に特異的に結合し、PD−1活性を阻害する抗体もしくはその抗原結合部分(“抗PD−L1抗体”)を含む組成物であって、ここで、該腫瘍が、検査された遺伝子の1メガベースあたり少なくとも約10個の変異の腫瘍遺伝子変異量(TMB)状態を有する、組成物。
- 投与前に対象から得られた生物学的サンプルのTMB状態が測定されることをさらに含む、請求項1記載の組成物。
- TMB状態が、腫瘍中の核酸を配列決定し、配列決定された核酸中のゲノム改変を同定することによって決定される、請求項1または2記載の組成物。
- ゲノム改変が、
(i)1以上の体細胞変異;
(ii)1以上の非同義変異;
(iii)1以上のミスセンス変異;
(iv)塩基対置換、塩基対挿入、塩基対欠失、コピー数変化(CNA)、遺伝子再配列およびそれらの組合せからなる群より選択される1以上の改変;または
(v)(i)から(iv)のいずれかの組合せ
を含む、請求項3記載の組成物。 - 腫瘍のTMB状態が、FOUNDATIONONE(登録商標) CDX(商標)アッセイによって測定した、検査されたゲノムの1メガベースあたり少なくとも約10個の変異、少なくとも約11個の変異、少なくとも約12個の変異、少なくとも約13個の変異、少なくとも約14個の変異、少なくとも約15個の変異、少なくとも約16個の変異、少なくとも約17個の変異、少なくとも約18個の変異、少なくとも約19個の変異、少なくとも約20個の変異、少なくとも約21個の変異、少なくとも約22個の変異、少なくとも約23個の変異、少なくとも約24個の変異、少なくとも約25個の変異、少なくとも約26個の変異、少なくとも約27個の変異、少なくとも約28個の変異、少なくとも約29個の変異または少なくとも約30個の変異を含む、請求項1から4のいずれか一項記載の組成物。
- 生物学的サンプルが、腫瘍組織生検、液体生検、血液、血清、血漿、exoRNA、循環腫瘍細胞、ctDNA、cfDNAまたはそれらの何れかの組合せを含む、請求項2から5のいずれか一項記載の組成物。
- TMB状態が、
(i)ゲノムシークエンシング、
(ii)エクソームシークエンシング、
(iii)ゲノムプロファイリング、または
(iv)(i)から(iii)のいずれかの組み合わせ
により決定される、請求項1から6のいずれか一項記載の組成物。 - ゲノムプロファイルが、ABL1、BRAF、CHEK1、FANCC、GATA3、JAK2、MITF、PDCD1LG2(PD−L2)、RBM10、STAT4、ABL2、BRCA1、CHEK2、FANCD2、GATA4、JAK3、MLH1、PDGFRA、RET、STK11、ACVR1B、BRCA2、CIC、FANCE、GATA6、JUN、MPL、PDGFRB、RICTOR、SUFU、AKT1、BRD4、CREBBP、FANCF、GID4(C17orf 39)、KAT6A(MYST3)、MRE11A、PDK1、RNF43、SYK、AKT2、BRIP1、CRKL、FANCG、GLl1、KDM5A、MSH2、PIK3C2B、ROS1、TAF1、AKT3、BTG1、CRLF2、FANCL、GNA11、KDM5C、MSH6、PIK3CA、RPTOR、TBX3、ALK、BTK、CSF1R、FAS、GNA13、KDM6A、MTOR、PIK3CB、RUNX1、TERC、AMER1(FAM123B)、C11orf30(EMSY)、CTCF、FAT1、GNAQ、KDR、MUTYH、PIK3CG、RUNX1T1、TERT(プロモーターのみ)、APC、CARD11、CTNNA1、FBXW7、GNAS、KEAP1、MYC、PIK3R1、SDHA、TET2、AR、CBFB、CTNN B1、FGF10、GPR124、KEL、MYCL(MYC L1)、PIK3R2、SDHB、TGFBR2、ARAF、CBL、CUL3、FGF14、GRIN2A、KIT、MYCN、PLCG2、SDHC、TNFAIP3、ARFRP1、CCND1、CYLD、FGF19、GRM3、KLHL6、MYD88、PMS2、SDHD、TNFRSF14、ARID1A、CCND2、DAXX、FGF23、GSK3B、KMT2A(MLL)、NF1、POLD1、SETD2、TOP1、ARID1B、CCND3、DDR2、FGF3、H3F3A、KMT2C(MLL3)、NF2、POLE、SF3B1、TOP2A、ARID2、CCNE1、DICER1、FGF4、HGF、KMT2D(MLL2)、NFE2L2、PPP2R1A、SLIT2、TP53、ASXL1、CD274(PD−L1)、DNMT3A、FGF6、HNF1A、KRAS、NFKBIA、PRDM1、SMAD2、TSC1、ATM、CD79A、DOT1L、FGFR1、HRAS、LMO1、NKX2−1、PREX2、SMAD3、TSC2、ATR、CD79B、EGFR、FGFR2、HSD3B1、LRP1B、NOTCH1、PRKAR1A、SMAD4、TSHR、ATRX、CDC73、EP300、FGFR3、HSP90AA1、LYN、NOTCH2、PRKCI、SMARCA4、U2AF1、AURKA、CDH1、EPHA3、FGFR4、IDH1、LZTR1、NOTCH3、PRKDC、SMARCB1、VEGFA、AURKB、CDK12、EPHA5、FH、IDH2、MAGI2、NPM1、PRSS8、SMO、VHL、AXIN1、CDK4、EPHA7、FLCN、IGF1R、MAP2K1(MEK1)、NRAS、PTCH1、SNCAIP、WISP3、AXL、CDK6、EPHB1、FLT1、IGF2、MAP2K2(MEK2)、NSD1、PTEN、SOCS1、WT1、BAP1、CDK8、ERBB2、FLT3、IKBKE、MAP2K4、NTRK1、PTPN11、SOX10、XPO1、BARD1、CDKN1A、ERBB3、FLT4、IKZF1、MAP3K1、NTRK2、QKI、SOX2、ZBTB2、BCL2、CDKN1B、ERBB4、FOXL2、IL7R、MCL1、NTRK3、RAC1、SOX9、ZNF217、BCL2L1、CDKN2A、ERG、FOXP1、INHBA、MDM2、NUP93、RAD50、SPEN、ZNF703、BCL2L2、CDKN2B、ERRFl1、FRS2、INPP4B、MDM4、PAK3、RAD51、SPOP、BCL6、CDKN2C、ESR1、FUBP1、IRF2、MED12、PALB2、RAF1、SPTA1、BCOR、CEBPA、EZH2、GABRA6、IRF4、MEF2B、PARK2、RANBP2、SRC、BCORL1、CHD2、FAM46C、GATA1、IRS2、MEN1、PAX5、RARA、STAG2、BLM、CHD4、FANCA、GATA2、JAK1、MET、PBRM1、RB1、STAT3およびそれらの組合せからなる群より選択される1以上の遺伝子を含む、請求項7記載の組成物。
- TMB状態がFOUNDATIONONE(登録商標) CDX(商標)アッセイによって測定される、請求項1から8のいずれか一項記載の組成物。
- ETV4、TMPRSS2、ETV5、BCR、ETV1、ETV6およびMYBの1以上のゲノム改変が同定されることをさらに含む、請求項1から9のいずれか一項記載の組成物。
- (a)抗PD−1抗体が、2、3または4週間毎に1回、体重1kgあたり0.1mgから20.0mgの範囲の体重ベースの用量で投与されるか、または少なくとも約200mg、少なくとも約220mg、少なくとも約240mg、少なくとも約260mg、少なくとも約280mg、少なくとも約300mg、少なくとも約320mg、少なくとも約340mg、少なくとも約360mg、少なくとも約380mg、少なくとも約400mg、少なくとも約420mg、少なくとも約440mg、少なくとも約460mg、少なくとも約480mg、少なくとも約500mgもしくは少なくとも約550mgの一定用量で投与される;あるいは
(b)抗PD−L1抗体が、2、3または4週間毎に1回、体重1kgあたり0.1mgから20.0mgの範囲の体重ベースの用量で投与されるか、または少なくとも約240mg、少なくとも約300mg、少なくとも約320mg、少なくとも約400mg、少なくとも約480mg、少なくとも約500mg、少なくとも約560mg、少なくとも約600mg、少なくとも約640mg、少なくとも約700mg、少なくとも約720mg、少なくとも約800mg、少なくとも約880mg、少なくとも約900mg、少なくとも約960mg、少なくとも約1000mg、少なくとも約1040mg、少なくとも約1100mg、少なくとも約1120mg、少なくとも約1200mg、少なくとも約1280mg、少なくとも約1300mg、少なくとも約1360mgもしくは少なくとも約1400mgの一定用量で投与される、
請求項1から10のいずれか一項記載の組成物。 - (a)抗PD-1抗体が、
(i)3週間毎に1回、体重1kgあたり2mgの用量で投与される;
(ii)2週間毎に1回、体重1kgあたり3mgの用量で投与される;
(iii)2週間毎に1回、約200mgの一定用量で投与される;
(iv)2週間毎に1回、約240mgの一定用量で投与される;または
(v)4週間毎に1回、約480mgの一定用量で投与される;あるいは
(b)抗PD−L1抗体が、
(i)3週間に1回、体重1kgあたり15mgの用量で投与される;
(ii)2週間毎に1回、体重1kgあたり10mgの用量で投与される;
(iii)3週間毎に1回、約1200mgの一定用量で投与される;または
(iv)2週間毎に1回、約800mgの一定用量で投与される、
請求項1から11のいずれか一項記載の組成物。 - 抗CTLA−4抗体が、2週間毎、3週間毎、4週間毎、5週間毎、6週間毎、7週間毎または8週間毎に1回、体重1kgあたり0.1mgから20.0mgの範囲の体重ベースの用量で投与されるか、または少なくとも約40mg、少なくとも約50mg、少なくとも約60mg、少なくとも約70mg、少なくとも約80mg、少なくとも約90mg、少なくとも約100mg、少なくとも約110mg、少なくとも約120mg、少なくとも約130mg、少なくとも約140mg、少なくとも約150mg、少なくとも約160mg、少なくとも約170mg、少なくとも約180mg、少なくとも約190mgもしくは少なくとも約200mgの一定用量で投与される、
請求項1から12のいずれか一項記載の組成物。 - 抗CTLA−4抗体が、
(i)6週間毎に1回、体重1kgあたり1mgの用量で投与される;
(ii)4週間毎に1回、体重1kgあたり1mgの用量で投与される;または
(iii)少なくとも約80mgの一定用量で投与される、
請求項1から13のいずれか一項記載の組成物。 - 該腫瘍が1%未満のPD−L1を有する、請求項1から14のいずれか一項記載の組成物。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862650845P | 2018-03-30 | 2018-03-30 | |
US62/650,845 | 2018-03-30 | ||
US201862671906P | 2018-05-15 | 2018-05-15 | |
US62/671,906 | 2018-05-15 | ||
PCT/US2019/024987 WO2019191676A1 (en) | 2018-03-30 | 2019-03-29 | Methods of treating tumor |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2021519771A true JP2021519771A (ja) | 2021-08-12 |
Family
ID=66484121
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020552752A Pending JP2021519771A (ja) | 2018-03-30 | 2019-03-29 | 腫瘍を処置する方法 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20210032344A1 (ja) |
EP (1) | EP3774911A1 (ja) |
JP (1) | JP2021519771A (ja) |
KR (1) | KR20200139724A (ja) |
CN (1) | CN111971306A (ja) |
WO (1) | WO2019191676A1 (ja) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP7173993B2 (ja) | 2017-05-19 | 2022-11-17 | ウーシー バイオロジクス(シャンハイ)カンパニー リミテッド | 細胞傷害性tリンパ球関連タンパク質4(ctla-4)に対する新規モノクローナル抗体 |
WO2019075468A1 (en) | 2017-10-15 | 2019-04-18 | Bristol-Myers Squibb Company | TUMOR TREATMENT METHODS |
CN111886256A (zh) * | 2018-03-23 | 2020-11-03 | 百时美施贵宝公司 | 抗mica和/或micb抗体及其用途 |
EP3870609A1 (en) * | 2018-10-23 | 2021-09-01 | Bristol-Myers Squibb Company | Methods of treating tumor |
KR20210146349A (ko) * | 2019-03-28 | 2021-12-03 | 브리스톨-마이어스 스큅 컴퍼니 | 종양을 치료하는 방법 |
KR102428408B1 (ko) * | 2019-10-31 | 2022-08-03 | 지니너스 주식회사 | 수정된 tmb를 포함하는 면역항암치료의 예후 예측 방법 |
WO2021092221A1 (en) * | 2019-11-06 | 2021-05-14 | Bristol-Myers Squibb Company | Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy |
CN110923329B (zh) * | 2020-02-06 | 2020-05-12 | 至本医疗科技(上海)有限公司 | Fgfr4点突变在预测非小细胞肺癌患者对免疫检查点抑制剂疗法敏感性中的应用 |
CN112921091B (zh) * | 2021-03-16 | 2022-01-21 | 南京先声医学检验实验室有限公司 | Flt3基因突变在预测非小细胞肺癌患者对免疫检查点抑制剂疗法敏感性中的应用 |
CN113481299B (zh) * | 2021-06-30 | 2022-05-10 | 苏州京脉生物科技有限公司 | 用于肺癌检测的靶向测序panel、试剂盒及获得靶向测序panel的方法 |
EP4310197A1 (en) | 2022-07-21 | 2024-01-24 | Fundación para la Investigación Biomédica del Hospital Universitario Puerta de Hierro Majadahonda | Method for identifying lung cancer patients for a combination treatment of immuno- and chemotherapy |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017087870A1 (en) * | 2015-11-18 | 2017-05-26 | Bristol-Myers Squibb Company | Treatment of lung cancer using a combination of an anti-pd-1 antibody and an anti-ctla-4 antibody |
Family Cites Families (87)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6355476B1 (en) | 1988-11-07 | 2002-03-12 | Advanced Research And Technologyinc | Nucleic acid encoding MIP-1α Lymphokine |
US6362325B1 (en) | 1988-11-07 | 2002-03-26 | Advanced Research And Technology Institute, Inc. | Murine 4-1BB gene |
US6303121B1 (en) | 1992-07-30 | 2001-10-16 | Advanced Research And Technology | Method of using human receptor protein 4-1BB |
JP4124480B2 (ja) | 1991-06-14 | 2008-07-23 | ジェネンテック・インコーポレーテッド | 免疫グロブリン変異体 |
US5851795A (en) | 1991-06-27 | 1998-12-22 | Bristol-Myers Squibb Company | Soluble CTLA4 molecules and uses thereof |
US6051227A (en) | 1995-07-25 | 2000-04-18 | The Regents Of The University Of California, Office Of Technology Transfer | Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling |
CN1232402A (zh) | 1996-10-11 | 1999-10-20 | 布里斯托尔-迈尔斯斯奎布公司 | 免疫调节的方法和组合物 |
KR100849443B1 (ko) | 1998-12-23 | 2008-07-31 | 화이자 인크. | Ctla-4에 대한 인간 단일클론 항체 |
EE05627B1 (et) | 1998-12-23 | 2013-02-15 | Pfizer Inc. | CTLA-4 vastased inimese monoklonaalsed antikehad |
PT2283867E (pt) | 1999-06-25 | 2014-08-29 | Immunogen Inc | Métodos de tratamento usando conjugados de anticorpo antierbb- maitansinóide |
ES2539411T3 (es) | 1999-08-23 | 2015-06-30 | Dana-Farber Cancer Institute, Inc. | PD-1, receptor para la B7-4 y su utilización |
CN1371416B (zh) | 1999-08-24 | 2012-10-10 | 梅达里克斯公司 | 人ctla-4抗体及其应用 |
JP2003520828A (ja) | 2000-01-27 | 2003-07-08 | ジェネティクス インスティテュート,エルエルシー | Ctla4(cd152)に対する抗体、これを含む結合体、およびその使用 |
PL375144A1 (en) | 2002-07-30 | 2005-11-28 | Bristol-Myers Squibb Company | Humanized antibodies against human 4-1bb |
CN101899114A (zh) | 2002-12-23 | 2010-12-01 | 惠氏公司 | 抗pd-1抗体及其用途 |
MXPA05009429A (es) | 2003-03-05 | 2005-12-12 | Halozyme Inc | Glicoproteina hialuronidasa soluble (shasegp), proceso para preparar la misma, usos y composiciones farmaceuticas que la comprenden. |
KR101420344B1 (ko) | 2003-07-02 | 2014-07-16 | 위니베르시따 디 제노바 | Pan-kir2dl nk-수용체 항체 및 진단 및 치료에서의 그 사용 방법 |
EP2292264A3 (en) | 2003-07-24 | 2012-12-19 | Innate Pharma | Methods and compositions for increasing the efficiency of therapeutic antibodies using NK cell potentiating compounds |
US7288638B2 (en) | 2003-10-10 | 2007-10-30 | Bristol-Myers Squibb Company | Fully human antibodies against human 4-1BB |
CA2601417C (en) | 2004-07-01 | 2018-10-30 | Novo Nordisk A/S | Human anti-kir antibodies |
CN104829720B (zh) | 2005-01-06 | 2019-01-01 | 诺和诺德公司 | Kir结合剂和使用其的方法 |
WO2006072625A2 (en) | 2005-01-06 | 2006-07-13 | Novo Nordisk A/S | Anti-kir combination treatments and methods |
ES2657443T3 (es) | 2005-03-25 | 2018-03-05 | Gitr, Inc. | Anticuerpos anti-GITR y usos de los mismos |
PL2439273T3 (pl) | 2005-05-09 | 2019-08-30 | Ono Pharmaceutical Co., Ltd. | Ludzkie przeciwciała monoklonalne przeciwko białku programowanej śmierci komórki 1(pd-1) oraz metody leczenia nowotworów z wykorzystaniem przeciwciał anty-pd-1 samodzielnie lub w połączeniu z innymi immunoterapeutykami |
RS54271B1 (en) | 2005-07-01 | 2016-02-29 | E. R. Squibb & Sons, L.L.C. | HUMAN MONOCLONIC ANTIBODIES FOR LIGAND PROGRAMMED DEATH 1 (PD-L1) |
CN101300272B (zh) | 2005-10-14 | 2013-09-18 | 依奈特制药公司 | 用于治疗增生性病症的组合物和方法 |
WO2007113648A2 (en) | 2006-04-05 | 2007-10-11 | Pfizer Products Inc. | Ctla4 antibody combination therapy |
AU2008204433B2 (en) | 2007-01-11 | 2014-03-13 | Novo Nordisk A/S | Anti-KIR antibodies, formulations, and uses thereof |
JP2008278814A (ja) | 2007-05-11 | 2008-11-20 | Igaku Seibutsugaku Kenkyusho:Kk | アゴニスティック抗ヒトgitr抗体による免疫制御の解除とその応用 |
EP2170959B1 (en) | 2007-06-18 | 2013-10-02 | Merck Sharp & Dohme B.V. | Antibodies to human programmed death receptor pd-1 |
ES2776406T3 (es) | 2007-07-12 | 2020-07-30 | Gitr Inc | Terapias de combinación que emplean moléculas de enlazamiento a GITR |
DK2195017T3 (en) | 2007-10-01 | 2015-01-19 | Bristol Myers Squibb Co | Human antibodies that bind mesothelin, and uses thereof |
CN101951959A (zh) | 2007-11-30 | 2011-01-19 | 百时美施贵宝公司 | 抗b7h4单克隆抗体-药物缀合物和使用方法 |
EP2262837A4 (en) | 2008-03-12 | 2011-04-06 | Merck Sharp & Dohme | PD-1 BINDING PROTEINS |
AR072999A1 (es) | 2008-08-11 | 2010-10-06 | Medarex Inc | Anticuerpos humanos que se unen al gen 3 de activacion linfocitaria (lag-3) y los usos de estos |
EP2367553B1 (en) | 2008-12-05 | 2017-05-03 | Novo Nordisk A/S | Combination therapy to enhance nk cell mediated cytotoxicity |
CN114835812A (zh) | 2008-12-09 | 2022-08-02 | 霍夫曼-拉罗奇有限公司 | 抗-pd-l1抗体及它们用于增强t细胞功能的用途 |
IN2012DN01920A (ja) | 2009-09-03 | 2015-07-24 | Schering Corp | |
LT3279215T (lt) | 2009-11-24 | 2020-04-10 | Medimmune Limited | Tiksliniai surišantys agentai prieš b7-h1 |
US9169325B2 (en) | 2010-04-13 | 2015-10-27 | Celldex Therapeutics, Inc. | Antibodies that bind human CD27 and uses thereof |
WO2012071411A2 (en) | 2010-11-22 | 2012-05-31 | Innate Pharma Sa | Nk cell modulating treatments and methods for treatment of hematological malignancies |
MX360254B (es) | 2011-03-10 | 2018-10-26 | Pfizer | Combinacion de terapias inmunomoduladoras local y sistemica para tratamiento mejorado del cancer. |
DK2699264T3 (en) | 2011-04-20 | 2018-06-25 | Medimmune Llc | ANTIBODIES AND OTHER MOLECULES BINDING B7-H1 AND PD-1 |
AU2012260601B2 (en) | 2011-05-25 | 2018-02-01 | Innate Pharma, S.A. | Anti-KIR antibodies for the treatment of inflammatory disorders |
WO2013039954A1 (en) | 2011-09-14 | 2013-03-21 | Sanofi | Anti-gitr antibodies |
PE20142361A1 (es) | 2011-09-30 | 2015-01-16 | Dana Farber Cancer Inst Inc | Peptidos terapeuticos |
US10428151B2 (en) | 2011-11-09 | 2019-10-01 | Bristol-Myers Squibb Company | Treatment of hematologic malignancies with an anti-CXCR4 antibody |
CN103987405B (zh) | 2011-11-28 | 2017-03-29 | 默克专利股份公司 | 抗pd‑l1抗体及其用途 |
SG11201407190TA (en) | 2012-05-15 | 2014-12-30 | Bristol Myers Squibb Co | Cancer immunotherapy by disrupting pd-1/pd-l1 signaling |
EP3553086A1 (en) | 2012-05-31 | 2019-10-16 | Sorrento Therapeutics Inc. | Antigen binding proteins that bind pd-l1 |
KR101549637B1 (ko) | 2012-06-08 | 2015-09-03 | 국립암센터 | 신규한 Th1 세포 전환용 에피토프 및 이의 용도 |
AR091649A1 (es) | 2012-07-02 | 2015-02-18 | Bristol Myers Squibb Co | Optimizacion de anticuerpos que se fijan al gen de activacion de linfocitos 3 (lag-3) y sus usos |
SI2904011T1 (sl) | 2012-10-02 | 2017-10-30 | Bristol-Myers Squibb Company | Kombinacija anti-kir protiteles in anti-pd-1 protiteles za zdravljenje raka |
BR112015021576A2 (pt) | 2013-03-15 | 2017-10-10 | Dana Farber Cancer Inst Inc | peptídeos terapêuticos |
LT2992017T (lt) | 2013-05-02 | 2021-02-25 | Anaptysbio, Inc. | Antikūnai nukreipti prieš programuotos žūties baltymą-1 (pd-1) |
WO2014194302A2 (en) | 2013-05-31 | 2014-12-04 | Sorrento Therapeutics, Inc. | Antigen binding proteins that bind pd-1 |
CN104250302B (zh) | 2013-06-26 | 2017-11-14 | 上海君实生物医药科技股份有限公司 | 抗pd‑1抗体及其应用 |
AR097306A1 (es) | 2013-08-20 | 2016-03-02 | Merck Sharp & Dohme | Modulación de la inmunidad tumoral |
TW201605896A (zh) | 2013-08-30 | 2016-02-16 | 安美基股份有限公司 | Gitr抗原結合蛋白 |
CN112552401B (zh) | 2013-09-13 | 2023-08-25 | 广州百济神州生物制药有限公司 | 抗pd1抗体及其作为治疗剂与诊断剂的用途 |
RS64268B1 (sr) | 2013-09-20 | 2023-07-31 | Bristol Myers Squibb Co | Kombinacija anti-lag-3 antitela i anti-pd-1 antitela za lečenje tumora |
CA2932767A1 (en) | 2013-12-06 | 2015-06-11 | Dana-Farber Cancer Institute, Inc. | Therapeutic peptides |
ME03527B (me) | 2013-12-12 | 2020-04-20 | Shanghai hengrui pharmaceutical co ltd | Pd-1 antitijelo, njegov fragment koji se vezuje na antigen, i njegova medicinska primjena |
TWI681969B (zh) | 2014-01-23 | 2020-01-11 | 美商再生元醫藥公司 | 針對pd-1的人類抗體 |
JOP20200094A1 (ar) | 2014-01-24 | 2017-06-16 | Dana Farber Cancer Inst Inc | جزيئات جسم مضاد لـ pd-1 واستخداماتها |
IL249092B (en) | 2014-05-28 | 2022-07-01 | Agenus Inc | Anti-gitr antibodies and methods of using them |
IL251464B2 (en) * | 2014-10-29 | 2023-03-01 | Five Prime Therapeutics Inc | Combination therapy for cancer |
MX2017007390A (es) * | 2014-12-16 | 2017-11-06 | Bristol Myers Squibb Co | Uso de inhibidores de punto de control inmunitario en neoplasmas de sistemas nerviosos centrales. |
US10239942B2 (en) | 2014-12-22 | 2019-03-26 | Pd-1 Acquisition Group, Llc | Anti-PD-1 antibodies |
EP3268392A2 (en) | 2015-03-13 | 2018-01-17 | CytomX Therapeutics, Inc. | Anti-pdl1 antibodies, activatable anti-pdl1 antibodies, and methods of use thereof |
SG10201913500TA (en) | 2015-05-29 | 2020-03-30 | Agenus Inc | Anti-ctla-4 antibodies and methods of use thereof |
WO2016197367A1 (en) | 2015-06-11 | 2016-12-15 | Wuxi Biologics (Shanghai) Co. Ltd. | Novel anti-pd-l1 antibodies |
EP3858859A1 (en) * | 2015-07-14 | 2021-08-04 | Bristol-Myers Squibb Company | Method of treating cancer using immune checkpoint inhibitor; antibody that binds to programmed death-1 receptor (pd-1) or programmed death ligand 1 (pd-l1) |
HRP20211645T1 (hr) | 2015-07-30 | 2022-02-04 | Macrogenics, Inc. | Molekule za vezanje pd-1 i postupci za njihovu uporabu |
WO2017020291A1 (en) | 2015-08-06 | 2017-02-09 | Wuxi Biologics (Shanghai) Co. Ltd. | Novel anti-pd-l1 antibodies |
WO2017024465A1 (en) | 2015-08-10 | 2017-02-16 | Innovent Biologics (Suzhou) Co., Ltd. | Pd-1 antibodies |
BR112018002824A2 (pt) | 2015-08-11 | 2018-11-06 | Open Monoclonal Tech Inc | anticorpo, polinucleotídeo, vetor, célula, métodos para expressar o anticorpo, para tratar uma condição associada com pd-1 e para tratar uma condição em um sujeito, kit, composição farmacêutica e uso do anticorpo |
WO2017024515A1 (en) | 2015-08-11 | 2017-02-16 | Wuxi Biologics (Cayman) Inc. | Novel anti-pd-1 antibodies |
AR105654A1 (es) | 2015-08-24 | 2017-10-25 | Lilly Co Eli | Anticuerpos pd-l1 (ligando 1 de muerte celular programada) |
PE20181322A1 (es) | 2015-09-01 | 2018-08-14 | Agenus Inc | Anticuerpo anti-pd1 y sus metodos de uso |
BR112018011781A2 (pt) | 2015-12-14 | 2018-12-04 | Macrogenics Inc | molécula biespecífica possuindo um ou mais sítios de ligação a epítopo capazes de ligação imunoespecífica a (um) epítopo(s) de pd-1 e um ou mais sítios de ligação a epítopo capazes de ligação imunoespecífica a (um) epítopo(s) de ctla-4, e composição farmacêutica |
AU2017207282A1 (en) | 2016-01-11 | 2018-07-05 | Armo Biosciences, Inc. | Interleukin-10 in production of antigen-specific CD8+ T cells and methods of use of same |
US20210206854A1 (en) * | 2016-01-27 | 2021-07-08 | Bristol-Myers Squibb Company | Treatment of lung cancer using a combination of an anti-pd-1 antibody and another anti-cancer agent |
WO2017132827A1 (en) | 2016-02-02 | 2017-08-10 | Innovent Biologics (Suzhou) Co., Ltd. | Pd-1 antibodies |
WO2017132825A1 (zh) | 2016-02-02 | 2017-08-10 | 华为技术有限公司 | 确定发射功率的方法、用户设备和基站 |
PE20190418A1 (es) | 2016-07-14 | 2019-03-19 | Bristol Myers Squibb Co | Anticuerpos contra proteina 3 que contiene el dominio de mucina e inmunoglobulina de linfocitos t (tim3) y sus usos |
WO2018183928A1 (en) * | 2017-03-31 | 2018-10-04 | Bristol-Myers Squibb Company | Methods of treating tumor |
-
2019
- 2019-03-29 CN CN201980023876.9A patent/CN111971306A/zh active Pending
- 2019-03-29 EP EP19723525.2A patent/EP3774911A1/en active Pending
- 2019-03-29 JP JP2020552752A patent/JP2021519771A/ja active Pending
- 2019-03-29 US US17/044,163 patent/US20210032344A1/en not_active Abandoned
- 2019-03-29 WO PCT/US2019/024987 patent/WO2019191676A1/en active Application Filing
- 2019-03-29 KR KR1020207030899A patent/KR20200139724A/ko unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017087870A1 (en) * | 2015-11-18 | 2017-05-26 | Bristol-Myers Squibb Company | Treatment of lung cancer using a combination of an anti-pd-1 antibody and an anti-ctla-4 antibody |
Non-Patent Citations (2)
Title |
---|
"FDA Approves Foundation Medicine's FoundationOne CDxtm, the First and Only Comprehensive Genomic Pro", BUSINESSWIRE, JPN6023002133, 30 November 2017 (2017-11-30), ISSN: 0004971155 * |
JOURNAL OF CLINICAL ONCOLOGY, vol. 36, no. 7, JPN6023002134, 16 January 2018 (2018-01-16), pages 633 - 641, ISSN: 0004971154 * |
Also Published As
Publication number | Publication date |
---|---|
US20210032344A1 (en) | 2021-02-04 |
CN111971306A (zh) | 2020-11-20 |
WO2019191676A1 (en) | 2019-10-03 |
EP3774911A1 (en) | 2021-02-17 |
KR20200139724A (ko) | 2020-12-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7458188B2 (ja) | 腫瘍を処置する方法 | |
US11919957B2 (en) | Methods of treating tumor | |
US20210032344A1 (en) | Methods of treating tumor | |
US20230279114A1 (en) | Methods of treating a tumor using an anti-pd-1 antibody | |
US20210380693A1 (en) | Methods of treating tumor | |
US20220195046A1 (en) | Methods of treating tumor | |
WO2021092221A1 (en) | Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy | |
US20240093303A1 (en) | Methods and biomarkers in cancer | |
WO2023196987A1 (en) | Methods of treating tumor | |
EA046134B1 (ru) | Способы лечения опухоли |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220328 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230124 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20230126 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230421 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230718 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20231017 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20240116 |