JP7399852B2 - 多重特異性抗体とその作製及び使用方法 - Google Patents
多重特異性抗体とその作製及び使用方法 Download PDFInfo
- Publication number
- JP7399852B2 JP7399852B2 JP2020520429A JP2020520429A JP7399852B2 JP 7399852 B2 JP7399852 B2 JP 7399852B2 JP 2020520429 A JP2020520429 A JP 2020520429A JP 2020520429 A JP2020520429 A JP 2020520429A JP 7399852 B2 JP7399852 B2 JP 7399852B2
- Authority
- JP
- Japan
- Prior art keywords
- seq
- amino acid
- contained
- acid sequence
- domain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title description 32
- 238000004519 manufacturing process Methods 0.000 title description 6
- 230000027455 binding Effects 0.000 claims description 158
- 206010028980 Neoplasm Diseases 0.000 claims description 67
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 42
- -1 poly(ethylene glycol) Polymers 0.000 claims description 37
- 239000003814 drug Substances 0.000 claims description 32
- 201000011510 cancer Diseases 0.000 claims description 29
- 239000000178 monomer Substances 0.000 claims description 29
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 claims description 26
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 claims description 26
- 229940124597 therapeutic agent Drugs 0.000 claims description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 238000011282 treatment Methods 0.000 claims description 16
- 229940127089 cytotoxic agent Drugs 0.000 claims description 14
- 229940127121 immunoconjugate Drugs 0.000 claims description 14
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 13
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 claims description 12
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 claims description 12
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 11
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 11
- 102100022464 5'-nucleotidase Human genes 0.000 claims description 7
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 claims description 7
- 101150013553 CD40 gene Proteins 0.000 claims description 7
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 claims description 7
- 101000678236 Homo sapiens 5'-nucleotidase Proteins 0.000 claims description 7
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 claims description 7
- 101000831007 Homo sapiens T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 claims description 7
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 claims description 7
- 101000666896 Homo sapiens V-type immunoglobulin domain-containing suppressor of T-cell activation Proteins 0.000 claims description 7
- 102000017578 LAG3 Human genes 0.000 claims description 7
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 claims description 7
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims description 7
- 102100024834 T-cell immunoreceptor with Ig and ITIM domains Human genes 0.000 claims description 7
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 claims description 7
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 claims description 7
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 claims description 7
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 claims description 7
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 claims description 7
- 102100038282 V-type immunoglobulin domain-containing suppressor of T-cell activation Human genes 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 239000002254 cytotoxic agent Substances 0.000 claims description 7
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- IJJVMEJXYNJXOJ-UHFFFAOYSA-N fluquinconazole Chemical compound C=1C=C(Cl)C=C(Cl)C=1N1C(=O)C2=CC(F)=CC=C2N=C1N1C=NC=N1 IJJVMEJXYNJXOJ-UHFFFAOYSA-N 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 101001109501 Homo sapiens NKG2-D type II integral membrane protein Proteins 0.000 claims description 6
- 102100022680 NKG2-D type II integral membrane protein Human genes 0.000 claims description 6
- 102000004190 Enzymes Human genes 0.000 claims description 5
- 108090000790 Enzymes Proteins 0.000 claims description 5
- 101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 claims description 5
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 5
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 5
- 239000003053 toxin Substances 0.000 claims description 5
- 231100000765 toxin Toxicity 0.000 claims description 5
- 108700012359 toxins Proteins 0.000 claims description 5
- 102100027207 CD27 antigen Human genes 0.000 claims description 4
- 229940123587 Cell cycle inhibitor Drugs 0.000 claims description 4
- 229940122029 DNA synthesis inhibitor Drugs 0.000 claims description 4
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 claims description 4
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 claims description 4
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 claims description 4
- 101000955999 Homo sapiens V-set domain-containing T-cell activation inhibitor 1 Proteins 0.000 claims description 4
- 229940123573 Protein synthesis inhibitor Drugs 0.000 claims description 4
- 229940123752 RNA synthesis inhibitor Drugs 0.000 claims description 4
- 229940078123 Ras inhibitor Drugs 0.000 claims description 4
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 claims description 4
- 229940046836 anti-estrogen Drugs 0.000 claims description 4
- 230000001833 anti-estrogenic effect Effects 0.000 claims description 4
- 239000002872 contrast media Substances 0.000 claims description 4
- 239000000328 estrogen antagonist Substances 0.000 claims description 4
- 229940043355 kinase inhibitor Drugs 0.000 claims description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 4
- 239000000007 protein synthesis inhibitor Substances 0.000 claims description 4
- 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 claims description 4
- HKZAAJSTFUZYTO-LURJTMIESA-N (2s)-2-[[2-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]acetyl]amino]-3-hydroxypropanoic acid Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O HKZAAJSTFUZYTO-LURJTMIESA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 claims description 3
- 229930195731 calicheamicin Natural products 0.000 claims description 3
- 230000012010 growth Effects 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- 230000002209 hydrophobic effect Effects 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 31
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims 3
- 239000012270 PD-1 inhibitor Substances 0.000 claims 1
- 239000012668 PD-1-inhibitor Substances 0.000 claims 1
- 230000000394 mitotic effect Effects 0.000 claims 1
- 229940121655 pd-1 inhibitor Drugs 0.000 claims 1
- 231100000167 toxic agent Toxicity 0.000 claims 1
- 239000003440 toxic substance Substances 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 96
- 239000000427 antigen Substances 0.000 description 90
- 108091007433 antigens Proteins 0.000 description 90
- 102000036639 antigens Human genes 0.000 description 90
- 210000001744 T-lymphocyte Anatomy 0.000 description 55
- 102000008096 B7-H1 Antigen Human genes 0.000 description 37
- 239000012634 fragment Substances 0.000 description 36
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 36
- 239000000203 mixture Substances 0.000 description 33
- 101001103039 Homo sapiens Inactive tyrosine-protein kinase transmembrane receptor ROR1 Proteins 0.000 description 31
- 238000003556 assay Methods 0.000 description 31
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 27
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 27
- 208000025324 B-cell acute lymphoblastic leukemia Diseases 0.000 description 25
- 101001103036 Homo sapiens Nuclear receptor ROR-alpha Proteins 0.000 description 25
- 102100039615 Inactive tyrosine-protein kinase transmembrane receptor ROR1 Human genes 0.000 description 25
- 230000000694 effects Effects 0.000 description 21
- 230000003013 cytotoxicity Effects 0.000 description 19
- 231100000135 cytotoxicity Toxicity 0.000 description 19
- 239000012636 effector Substances 0.000 description 19
- 210000004881 tumor cell Anatomy 0.000 description 18
- 108010087914 epidermal growth factor receptor VIII Proteins 0.000 description 16
- 239000002953 phosphate buffered saline Substances 0.000 description 16
- 108060003951 Immunoglobulin Proteins 0.000 description 15
- 102000018358 immunoglobulin Human genes 0.000 description 15
- 210000003071 memory t lymphocyte Anatomy 0.000 description 14
- 108090000623 proteins and genes Proteins 0.000 description 14
- 239000002609 medium Substances 0.000 description 12
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 11
- 150000001413 amino acids Chemical class 0.000 description 11
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- 238000010790 dilution Methods 0.000 description 9
- 239000012895 dilution Substances 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 229960003008 blinatumomab Drugs 0.000 description 8
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 230000001404 mediated effect Effects 0.000 description 8
- 230000004044 response Effects 0.000 description 8
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 7
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 7
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 7
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 210000004899 c-terminal region Anatomy 0.000 description 7
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 7
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 7
- 229940072221 immunoglobulins Drugs 0.000 description 7
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 6
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 6
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 102000049583 human ROR1 Human genes 0.000 description 6
- 108010054624 red fluorescent protein Proteins 0.000 description 6
- 229940045513 CTLA4 antagonist Drugs 0.000 description 5
- 229920001917 Ficoll Polymers 0.000 description 5
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 description 5
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 5
- 101000652359 Homo sapiens Spermatogenesis-associated protein 2 Proteins 0.000 description 5
- 108091028043 Nucleic acid sequence Proteins 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000028993 immune response Effects 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 229960003881 letrozole Drugs 0.000 description 5
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 5
- 150000007523 nucleic acids Chemical group 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 229920001184 polypeptide Polymers 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 230000011664 signaling Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000009870 specific binding Effects 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- BGFTWECWAICPDG-UHFFFAOYSA-N 2-[bis(4-chlorophenyl)methyl]-4-n-[3-[bis(4-chlorophenyl)methyl]-4-(dimethylamino)phenyl]-1-n,1-n-dimethylbenzene-1,4-diamine Chemical compound C1=C(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(N(C)C)=CC=C1NC(C=1)=CC=C(N(C)C)C=1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 BGFTWECWAICPDG-UHFFFAOYSA-N 0.000 description 4
- 206010003571 Astrocytoma Diseases 0.000 description 4
- 108010008014 B-Cell Maturation Antigen Proteins 0.000 description 4
- 102000006942 B-Cell Maturation Antigen Human genes 0.000 description 4
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 4
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 4
- 108091007741 Chimeric antigen receptor T cells Proteins 0.000 description 4
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 102000018651 Epithelial Cell Adhesion Molecule Human genes 0.000 description 4
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 description 4
- 102000018152 Frizzled domains Human genes 0.000 description 4
- 108050007261 Frizzled domains Proteins 0.000 description 4
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 4
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 4
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 4
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 description 4
- 101000914321 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 7 Proteins 0.000 description 4
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 4
- 101000998120 Homo sapiens Interleukin-3 receptor subunit alpha Proteins 0.000 description 4
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 description 4
- 101000617725 Homo sapiens Pregnancy-specific beta-1-glycoprotein 2 Proteins 0.000 description 4
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 4
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 4
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 4
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 4
- 102100033493 Interleukin-3 receptor subunit alpha Human genes 0.000 description 4
- 101150113776 LMP1 gene Proteins 0.000 description 4
- 102000003735 Mesothelin Human genes 0.000 description 4
- 108090000015 Mesothelin Proteins 0.000 description 4
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 description 4
- 102100022019 Pregnancy-specific beta-1-glycoprotein 2 Human genes 0.000 description 4
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 4
- 101150117918 Tacstd2 gene Proteins 0.000 description 4
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 4
- 102100027212 Tumor-associated calcium signal transducer 2 Human genes 0.000 description 4
- 229960004397 cyclophosphamide Drugs 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 102000048776 human CD274 Human genes 0.000 description 4
- 210000000987 immune system Anatomy 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 229960002621 pembrolizumab Drugs 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 4
- 210000000130 stem cell Anatomy 0.000 description 4
- 229940055760 yervoy Drugs 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 3
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 3
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 3
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 3
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 3
- 241000283707 Capra Species 0.000 description 3
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 3
- 102100029722 Ectonucleoside triphosphate diphosphohydrolase 1 Human genes 0.000 description 3
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 description 3
- 101001012447 Homo sapiens Ectonucleoside triphosphate diphosphohydrolase 1 Proteins 0.000 description 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 3
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 3
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 3
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 3
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 3
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 3
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 3
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 3
- 101150030213 Lag3 gene Proteins 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229940126547 T-cell immunoglobulin mucin-3 Drugs 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 229960003437 aminoglutethimide Drugs 0.000 description 3
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 3
- 229960002932 anastrozole Drugs 0.000 description 3
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 3
- 230000000890 antigenic effect Effects 0.000 description 3
- 229960004117 capecitabine Drugs 0.000 description 3
- 230000006037 cell lysis Effects 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- 238000010367 cloning Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 125000000151 cysteine group Chemical class N[C@@H](CS)C(=O)* 0.000 description 3
- 229960002448 dasatinib Drugs 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 239000000539 dimer Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229960001433 erlotinib Drugs 0.000 description 3
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 3
- 229960000255 exemestane Drugs 0.000 description 3
- 229950011548 fadrozole Drugs 0.000 description 3
- 229960004421 formestane Drugs 0.000 description 3
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 3
- 229960002258 fulvestrant Drugs 0.000 description 3
- 230000005714 functional activity Effects 0.000 description 3
- 229960002584 gefitinib Drugs 0.000 description 3
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 3
- 210000004408 hybridoma Anatomy 0.000 description 3
- 229960002411 imatinib Drugs 0.000 description 3
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229940090044 injection Drugs 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 229960004891 lapatinib Drugs 0.000 description 3
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 229960001346 nilotinib Drugs 0.000 description 3
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 3
- 229960003301 nivolumab Drugs 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 210000001672 ovary Anatomy 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229960003787 sorafenib Drugs 0.000 description 3
- 229960001796 sunitinib Drugs 0.000 description 3
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 3
- 229960001603 tamoxifen Drugs 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 3
- 229960005353 testolactone Drugs 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 229960001771 vorozole Drugs 0.000 description 3
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 206010061424 Anal cancer Diseases 0.000 description 2
- 208000007860 Anus Neoplasms Diseases 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 102000057297 Pepsin A Human genes 0.000 description 2
- 108090000284 Pepsin A Proteins 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 108091008874 T cell receptors Proteins 0.000 description 2
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 2
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 2
- 239000004012 Tofacitinib Substances 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229960001686 afatinib Drugs 0.000 description 2
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 2
- 230000009830 antibody antigen interaction Effects 0.000 description 2
- 239000000611 antibody drug conjugate Substances 0.000 description 2
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 2
- 229940049595 antibody-drug conjugate Drugs 0.000 description 2
- 210000000612 antigen-presenting cell Anatomy 0.000 description 2
- 201000011165 anus cancer Diseases 0.000 description 2
- 229960003982 apatinib Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960001561 bleomycin Drugs 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229960001467 bortezomib Drugs 0.000 description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229940127093 camptothecin Drugs 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 2
- 229960003669 carbenicillin Drugs 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- BFSMGDJOXZAERB-UHFFFAOYSA-N dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 description 2
- 229960002465 dabrafenib Drugs 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 230000008029 eradication Effects 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005167 everolimus Drugs 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 2
- 235000008191 folinic acid Nutrition 0.000 description 2
- 239000011672 folinic acid Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 229940126546 immune checkpoint molecule Drugs 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 229960001691 leucovorin Drugs 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 230000000869 mutational effect Effects 0.000 description 2
- WPEWQEMJFLWMLV-UHFFFAOYSA-N n-[4-(1-cyanocyclopentyl)phenyl]-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide Chemical compound C=1C=CN=C(NCC=2C=CN=CC=2)C=1C(=O)NC(C=C1)=CC=C1C1(C#N)CCCC1 WPEWQEMJFLWMLV-UHFFFAOYSA-N 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 2
- 229960000572 olaparib Drugs 0.000 description 2
- 229960003278 osimertinib Drugs 0.000 description 2
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 229960005079 pemetrexed Drugs 0.000 description 2
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 2
- 229940111202 pepsin Drugs 0.000 description 2
- 210000005259 peripheral blood Anatomy 0.000 description 2
- 239000011886 peripheral blood Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 2
- 229960000624 procarbazine Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000007420 reactivation Effects 0.000 description 2
- 230000006798 recombination Effects 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- 210000003289 regulatory T cell Anatomy 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 229960000235 temsirolimus Drugs 0.000 description 2
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 2
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 2
- 229960001350 tofacitinib Drugs 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 2
- 229960004066 trametinib Drugs 0.000 description 2
- 230000026683 transduction Effects 0.000 description 2
- 238000010361 transduction Methods 0.000 description 2
- 229960000575 trastuzumab Drugs 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 2
- 229960003862 vemurafenib Drugs 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000012114 Alexa Fluor 647 Substances 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 241001302160 Escherichia coli str. K-12 substr. DH10B Species 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101100383038 Homo sapiens CD19 gene Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 229940123309 Immune checkpoint modulator Drugs 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
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- 206010046431 Urethral cancer Diseases 0.000 description 1
- 206010046458 Urethral neoplasms Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000004900 c-terminal fragment Anatomy 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 208000030381 cutaneous melanoma Diseases 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 230000008073 immune recognition Effects 0.000 description 1
- 230000006058 immune tolerance Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229940118034 ipilimumab injection Drugs 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 229960005558 mertansine Drugs 0.000 description 1
- 208000021039 metastatic melanoma Diseases 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 108010093470 monomethyl auristatin E Proteins 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 210000004985 myeloid-derived suppressor cell Anatomy 0.000 description 1
- 210000004898 n-terminal fragment Anatomy 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000000174 oncolytic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 229940043515 other immunoglobulins in atc Drugs 0.000 description 1
- 229950007318 ozogamicin Drugs 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 208000017426 precursor B-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- HNMATTJJEPZZMM-BPKVFSPJSA-N s-[(2r,3s,4s,6s)-6-[[(2r,3s,4s,5r,6r)-5-[(2s,4s,5s)-5-[acetyl(ethyl)amino]-4-methoxyoxan-2-yl]oxy-6-[[(2s,5z,9r,13e)-13-[2-[[4-[(2e)-2-[1-[4-(4-amino-4-oxobutoxy)phenyl]ethylidene]hydrazinyl]-2-methyl-4-oxobutan-2-yl]disulfanyl]ethylidene]-9-hydroxy-12-(m Chemical compound C1[C@H](OC)[C@@H](N(CC)C(C)=O)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@@](C/3=C/CSSC(C)(C)CC(=O)N\N=C(/C)C=3C=CC(OCCCC(N)=O)=CC=3)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HNMATTJJEPZZMM-BPKVFSPJSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000003708 skin melanoma Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960002360 vintafolide Drugs 0.000 description 1
- KUZYSQSABONDME-QRLOMCMNSA-N vintafolide Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)NNC(=O)OCCSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(O)=O)NC(=O)CC[C@H](NC(=O)C=4C=CC(NCC=5N=C6C(=O)NC(N)=NC6=NC=5)=CC=4)C(O)=O)C(O)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KUZYSQSABONDME-QRLOMCMNSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- 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
-
- 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
- C07K16/2809—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 the T-cell receptor (TcR)-CD3 complex
-
- 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
- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
表1にリストされた四重特異性抗体について、U87細胞株の表面に発現したEGFRvIII抗原への結合を、FACS法を使用して評価した。四重特異性抗体をU87細胞株とインキュベートした後、Alexa Fluor 647蛍光色素に直接結合した二次抗ヒト抗体で検出した。四重特異性抗体の細胞結合を、フローサイトメーターBD LSRFortessaで分析した。試験した全ての抗体は、1桁及びサブナノモル範囲のKDで抗原に結合した(表2)。観察された結合性の違いは3倍の範囲内であり、分子内の結合ドメインの位置及び隣接ドメインとの相互作用によって駆動され得る。
表1に記載されている四重特異性抗体のそれぞれの抗原への結合親和性とキネティクスを、ForteBio Octet RED96装置の表面プラズモン共鳴により評価した。抗原をセンサーチップ表面に固定化し、固定化抗原の上に試験抗体を飛ばした。全ての分子が抗原への高い結合を示した(表3)。SI-39E29、SI-39E18、及びSI-39E23は、試験した他の抗体よりもCD3 e/d抗原への低い結合が見られた。表3は、表1にリストされた四重特異性抗体のEGFRvIII、4-1BB、PD-L1及びCD3抗原への結合を示す。
表1にリストされた四重特異性抗体について、PBMCをリダイレクトし、EGFRvIII でトランスフェクトされたU87腫瘍細胞株(U87vIII)を溶解する能力を評価した。PBMCをフィコール勾配により分離した。U87vIII腫瘍細胞株は、レンチウィルス形質導入(Sartorius)を介して送達される核局在化赤色蛍光蛋白質(RFP)を安定して発現していた。U87vIII腫瘍細胞をPBMCと共培養した。腫瘍細胞の溶解を、RFP標識腫瘍細胞核を数えることにより評価した。ライブセルイメージャーIncuCyte(Sartorius)で画像を取得した。SI-39E18及びSI-39E13四重特異性抗体は、96時間で最高の効果を示し、SI-39E10が続いた。SI-39E4、SI-39E23、及びSI-39E29は、表1に示した他の抗体よりもこの研究で低い有効性を示した(図2)。
表4にリストされた四重特異性抗体について、白血病細胞株カスミ-2を溶解する能力を評価した。PBMCをフィコール勾配により分離した。カスミ-2腫瘍細胞をPBMCと共培養した。腫瘍細胞溶解を、96時間の共培養後に存在する生きている腫瘍細胞の数をカウントすることにより、BD LSRFortessaフローサイトメーターで評価した。四重特異性抗体SI-38E14は、この研究で最も強力な活性を示し、SI-38E38が続いた(図3)。表4は、CD19腫瘍抗原認識ドメインを有す実施例の四重特異性抗体を示す。
表5にリストされた四重特異性抗体について、PBMCをリダイレクトし、EGFRvIII腫瘍細胞株(U87vIII)でトランスフェクトされたU87を溶解する能力について評価した。PBMCをフィコール勾配により分離した。U87vIII腫瘍細胞株は、レンチウィルス形質導入(Sartorius)を介して送達される核局在化赤色蛍光蛋白質(RFP)を安定して発現していた。U87vIII腫瘍細胞をPBMCと共培養した。腫瘍細胞の溶解を、RFP標識腫瘍細胞核を数えることにより評価した。ライブセルイメージャーIncuCyte(Sartorius)で画像を取得した。抗体の活性を、96時間のインキュベーション後に評価した。異なる4-1BBドメインを持つ抗体SI-39E4、SI-39E2及びSI-39E3は同様の活性を示した(図4)。サイレント(機能的ではない)FITCドメイン、SI-39E1及びSI-39E5で置き換えられたPD-L1及び4-1BBドメインを持つ抗体は、溶解活性の低下を示した。この観察により、4-1BB及びPD-L1ドメインの機能的寄与が確認される。表5は、EGFRvIII腫瘍抗原結合ドメインを有す実施例の四重特異性抗体を示す。FITC対照抗体。
表1及び2にリストされた四重特異性特異性抗体について、全長ヒトROR1を安定的に発現するチャイニーズハムスター卵巣細胞(CHO)細胞への結合を試験した。抗体を2X最終濃度で調製し、50 ulのPBS/2%FBSで96ウェルプレートの3ウェルで1:5に滴定し、50 ul PBS/2%FBS中の5,000 ROR1-CHO細胞を加えた。この混合物を氷上で30分間インキュベートし、200μlPBS/2%FBSで1回洗浄した後、ストックの1:1000希釈の二次抗体PEヤギ抗ヒトIgG Fcを加え、混合物を氷上で30分間インキュベートした。細胞を2x200ul PBS/2%FBSで洗浄し、50 ul PBS/2%FBSに再懸濁し、BD LSRFORTESSAで分析した。結合プロファイルを図5に示す。ROR1のIgドメインに特異的な323H7結合ドメインを有す四重特異性抗体SI-35E18、19、及び20は、ROR1のフリズルドドメインに特異的な338H4結合ドメインを有す四重特異性抗体SI-3521、22、及び23よりも高い結合性を示した。さらに、ROR1のクリングルドメインに特異的な330F11結合ドメインを有す四重特異性抗体SI-3524、25、及び26は結合しなかった。
表6にリストされた四重特異性特異性抗体について、全長ヒトROR1を安定して発現するチャイニーズハムスター卵巣細胞(CHO)細胞への結合を試験した。抗体を2倍の最終濃度で調製し、50ulのPBS/2%FBS中の96ウェルプレートの3ウェルで1:5に滴定し、50ul PBS/2%FBS中の5,000 ROR1-CHO細胞を加えた。この混合物を氷上で30分間インキュベートし、200ul PBS/2%FBSで1回洗浄し、ストックの1:1000希釈の二次抗体PEヤギ抗ヒトIgG Fcを加え、混合物を氷上で30分間インキュベートした。細胞を2x200 ul PBS/2%FBSで洗浄し、50 ul PBS/2%FBSに再懸濁し、BD LSRFortessaで分析した。結合プロファイルを図6に示す。対照SI-27E12を除く全ての四重特異性抗体は、41BB結合ドメイン、460C3、420H5、又は466F6を含み、さまざまな強度で41BB発現CHO細胞に結合した。表6は、実施例の四重特異性抗体のリストを示す。
表6にリストされた四重特異性特異性抗体について、全長ヒトROR1を安定して発現するチャイニーズハムスター卵巣細胞(CHO)細胞への結合を試験した。抗体を2X最終濃度で調製し、50ulのPBS/2%FBS中の96ウェルプレートの3ウェルで1:5に滴定し、50ul PBS/2%FBS中の5,000 ROR1-CHO細胞を加えた。この混合物を氷上で30分間インキュベートし、200μlPBS/2%FBSで1回洗浄した後、ストックの1:1000希釈の二次抗体PEヤギ抗ヒトIgG Fcを加え、混合物を氷上で30分間インキュベートした。細胞を2x200ul PBS/2%FBSで洗浄し、50 ul PBS/2%FBSに再懸濁し、BD LSRFORTESSAで分析した。結合プロファイルを図7に示す。対照SI-27E15を除く全ての四重特異性抗体は、同じPD-L1結合ドメインPL230C6を含み、PD-L1発現CHO細胞と非常に類似した結合強度を示した。
表6にリストされた四重特異性特異性抗体について、エフェクターとしてヒト末梢血単核細胞(PBMC)を使用して、B-ALL細胞株カスミ2に対するRTCC活性を試験した。カスミ2の標的細胞5x10e6を、37℃で20分間、10 mlの培地で0.5 uMのCFSE(Invitrogen、#C34554)で標識した。細胞を50mlの培地で3回洗浄した後、10mlに再懸濁し再カウントした。抗体を2X最終濃度で調製し、200 ulのRPMI+10%FBSの96ウェルプレートの10ウェルで1:3に滴定した。ヒトPBMCを、正常なヒト末梢血から収集された濃縮白血球除去製品である「ロイコパック」からの標準フィコール密度勾配により精製した。最終の96ウェルプレートで、100ulの標的細胞(5,000)、50ulのPBMC(25,000)、及び100ulの各抗体希釈液をアッセイの各ウェルに加えることにより、標的細胞、PBMC、及び連続滴定抗体を組み合わせた。アッセイプレートを37℃で約72時間インキュベートした後、各アッセイウェルの内容物を回収し、残っているCFSE標識標的細胞の数について分析した。図8に示すように、四重特異性抗体はすべて、同じPD-L1結合ドメインPL230C6、同じROR1結合ドメイン323H7、及び同じCD3結合ドメイン284A10を含み、41BB結合ドメイン460C3、420H5、及び466F6の1つを有し、41BB結合ドメインを持たないが、四重特異性抗体SI-35E18、19、20と同様に強力であるように見える対照SI-27E12を除いた対照と比較してより大きなRTCC活性を示した。
表6にリストされた四重特異性特異性抗体について、エフェクターとしてヒトCD8+、CD45RO+メモリーT細胞を使用して、B-ALL細胞株カスミ2に対するRTCC活性を試験した。カスミ2標的細胞5x10e6を、37℃で20分間、10 mlの培地で0.5 uMのCFSE(Invitrogen、#C34554)で標識した。細胞を50mlの培地で3回洗浄した後、10mlに再懸濁し再カウントした。抗体を2X最終濃度で調製し、200 ulのRPMI + 10%FBSの96ウェルプレートの10ウェルで1:3に滴定した。製造元のプロトコルに従って、EasySepTMヒトメモリーCD8+T細胞濃縮キット(Stemcell Technologies、#19159)を使用して、正常なドナーの末梢血単核細胞からヒトCD8+、CD45RO+メモリーT細胞を濃縮した。最終細胞集団を、FACS分析により98%CD8+、CD45RO+T細胞であると決定した(データ非表示)。最終の96ウェルプレートで、100 ulの標的細胞(5,000)、50 ulのCD8+、CD45RO+メモリーT細胞(25,000)、及び100 ulの各抗体希釈液をアッセイの各ウェルに加えることにより、標的細胞、T細胞、及び連続滴定抗体を組み合わせた。アッセイプレートを37℃で約72時間インキュベートした後、各アッセイウェルの内容物を回収し、残っているCFSE標識標的細胞の数について分析した。図9に示すように、四重特異性抗体はすべて、同じPD-L1結合ドメインPL230C6、同じROR1結合ドメイン323H7、及び同じCD3結合ドメイン284A10を含み、41BB結合ドメイン460C3、420H5、及び466F6の1つをし、41BB、PD-L1、ROR1、又はCD3結合ドメインのいずれも含まない対照と比較して、より大きなRTCC活性を示した。
表6にリストされた四重特異性特異性抗体について、エフェクターとしてヒトCD8+、CD45RA+メモリーT細胞を使用して、B-ALL細胞株カスミ2に対するRTCC活性を試験した。カスミ2標的細胞5x10e6を、37℃で20分間、10 mlの培地で0.5 uMのCFSE(Invitrogen、#C34554)で標識した。細胞を50mlの培地で3回洗浄した後、10mlに再懸濁し再カウントした。抗体を2X最終濃度で調製し、200 ulのRPMI + 10%FBSの96ウェルプレートの10ウェルで1:3に滴定した。製造元のプロトコルに従って、EasySepTMヒトナイーブCD8+T細胞単離キット(Stemcell Technologies、#19258)を使用して、正常なドナーの末梢血単核細胞からヒトCD8+、CD45RA+メモリーT細胞を濃縮した。最終細胞集団を、FACS分析により98%CD8+、CD45RA+T細胞であると決定した(データ非表示)。最終の96ウェルプレートで、100 ulの標的細胞(5,000)、50 ulのCD8+、CD45RO+T細胞(25,000)、及び100 ulの各抗体希釈液をアッセイの各ウェルに加えることにより、標的細胞、T細胞、及び連続滴定抗体を組み合わせた。アッセイプレートを37℃で約72時間インキュベートした後、各アッセイウェルの内容物を回収し、残っているCFSE標識標的細胞の数について分析した。図10に示すように、四重特異性抗体はすべて、同じPD-L1結合ドメインPL230C6、同じROR1結合ドメイン323H7、同じCD3結合ドメイン284A10を含み、41BB結合ドメイン460C3、420H5、及び466F6の1つを有し、41BB、PD-L1、ROR1、又はCD3結合ドメインのいずれも含まない対照と比較して、より大きなRTCC活性を示した。
表6にリストされた四重特異性特異性抗体について、エフェクターとしてヒト末梢血単核細胞(PBMC)を使用して、B-ALL細胞株カスミ2に対するRTCC活性を試験した。カスミ2標的細胞5x10e6を、37℃で20分間、10 mlの培地で0.5 uMのCFSE(Invitrogen、#C34554)で標識した。細胞を50mlの培地で3回洗浄した後、10mlに再懸濁し再カウントした。抗体を2X最終濃度で調製し、200 ulのRPMI + 10%FBSの96ウェルプレートの10ウェルで1:3に滴定した。ヒトPBMCを、正常なヒト末梢血から収集された濃縮白血球除去製品である「ロイコパック」からの標準フィコール密度勾配により精製した。最終の96ウェルプレートで、100 ulの標的細胞(5,000)、50 ulのPBMC(25,000)、及び100 ulの各抗体希釈液をアッセイの各ウェルに加えることにより、標的細胞、PBMC、及び連続滴定抗体を組み合わせた。アッセイプレートを37℃で約72時間インキュベートした後、各アッセイウェルの内容物を回収し、残っているCFSE標識標的細胞の数について分析した。図11に示すように、四重特異性抗体はすべて、同じPD-L1結合ドメインPL230C6、同じROR1結合ドメイン338H4、及び同じCD3結合ドメイン284A10を含み、41BB結合ドメイン460C3、420H5、及び466F6の1つを有し、41BB結合ドメインを持たないが、四重特異性抗体SI-35E18、19、及び20と同様に強力であるように見える対照SI-35E36を除いた対照と比較してより大きなRTCC活性を示した。
表6にリストされた四重特異性特異性抗体について、エフェクターとしてヒトCD8+、CD45RO+メモリーT細胞を使用して、B-ALL細胞株カスミ2に対するRTCC活性を試験した。カスミ2標的細胞5x10e6を、37℃で20分間、10 mlの培地で0.5 uMのCFSE(Invitrogen、#C34554)で標識した。細胞を50mlの培地で3回洗浄した後、10mlに再懸濁し再カウントした。抗体を2X最終濃度で調製し、200 ulのRPMI + 10%FBSの96ウェルプレートの10ウェルで1:3に滴定した。製造元のプロトコルに従って、EasySepTMヒトメモリーCD8+T細胞濃縮キット(Stemcell Technologies、#19159)を使用して、正常なドナーの末梢血単核細胞からヒトCD8+、CD45RO+メモリーT細胞を濃縮した。最終細胞集団を、FACS分析により98%CD8+、CD45RO+T細胞であると決定した(データ非表示)。最終の96ウェルプレートで、100 ulの標的細胞(5,000)、50 ulのCD8+、CD45RO+メモリーT細胞(25,000)、及び100 ulの各抗体希釈液をアッセイの各ウェルに加えることにより、標的細胞、T細胞、及び連続滴定抗体を組み合わせた。アッセイプレートを37℃で約72時間インキュベートした後、各アッセイウェルの内容物を回収し、残っているCFSE標識標的細胞の数について分析した。図12に示すように、四重特異性抗体はすべて、同じPD-L1結合ドメインPL230C6、同じROR1結合ドメイン338H4、同じCD3結合ドメイン284A10を含み、41BB結合ドメイン460C3、420H5、及び466F6の1つを有し、41BB、PD-L1、ROR1、又はCD3結合ドメインのいずれも含まない対照と比較して、より大きなRTCC活性を示した。
表6にリストされた四重特異性特異性抗体について、エフェクターとしてヒトCD8+、CD45RA+メモリーT細胞を使用して、B-ALL細胞株カスミ2に対するRTCC活性を試験した。カスミ2標的細胞5x10e6を、37℃で20分間、10 mlの培地で0.5 uMのCFSE(Invitrogen、#C34554)で標識した。細胞を50mlの培地で3回洗浄した後、10mlに再懸濁し再カウントした。抗体を2X最終濃度で調製し、200 ulのRPMI + 10%FBSの96ウェルプレートの10ウェルで1:3に滴定した。製造元のプロトコルに従って、EasySepTMヒトナイーブCD8+T細胞単離キット(Stemcell Technologies、#19258)を使用して、正常なドナーの末梢血単核細胞からヒトCD8+、CD45RA+メモリーT細胞を濃縮した。最終細胞集団を、FACS分析により98%CD8+、CD45RA+T細胞であると決定した(データ非表示)。最終の96ウェルプレートで、100 ulの標的細胞(5,000)、50 ulのCD8+、CD45RO+T細胞(25,000)、及び100 ulの各抗体希釈液をアッセイの各ウェルに加えることにより、標的細胞、T細胞、及び連続滴定抗体を組み合わせた。アッセイプレートを37℃で約72時間インキュベートした後、各アッセイウェルの内容物を回収し、残っているCFSE標識標的細胞の数について分析した。図13に示すように、四重特異性抗体はすべて、同じPD-L1結合ドメインPL230C6、同じROR1結合ドメイン338H4、同じCD3結合ドメイン284A10を含み、41BB結合ドメイン460C3、420H5、及び466F6の1つを有し、41BB、PD-L1、ROR1、又はCD3結合ドメインのいずれも含まない対照と比較して、より大きなRTCC活性を示さなかった。これは、CD8+、CD45RA+ナイーブT細胞でRTCC活性を示す、実施例6、図10に示される四重特異性抗体とは対照的である。
アミノ酸配列中のCDRは下線
>配列番号01 抗CD3 284A10 VHv1 nt
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCA
>配列番号02 抗CD3 284A10 VHv1 aa
EVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSS
>配列番号03 抗CD3 284A10 VLv1 nt
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>配列番号04 抗CD3 284A10 VLv1 aa
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIK
>配列番号05 抗CD3 480C8 VHv1 nt
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGAATCGACCTCAGTAGCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTAATAGTAAGAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCA
>配列番号06 抗CD3 480C8 VHv1 aa
EVQLVESGGGLVQPGGSLRLSCAASGIDLSSNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAINSKNIWGQGTLVTVSS
>配列番号07 抗CD3 480C8 VLv1 nt
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>配列番号08 抗CD3 480C8 VLv1 aa
DIQMTQSPSTLSASVGDRVTITCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNAFGGGTKVEIK
>配列番号09 抗PD-L1 PL230C6 VHv3 nt
CAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGAATCGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCCAGAGATTATATGAGTGGTTCCCACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTAGT
>配列番号10 抗PD-L1 PL230C6 VHv3 aa
QSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGIITYSGSRYYANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSS
>配列番号11 抗PD-L1 PL230C6 VLv2 nt
GCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCAAGTGTCAGGCCAGTGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATTCTGCATCCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>配列番号12 抗PD-L1 PL230C6 VLv2 aa
AYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIK
>配列番号13 抗PD-L1 PL221G5 VHv1 nt
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC
>配列番号14 抗PD-L1 PL221G5 VHv1 aa
EVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSS
>配列番号15 抗PD-L1 PL221G5 VLv1 nt
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>配列番号16 抗PD-L1 PL221G5 VLv1 aa
DIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIK
>配列番号17 抗PD-1 PD224D1 VHv2 nt
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCTCCCTAAGTAGCTATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGCTACATTGGTGATACTACTGGCATAGCCTACGCGAGCTGGGCGAATGGCAGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGGCTGGTCCTACTTAGACATCTGGGGCCAAGGGACCCTGGTCACCGTCTCGAGC
>配列番号18 抗PD-1 PD224D1 VHv2 aa
EVQLVESGGGLVQPGGSLRLSCTASGFSLSSYAMSWVRQAPGKGLEYIGYIGDTTGIAYASWANGRFTISKDNTKNTVDLQMNSLRAEDTAVYYCARGWSYLDIWGQGTLVTVSS
>配列番号19 抗PD-1 PD224D1 VLv2 nt
GCCCTTGTGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAACATTTACAGCAATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATCAGGCCTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATATGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAAGGCGGTTATTATAGTGCTGCCCTTAATACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>配列番号20 抗PD-1 PD224D1 VLv2 aa
ALVMTQSPSSLSASVGDRVTITCQASQNIYSNLAWYQQKPGKVPKLLIYQASTLASGVPSRFSGSGYGTDFTLTISSLQPEDVATYYCQGGYYSAALNTFGGGTKVEIK
>配列番号21 抗4-1BB 420H5 VHv3 nt
CAGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCAACTACTGGATATGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTTATGTTGGTAGTAGTGGTGACACTTACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGATAGTAGTAGTTATTATATGTTTAACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC
>配列番号22 抗4-1BB 420H5 VHv3 aa
QSLVESGGGLVQPGGSLRLSCAASGFSFSSNYWICWVRQAPGKGLEWIACIYVGSSGDTYYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSSSYYMFNLWGQGTLVTVSS
>配列番号23 抗4-1BB 420H5 VLv3 nt
GCCCTTGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATACCTATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTTATGCATCCGATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCGGTTACTATACTAGTAGTGCTGATACGAGGGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>配列番号24 抗4-1BB 420H5 VLv3 aa
ALVMTQSPSTLSASVGDRVTINCQASEDIDTYLAWYQQKPGKAPKLLIFYASDLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGGYYTSSADTRGAFGGGTKVEIK
>配列番号25 抗4-1BB 466F6 VHv2 nt
CGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCGAGCTCCGCGAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC
>配列番号26 抗4-1BB 466F6 VHv2 aa
RSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSS
>配列番号27 抗4-1BB 466F6 VLv5 nt
GACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>配列番号28 抗4-1BB 466F6 VLv5 aa
DVVMTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIK
>配列番号29 抗4-1BB 460C3 VHv1 nt
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGAATCGACTTCAGTAGGAGATACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATATATACTGGTAGCCGCGATACTCCTCACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGAAGGTAGCCTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC
>配列番号30 抗4-1BB 460C3 VHv1 aa
EVQLLESGGGLVQPGGSLRLSCAASGIDFSRRYYMCWVRQAPGKGLEWIACIYTGSRDTPHYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGSLWGQGTLVTVSS
>配列番号31 抗4-1BB 460C3 VLv1 nt
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTCTCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGGTTACAATACTGTTATTGATACTTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>配列番号32 抗4-1BB 460C3 VLv1 aa
DIQMTQSPSTLSASVGDRVTITCQSSQSVYSNWFSWYQQKPGKAPKLLIYSASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGYNTVIDTFAFGGGTKVEIK
>配列番号33 抗ROR1 324C6 VHv2 nt
CAGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCTCCCTCAGTAGGTACTACATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAACCATTTATACTAGTGGTAGTACATGGTACGCGAGCTGGACAAAAGGCAGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGATCCTATTATGGCGGTGATAAGACTGGTTTAGGCATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCA
>配列番号34 抗ROR1 324C6 VHv2 nt
QSLVESGGGLVQPGGSLRLSCTASGFSLSRYYMTWVRQAPGKGLEWIGTIYTSGSTWYASWTKGRFTISKDNTKNTVDLQMNSLRAEDTAVYYCARSYYGGDKTGLGIWGQGTLVTVSS
>配列番号35 抗ROR1 324C6 VLv1 nt
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTGATAGTTGGTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATCAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAATCTGCTTATGGTGTTAGTGGTACTAGTAGTTATTTATATACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>配列番号36 抗ROR1 324C6 VLv1 aa
DIQMTQSPSTLSASVGDRVTITCQASQSIDSWLSWYQQKPGKAPKLLIYQASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQSAYGVSGTSSYLYTFGGGTKVEIK
>配列番号37 抗ROR1 323H7 VHv4 nt
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCA
>配列番号38 抗ROR1 323H7 VHv4 aa
EVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIYVNNDDTDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSS
>配列番号39 抗ROR1 323H7 VLv1 nt
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCTTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>配列番号40 抗ROR1 323H7 VLv1 aa
DIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIK
>配列番号41 抗ROR1 338H4 VHv3 nt
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCTCCCTCAGTAGCTATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAGGGGGCTGGAGTGGATCGGAATCATTTATGCTAGTGGTAGCACATACTACGCGAGCTCGGCGAAAGGCAGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAATTTATGACGGCATGGACCTCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCA
>配列番号42 抗ROR1 338H4 VHv3 aa
EVQLVESGGGLVQPGGSLRLSCTASGFSLSSYAMSWVRQAPGRGLEWIGIIYASGSTYYASSAKGRFTISKDNTKNTVDLQMNSLRAEDTAVYYCARIYDGMDLWGQGTLVTVSS
>配列番号43 抗ROR1 338H4 VLv4 nt
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGCCAGTCAGAACATTTACAGCTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCGCCTGATCTATCTGGCATCTACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTACACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAAAGCAATTATAACGGTAATTATGGTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>配列番号44 抗ROR1 338H4 VLv4 aa
DIQMTQSPSSLSASVGDRVTINCQASQNIYSYLSWYQQKPGKVPKRLIYLASTLASGVPSRFSGSGSGTDYTLTISSLQPEDVATYYCQSNYNGNYGFGGGTKVEIK
>配列番号45 抗ROR1 330F11 VHv1 nt
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCCTCAATAACTACTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAACCATTAGTAGTGGTGCGTATACATGGTTCGCCACCTGGGCGACAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGATATTCTTCTACTACTGATTGGACCTACTTTAACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCA
>配列番号46 抗ROR1 330F11 VHv1 aa
EVQLVESGGGLVQPGGSLRLSCAASGFSLNNYWMSWVRQAPGKGLEWIGTISSGAYTWFATWATGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYSSTTDWTYFNIWGQGTLVTVSS
>配列番号47 抗ROR1 330F11 VLv1 nt
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAATAACTACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAGGGCATCCACTCTGGAATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAAGCTATAATGGTGTTGGTAGGACTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>配列番号48 抗ROR1 330F11 VLv1 aa
DIQMTQSPSTLSASVGDRVTITCQASQSINNYLAWYQQKPGKAPKLLIYRASTLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQSYNGVGRTAFGGGTKVEIK
>配列番号49 抗EGFRvIII mAb 806 VH nt
GATGTGCAGCTTCAGGAGTCGGGACCTAGCCTGGTGAAACCTTCTCAGTCTCTGTCCCTCACCTGCACTGTCACTGGCTACTCAATCACCAGTGATTTTGCCTGGAACTGGATTCGGCAGTTTCCAGGAAACAAGCTGGAGTGGATGGGCTACATAAGTTATAGTGGTAACACTAGGTACAACCCATCTCTCAAAAGTCGAATCTCTATCACTCGCGACACATCCAAGAACCAATTCTTCCTGCAGTTGAACTCTGTGACTATTGAGGACACAGCCACATATTACTGTGTAACGGCGGGACGCGGGTTTCCTTATTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA
>配列番号50 抗EGFRvIII mAb 806 VH aa
DVQLQESGPSLVKPSQSLSLTCTVTGYSITSDFAWNWIRQFPGNKLEWMGYISYSGNTRYNPSLKSRISITRDTSKNQFFLQLNSVTIEDTATYYCVTAGRGFPYWGQGTLVTVSA
>配列番号51 抗EGFRvIII mAb 806 VL nt
GACATCCTGATGACCCAATCTCCATCCTCCATGTCTGTATCTCTGGGAGACACAGTCAGCATCACTTGCCATTCAAGTCAGGACATTAACAGTAATATAGGGTGGTTGCAGCAGAGACCAGGGAAATCATTTAAGGGCCTGATCTATCATGGAACCAACTTGGACGATGAAGTTCCATCAAGGTTCAGTGGCAGTGGATCTGGAGCCGATTATTCTCTCACCATCAGCAGCCTGGAATCTGAAGATTTTGCAGACTATTACTGTGTACAGTATGCTCAGTTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA
>配列番号52 抗EGFRvIII mAb 806 VL aa
DILMTQSPSSMSVSLGDTVSITCHSSQDINSNIGWLQQRPGKSFKGLIYHGTNLDDEVPSRFSGSGSGADYSLTISSLESEDFADYYCVQYAQFPWTFGGGTKLEIK
>配列番号53 抗CD19 21D4 VH nt
GAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAGAAACCAGGAGAGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTAGCAGTTCATGGATCGGCTGGGTGCGCCAGGCACCTGGGAAAGGCCTGGAATGGATGGGGATCATCTATCCTGATGACTCTGATACCAGATACAGTCCATCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCAGGACTGCCTACCTGCAGTGGAGTAGCCTGAAGGCCTCGGACACCGCTATGTATTACTGTGCGAGACATGTTACTATGATTTGGGGAGTTATTATTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
>配列番号54 抗CD19 21D4 VH aa
EVQLVQSGAEVKKPGESLKISCKGSGYSFSSSWIGWVRQAPGKGLEWMGIIYPDDSDTRYSPSFQGQVTISADKSIRTAYLQWSSLKASDTAMYYCARHVTMIWGVIIDFWGQGTLVTVSS
>配列番号55 抗CD19 21D4 VL nt
GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAACAGTTTAATAGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA
>配列番号56 抗CD19 21D4 VL aa
AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPFTFGPGTKVDIK
>配列番号57 抗FITC 4-4-20 VH nt
GAGGTGAAGCTGGATGAGACTGGAGGAGGCTTGGTGCAACCTGGGAGGCCCATGAAACTCTCCTGTGTTGCCTCTGGATTCACTTTTAGTGACTACTGGATGAACTGGGTCCGCCAGTCTCCAGAGAAAGGACTGGAGTGGGTAGCACAAATTAGAAACAAACCTTATAATTATGAAACATATTATTCAGATTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGTAGTGTCTACCTGCAAATGAACAACTTAAGAGTTGAAGACATGGGTATCTATTACTGTACGGGTTCTTACTATGGTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA
>配列番号58 抗FITC 4-4-20 VH aa
EVKLDETGGGLVQPGRPMKLSCVASGFTFSDYWMNWVRQSPEKGLEWVAQIRNKPYNYETYYSDSVKGRFTISRDDSKSSVYLQMNNLRVEDMGIYYCTGSYYGMDYWGQGTSVTVSS
>配列番号59 抗FITC 4-4-20 VL nt
GATGTCGTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCCTTGTACACAGTAATGGAAACACCTATTTACGTTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGGTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCAAAGTACACATGTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA
>配列番号60 抗FITC 4-4-20 VL aa
DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLRWYLQKPGQSPKVLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPWTFGGGTKLEIK
>配列番号61 ヒトIgG1ヌル (ADCC/CDCヌル変異を有すG1m-fa) nt
GCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT
>配列番号62 ヒトIgG1ヌル (ADCC/CDCヌル変異を有すG1m-fa) aa
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
>配列番号63 ヒトIgカッパnt
CGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>配列番号64 ヒトIgカッパaa
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>配列番号65 SI-35E18 (60C3-L1H1-scFv x PL230C6-Fab x 323H7-H4L1-scFv x 284A10-H1L1-scFv) 重鎖nt
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAGTAACTGGTTCTCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGGTTACAATACTGTTATTGATACTTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGAATCGACTTCAGTAGGAGATACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATATATACTGGTAGCCGCGATACTCCTCACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGAAGGTAGCCTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGAATCGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCCAGAGATTATATGAGTGGTTCCCACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTAGTGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCTTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>配列番号66 SI-35E18 (460C3-L1H1-scFv x PL230C6-Fab x 323H7-H4L1-scFv x 284A10-H1L1-scFv) 重鎖aa
DIQMTQSPSTLSASVGDRVTITCQSSQSVYSNWFSWYQQKPGKAPKLLIYSASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCAGGYNTVIDTFAFGGGTKVEIK (抗4-1BB 460C3 VLv1)
GGGGSGGGGSGGGGSGGGGS (Gly4Ser)x4リンカー
EVQLLESGGGLVQPGGSLRLSCAASGIDFSRRYYMCWVRQAPGKGLEWIACIYTGSRDTPHYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGSLWGQGTLVTVSS (抗4-1BB 460C3 VHv1)
GGGGSGGGGS (Gly4Ser)x2リンカー
QSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGIITYSGSRYYANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSS (抗PD-L1 PL230C6 VHv3)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (ヒトIgG1ヌル)
GGGGSGGGGS (Gly4Ser)x2リンカー
EVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIYVNNDDTDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSS (抗ROR1 323H7 VHv4)
GGGGSGGGGSGGGGSGGGGS (Gly4Ser)x4リンカー
DIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIK (抗ROR1 323H7 VLv1)
GGGGSGGGGS (Gly4Ser)x2リンカー
EVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSS (抗CD3 284A10 VHv1)
GGGGSGGGGSGGGGSGGGGS (Gly4Ser)x4リンカー
DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIK (抗CD3 284A10 VLv1)
>配列番号67 SI-35E18 (460C3-L1H1-scFv x PL230C6-Fab x 323H7-H4L1-scFv x 284A10-H1L1-scFv) 軽鎖nt
GCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCAAGTGTCAGGCCAGTGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATTCTGCATCCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
>配列番号68 SI-35E18 (460C3-L1H1-scFv x PL230C6-Fab x 323H7-H4L1-scFv x 284A10-H1L1-scFv) 軽鎖aa
AYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIK (抗PD-L1 PL230C6 VLv2)
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (ヒトIgカッパ)
他の配列:
配列インデックス:
Claims (10)
- N末端及びC末端を有する四重特異性抗体モノマーであって、
N末端からC末端まで直列に、
N末端に第一のscFvドメイン、
Fabドメイン、
Fcドメイン、
第二のscFvドメイン、及び
C末端に第三のscFvドメイン、
を含み、
Fabドメインの重鎖に第一のscFvドメイン及びFcドメインが結合し、Fcドメインの二本鎖のそれぞれに第二のscFvドメインが結合し、
第一のscFvドメインは、4-1BBに対して結合特異性を有し、配列番号26に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号28に示されるアミノ酸配列に含まれるVL-CDR1~3を含み、Fabドメインは、PD-L1に対して結合特異性を有し、配列番号10に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号12に示されるアミノ酸配列に含まれるVL-CDR1~3を含み、第二のscFvドメインは、CD3に対して結合特異性を有し、配列番号2に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号4に示されるアミノ酸配列に含まれるVL-CDR1~3を含み、第三のscFvドメインは、CD19に対して結合特異性を有し、配列番号54に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号56に示されるアミノ酸配列に含まれるVL-CDR1~3を含み;又は
第一のscFvドメインは、PD-L1に対して結合特異性を有し、配列番号10に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号12に示されるアミノ酸配列に含まれるVL-CDR1~3を含み、Fabドメインは、4-1BBに対して結合特異性を有し、配列番号26に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号28に示されるアミノ酸配列に含まれるVL-CDR1~3を含み、第二のscFvドメインは、CD19に対して結合特異性を有し、配列番号54に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号56に示されるアミノ酸配列に含まれるVL-CDR1~3を含み、第三のscFvドメインは、CD3に対して結合特異性を有し、配列番号2に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号4に示されるアミノ酸配列に含まれるVL-CDR1~3を含み;又は
第一のscFvドメインは、4-1BBに対して結合特異性を有し、配列番号26に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号28に示されるアミノ酸配列に含まれるVL-CDR1~3を含み、Fabドメインは、CD19に対して結合特異性を有し、配列番号54に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号56に示されるアミノ酸配列に含まれるVL-CDR1~3を含み、第二のscFvドメインは、CD3に対して結合特異性を有し、配列番号2に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号4に示されるアミノ酸配列に含まれるVL-CDR1~3を含み、第三のscFvドメインは、PD-L1に対して結合特異性を有し、配列番号14に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号16に示されるアミノ酸配列に含まれるVL-CDR1~3を含み;又は
第一のscFvドメインは、CD19に対して結合特異性を有し、配列番号54に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号56に示されるアミノ酸配列に含まれるVL-CDR1~3を含み、Fabドメインは、CD3に対して結合特異性を有し、配列番号2に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号4に示されるアミノ酸配列に含まれるVL-CDR1~3を含み、第二のscFvドメインは、4-1BBに対して結合特異性を有し、配列番号26に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号28に示されるアミノ酸配列に含まれるVL-CDR1~3を含み、第三のscFvドメインは、PD-L1に対して結合特異性を有し、配列番号14に示されるアミノ酸配列に含まれるVH-CDR1~3及び配列番号16に示されるアミノ酸配列に含まれるVL-CDR1~3を含み、
前記VH-CDR1~3は、重鎖可変領域(VH)に含まれる相補性決定領域(CDR)1~3であり、前記VL-CDR1~3は、軽鎖可変領域(VL)に含まれる相補性決定領域(CDR)1~3である、四重特異性抗体モノマー。 - 前記第一のscFvドメイン、第二のscFvドメイン、又は第三のscFvドメインがgly-gly-gly-gly-ser(G4S)nリンカーを含み、前記nは2、3、又は4である、請求項1に記載の四重特異性抗体モノマー。
- 請求項1に記載の四重特異性抗体モノマーを含む四重特異性抗体。
- 請求項3に記載の精製された四重特異性抗体を含む、がんの治療又は予防用の医薬組成物。
- リンカーを介して請求項3に記載の四重特異性抗体に連結された細胞毒性剤又は造影剤を含み、
前記リンカーが、エステル結合、エーテル結合、アミド結合、ジスルフィド結合、イミド結合、スルホン結合、リン酸結合、リンエステル結合、ペプチド結合、疎水性ポリ(エチレングリコール)リンカー、又はそれらの組み合わせを含む、
免疫複合体。 - 前記細胞毒性剤又は造影剤が、カリケアマイシン、有糸分裂阻害剤、毒素、放射性同位体、毒素、治療薬、又はそれらの組み合わせの一群から選ばれる、化学療法剤、増殖阻害剤、又は細胞毒性剤を含む、請求項5に記載の免疫複合体。
- 薬学的に許容される担体と、請求項3に記載の四重特異性抗体、請求項5に記載の免疫複合体の1つ又はその両方とを含む、医薬組成物。
- 放射性同位体、放射性核種、毒素、化学療法剤又はそれらの組み合わせから選択される治療薬をさらに含む、請求項7に記載の医薬組成物。
- がんを有するヒト対象の治療用の医薬組成物であって、請求項3に記載の有効量の四重特異性抗体を含む、医薬組成物。
- 前記治療が、有効量の治療薬を共投与する工程を含み、前記治療薬が、抗体、化学療法剤、酵素、抗エストロゲン剤、受容体チロシンキナーゼ阻害剤、キナーゼ阻害剤、細胞周期阻害剤、チェックポイント阻害剤、DNA、RNA又は、蛋白質合成阻害剤、RAS阻害剤、PD1阻害剤、PD-L1、CTLA4、4-1BB、OX40、GITR、ICOS、LIGHT、TIM3、LAG3、TIGIT、CD40、CD27、HVEM、BTLA、VISTA、B7H4、CSF1R、NKG2D、CD73、又はそれらの組み合わせを含む、請求項9に記載の医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762524557P | 2017-06-25 | 2017-06-25 | |
US62/524,557 | 2017-06-25 | ||
PCT/US2018/039156 WO2019005639A2 (en) | 2017-06-25 | 2018-06-22 | MULTISPECIFIC ANTIBODIES AND METHODS OF PREPARATION AND USE THEREOF |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2020530777A JP2020530777A (ja) | 2020-10-29 |
JPWO2019005639A5 JPWO2019005639A5 (ja) | 2022-02-07 |
JP7399852B2 true JP7399852B2 (ja) | 2023-12-18 |
Family
ID=64742644
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020520429A Active JP7399852B2 (ja) | 2017-06-25 | 2018-06-22 | 多重特異性抗体とその作製及び使用方法 |
Country Status (11)
Country | Link |
---|---|
US (1) | US11787863B2 (ja) |
EP (1) | EP3645049A4 (ja) |
JP (1) | JP7399852B2 (ja) |
KR (1) | KR20200092301A (ja) |
CN (4) | CN116041530A (ja) |
AU (1) | AU2018295118A1 (ja) |
CA (1) | CA3068045A1 (ja) |
IL (2) | IL313468A (ja) |
RU (1) | RU2020102662A (ja) |
SG (1) | SG11201912864SA (ja) |
WO (1) | WO2019005639A2 (ja) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116535508A (zh) * | 2017-06-25 | 2023-08-04 | 西雅图免疫公司 | 抗pd-l1抗体及其制备和使用方法 |
US20220002425A1 (en) * | 2017-06-25 | 2022-01-06 | Systimmune, Inc. | Guidance and navigation control proteins and method of making and using thereof |
CN117946278A (zh) * | 2017-06-25 | 2024-04-30 | 西雅图免疫公司 | 多特异性抗体及其制备和使用方法 |
CN111527108A (zh) * | 2018-03-27 | 2020-08-11 | 西雅图免疫公司 | 制导和导航控制蛋白的制造和使用方法 |
CN118420771A (zh) * | 2019-11-06 | 2024-08-02 | 西雅图免疫公司 | 制导和导航控制蛋白及其制备和使用方法 |
US20240067741A1 (en) * | 2019-11-19 | 2024-02-29 | Systimmune, Inc. | Anti-4-1bb antibodies and methods of making and using thereof |
EP3988568A1 (en) * | 2020-10-21 | 2022-04-27 | Numab Therapeutics AG | Combination treatment |
WO2023198635A1 (en) * | 2022-04-11 | 2023-10-19 | Astrazeneca Ab | T cell binding proteins |
WO2024137697A1 (en) * | 2022-12-20 | 2024-06-27 | Oncternal Therapeutics, Inc. | Combination therapies for the treatment of cancer |
US20240294651A1 (en) | 2023-01-30 | 2024-09-05 | Kymab Limited | Antibodies |
CN116143934B (zh) * | 2023-03-21 | 2023-07-25 | 诺赛联合(北京)生物医学科技有限公司 | 一种干细胞外泌体提取试剂盒及其应用 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004531263A (ja) | 2001-05-11 | 2004-10-14 | ルードヴィッヒ インスティテュート フォー キャンサー リサーチ | 特異的結合タンパク質およびその使用 |
JP2006512407A (ja) | 2002-09-27 | 2006-04-13 | ゼンコー・インコーポレイテッド | 最適化Fc変異体およびそれらの生成方法 |
JP2008543339A (ja) | 2005-06-20 | 2008-12-04 | メダレックス インコーポレーティッド | Cd19抗体およびその使用法 |
WO2010112193A1 (en) | 2009-04-02 | 2010-10-07 | Roche Glycart Ag | Multispecific antibodies comprising full length antibodies and single chain fab fragments |
JP2016525551A (ja) | 2013-07-25 | 2016-08-25 | シトムクス セラピューティクス,インコーポレイティド | 多重特異性抗体、多重特異性活性化可能抗体、及びそれらの使用方法 |
WO2016105450A3 (en) | 2014-12-22 | 2016-10-06 | Xencor, Inc. | Trispecific antibodies |
JP2020530306A (ja) | 2017-06-25 | 2020-10-22 | システィミューン, インク.Systimmune, Inc. | 多重特異性抗体とその作製及び使用方法 |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104072613A (zh) * | 2007-11-13 | 2014-10-01 | Evec股份有限公司 | 与hGM-CSF结合的单克隆抗体及包含它的药物组合物 |
US9365644B2 (en) * | 2008-04-23 | 2016-06-14 | Epitomics, Inc. | Anti-TNFα antibody |
TW201100543A (en) * | 2009-05-27 | 2011-01-01 | Hoffmann La Roche | Tri-or tetraspecific antibodies |
GB201020995D0 (en) * | 2010-12-10 | 2011-01-26 | Bioinvent Int Ab | Biological materials and uses thereof |
US9580509B2 (en) * | 2011-11-07 | 2017-02-28 | Medimmune, Llc | Multispecific and multivalent binding proteins and uses thereof |
US9758591B2 (en) * | 2012-08-24 | 2017-09-12 | The Regents Of The University Of California | Antibodies and vaccines for use in treating ROR1 cancers and inhibiting metastasis |
US9732150B2 (en) * | 2013-03-14 | 2017-08-15 | Alderbio Holdings Llc | Therapeutic use of antibodies to HGF |
KR102286053B1 (ko) * | 2013-06-26 | 2021-08-04 | 누맙 세러퓨틱스 아게 | 신규한 항체 기본구조 |
EP3060579A1 (en) * | 2013-10-25 | 2016-08-31 | Numab AG | Bispecific constructs and their use in the treatment of various diseases |
EP3107569A4 (en) * | 2014-02-20 | 2018-02-21 | Alder Biopharmaceuticals, Inc. | Anti-acth antibodies and use thereof |
UA117289C2 (uk) * | 2014-04-02 | 2018-07-10 | Ф. Хоффманн-Ля Рош Аг | Мультиспецифічне антитіло |
JP6640232B2 (ja) * | 2015-02-06 | 2020-02-05 | ユニバーシティ オブ メリーランド,ボルチモア | クロストリジウム・ディフィシル感染症の治療のための、クロストリジウム・ディフィシルのトキシンa及びトキシンbに対する四重特異性の八量体型結合剤及び抗体 |
CN104829733B (zh) * | 2015-05-25 | 2018-06-05 | 广州百暨基因科技有限公司 | 抗原结合单元稳定的嵌合抗原受体及制备方法与应用 |
WO2017049004A1 (en) * | 2015-09-15 | 2017-03-23 | Amgen Inc. | Tetravalent bispecific and tetraspecific antigen binding proteins and uses thereof |
US20220002425A1 (en) * | 2017-06-25 | 2022-01-06 | Systimmune, Inc. | Guidance and navigation control proteins and method of making and using thereof |
CN111527108A (zh) * | 2018-03-27 | 2020-08-11 | 西雅图免疫公司 | 制导和导航控制蛋白的制造和使用方法 |
-
2018
- 2018-06-22 US US16/615,122 patent/US11787863B2/en active Active
- 2018-06-22 WO PCT/US2018/039156 patent/WO2019005639A2/en unknown
- 2018-06-22 RU RU2020102662A patent/RU2020102662A/ru unknown
- 2018-06-22 JP JP2020520429A patent/JP7399852B2/ja active Active
- 2018-06-22 CN CN202310141062.3A patent/CN116041530A/zh active Pending
- 2018-06-22 SG SG11201912864SA patent/SG11201912864SA/en unknown
- 2018-06-22 KR KR1020207002328A patent/KR20200092301A/ko not_active Application Discontinuation
- 2018-06-22 CN CN201880039401.4A patent/CN110831973B/zh active Active
- 2018-06-22 IL IL313468A patent/IL313468A/en unknown
- 2018-06-22 AU AU2018295118A patent/AU2018295118A1/en active Pending
- 2018-06-22 CN CN202310922275.XA patent/CN116948035A/zh active Pending
- 2018-06-22 IL IL271257A patent/IL271257B1/en unknown
- 2018-06-22 CA CA3068045A patent/CA3068045A1/en active Pending
- 2018-06-22 CN CN202310141321.2A patent/CN116199785A/zh active Pending
- 2018-06-22 EP EP18825293.6A patent/EP3645049A4/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004531263A (ja) | 2001-05-11 | 2004-10-14 | ルードヴィッヒ インスティテュート フォー キャンサー リサーチ | 特異的結合タンパク質およびその使用 |
JP2006512407A (ja) | 2002-09-27 | 2006-04-13 | ゼンコー・インコーポレイテッド | 最適化Fc変異体およびそれらの生成方法 |
JP2008543339A (ja) | 2005-06-20 | 2008-12-04 | メダレックス インコーポレーティッド | Cd19抗体およびその使用法 |
WO2010112193A1 (en) | 2009-04-02 | 2010-10-07 | Roche Glycart Ag | Multispecific antibodies comprising full length antibodies and single chain fab fragments |
JP2016525551A (ja) | 2013-07-25 | 2016-08-25 | シトムクス セラピューティクス,インコーポレイティド | 多重特異性抗体、多重特異性活性化可能抗体、及びそれらの使用方法 |
WO2016105450A3 (en) | 2014-12-22 | 2016-10-06 | Xencor, Inc. | Trispecific antibodies |
JP2020530306A (ja) | 2017-06-25 | 2020-10-22 | システィミューン, インク.Systimmune, Inc. | 多重特異性抗体とその作製及び使用方法 |
Also Published As
Publication number | Publication date |
---|---|
AU2018295118A1 (en) | 2020-02-06 |
WO2019005639A3 (en) | 2019-02-07 |
CA3068045A1 (en) | 2019-01-03 |
CN116199785A (zh) | 2023-06-02 |
RU2020102662A (ru) | 2021-07-27 |
CN116948035A (zh) | 2023-10-27 |
SG11201912864SA (en) | 2020-01-30 |
US20220002406A1 (en) | 2022-01-06 |
IL271257A (en) | 2020-01-30 |
CN116041530A (zh) | 2023-05-02 |
EP3645049A4 (en) | 2021-06-30 |
JP2020530777A (ja) | 2020-10-29 |
KR20200092301A (ko) | 2020-08-03 |
EP3645049A2 (en) | 2020-05-06 |
CN110831973A (zh) | 2020-02-21 |
US11787863B2 (en) | 2023-10-17 |
CN110831973B (zh) | 2023-08-15 |
IL313468A (en) | 2024-08-01 |
WO2019005639A2 (en) | 2019-01-03 |
IL271257B1 (en) | 2024-07-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7399852B2 (ja) | 多重特異性抗体とその作製及び使用方法 | |
JP7356970B2 (ja) | 多重特異性抗体とその作製及び使用方法 | |
JP7474193B2 (ja) | 多重特異性抗体とその作製及び使用方法 | |
CN110799539B (zh) | 抗4-1bb抗体及其制备和使用方法 | |
AU2019243448B2 (en) | Guidance and navigation control proteins and method of making and using thereof | |
US20220002425A1 (en) | Guidance and navigation control proteins and method of making and using thereof | |
US20240279333A1 (en) | Multi-specific antibodies and methods of making and using thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210622 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220106 |
|
A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20220630 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220906 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20221206 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230203 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230302 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20230509 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230906 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20230907 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20230927 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20231107 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20231206 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7399852 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |