TW202207990A - 含有α-烯醇酶抗體之藥物共軛物及其用途 - Google Patents
含有α-烯醇酶抗體之藥物共軛物及其用途 Download PDFInfo
- Publication number
- TW202207990A TW202207990A TW110116808A TW110116808A TW202207990A TW 202207990 A TW202207990 A TW 202207990A TW 110116808 A TW110116808 A TW 110116808A TW 110116808 A TW110116808 A TW 110116808A TW 202207990 A TW202207990 A TW 202207990A
- Authority
- TW
- Taiwan
- Prior art keywords
- cancer
- antibody
- seq
- eno
- immunoconjugate
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims abstract description 55
- 229940079593 drug Drugs 0.000 title description 28
- 102000012288 Phosphopyruvate Hydratase Human genes 0.000 title description 4
- 108010022181 Phosphopyruvate Hydratase Proteins 0.000 title description 4
- 101150015836 ENO1 gene Proteins 0.000 claims abstract description 41
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 29
- 201000011510 cancer Diseases 0.000 claims abstract description 27
- 229940127121 immunoconjugate Drugs 0.000 claims abstract description 20
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 20
- 230000027455 binding Effects 0.000 claims abstract description 15
- 239000012634 fragment Substances 0.000 claims abstract description 12
- 238000011282 treatment Methods 0.000 claims abstract description 12
- 208000026278 immune system disease Diseases 0.000 claims abstract description 11
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 11
- 210000004027 cell Anatomy 0.000 claims description 44
- -1 anthracycline Chemical compound 0.000 claims description 28
- 230000000295 complement effect Effects 0.000 claims description 16
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 claims description 12
- 150000001413 amino acids Chemical class 0.000 claims description 12
- 108010093470 monomethyl auristatin E Proteins 0.000 claims description 11
- 235000001014 amino acid Nutrition 0.000 claims description 10
- 229940127089 cytotoxic agent Drugs 0.000 claims description 10
- 239000002254 cytotoxic agent Substances 0.000 claims description 9
- 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 description 8
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 8
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical class 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 claims description 8
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 8
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 claims description 7
- 206010060862 Prostate cancer Diseases 0.000 claims description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 7
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 7
- 108010059074 monomethylauristatin F Proteins 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 108010006654 Bleomycin Proteins 0.000 claims description 6
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 6
- 235000018417 cysteine Nutrition 0.000 claims description 6
- 201000007270 liver cancer Diseases 0.000 claims description 6
- 208000014018 liver neoplasm Diseases 0.000 claims description 6
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- HXCHCVDVKSCDHU-PJKCJEBCSA-N s-[(2r,3s,4s,6s)-6-[[(2r,3s,4s,5r,6r)-5-[(2s,4s,5s)-5-(ethylamino)-4-methoxyoxan-2-yl]oxy-4-hydroxy-6-[[(2s,5z,9r,13e)-9-hydroxy-12-(methoxycarbonylamino)-13-[2-(methyltrisulfanyl)ethylidene]-11-oxo-2-bicyclo[7.3.1]trideca-1(12),5-dien-3,7-diynyl]oxy]-2-m 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-PJKCJEBCSA-N 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 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 claims description 5
- 208000011231 Crohn disease Diseases 0.000 claims description 5
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 5
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 5
- 229960002949 fluorouracil Drugs 0.000 claims description 5
- 201000005787 hematologic cancer Diseases 0.000 claims description 5
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 5
- 229960001101 ifosfamide Drugs 0.000 claims description 5
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 5
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 claims description 5
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 239000003053 toxin Substances 0.000 claims description 5
- 231100000765 toxin Toxicity 0.000 claims description 5
- 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 claims description 4
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 4
- 108010092160 Dactinomycin Proteins 0.000 claims description 4
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 4
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 4
- 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 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 229930126263 Maytansine Natural products 0.000 claims description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 4
- 229930012538 Paclitaxel Natural products 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003242 anti bacterial agent Substances 0.000 claims description 4
- 229940088710 antibiotic agent Drugs 0.000 claims description 4
- 229930195731 calicheamicin Natural products 0.000 claims description 4
- 229960004397 cyclophosphamide Drugs 0.000 claims description 4
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 4
- 239000000032 diagnostic agent Substances 0.000 claims description 4
- 229960004679 doxorubicin Drugs 0.000 claims description 4
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 4
- 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 claims description 4
- 235000008191 folinic acid Nutrition 0.000 claims description 4
- 239000011672 folinic acid Substances 0.000 claims description 4
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 229960001691 leucovorin Drugs 0.000 claims description 4
- DHMTURDWPRKSOA-RUZDIDTESA-N lonafarnib Chemical compound C1CN(C(=O)N)CCC1CC(=O)N1CCC([C@@H]2C3=C(Br)C=C(Cl)C=C3CCC3=CC(Br)=CN=C32)CC1 DHMTURDWPRKSOA-RUZDIDTESA-N 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 239000003550 marker Substances 0.000 claims description 4
- 229960001428 mercaptopurine Drugs 0.000 claims description 4
- 229960000485 methotrexate Drugs 0.000 claims description 4
- 229960001156 mitoxantrone Drugs 0.000 claims description 4
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 claims description 4
- 229960001592 paclitaxel Drugs 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 claims description 4
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[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 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 4
- PVYJZLYGTZKPJE-UHFFFAOYSA-N streptonigrin Chemical compound C=1C=C2C(=O)C(OC)=C(N)C(=O)C2=NC=1C(C=1N)=NC(C(O)=O)=C(C)C=1C1=CC=C(OC)C(OC)=C1O PVYJZLYGTZKPJE-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 229960001196 thiotepa Drugs 0.000 claims description 4
- 229960003087 tioguanine Drugs 0.000 claims description 4
- 210000001519 tissue Anatomy 0.000 claims description 4
- FDAYLTPAFBGXAB-UHFFFAOYSA-N 2-chloro-n,n-bis(2-chloroethyl)ethanamine Chemical compound ClCCN(CCCl)CCCl FDAYLTPAFBGXAB-UHFFFAOYSA-N 0.000 claims description 3
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 3
- 229930193152 Dynemicin Natural products 0.000 claims description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims 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 claims description 3
- 206010020751 Hypersensitivity Diseases 0.000 claims description 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 3
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims description 3
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 3
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 3
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 3
- 206010025323 Lymphomas Diseases 0.000 claims description 3
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 claims description 3
- 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 claims description 3
- 206010035664 Pneumonia Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 3
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- 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 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 230000007815 allergy Effects 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- 229960004562 carboplatin Drugs 0.000 claims description 3
- 229960004630 chlorambucil Drugs 0.000 claims description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 3
- 229960000684 cytarabine Drugs 0.000 claims description 3
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 claims description 3
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 claims description 3
- 229950004683 drostanolone propionate Drugs 0.000 claims description 3
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 claims description 3
- 229950006700 edatrexate Drugs 0.000 claims 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 claims description 3
- 229960000390 fludarabine Drugs 0.000 claims description 3
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims 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 claims description 3
- 229960005277 gemcitabine Drugs 0.000 claims description 3
- 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 claims description 3
- 238000003384 imaging method Methods 0.000 claims 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 claims description 3
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 3
- 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 claims description 3
- MQXVYODZCMMZEM-ZYUZMQFOSA-N mannomustine Chemical compound ClCCNC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CNCCCl MQXVYODZCMMZEM-ZYUZMQFOSA-N 0.000 claims description 3
- 229950008612 mannomustine Drugs 0.000 claims description 3
- 229960005485 mitobronitol Drugs 0.000 claims description 3
- 229960001756 oxaliplatin Drugs 0.000 claims description 3
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 3
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 3
- 229960002930 sirolimus Drugs 0.000 claims description 3
- 229960003787 sorafenib Drugs 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 claims description 3
- 229960001278 teniposide Drugs 0.000 claims description 3
- 229960004560 triaziquone Drugs 0.000 claims description 3
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 claims description 3
- 229960003048 vinblastine Drugs 0.000 claims description 3
- 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 claims description 3
- 229960004355 vindesine Drugs 0.000 claims description 3
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 claims description 3
- 229940053867 xeloda Drugs 0.000 claims description 3
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 claims description 2
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 claims description 2
- FLWWDYNPWOSLEO-HQVZTVAUSA-N (2s)-2-[[4-[1-(2-amino-4-oxo-1h-pteridin-6-yl)ethyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1C(C)N(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FLWWDYNPWOSLEO-HQVZTVAUSA-N 0.000 claims description 2
- DLKUYSQUHXBYPB-NSSHGSRYSA-N (2s,4r)-4-[[2-[(1r,3r)-1-acetyloxy-4-methyl-3-[3-methylbutanoyloxymethyl-[(2s,3s)-3-methyl-2-[[(2r)-1-methylpiperidine-2-carbonyl]amino]pentanoyl]amino]pentyl]-1,3-thiazole-4-carbonyl]amino]-2-methyl-5-(4-methylphenyl)pentanoic acid Chemical compound N([C@@H]([C@@H](C)CC)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)C=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(O)=O)CC=1C=CC(C)=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C DLKUYSQUHXBYPB-NSSHGSRYSA-N 0.000 claims description 2
- CGMTUJFWROPELF-YPAAEMCBSA-N (3E,5S)-5-[(2S)-butan-2-yl]-3-(1-hydroxyethylidene)pyrrolidine-2,4-dione Chemical compound CC[C@H](C)[C@@H]1NC(=O)\C(=C(/C)O)C1=O CGMTUJFWROPELF-YPAAEMCBSA-N 0.000 claims description 2
- XRBSKUSTLXISAB-XVVDYKMHSA-N (5r,6r,7r,8r)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzodioxole-6-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H](CO)[C@@H]2C(O)=O)=C1 XRBSKUSTLXISAB-XVVDYKMHSA-N 0.000 claims description 2
- XRBSKUSTLXISAB-UHFFFAOYSA-N (7R,7'R,8R,8'R)-form-Podophyllic acid Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C(CO)C2C(O)=O)=C1 XRBSKUSTLXISAB-UHFFFAOYSA-N 0.000 claims description 2
- AESVUZLWRXEGEX-DKCAWCKPSA-N (7S,9R)-7-[(2S,4R,5R,6R)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione iron(3+) Chemical compound [Fe+3].COc1cccc2C(=O)c3c(O)c4C[C@@](O)(C[C@H](O[C@@H]5C[C@@H](N)[C@@H](O)[C@@H](C)O5)c4c(O)c3C(=O)c12)C(=O)CO AESVUZLWRXEGEX-DKCAWCKPSA-N 0.000 claims description 2
- JXVAMODRWBNUSF-KZQKBALLSA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-5-[[(2s,4as,5as,7s,9s,9ar,10ar)-2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl]oxy]-4-(dimethylamino)-6-methyloxan-2-yl]oxy-10-[(2s,4s,5s,6s)-4-(dimethylamino)-5-hydroxy-6-methyloxan-2 Chemical compound O([C@@H]1C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C2[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@H]4O[C@@H]5O[C@@H](C)C(=O)C[C@@H]5O[C@H]4C3)[C@H](C2)N(C)C)C[C@]1(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 JXVAMODRWBNUSF-KZQKBALLSA-N 0.000 claims description 2
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 claims description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims description 2
- AGNGYMCLFWQVGX-AGFFZDDWSA-N (e)-1-[(2s)-2-amino-2-carboxyethoxy]-2-diazonioethenolate Chemical compound OC(=O)[C@@H](N)CO\C([O-])=C\[N+]#N AGNGYMCLFWQVGX-AGFFZDDWSA-N 0.000 claims description 2
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 claims description 2
- BTOTXLJHDSNXMW-POYBYMJQSA-N 2,3-dideoxyuridine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=O)C=C1 BTOTXLJHDSNXMW-POYBYMJQSA-N 0.000 claims description 2
- BOMZMNZEXMAQQW-UHFFFAOYSA-N 2,5,11-trimethyl-6h-pyrido[4,3-b]carbazol-2-ium-9-ol;acetate Chemical compound CC([O-])=O.C[N+]1=CC=C2C(C)=C(NC=3C4=CC(O)=CC=3)C4=C(C)C2=C1 BOMZMNZEXMAQQW-UHFFFAOYSA-N 0.000 claims description 2
- QCXJFISCRQIYID-IAEPZHFASA-N 2-amino-1-n-[(3s,6s,7r,10s,16s)-3-[(2s)-butan-2-yl]-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-10-propan-2-yl-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]-4,6-dimethyl-3-oxo-9-n-[(3s,6s,7r,10s,16s)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propa Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N=C2C(C(=O)N[C@@H]3C(=O)N[C@H](C(N4CCC[C@H]4C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]3C)=O)[C@@H](C)CC)=C(N)C(=O)C(C)=C2O2)C2=C(C)C=C1 QCXJFISCRQIYID-IAEPZHFASA-N 0.000 claims description 2
- VNBAOSVONFJBKP-UHFFFAOYSA-N 2-chloro-n,n-bis(2-chloroethyl)propan-1-amine;hydrochloride Chemical compound Cl.CC(Cl)CN(CCCl)CCCl VNBAOSVONFJBKP-UHFFFAOYSA-N 0.000 claims description 2
- PWMYMKOUNYTVQN-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine Chemical compound C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 PWMYMKOUNYTVQN-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 claims description 2
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 claims description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims description 2
- 229960005538 6-diazo-5-oxo-L-norleucine Drugs 0.000 claims description 2
- YCWQAMGASJSUIP-YFKPBYRVSA-N 6-diazo-5-oxo-L-norleucine Chemical compound OC(=O)[C@@H](N)CCC(=O)C=[N+]=[N-] YCWQAMGASJSUIP-YFKPBYRVSA-N 0.000 claims description 2
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 claims description 2
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 claims description 2
- 108010088751 Albumins Proteins 0.000 claims description 2
- CEIZFXOZIQNICU-UHFFFAOYSA-N Alternaria alternata Crofton-weed toxin Natural products CCC(C)C1NC(=O)C(C(C)=O)=C1O CEIZFXOZIQNICU-UHFFFAOYSA-N 0.000 claims description 2
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 claims description 2
- 229940122361 Bisphosphonate Drugs 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- SHHKQEUPHAENFK-UHFFFAOYSA-N Carboquone Chemical compound O=C1C(C)=C(N2CC2)C(=O)C(C(COC(N)=O)OC)=C1N1CC1 SHHKQEUPHAENFK-UHFFFAOYSA-N 0.000 claims description 2
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 claims description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims description 2
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 claims description 2
- XCDXSSFOJZZGQC-UHFFFAOYSA-N Chlornaphazine Chemical compound C1=CC=CC2=CC(N(CCCl)CCCl)=CC=C21 XCDXSSFOJZZGQC-UHFFFAOYSA-N 0.000 claims description 2
- MKQWTWSXVILIKJ-LXGUWJNJSA-N Chlorozotocin Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)NC(=O)N(N=O)CCCl MKQWTWSXVILIKJ-LXGUWJNJSA-N 0.000 claims description 2
- 229930188224 Cryptophycin Natural products 0.000 claims description 2
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 claims description 2
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 claims description 2
- 108010002156 Depsipeptides Proteins 0.000 claims description 2
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 2
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 claims 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 claims description 2
- OBMLHUPNRURLOK-XGRAFVIBSA-N Epitiostanol Chemical compound C1[C@@H]2S[C@@H]2C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 OBMLHUPNRURLOK-XGRAFVIBSA-N 0.000 claims description 2
- 229930189413 Esperamicin Natural products 0.000 claims description 2
- PVDUPJHSLJKVSR-RZVRUWJTSA-N FC(F)N[C@@H](CCCN)C(=O)O.FC(F)N[C@@H](CCCN)C(=O)O Chemical compound FC(F)N[C@@H](CCCN)C(=O)O.FC(F)N[C@@H](CCCN)C(=O)O PVDUPJHSLJKVSR-RZVRUWJTSA-N 0.000 claims 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 claims description 2
- 208000032672 Histiocytosis haematophagic Diseases 0.000 claims description 2
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 claims description 2
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 claims description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 2
- 229920001491 Lentinan Polymers 0.000 claims description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 claims description 2
- 208000004987 Macrophage activation syndrome Diseases 0.000 claims description 2
- VJRAUFKOOPNFIQ-UHFFFAOYSA-N Marcellomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CC(O)C(O)C(C)O1 VJRAUFKOOPNFIQ-UHFFFAOYSA-N 0.000 claims description 2
- IVDYZAAPOLNZKG-KWHRADDSSA-N Mepitiostane Chemical compound O([C@@H]1[C@]2(CC[C@@H]3[C@@]4(C)C[C@H]5S[C@H]5C[C@@H]4CC[C@H]3[C@@H]2CC1)C)C1(OC)CCCC1 IVDYZAAPOLNZKG-KWHRADDSSA-N 0.000 claims description 2
- 229930192392 Mitomycin Natural products 0.000 claims description 2
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 2
- SYNHCENRCUAUNM-UHFFFAOYSA-N Nitrogen mustard N-oxide hydrochloride Chemical compound Cl.ClCC[N+]([O-])(C)CCCl SYNHCENRCUAUNM-UHFFFAOYSA-N 0.000 claims description 2
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 claims description 2
- 208000001132 Osteoporosis Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- VREZDOWOLGNDPW-ALTGWBOUSA-N Pancratistatin Chemical compound C1=C2[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-ALTGWBOUSA-N 0.000 claims description 2
- VREZDOWOLGNDPW-MYVCAWNPSA-N Pancratistatin Natural products O=C1N[C@H]2[C@H](O)[C@H](O)[C@H](O)[C@H](O)[C@@H]2c2c1c(O)c1OCOc1c2 VREZDOWOLGNDPW-MYVCAWNPSA-N 0.000 claims description 2
- 108010057150 Peplomycin Proteins 0.000 claims description 2
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)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]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 claims description 2
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 claims description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 2
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 claims description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- OWPCHSCAPHNHAV-UHFFFAOYSA-N Rhizoxin Natural products C1C(O)C2(C)OC2C=CC(C)C(OC(=O)C2)CC2CC2OC2C(=O)OC1C(C)C(OC)C(C)=CC=CC(C)=CC1=COC(C)=N1 OWPCHSCAPHNHAV-UHFFFAOYSA-N 0.000 claims description 2
- 229920000519 Sizofiran Polymers 0.000 claims description 2
- CGMTUJFWROPELF-UHFFFAOYSA-N Tenuazonic acid Natural products CCC(C)C1NC(=O)C(=C(C)/O)C1=O CGMTUJFWROPELF-UHFFFAOYSA-N 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- UMILHIMHKXVDGH-UHFFFAOYSA-N Triethylene glycol diglycidyl ether Chemical compound C1OC1COCCOCCOCCOCC1CO1 UMILHIMHKXVDGH-UHFFFAOYSA-N 0.000 claims description 2
- FYAMXEPQQLNQDM-UHFFFAOYSA-N Tris(1-aziridinyl)phosphine oxide Chemical compound C1CN1P(N1CC1)(=O)N1CC1 FYAMXEPQQLNQDM-UHFFFAOYSA-N 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 241000700605 Viruses Species 0.000 claims description 2
- SPJCRMJCFSJKDE-ZWBUGVOYSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] 2-[4-[bis(2-chloroethyl)amino]phenyl]acetate Chemical compound O([C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)C(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 SPJCRMJCFSJKDE-ZWBUGVOYSA-N 0.000 claims description 2
- IFJUINDAXYAPTO-UUBSBJJBSA-N [(8r,9s,13s,14s,17s)-17-[2-[4-[4-[bis(2-chloroethyl)amino]phenyl]butanoyloxy]acetyl]oxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4OC(=O)COC(=O)CCCC=1C=CC(=CC=1)N(CCCl)CCCl)C)CC2=CC=3OC(=O)C1=CC=CC=C1 IFJUINDAXYAPTO-UUBSBJJBSA-N 0.000 claims description 2
- XZSRRNFBEIOBDA-CFNBKWCHSA-N [2-[(2s,4s)-4-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1h-tetracen-2-yl]-2-oxoethyl] 2,2-diethoxyacetate Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)C(OCC)OCC)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 XZSRRNFBEIOBDA-CFNBKWCHSA-N 0.000 claims description 2
- ZOZKYEHVNDEUCO-XUTVFYLZSA-N aceglatone Chemical compound O1C(=O)[C@H](OC(C)=O)[C@@H]2OC(=O)[C@@H](OC(=O)C)[C@@H]21 ZOZKYEHVNDEUCO-XUTVFYLZSA-N 0.000 claims description 2
- 229950002684 aceglatone Drugs 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 229930183665 actinomycin Natural products 0.000 claims description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 claims description 2
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 2
- 229960000473 altretamine Drugs 0.000 claims description 2
- 229960003437 aminoglutethimide Drugs 0.000 claims description 2
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 claims description 2
- 229960002749 aminolevulinic acid Drugs 0.000 claims description 2
- 229960003896 aminopterin Drugs 0.000 claims description 2
- 229960001220 amsacrine Drugs 0.000 claims description 2
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 claims description 2
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 claims description 2
- 229950000242 ancitabine Drugs 0.000 claims description 2
- 239000003098 androgen Substances 0.000 claims description 2
- 229940030486 androgens Drugs 0.000 claims description 2
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 2
- 230000000340 anti-metabolite Effects 0.000 claims description 2
- 229940100197 antimetabolite Drugs 0.000 claims description 2
- 239000002256 antimetabolite Substances 0.000 claims description 2
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 claims description 2
- 201000008937 atopic dermatitis Diseases 0.000 claims description 2
- 229960002756 azacitidine Drugs 0.000 claims description 2
- 229950011321 azaserine Drugs 0.000 claims description 2
- 150000001541 aziridines Chemical class 0.000 claims description 2
- 229940049706 benzodiazepine Drugs 0.000 claims description 2
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 claims description 2
- 230000003115 biocidal effect Effects 0.000 claims description 2
- 229950008548 bisantrene Drugs 0.000 claims description 2
- 150000004663 bisphosphonates Chemical class 0.000 claims description 2
- 229960001467 bortezomib Drugs 0.000 claims description 2
- 229960005520 bryostatin Drugs 0.000 claims description 2
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 claims description 2
- MUIWQCKLQMOUAT-AKUNNTHJSA-N bryostatin 20 Natural products COC(=O)C=C1C[C@@]2(C)C[C@]3(O)O[C@](C)(C[C@@H](O)CC(=O)O[C@](C)(C[C@@]4(C)O[C@](O)(CC5=CC(=O)O[C@]45C)C(C)(C)C=C[C@@](C)(C1)O2)[C@@H](C)O)C[C@H](OC(=O)C(C)(C)C)C3(C)C MUIWQCKLQMOUAT-AKUNNTHJSA-N 0.000 claims description 2
- 108700002839 cactinomycin Proteins 0.000 claims description 2
- 229950009908 cactinomycin Drugs 0.000 claims description 2
- 229950009823 calusterone Drugs 0.000 claims description 2
- IVFYLRMMHVYGJH-PVPPCFLZSA-N calusterone Chemical compound C1C[C@]2(C)[C@](O)(C)CC[C@H]2[C@@H]2[C@@H](C)CC3=CC(=O)CC[C@]3(C)[C@H]21 IVFYLRMMHVYGJH-PVPPCFLZSA-N 0.000 claims description 2
- 229940127093 camptothecin Drugs 0.000 claims 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 claims description 2
- 229960004117 capecitabine Drugs 0.000 claims description 2
- 229960002115 carboquone Drugs 0.000 claims description 2
- 229960003261 carmofur Drugs 0.000 claims description 2
- 229960005243 carmustine Drugs 0.000 claims description 2
- 108010047060 carzinophilin Proteins 0.000 claims description 2
- 229950008249 chlornaphazine Drugs 0.000 claims description 2
- 229960001480 chlorozotocin Drugs 0.000 claims description 2
- 229960004316 cisplatin Drugs 0.000 claims description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 2
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 claims description 2
- 229960002286 clodronic acid Drugs 0.000 claims description 2
- 229960003901 dacarbazine Drugs 0.000 claims description 2
- 229960000640 dactinomycin Drugs 0.000 claims description 2
- 229960000975 daunorubicin Drugs 0.000 claims description 2
- 229960005052 demecolcine Drugs 0.000 claims description 2
- 229950003913 detorubicin Drugs 0.000 claims description 2
- WVYXNIXAMZOZFK-UHFFFAOYSA-N diaziquone Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 claims description 2
- 229950002389 diaziquone Drugs 0.000 claims 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 claims description 2
- 239000003534 dna topoisomerase inhibitor Substances 0.000 claims description 2
- 229960003668 docetaxel Drugs 0.000 claims description 2
- 229930188854 dolastatin Natural products 0.000 claims description 2
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 claims description 2
- 229950005454 doxifluridine Drugs 0.000 claims description 2
- 229960005501 duocarmycin Drugs 0.000 claims description 2
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 claims description 2
- 229930184221 duocarmycin Natural products 0.000 claims description 2
- XOPYFXBZMVTEJF-PDACKIITSA-N eleutherobin Chemical compound C(/[C@H]1[C@H](C(=CC[C@@H]1C(C)C)C)C[C@@H]([C@@]1(C)O[C@@]2(C=C1)OC)OC(=O)\C=C\C=1N=CN(C)C=1)=C2\CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O XOPYFXBZMVTEJF-PDACKIITSA-N 0.000 claims description 2
- XOPYFXBZMVTEJF-UHFFFAOYSA-N eleutherobin Natural products C1=CC2(OC)OC1(C)C(OC(=O)C=CC=1N=CN(C)C=1)CC(C(=CCC1C(C)C)C)C1C=C2COC1OCC(O)C(O)C1OC(C)=O XOPYFXBZMVTEJF-UHFFFAOYSA-N 0.000 claims description 2
- 229950000549 elliptinium acetate Drugs 0.000 claims description 2
- JOZGNYDSEBIJDH-UHFFFAOYSA-N eniluracil Chemical compound O=C1NC=C(C#C)C(=O)N1 JOZGNYDSEBIJDH-UHFFFAOYSA-N 0.000 claims description 2
- 229950010213 eniluracil Drugs 0.000 claims description 2
- 229950011487 enocitabine Drugs 0.000 claims description 2
- 229960001904 epirubicin Drugs 0.000 claims description 2
- 229950002973 epitiostanol Drugs 0.000 claims description 2
- 229930013356 epothilone Natural products 0.000 claims description 2
- 150000003883 epothilone derivatives Chemical class 0.000 claims description 2
- 229960001433 erlotinib Drugs 0.000 claims description 2
- 229950002017 esorubicin Drugs 0.000 claims description 2
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin 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[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 claims description 2
- LJQQFQHBKUKHIS-WJHRIEJJSA-N esperamicin Chemical compound O1CC(NC(C)C)C(OC)CC1OC1C(O)C(NOC2OC(C)C(SC)C(O)C2)C(C)OC1OC1C(\C2=C/CSSSC)=C(NC(=O)OC)C(=O)C(OC3OC(C)C(O)C(OC(=O)C=4C(=CC(OC)=C(OC)C=4)NC(=O)C(=C)OC)C3)C2(O)C#C\C=C/C#C1 LJQQFQHBKUKHIS-WJHRIEJJSA-N 0.000 claims description 2
- 229960001842 estramustine Drugs 0.000 claims description 2
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 claims description 2
- QSRLNKCNOLVZIR-KRWDZBQOSA-N ethyl (2s)-2-[[2-[4-[bis(2-chloroethyl)amino]phenyl]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound CCOC(=O)[C@H](CCSC)NC(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 QSRLNKCNOLVZIR-KRWDZBQOSA-N 0.000 claims description 2
- 229960005237 etoglucid Drugs 0.000 claims 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 claims description 2
- 229960000961 floxuridine Drugs 0.000 claims description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 2
- 235000019152 folic acid Nutrition 0.000 claims description 2
- 239000011724 folic acid Substances 0.000 claims description 2
- 229960000304 folic acid Drugs 0.000 claims description 2
- 150000002224 folic acids Chemical class 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 229960004783 fotemustine Drugs 0.000 claims description 2
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 claims description 2
- 229960002258 fulvestrant Drugs 0.000 claims description 2
- 229940044658 gallium nitrate Drugs 0.000 claims description 2
- 229960002584 gefitinib Drugs 0.000 claims description 2
- 150000004676 glycans Chemical class 0.000 claims description 2
- 229930182470 glycoside Natural products 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 claims description 2
- 229960001330 hydroxycarbamide Drugs 0.000 claims description 2
- 229940015872 ibandronate Drugs 0.000 claims description 2
- 229960000908 idarubicin Drugs 0.000 claims description 2
- 239000012216 imaging agent Substances 0.000 claims description 2
- 229960002411 imatinib Drugs 0.000 claims description 2
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 claims description 2
- 229950008097 improsulfan Drugs 0.000 claims description 2
- 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 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 229960004891 lapatinib Drugs 0.000 claims description 2
- 229940115286 lentinan Drugs 0.000 claims description 2
- 230000003902 lesion Effects 0.000 claims description 2
- 229960003881 letrozole Drugs 0.000 claims description 2
- 229960002247 lomustine Drugs 0.000 claims description 2
- 229950001750 lonafarnib Drugs 0.000 claims description 2
- YROQEQPFUCPDCP-UHFFFAOYSA-N losoxantrone Chemical compound OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO YROQEQPFUCPDCP-UHFFFAOYSA-N 0.000 claims description 2
- 229950008745 losoxantrone Drugs 0.000 claims description 2
- 229960004961 mechlorethamine Drugs 0.000 claims description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims description 2
- 229960001924 melphalan Drugs 0.000 claims description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 2
- 229950009246 mepitiostane Drugs 0.000 claims description 2
- VJRAUFKOOPNFIQ-TVEKBUMESA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-5-[(2s,4s,5s,6s)-5-[(2s,4s,5s,6s)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4-(dimethylamino)-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylat Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1C[C@H](O)[C@H](O)[C@H](C)O1 VJRAUFKOOPNFIQ-TVEKBUMESA-N 0.000 claims description 2
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 claims description 2
- 229960003539 mitoguazone Drugs 0.000 claims description 2
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 claims description 2
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 claims description 2
- 229950010913 mitolactol Drugs 0.000 claims description 2
- 229960004857 mitomycin Drugs 0.000 claims description 2
- 229960000350 mitotane Drugs 0.000 claims description 2
- 229960000951 mycophenolic acid Drugs 0.000 claims description 2
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 claims description 2
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 claims description 2
- 229960001420 nimustine Drugs 0.000 claims description 2
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 claims description 2
- 229950009266 nogalamycin Drugs 0.000 claims description 2
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@@]5(C)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 claims description 2
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 2
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 2
- VREZDOWOLGNDPW-UHFFFAOYSA-N pancratistatine Natural products C1=C2C3C(O)C(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-UHFFFAOYSA-N 0.000 claims description 2
- 229960002340 pentostatin Drugs 0.000 claims description 2
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 claims description 2
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 claims description 2
- 229950003180 peplomycin Drugs 0.000 claims description 2
- 229960000952 pipobroman Drugs 0.000 claims description 2
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 claims description 2
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 claims description 2
- 229950001100 piposulfan Drugs 0.000 claims description 2
- 229960001221 pirarubicin Drugs 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 150000003057 platinum Chemical class 0.000 claims description 2
- 229920001282 polysaccharide Polymers 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 229960004694 prednimustine Drugs 0.000 claims description 2
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 claims description 2
- 229960000624 procarbazine Drugs 0.000 claims description 2
- WOLQREOUPKZMEX-UHFFFAOYSA-N pteroyltriglutamic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(=O)NC(CCC(=O)NC(CCC(O)=O)C(O)=O)C(O)=O)C(O)=O)C=C1 WOLQREOUPKZMEX-UHFFFAOYSA-N 0.000 claims description 2
- 150000003212 purines Chemical class 0.000 claims description 2
- 229950010131 puromycin Drugs 0.000 claims description 2
- 150000003230 pyrimidines Chemical class 0.000 claims description 2
- 229960002185 ranimustine Drugs 0.000 claims description 2
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 claims description 2
- 229960000460 razoxane Drugs 0.000 claims description 2
- 206010038038 rectal cancer Diseases 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 229930002330 retinoic acid Natural products 0.000 claims description 2
- OWPCHSCAPHNHAV-LMONGJCWSA-N rhizoxin Chemical compound C/C([C@H](OC)[C@@H](C)[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@]2([H])OC(=O)C[C@@](C2)(C[C@@H]2O[C@H]2C(=O)O1)[H])=C\C=C\C(\C)=C\C1=COC(C)=N1 OWPCHSCAPHNHAV-LMONGJCWSA-N 0.000 claims description 2
- 229950004892 rodorubicin Drugs 0.000 claims description 2
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229930182947 sarcodictyin Natural products 0.000 claims description 2
- 229950001403 sizofiran Drugs 0.000 claims description 2
- 229950006315 spirogermanium Drugs 0.000 claims description 2
- 229960001052 streptozocin Drugs 0.000 claims description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 claims description 2
- 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 claims description 2
- 229960001796 sunitinib Drugs 0.000 claims description 2
- 239000013589 supplement Substances 0.000 claims description 2
- 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 claims description 2
- 229960005353 testolactone Drugs 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 claims description 2
- 229950011457 tiamiprine Drugs 0.000 claims description 2
- 229940044693 topoisomerase inhibitor Drugs 0.000 claims description 2
- 229950001353 tretamine Drugs 0.000 claims description 2
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 claims description 2
- 229960001727 tretinoin Drugs 0.000 claims description 2
- 229930013292 trichothecene Natural products 0.000 claims description 2
- 150000003327 trichothecene derivatives Chemical class 0.000 claims description 2
- 229960001670 trilostane Drugs 0.000 claims description 2
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 claims description 2
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 claims description 2
- 229960001099 trimetrexate Drugs 0.000 claims description 2
- 229960000875 trofosfamide Drugs 0.000 claims description 2
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 claims description 2
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 claims description 2
- 229930184737 tubulysin Natural products 0.000 claims description 2
- GFNNBHLJANVSQV-UHFFFAOYSA-N tyrphostin AG 1478 Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1 GFNNBHLJANVSQV-UHFFFAOYSA-N 0.000 claims description 2
- 229950009811 ubenimex Drugs 0.000 claims description 2
- 229960001055 uracil mustard Drugs 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- LLDWLPRYLVPDTG-UHFFFAOYSA-N vatalanib succinate Chemical compound OC(=O)CCC(O)=O.C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 LLDWLPRYLVPDTG-UHFFFAOYSA-N 0.000 claims description 2
- 229960004528 vincristine Drugs 0.000 claims 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 claims 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 claims description 2
- 229960002066 vinorelbine Drugs 0.000 claims description 2
- 229950009268 zinostatin Drugs 0.000 claims description 2
- 229960000641 zorubicin Drugs 0.000 claims description 2
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 7
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims 2
- 206010017758 gastric cancer Diseases 0.000 claims 2
- 201000000849 skin cancer Diseases 0.000 claims 2
- 201000011549 stomach cancer Diseases 0.000 claims 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 claims 2
- 102000009027 Albumins Human genes 0.000 claims 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims 1
- GSQYGQFRWIGVPR-UHFFFAOYSA-N C1CC1.C1=CC=CC2=NC3=CC=CC=C3C=C12 Chemical class C1CC1.C1=CC=CC2=NC3=CC=CC=C3C=C12 GSQYGQFRWIGVPR-UHFFFAOYSA-N 0.000 claims 1
- 208000034578 Multiple myelomas Diseases 0.000 claims 1
- 229940100198 alkylating agent Drugs 0.000 claims 1
- 239000002168 alkylating agent Substances 0.000 claims 1
- 229960002092 busulfan Drugs 0.000 claims 1
- 239000003560 cancer drug Substances 0.000 claims 1
- GEHLEADVHVVTET-UHFFFAOYSA-N ethyl(methyl)azanium;chloride Chemical compound [Cl-].CC[NH2+]C GEHLEADVHVVTET-UHFFFAOYSA-N 0.000 claims 1
- WHRIKZCFRVTHJH-UHFFFAOYSA-N ethylhydrazine Chemical compound CCNN WHRIKZCFRVTHJH-UHFFFAOYSA-N 0.000 claims 1
- 230000002519 immonomodulatory effect Effects 0.000 claims 1
- 125000005647 linker group Chemical group 0.000 claims 1
- 201000001441 melanoma Diseases 0.000 claims 1
- 230000001394 metastastic effect Effects 0.000 claims 1
- 206010061289 metastatic neoplasm Diseases 0.000 claims 1
- 201000000050 myeloid neoplasm Diseases 0.000 claims 1
- 239000002105 nanoparticle Substances 0.000 claims 1
- 229910052609 olivine Inorganic materials 0.000 claims 1
- 239000010450 olivine Substances 0.000 claims 1
- 229960005322 streptomycin Drugs 0.000 claims 1
- 229960003604 testosterone Drugs 0.000 claims 1
- 206010044412 transitional cell carcinoma Diseases 0.000 claims 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 claims 1
- 239000000611 antibody drug conjugate Substances 0.000 description 84
- 229940049595 antibody-drug conjugate Drugs 0.000 description 84
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 22
- 241000699670 Mus sp. Species 0.000 description 18
- 239000000562 conjugate Substances 0.000 description 15
- 201000010099 disease Diseases 0.000 description 15
- 239000000872 buffer Substances 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 230000003013 cytotoxicity Effects 0.000 description 10
- 231100000135 cytotoxicity Toxicity 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
- 210000001616 monocyte Anatomy 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- 239000000427 antigen Substances 0.000 description 8
- 108091007433 antigens Proteins 0.000 description 8
- 102000036639 antigens Human genes 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 230000021615 conjugation Effects 0.000 description 8
- 210000004408 hybridoma Anatomy 0.000 description 8
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 7
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 201000002491 encephalomyelitis Diseases 0.000 description 7
- 230000003834 intracellular effect Effects 0.000 description 7
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 6
- 238000011740 C57BL/6 mouse Methods 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 6
- 108090000695 Cytokines Proteins 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 102000013566 Plasminogen Human genes 0.000 description 6
- 108010051456 Plasminogen Proteins 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 5
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 5
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 5
- 210000004072 lung Anatomy 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 239000001509 sodium citrate Substances 0.000 description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 5
- IADUWZMNTKHTIN-MLSWMBHTSA-N (2,5-dioxopyrrolidin-1-yl) 4-[[3-[3-[[(2S)-1-[[(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl]oxy]-1-oxopropan-2-yl]-methylamino]-3-oxopropyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]methyl]cyclohexane-1-carboxylate Chemical compound CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)[C@H](C)N(C)C(=O)CCSC2CC(=O)N(CC3CCC(CC3)C(=O)ON3C(=O)CCC3=O)C2=O)[C@]2(C)O[C@H]2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2 IADUWZMNTKHTIN-MLSWMBHTSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 4
- 108010072051 Glatiramer Acetate Proteins 0.000 description 4
- 108090001005 Interleukin-6 Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- 102100024952 Protein CBFA2T1 Human genes 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 210000003719 b-lymphocyte Anatomy 0.000 description 4
- 229960001561 bleomycin Drugs 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 229940038717 copaxone Drugs 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 238000011275 oncology therapy Methods 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 239000012460 protein solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 4
- 108700012359 toxins Proteins 0.000 description 4
- 239000013598 vector Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010061818 Disease progression Diseases 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 101000882335 Homo sapiens Alpha-enolase Proteins 0.000 description 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 102000029749 Microtubule Human genes 0.000 description 3
- 108091022875 Microtubule Proteins 0.000 description 3
- 208000007542 Paresis Diseases 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 3
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 description 3
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000010367 cloning Methods 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 229940039227 diagnostic agent Drugs 0.000 description 3
- 230000005750 disease progression Effects 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 102000048964 human ENO1 Human genes 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 210000003712 lysosome Anatomy 0.000 description 3
- 230000001868 lysosomic effect Effects 0.000 description 3
- 210000004688 microtubule Anatomy 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 235000019419 proteases Nutrition 0.000 description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- JSHOVKSMJRQOGY-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-(pyridin-2-yldisulfanyl)butanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCSSC1=CC=CC=N1 JSHOVKSMJRQOGY-UHFFFAOYSA-N 0.000 description 2
- GKSPIZSKQWTXQG-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-[1-(pyridin-2-yldisulfanyl)ethyl]benzoate Chemical compound C=1C=C(C(=O)ON2C(CCC2=O)=O)C=CC=1C(C)SSC1=CC=CC=N1 GKSPIZSKQWTXQG-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- 102100027211 Albumin Human genes 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 108010016626 Dipeptides Proteins 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 101000897480 Homo sapiens C-C motif chemokine 2 Proteins 0.000 description 2
- 101000945318 Homo sapiens Calponin-1 Proteins 0.000 description 2
- 101000652736 Homo sapiens Transgelin Proteins 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 206010033799 Paralysis Diseases 0.000 description 2
- 108010081690 Pertussis Toxin Proteins 0.000 description 2
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 2
- 102100031013 Transgelin Human genes 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000021164 cell adhesion Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000023549 cell-cell signaling Effects 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 210000001163 endosome Anatomy 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 231100000518 lethal Toxicity 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 230000002132 lysosomal effect Effects 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 229960003330 pentetic acid Drugs 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 230000005945 translocation Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- UFIVODCEJLHUTQ-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-(1-phenylethyldisulfanyl)-2h-pyridine-1-carboxylate Chemical compound C=1C=CC=CC=1C(C)SSC1C=CC=CN1C(=O)ON1C(=O)CCC1=O UFIVODCEJLHUTQ-UHFFFAOYSA-N 0.000 description 1
- FLCQLSRLQIPNLM-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-acetylsulfanylacetate Chemical compound CC(=O)SCC(=O)ON1C(=O)CCC1=O FLCQLSRLQIPNLM-UHFFFAOYSA-N 0.000 description 1
- JWDFQMWEFLOOED-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(pyridin-2-yldisulfanyl)propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSSC1=CC=CC=N1 JWDFQMWEFLOOED-UHFFFAOYSA-N 0.000 description 1
- NBKZGRPRTQELKX-UHFFFAOYSA-N (2-methylpropan-2-yl)oxymethanone Chemical compound CC(C)(C)O[C]=O NBKZGRPRTQELKX-UHFFFAOYSA-N 0.000 description 1
- AGGWFDNPHKLBBV-YUMQZZPRSA-N (2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]-5-(carbamoylamino)pentanoic acid Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCNC(N)=O AGGWFDNPHKLBBV-YUMQZZPRSA-N 0.000 description 1
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- INAUWOVKEZHHDM-PEDBPRJASA-N (7s,9s)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-7-[(2r,4s,5s,6s)-5-hydroxy-6-methyl-4-morpholin-4-yloxan-2-yl]oxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1 INAUWOVKEZHHDM-PEDBPRJASA-N 0.000 description 1
- RCFNNLSZHVHCEK-IMHLAKCZSA-N (7s,9s)-7-(4-amino-6-methyloxan-2-yl)oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound [Cl-].O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)C1CC([NH3+])CC(C)O1 RCFNNLSZHVHCEK-IMHLAKCZSA-N 0.000 description 1
- FONKWHRXTPJODV-DNQXCXABSA-N 1,3-bis[2-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-3h-pyrrolo[3,2-e]indole-6-carbonyl]-1h-indol-5-yl]urea Chemical compound C1([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C4=CC(O)=C5NC=C(C5=C4[C@H](CCl)C3)C)=C2C=C(O)C2=C1C(C)=CN2 FONKWHRXTPJODV-DNQXCXABSA-N 0.000 description 1
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JHFAEUICJHBVHB-UHFFFAOYSA-N 1h-indol-2-ol Chemical compound C1=CC=C2NC(O)=CC2=C1 JHFAEUICJHBVHB-UHFFFAOYSA-N 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- YIMDLWDNDGKDTJ-QLKYHASDSA-N 3'-deamino-3'-(3-cyanomorpholin-4-yl)doxorubicin Chemical compound N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1C#N YIMDLWDNDGKDTJ-QLKYHASDSA-N 0.000 description 1
- WYXSYVWAUAUWLD-SHUUEZRQSA-N 6-azauridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=N1 WYXSYVWAUAUWLD-SHUUEZRQSA-N 0.000 description 1
- DALMAZHDNFCDRP-VMPREFPWSA-N 9h-fluoren-9-ylmethyl n-[(2s)-1-[[(2s)-5-(carbamoylamino)-1-[4-(hydroxymethyl)anilino]-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound O=C([C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(C)C)NC1=CC=C(CO)C=C1 DALMAZHDNFCDRP-VMPREFPWSA-N 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 101710165425 Alpha-enolase Proteins 0.000 description 1
- 102100038910 Alpha-enolase Human genes 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- MBABCNBNDNGODA-LTGLSHGVSA-N Bullatacin Natural products O=C1C(C[C@H](O)CCCCCCCCCC[C@@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 MBABCNBNDNGODA-LTGLSHGVSA-N 0.000 description 1
- KGGVWMAPBXIMEM-ZRTAFWODSA-N Bullatacinone Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@H]2OC(=O)[C@H](CC(C)=O)C2)CC1 KGGVWMAPBXIMEM-ZRTAFWODSA-N 0.000 description 1
- KGGVWMAPBXIMEM-JQFCFGFHSA-N Bullatacinone Natural products O=C(C[C@H]1C(=O)O[C@H](CCCCCCCCCC[C@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)C1)C KGGVWMAPBXIMEM-JQFCFGFHSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 108090000712 Cathepsin B Proteins 0.000 description 1
- 102000005600 Cathepsins Human genes 0.000 description 1
- 108010084457 Cathepsins Proteins 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 229940126161 DNA alkylating agent Drugs 0.000 description 1
- 239000012624 DNA alkylating agent Substances 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- AUGQEEXBDZWUJY-ZLJUKNTDSA-N Diacetoxyscirpenol Chemical compound C([C@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)C)O2 AUGQEEXBDZWUJY-ZLJUKNTDSA-N 0.000 description 1
- AUGQEEXBDZWUJY-UHFFFAOYSA-N Diacetoxyscirpenol Natural products CC(=O)OCC12CCC(C)=CC1OC1C(O)C(OC(C)=O)C2(C)C11CO1 AUGQEEXBDZWUJY-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 101710184673 Enolase 1 Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010088842 Fibrinolysin Proteins 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 108010009504 Gly-Phe-Leu-Gly Chemical group 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 206010061269 Malignant peritoneal neoplasm Diseases 0.000 description 1
- 241000237852 Mollusca Species 0.000 description 1
- 206010027925 Monoparesis Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 229930187135 Olivomycin Natural products 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 206010033892 Paraplegia Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- RFCVXVPWSPOMFJ-STQMWFEESA-N Phe-Leu Chemical group CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 RFCVXVPWSPOMFJ-STQMWFEESA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- NSFWWJIQIKBZMJ-YKNYLIOZSA-N Roridin A Chemical compound C([C@]12[C@]3(C)[C@H]4C[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)[C@@H](O)[C@H](C)CCO[C@H](\C=C\C=C/C(=O)O4)[C@H](O)C)O2 NSFWWJIQIKBZMJ-YKNYLIOZSA-N 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 229910052772 Samarium Inorganic materials 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- BXFOFFBJRFZBQZ-QYWOHJEZSA-N T-2 toxin Chemical compound C([C@@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@H]1[C@]3(COC(C)=O)C[C@@H](C(=C1)C)OC(=O)CC(C)C)O2 BXFOFFBJRFZBQZ-QYWOHJEZSA-N 0.000 description 1
- 229940122429 Tubulin inhibitor Drugs 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 1
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical compound [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229950004955 adozelesin Drugs 0.000 description 1
- BYRVKDUQDLJUBX-JJCDCTGGSA-N adozelesin Chemical compound C1=CC=C2OC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)NC=C5C)=CC2=C1 BYRVKDUQDLJUBX-JJCDCTGGSA-N 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000008209 arabinosides Chemical class 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229950006844 bizelesin Drugs 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- MBABCNBNDNGODA-LUVUIASKSA-N bullatacin Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-LUVUIASKSA-N 0.000 description 1
- 238000010805 cDNA synthesis kit Methods 0.000 description 1
- 229950007509 carzelesin Drugs 0.000 description 1
- BBZDXMBRAFTCAA-AREMUKBSSA-N carzelesin Chemical compound C1=2NC=C(C)C=2C([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)C3=CC4=CC=C(C=C4O3)N(CC)CC)=C2C=C1OC(=O)NC1=CC=CC=C1 BBZDXMBRAFTCAA-AREMUKBSSA-N 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000002228 disulfide group Chemical group 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003118 drug derivative Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 229940120655 eloxatin Drugs 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 229940087861 faslodex Drugs 0.000 description 1
- 229940087476 femara Drugs 0.000 description 1
- 229940001501 fibrinolysin Drugs 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 230000034659 glycolysis Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 210000001822 immobilized cell Anatomy 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 108700016226 indium-bleomycin Proteins 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000004054 inflammatory process Effects 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
- 230000003993 interaction Effects 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 230000001589 lymphoproliferative effect Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229940080607 nexavar Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- CZDBNBLGZNWKMC-MWQNXGTOSA-N olivomycin Chemical class O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1)O[C@H]1O[C@@H](C)[C@H](O)[C@@H](OC2O[C@@H](C)[C@H](O)[C@@H](O)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@H](O)[C@H](OC)[C@H](C)O1 CZDBNBLGZNWKMC-MWQNXGTOSA-N 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 201000002524 peritoneal carcinoma Diseases 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 108010073101 phenylalanylleucine Proteins 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000033885 plasminogen activation Effects 0.000 description 1
- 210000002706 plastid Anatomy 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- RXZQNZROTOXEFG-UHFFFAOYSA-N prop-1-ene-1,2,3-tricarboxamide Chemical compound NC(=O)CC(C(N)=O)=CC(N)=O RXZQNZROTOXEFG-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940099538 rapamune Drugs 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 125000006853 reporter group Chemical group 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- MBABCNBNDNGODA-WPZDJQSSSA-N rolliniastatin 1 Natural products O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@H]1[C@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-WPZDJQSSSA-N 0.000 description 1
- IMUQLZLGWJSVMV-UOBFQKKOSA-N roridin A Natural products CC(O)C1OCCC(C)C(O)C(=O)OCC2CC(=CC3OC4CC(OC(=O)C=C/C=C/1)C(C)(C23)C45CO5)C IMUQLZLGWJSVMV-UOBFQKKOSA-N 0.000 description 1
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 1
- 150000003349 semicarbazides Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- ICXJVZHDZFXYQC-UHFFFAOYSA-N spongistatin 1 Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(OC(C)=O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC(Cl)=C)OC1C2C ICXJVZHDZFXYQC-UHFFFAOYSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- CIOAGBVUUVVLOB-OUBTZVSYSA-N strontium-89 Chemical compound [89Sr] CIOAGBVUUVVLOB-OUBTZVSYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- RCINICONZNJXQF-XAZOAEDWSA-N taxol® Chemical compound O([C@@H]1[C@@]2(CC(C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3(C21)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-XAZOAEDWSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 230000000451 tissue damage Effects 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
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- VEDJZFSRVVQBIL-UHFFFAOYSA-N trisilane Chemical compound [SiH3][SiH2][SiH3] VEDJZFSRVVQBIL-UHFFFAOYSA-N 0.000 description 1
- 239000000439 tumor marker Substances 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 229940094060 tykerb Drugs 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6843—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a material from animals or humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- 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
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
Landscapes
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Enzymes And Modification Thereof (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
Abstract
一種免疫共軛物包括抗ENO-1抗體,或其結合片段,以及具有以下公式之治療劑或標記物:Ab-(L-D)m
,其中Ab為該抗ENO-1抗體或其結合片段,L為連接子或直接鍵,D為治療劑或標記物,m為1至12的整數。該抗體可為單株抗體,其可為人源化抗體或全人類抗體。一種治療發炎性疾病、免疫疾病,或癌症之方法,包括對一需要這種治療的受試者施用醫藥有效量之免疫共軛物,其包含針對ENO-1的抗體,或其結合片段,以及與該抗體共價共軛之治療劑。
Description
本申請主張於2020年5月11日申請之美國臨時案第63/022,702號之優先權,針對所有目的係將其以引用之方式併入本文。
本發明關於一種含有抗人類α-烯醇酶蛋白(ENOlase protein,ENO-1)抗體及其治療用途之抗體-藥物共軛物。本發明還關於一種用於治療發炎性疾病或免疫疾病之方法,或透過對一受試者施用抗α-烯醇酶蛋白(ENO-1)抗體-藥物共軛物(antibody-drug conjugate,ADC)來抑制腫瘤生長以及轉移。
抗體-藥物共軛物(Antibody-drug conjugates,ADCs)可提供標靶療法以治療各種疾病或病症,如癌症。ADCs為包含與生物活性劑,如細胞毒性劑或藥物相關的抗體的複雜分子。透過結合抗體的獨特標靶與藥物的治療效果,抗體-藥物共軛物可區分正常以及癌細胞,進而最小化副作用。
ADCs通常包括一細胞毒性藥物(例如,微管蛋白抑制劑或DNA烷基化劑),其耦合至以一標記物,例如腫瘤標記物,為特異性標靶的抗體。抗體在體內追蹤這些蛋白質並將其自身連接到癌細胞的表面。抗體與該標靶蛋白(抗原)之間的結合觸發腫瘤細胞內的訊號,然後將該ADC內化。在該ADC內化後,可釋放該細胞毒性藥物並殺死該腫瘤。由於該特異性標靶,該藥物具有較低的副作用。
α-烯醇酶(Enolase-1,ENO-1)為一種多功能蛋白,首先被發現作為醣分解途徑的關鍵酶。在正常情況下,ENO-1在細胞質液中表現。然而,ENO-1還被發現在許多癌細胞的細胞表面上表現作為一纖維蛋白溶酶原受體以及在活化的造血細胞上,例如嗜中性白血球、淋巴細胞以及單核細胞。已知纖維蛋白溶酶原受體蛋白的上調可誘導尿激酶纖維蛋白溶酶原活化系統的級聯反應,並導致細胞外基質降解。結果導致癌細胞轉移增加以及免疫細胞的浸潤。發炎性刺激物,例如LPS,會透過轉譯後修飾以及易位至細胞表面而上調在人類血液單核細胞以及在U937單核細胞上ENO-1細胞表面的表現。
據信ENO-1的易位由MAP激酶訊號傳遞途徑調節。這代表ENO-1在細胞表面表現的增加可能在發炎性疾病中具有重要的作用。針對ENO-1的自身抗體已在可變自體免疫以及發炎性疾病中被發現,包括紅斑性狼瘡、全身性硬化症、貝雪氏病(Behcet’s disease)、潰瘍性結腸炎以及克羅恩氏病(Crohn’s disease)。已知透過ENO-1的纖維蛋白溶酶原受體活性,ENO-1藉由增加單核細胞及巨噬細胞的侵襲活性在類風濕性關節炎患者的疾病進展中具有關鍵作用。
總而言之,具有在細胞表面上調的ENO-1表現作為增加侵襲活性的纖維蛋白溶酶原受體的單核細胞對多發性硬化症、類風濕性關節炎,以及相關免疫障礙的疾病進展非常重要。因此,以在單核細胞的細胞表面上的ENO-1為標靶具有良好的潛力來治療發炎性疾病,例如多發性硬化症、類風濕性關節炎、克羅恩氏病、潰瘍性結腸炎,以及全身性紅斑性狼瘡,或相關免疫疾病,如慢性阻塞性肺病(chronic obstructive pulmonary disease,COPD)、氣喘、過敏、牛皮癬、第1型糖尿病、動脈粥樣硬化以及骨質疏鬆症。
此外,作為纖維蛋白溶酶原受體的癌細胞表面上的ENO-1的表現可增加該癌細胞的侵襲活性。因此,ENO-1也是癌症治療的潛在目標。
儘管針對ENO-1的抗體是有用的,但仍需使用抗ENO-1 ADCs的改良治療劑。
本發明關於一種含有ENO-1抗體的抗體-藥物共軛物及其治療用途。
本發明之一態樣關於一種免疫共軛物。根據本揭露之一具體實施例的免疫共軛物包括一抗ENO-1抗體,或其結合片段,以及具有式:Ab-(L-D)m
的治療劑或標記物,其中Ab為抗ENO-1抗體或其結合片段,L為連接子或直接鍵,D為治療劑或標記物,m為1至12的整數。
根據本發明之任何具體實施例,該Ab可包含一重鏈可變結構域,其具有三個互補區域,包括HCDR1(GYTFTSCVMN;SEQ ID NO: 1)、HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO: 2),以及HCDR3(EGFYYGNFDN;SEQ ID NO: 3)以及一輕鏈可變結構域,其具有三個互補區域,包括LCDR1(RASENIYSYLT;SEQ ID NO: 4)、LCDR2(NAKTLPE;SEQ ID NO: 5),以及LCDR3(QHHYGTPYT;SEQ ID NO: 6)。
根據本發明之任何具體實施例,該Ab可包含一重鏈可變結構域,其具有三個互補區域,包括HCDR1(GYTFTSXVMN,其中X為除了半胱胺酸之外的任何胺基酸;SEQ ID NO: 7)、HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO: 2),以及HCDR3(EGFYYGNFDN;SEQ ID NO: 3),以及一輕鏈可變結構域,其具有三個互補區域,包括LCDR1(RASENIYSYLT;SEQ ID NO: 4)、LCDR2(NAKTLPE;SEQ ID NO: 5),以及LCDR3(QHHYGTPYT;SEQ ID NO: 6)。
該連接子L可為直接鍵,其中有效負載D與該抗體或其結合片段直接連接(共軛)。連接子可為蛋白質修飾或共軛物中常用的任何連接子,例如短胜肽(例如,val-cit)、短的有機分子連接子(例如,琥珀醯亞胺基-4(N-馬來醯亞胺甲基)環己烷-1-羧酸酯,succinimidyl-4 (N-maleimidomethyl) cyclohexane-1-carboxylate,SMCC),或類似物。
該有效負載D可為治療劑,例如細胞毒性劑。可與本發明之具體實施例一起使用的細胞毒性劑的實例可包括一化療藥美登木素生物鹼(maytansinoid)(例如,DM1或DM4)、單甲基澳瑞他汀E(monomethyl auristatin E,MMAE)、單甲基澳瑞他汀F(MMAF)、紫杉醇等。
該有效負載D可被用於診斷或成像的標籤或試劑。成像劑的實例可包括二亞乙基三胺五乙酸(Diethylenetriaminepentaacetic acid,DTPA)或1,4,7,10-四氮環十二烷-1,4,7,10-四乙酸(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid,DOTA)。
根據本發明之某些具體實施例,該抗體可為單株抗體,其可為人源化抗體或全人類抗體。
本發明之一態樣涉及用於診斷或成像細胞或表現ENO-1的組織之方法。根據本發明本揭露之一具體實施例之方法可包括給予一受試者一上述免疫共軛物。
根據本發明之某些具體實施例,人類ENO-1蛋白相關的疾病或病症可能為因為人類ENO-1蛋白的異常活化或表現而產生的任何病症。這類疾病的實例包括人類ENO-1蛋白與其配體異常相互作用,進而改變細胞黏附或細胞訊號性質。細胞黏附或細胞訊號傳遞性質的這種改變可導致腫瘤疾病及/或發炎或免疫疾病。
本發明之一態樣涉及治療發炎性疾病或免疫疾病之方法,如多發性硬化、類風濕性關節炎、克羅恩氏病、潰瘍性結腸炎、全身性紅斑性狼瘡、或相對免疫疾病,如慢性阻塞性肺病(COPD)、異位性皮膚炎、特發性肺纖維化、非酒精性脂肪肝炎、氣喘、過敏、牛皮癬、牛皮癬性關節炎、第1型糖尿病、動脈粥樣硬化、骨質疏鬆症、系統性硬化、病毒誘導肺炎,或巨噬細胞活化症候群。
本發明之一態樣涉及治療癌症之方法。根據本發明之一具體實施例之方法可包括對一需要癌症治療的受試者施用醫藥上有效量的上述免疫共軛物。該癌症為一種高度ENO-1表現的癌症,如肺癌、乳癌、胰臟癌、肝癌、直腸癌,以及前列腺癌。
本發明所屬技術領域中具有通常知識者將理解,醫藥上有效量取決於許多因素,如患者病症、年齡、疾病狀態、施用途徑等,且這種有效量可基於常規實踐中的這些因素來確定,而無需過度實驗。
透過以下描述所請發明之其他態樣將變得顯而易見。
一般定義
除非另有說明,否則本發明之實施將採用本領域技術內的分子生物學、微生物學、重組DNA,以及免疫學的常規技術。這些技術在文獻中被充分解釋。參閱,例如,Molecular Cloning A Laboratory Manual,第2版,由Sambrook、Fritch以及Maniatis編輯(冷泉港實驗室出版社,1989年);DNA Cloning,第I及II卷(D. N. Glover編輯,1985年);Culture Of Animal Cells(R.I. Froundney,Alan R. Liss公司,1987年);Immobilized Cells And Enzymes(IRL出版社,1986年);B. Perbal,A Practical Guide To Molecular Cloning(1984年);Methods In Enzymology博士論文(Academic出版社公司,紐約);Gene Transfer Vectors For Mammalian Cells(J. H. Miller以及M. P. Calos編輯,1987年,冷泉港實驗室);Methods In Enzymology,第154及155卷(Wu等人編輯),Immunochemical Methods In Cell And Molecular Biology(Mayer與Walker編輯,Academic出版社,倫敦,1987年);Antibodies: A Laboratory Manual,由Harlow與Lane編輯(冷泉港實驗室出版社,1988年);以及Handbook Of Experimental Immunology,第I-IV卷(D. M. Weir與C. Blackwell編輯,1986年)。
術語「抗體」以及「免疫球蛋白」在最廣泛的意義上可互換地使用,包括單株抗體(例如,全長或完整的單株抗體)、多株抗體、單價、多價抗體、多特異性抗體(例如,雙特異性抗體,只要它們表現出所需的生物活性)且還可包括某些抗體片段(如本文更詳細描述的)。抗體可為嵌合、人類的、人源化的及/或親和力成熟的。
術語「變量」係指以下事實:可變結構域的某些部分在抗體之間的序列差異很大,並用於每種特定抗體對其特定抗原的結合和特異性。然而,可變性並非均勻地分佈在整個抗體的可變結構域中。它集中在輕鏈及重鏈可變結構域兩者都存在的一個名為互補性決定區域(complementarity-determining regions,CDRs)或高變異區域的三個區段。可變結構域的較高度保守的部分稱為框架(framework,FR)。天然重鏈以及輕鏈的可變結構域各自包括四個FR區域,主要採用β-褶板構造,透過三個CDRs連接,其形成環連接,並在一些情況下形成該β-褶板結構的一部分。每個鏈中的CDRs在FR區附近保持在一起,並與來自其他鏈的CDRs接在一起,有助於形成抗體的抗原結合位點(見Kabat等人,Sequences of Proteins of Immunological Interest,第五版,國家衛生研究院,貝塞斯達市,馬里蘭州(1991年))。恆定結構域不直接涉及將抗體結合到抗原,但表現出各種效應功能,例如抗體在抗體依賴性細胞毒性中的參與。
抗體可為全長的,或可包含具有一抗原結合部分的抗體的一片段(或多個片段),包括但不限於Fab、F(ab')2
、Fab'、F(ab)'、Fv、單鏈Fv(scFv)、二價scFv(bi-scFv)、三價scFv(tri-scFv)、Fd、dAb片段(例如,Ward等人,Nature,341 :544-546(1989年))、一 CDR、雙體、三體、四體、線性抗體、單鏈抗體分子,以及由抗體片段形成的多特異性抗體。透過使用重組方法或合成連接子透過連接抗體片段產生的單鏈抗體也包括在本發明內。Bird等人,Science,1988年,242:423-426。Huston等人,Proc. Natl. Acad. Sci. USA,1988年,85:5879-5883。
具有一可變重鏈區以及一可變輕鏈區的抗體,該可變重鏈區以及該可變輕鏈區與由參考抗體所產生的抗體之可變重鏈區以及可變輕鏈區具有至少約70%,至少約75%,至少約80%,至少約81%,至少約82%,至少約為83%,至少約84%,至少約85%,至少約86%,至少約87%,至少約88%,至少約89%,至少約90%,至少約91%,至少約92%,至少約93%,至少約94%,至少約95%,至少約96%,至少約97%,至少約98%,至少約99%或約100%的同源性,亦可與ENO-1結合。同源性可存在於胺基酸或核苷酸序列的層級。
術語「可變結構域殘基的Kabat編號」或「胺基酸位置的Kabat編號」,及其變化,係指用於重鏈可變結構域或輕鏈可變結構域的Kabat等人抗體彙編的編號系統,Kabat等人,Sequences of Proteins of Immunological Interest,第5版,公共衛生服務部,國家衛生研究院,貝塞斯達市,馬里蘭州(1991年)。使用該編號系統,實際的線性胺基酸序列可能包含更少或更多對應於可變結構域的FR或HVR的縮短或插入的胺基酸。例如,一重鏈可變結構域可包括在H2殘基52之後的單個胺基酸插入(根據Kabat的殘基52a)以及在重鏈FR殘基82之後的插入殘基(例如,根據Kabat的殘基82a、82b,以及82c等)。可透過在一給定的抗體序列的同源區與一「標準」Kabat編號序列進行比對來確定該給定的抗體的殘基的Kabat編號。
術語「癌症」以及「癌症的」係指或描述哺乳動物中的生理條件,該生理條件通常的特徵在於由不受控的細胞生長/增殖。癌症的實例包括,但不限於惡性腫瘤、淋巴瘤(例如,霍奇金氏(Hodgkin)以及非霍奇金氏淋巴瘤)、胚細胞瘤、肉瘤,以及血癌。這些癌症的更具體的實例包括鱗狀細胞癌、小細胞肺癌、非小細胞肺癌、肺腺癌、肺鱗狀癌、腹膜癌、肝細胞癌、胃腸癌、胰臟癌、神經膠質母細胞瘤、子宮頸癌、卵巢癌、肝臟癌、膀胱癌、肝癌、乳癌、大腸癌、大腸直腸癌、子宮內膜或子宮癌、唾腺癌、腎癌、肝臟癌、前列腺癌、外陰癌、甲狀腺癌、肝癌、血癌以及其他淋巴增生病變,以及各種類型的頭頸癌。
如本文所用,「治療」係指試圖改變所處理的個體或細胞的自然過程的臨床干預,且可用於預防或在臨床病理過程中進行。治療的理想效果包括預防疾病的發生或復發、減輕症狀、對疾病的任何直接或間接病理後果的減少、預防或減少發炎及/或組織/器官損傷、降低疾病進展的速度、改善或緩和疾病狀態,以及緩解或改善預後。於一些具體實施例中,本發明之抗體用於延遲疾病或病症的發展。
「個人」或「受試者」為脊椎動物。於某些具體實施例中,該脊椎動物為哺乳動物。哺乳動物包括,但不限於,農場動物(如奶牛)、運動動物、寵物(如貓、狗及馬)、靈長類動物、小鼠以及大鼠。於某些具體實施例中,該脊椎動物為人類。
「有效量」係指在劑量以及所需時間內的有效量,以達到所需的治療或預防效果。
本發明之物質/分子的「治療有效量」可根據例如個體的疾病狀態、年齡、性別,以及體重等因素,以及該物質/分子的能力而變化,以在該個體內引發所需的反應。治療有效量也是該物質/分子的任何毒性或有害作用都被治療有益作用所超過的量。「預防有效量」係指在劑量以及所需時間內有效的量,以達到所需的預防效果。通常但不一定是,由於一預防劑量係用於染病前或染病早期階段的受試者中,該預防有效量將小於該治療有效量。
如本文所用之術語「治療劑」係指抑制或防止細胞功能及/或導致細胞破壞的物質。該術語目的在於包括放射性同位素(例如,211
At、131
I、125
I、90
Y、186
Re、188
Re、153
Sm、212
Bi、32
P、60
C,以及鎦-177、鍶-89以及釤(153
Sm)的放射性同位素)、免疫調節劑、細胞毒性劑,以及毒素,例如小分子毒素或細菌、真菌、植物或動物來源的酶促活性毒素,包括合成類似物及其衍生物。
「細胞毒性劑」為一種可用於治療癌症的化合物。化學治療劑的實例包括美登木素生物鹼1(maytansinoids 1,DM1)、美登木素生物鹼4(DM4)、單甲基澳瑞他汀E(Monomethyl auristatin E,MMAE),單甲基澳瑞他汀F(MMAF)、蒽環素、吡咯洛唑二氮雜,α-蠅蕈素、微管溶素(tubulysin)、苯二氮平類藥物、厄洛替尼(erlotinib)(TARCEVA®
,Genentech/OSI製藥公司)、硼替佐米(Bortezomib)(VELCADE®
,Millenium製藥公司)、氟維司群(Fulvestrant)(FASLODEX®
,Astrazeneca公司)、舒尼替尼(Sunitinib)(SUTENT®
,Su11248,Pfizer公司)、來曲唑(letrozole)(FEMARA®
,Novartis公司)、甲磺酸伊馬替尼(imatinib)(GLEEVEC®
,Novartis公司)、PTK787/ZK 222584(Novartis公司)、奧沙利鉑(Oxaliplatin)(ELOXATIN®
,Sanofi公司)、菊白葉酸(leucovorin)、雷帕黴素(Sirolimus,RAPAMUNE®
,Wyeth公司)、拉帕替尼(lapatinib)(TYKERB®
,GSK572016,GlaxoSmithKline公司)、洛那法尼(lonafarnib)(SARASAR®
,SCH 66336)、索拉非尼(sorafenib)(NEXAVAR®
,Bay43-9006,Bayer Labs.公司),以及吉非替尼(gefitinib)(IRESSA®
,Astrazeneca公司)、AG1478、AG1571(SU 5271;Sugen公司),烷基化試劑,如噻替哌(thiotepa)以及CYTOXAN®
環膦醯胺;亞烷基磺酸鹽,如白消安(busulfan)、英丙舒凡(improsulfan)以及哌泊舒凡(piposulfan);氮丙啶類,如苯唑多巴(benzodopa)、卡波醌(carboquone)、米得哌(meturedopa)以及烏得哌(uredopa);吖環丙烷(ethylenimines)以及甲基蜜胺類(methylamelamines),包括六甲蜜胺(altretamine)、三乙烯三聚氰胺(triethylenemelamine)、三亞乙基磷醯胺(triethylenephosphoramide)、三亞乙基硫代磷醯胺(triethylenethiophosphoramide)以及三甲基蜜胺(trimethylomelamine);內酯(acetogenins)(特別是布拉他辛(bullatacin)以及布拉他辛酮(bullatacinone));一種喜樹鹼(camptothecin)(包括合成模擬托普樂肯(Topotecan));苔蘚蟲素(bryostatin);卡利斯他汀(callystatin);CC-1065(包括其阿多來新(adozelesin)、卡折來新(carzelesin)以及比塞萊新(bizelesin)合成類似物);念珠藻素(cryptophycins)(特別是念珠藻素1以及念珠藻素8);尾海兔素(dolastatin);杜卡黴素(duocarmycin)(包括合成類似物,KW-2189以及CB1-TM1);艾榴塞洛素(eleutherobin);胰抑素(pancratistatin);珊瑚素(sarcodictyin);海綿素(spongistatin);氮芥劑如氯芥苯丁酸(chlorambucil)、萘氮芥(chlornaphazine)、氯萘嗪(cholophosphamide)、環磷醯胺(cholophosphamide)、雌莫司汀(estramustine)、異環磷醯胺(ifosfamide)、甲氯乙胺(mechlorethamine)、鹽酸甲乙胺鹽酸鹽(mechlorethamine oxide hydrochloride)、美法侖(melphalan)、新氮芥(novembichin)、苯芥膽甾醇(phenesterine)、潑尼氮芥(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亞硝基脲(nitrosureas),如卡莫司汀(carmustine)、氯脲霉素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)以及雷諾氮芥(ranimustine);抗生素,如烯二炔抗生素(例如,卡奇黴素(calicheamicin),尤其是卡奇黴素γ1以及卡奇黴素ω1(Angew Chem. Intl. Ed. Engl.(1994年)33:183-186);達尼黴素(dynemicin),包括達尼黴素A;雙磷酸鹽類,如氯磷酸鹽(clodronate);埃司帕黴素(esperamicin);以及新卡他汀發色團(neocarzinostatin chromophore)以及相關的色素蛋白烯二炔抗生素發色團)、阿克拉黴素(aclacinomysins)、放線菌黴素(actinomycin)、安麯黴素(authramycin)、茜素(azaserine)、博萊黴素(bleomycins)、放線菌素(cactinomycin)、卡拉黴素(carabicin)、洋紅黴素(caminomycin)、嗜癌菌素(carzinophilin)、色黴素(chromomycinis)、放線菌素(dactinomycin)、道諾黴素(daunorubicin)、艾黴素(detorubicin)、6-重氮-5-氧代-L-正白胺酸、ADRIAMYCIN®
阿黴素(doxorubicin)(包括嗎啉代阿黴素、氰基嗎啉代阿黴素、2-吡咯啉-阿黴素以及去氧阿黴素)、泛艾黴素(epirubicin)、表阿黴素(esorubicin)、艾達黴素(idarubicin)、麻西羅黴素(marcellomycin),絲裂黴素(mitomycins),如絲裂黴素C、黴酚酸(mycophenolic acid)、諾加黴素(nogalamycin)、橄欖黴素(olivomycins)、培洛黴素(peplomycin)、泊非黴素(potfiromycin)、嘌呤黴素(puromycin)、喹納黴素(quelamycin)、羅黴素(rodorubicin)、鏈黑菌素(streptonigrin)、鏈脲佐菌素(streptozocin)、結核菌素(tubercidin)、苯丁抑制素(ubenimex)、新制癌菌素(zinostatin)、紅柔黴素(zorubicin);抗代謝物,如氨甲蝶呤(methotrexate)以及5-氟尿嘧啶(5-fluorouracil,5-FU);葉酸類似物,如二甲葉酸(denopterin)、蝶羅呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤類似物,如氟達拉濱(fludarabine)、6-巰基嘌呤(6-mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鳥嘌呤(thioguanine);嘧啶類似物,如安西他濱(ancitabine)、阿扎胞苷(azacitidine)、6-硫唑脲嘧啶(6-azauridine)、卡莫呋(carmofur)、阿糖胞苷(cytarabine)、雙去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、伊諾他濱(enocitabine)、氟尿苷(floxuridine);雄激素,如鈣雌酮(calusterone)、屈他雄酮丙酸酯(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄酮(mepitiostane)、睾內酯酮(testolactone);抗腎上腺劑,如胺魯米特(aminoglutethimide)、米托坦(mitotane)、三矽烷(trilostane);葉酸補充劑,如醛葉酸(folinic acid);乙醯格雷酮(aceglatone);醛磷醯胺糖苷(aldophosphamide glycoside);胺乙醯丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);阿莫司汀(bestrabucil);比生群(bisantrene);依達曲沙(edatraxate);地磷醯胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);艾福米辛(elformithine);依利醋銨(elliptinium acetate);埃博黴素(epothilone);依託格魯(etoglucid);硝酸鎵;羥基脲; 香菇多醣(lentinan);氯尼達明(lonidainine);美登木素生物鹼(maytansinoids),如美登素(maytansine)以及安絲菌素(ansamitocins);米托脲腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidanmol);硝拉維林(nitraerine);噴司他丁(pentostatin);蛋胺氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基醯肼(ethylhydrazide);甲基芐肼(procarbazine);PSK®多醣複合物(JHS Natural Products公司,尤金市,奧勒岡州);雷佐生(razoxane);根黴素(rhizoxin);西佐喃(sizofiran);鍺螺胺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);三亞胺醌(Triaziquone);2,2’,2’’-三氯三乙胺(trichlorotriethylamine);新月毒素(trichothecenes)(特別是T-2毒素、黏液黴素A(verracurin A)、羅丹丁A(roridin A)以及蛇形菌素(anguidine));烏拉坦(urethan);長春地辛(vindesine);達卡巴仁(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);溴丙哌嗪(pipobroman);甲托辛(gacytosine);阿糖胞苷(arabinoside)(「Ara-C」);環磷醯胺(cyclophosphamide);噻替哌(thiotepa);類紫杉醇(taxoids),例如TAXOL®
紫杉醇(paclitaxel)(Bristol-Myers Squibb Oncology公司,普林斯頓,紐澤西州),ABRAXANE™不含Cremophor,紫杉醇的白蛋白工程化奈米粒子製劑(American Pharmaceutical Partners,紹姆堡,伊利諾州),以及TAXOTERE®
歐洲紫杉醇(docetaxel)(Rhône-Poulenc Rorer公司,安東尼,法國);苯丁酸氮芥(chloranbucil);GEMZAR®
吉西他濱(gemcitabine);6-硫鳥嘌呤(6-thioguanine);巰基嘌呤(mercaptopurine);氨甲蝶呤(methotrexate);鉑類似物,如順鉑(cisplatin)以及卡鉑(carboplatin);長春花鹼(vinblastine);鉑;依託泊苷(etoposide)(VP-16);異環磷醯胺(ifosfamide);米托蔥醌(mitoxantrone);長春新鹼(vincristine);NAVELBINE®
溫諾平(vinorelbine);米托蔥醌(novantrone);替尼泊苷(teniposide);依達曲沙(edatrexate);道諾黴素(daunomycin);胺基蝶呤(aminopterin;);截瘤達(xeloda);伊班膦酸(ibandronate);CPT-11;拓撲異構酶抑制劑RFS 2000;二氟甲基鳥胺酸(difluoromethylornithine,DMFO);維他命A酸類(retinoids),如視黃酸(retinoic acid);卡培他濱(capecitabine)(XELODA®
,Roche公司);以及上述任何一種的醫藥上可接受的鹽類、酸類或衍生物。
示例性
ADC
連接子
該ADC的合適示例性連接子描述於,例如美國專利第7,595,292號(PCT公開號WO2005/007197)中。針對連接子的整個內容在此引入作為參考。該連接子,L,透過共價鍵,不包含二硫化物基團,將抗體附著至一藥物部分體上。該連接子為一雙功能或多功能部分體,其可用於將一種或多種治療劑或標記物(D)以及一抗體單元(Ab)連接起來以形成式(I)之抗體-藥物共軛物(ADCs)。使用具有反應性官能度以將該藥物連接至該抗體上的連接子可方便地製備抗體-藥物共軛物(ADCs)。一半胱胺酸硫醇,或一胺類,例如抗體(Ab)的N端或胺基酸側鏈如離胺酸,可與一連接子試劑、藥物部分體或藥物連接子試劑的官能基團形成一鍵結。
該連接子較佳為細胞外穩定的。在運輸或遞送至一細胞前,該抗體-藥物共軛物(ADCs)較佳為穩定且保持完整的,亦即該抗體與該藥物部分體保持連結。該連接子在標靶細胞外穩定,且可在細胞內以一定的有效速率切割。有效的連接子將:(i)保持該抗體的特異性結合特性;(ii)允許細胞內遞送該共軛物或藥物部分體;(iii)保持穩定及完整,亦即未切割,直至該共軛物已遞送或運輸至其目標位點;以及(iv)保持細胞毒性、細胞殺傷作用或該治療劑或標記部分體的細胞抑制效果。該ADC的穩定性可透過標準分析技術,例如質譜、HPLC,以及分離/分析技術LC/MS來測量。
該抗體以及該治療劑或標記部分體的共價附著需要該連接子具有兩個反應性官能基團,亦即在反應意義上的二價。對附著有用的兩個或更多個功能或生物活性部分體的二價連接子試劑,例如胜肽、核酸、藥物、毒素、抗體、不完全抗原,以及報導子基團為已知的,且已經描述其所得到的共軛物之方法(Hermanson,G. T.(1996年)Bioconjugate Techniques
; Academic Press出版社:紐約,p234-242)。
通常,該抗體-藥物共軛物化合物包含一介於該治療劑或標記單元以及該抗體單元之間的一連接子單元。於某些具體實施例中,該連接子在細胞內條件下可裂解,使得該連接子的切割在細胞內環境中釋放來自該抗體的該藥物單元。於其他具體實施例中,該連接子單元不可切割,且該藥物例如透過抗體降解釋放。
於某些具體實施例中,該連接子由存在於該細胞內環境中的一切割劑(例如,在溶酶體或胞內體或胞膜窖內)裂解。該連接子可為,例如,透過細胞內胜肽酶或蛋白酶切割的胜肽基連接子,包括,但不限於,溶酶體或胞內體蛋白酶。於某些具體實施例中,該胜肽基連接子為至少兩個胺基酸長或至少三個胺基酸長。切割劑可包括組織蛋白酶B及D以及血漿纖維溶素,所有這些都是已知用於水解二胜肽藥物衍生物,導致標靶細胞內的活性藥物之釋放(參閱,例如,Dubowchik與Walker,1999年,Pharm. Therapeutics 83:67-123)。最典型為胜肽基連接子,其被存在於158P1D7表現細胞中的酶裂解。例如,可使用由在癌組織中高度表現的硫醇依賴性蛋白酶組織蛋白酶-B所切割的一胜肽基連接子(例如,Phe-Leu或Gly-Phe-Leu-Gly連接子)。這些連接子的其他實例描述於例如美國專利第6,214,345號中,其全文並出於所有目的透過引用併入本文。於一特定具體實施例中,透過一細胞內蛋白酶裂解的胜肽基連接子為Val-Cit連接子或Phe-Lys連接子(參閱,例如,美國專利第6,214,345號,其描述帶有該val-cit連接子的阿黴素(doxorubicin)之合成)。使用該治療劑的細胞內蛋白水解釋放的一個優點是當共軛時該試劑通常為減弱的,且該共軛物的血清穩定性通常很高。
於其他具體實施例中,該可切割的連接子為pH敏感的,亦即對某些pH值的水解敏感。通常,在酸性條件下可水解pH敏感的連接子。例如,可使用可在溶酶體中可水解的酸不穩定的連接子(例如,腙、縮胺脲、硫半卡腙、順式烏頭醯胺、原酸酯、縮醛、縮酮等)。(參閱,例如,美國專利第5,122,368號;第5,824,805號;第5,622,929號;Dubowchik與Walker,1999年,Pharm. Therapeutics 83:67-123;Neville等人,1989年,Biol. Chem. 264:14653-14661)。這種連接子在中性pH條件下相對穩定,例如血液中的那些環境,但在低於pH 5.5或5.0,溶酶體的近似pH下則不穩定。於某些具體實施例中,該可水解連接子為一硫代醚連接子(例如,透過一醯基腙鍵連接到該治療劑上的硫醚(參閱,例如,美國專利第5,622,929號))。
於其他具體實施例中,該連接子在還原條件下可裂解(例如,二硫化物連接子)。各種二硫鍵連接子為本領域已知的,包括,例如,可使用SATA(N-琥珀醯亞胺基-S-乙醯硫代乙酸酯)、SPDP(N-琥珀醯亞胺基-3-(2-吡啶二硫基)丙酸鹽)、SPDB(N-琥珀醯亞胺基-3-(2-吡啶二硫基)丁酸鹽)以及SMPT(N-琥珀醯亞胺基-氧基羰基-α-甲基-α-(2-吡啶基-二硫基)甲苯)、SPDB以及SMPT形成的那些。(參閱,例如,Thorpe等人,1987年,Cancer Res. 47:5924-5931;Wawrzynczak等人,In Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer(CW Vogel編輯,牛津大學出版社,1987年。另見美國專利第4,880,935號)。
在其他特定具體實施例中,該連接子為丙二酸連接子(Johnson等人,1995年,Anticancer Res. 15:1387-93)、馬來醯亞胺苯甲醯連接子(Lau等人,1995年,Bioorg-Med-Chem. 3(10):1299-1304),或3'-N-醯胺類似物(Lau等人,1995年,Bioorg-Med-Chem. 3(10):1305-12)。
於其他具體實施例中,該連接子單元不可切割,且透過抗體降解釋放藥物。(參閱美國專利公開第2005/0238649號,其整體以及所有目的透過引用合併於本文)。
通常,該連接子對細胞外環境基本上不敏感。如本文所用,在涉及連接子的內容中,「對細胞外環境基本上不敏感」,代表在一抗體-藥物共軛物化合物的樣品中不超過約20%,通常不超過約15%,更通常不超過約10%,甚至更通常不超過約5%,不超過約3%,或不超過約1%的該連接子,當該抗體-藥物共軛物化合物存在於細胞外環境中(例如,在血漿中)該連接子被裂解。例如,透過將血漿與該抗體-藥物共軛物化合物一起作用一段預定的時間段(例如,2、4、8、16,或24小時),然後定量在血漿中存在的游離藥物量,可確定該連接子是否基本上對該細胞外環境基本上不敏感。
在其他非相互排斥的具體實施例中,該連接子促進細胞內化。於某些具體實施例中,當與治療劑共軛時,該連接子促進細胞內化(亦即,在如本文所述之抗體-藥物共軛物化合物的連接子-治療劑部分體的環境中)。
各種可與本發明組合物以及方法一起使用之各種示例性連接子描述於PCT專利公開第WO 2004-010957號、美國專利公開第2006/0074008號、美國專利公開第20050238649號,以及美國專利公開第2006/0024317號(透過引用將每個整體併入本文並用於所有目的)。
本發明之具體實施例涉及含有ENO-1抗體的抗體-藥物共軛物及其治療用途。ENO-1為一種多功能蛋白質,其被發現在許多癌細胞的細胞表面上表現作為纖維蛋白溶酶原受體以及在活化的造血細胞上,例如嗜中性白血球、淋巴細胞以及單核細胞。因此,基於針對ENO-1的抗體的ADCs可為有用的診斷及/或處理劑。
然而,快速的內化或缺乏治療性抗體的ADCC活性可能導致抗體無效以及抗性。因此,需要增強基於抗ENO-1的治療劑的治療效果。一種方法是以抗ENO-1抗體(亦即,抗體-藥物共軛物)將有效負載共軛。透過將抗ENO-1抗體共軛到有效負載(亦即,ADCs),本發明之具體實施例比裸抗ENO-1抗體更有效,進而能夠使用較少的抗體。
根據本發明之具體實施例,抗ENO-1抗體或其結合片段可耦合至一藥物、診斷劑,或一治療劑。因此,本文所用之術語「抗體-藥物共軛物」(ADC)可指一抗體部分(其可為整個抗體或其結合片段)耦合至一有效負載(其可為一藥物、一診斷劑或一治療劑)。
本發明之ADCs包含用於治療或診斷用途的有效負載。相較於裸抗ENO-1抗體,這些ADCs具有更好的生物活性,且需要更少的量來達到所需的效果。
以下具體實例將說明本發明之具體實施例。本發明所屬技術領域中具有通常知識者將理解的是,這些示例僅用於說明,且在不脫離本發明之範圍的情況下,可進行其他修改以及變化。實施例
除非另有說明,否則每個1
H NMR數據均500 MHz獲得。除非另有說明,否則本文使用之縮寫如下:
BU:丁基;BN:芐基;BOC:叔丁氧基羰基;BOP:苯並三唑-1-基氧基三/二甲基胺基鏻六氟磷酸鹽;DCC:二環己基碳二亞胺;DMF:N,N-二甲基甲醯胺;DMAP:4-二甲基胺基吡啶;EDC:1-(3-二甲基胺基丙基)3-乙基碳二亞胺鹽酸酯;EtOAc:乙酸乙酯;Eq.:當量;HOBt:羥基苯齊唑;LAH:氫化鋁鋰;MeOH:甲醇;MHz:百萬赫;MS(ES):質譜計-電子噴霧;NMP:N-甲基吡咯烷酮;Ph:苯基;Pr:丙基;TEA:三乙胺;THF:四氫呋喃;TLC:薄層色層分析;Tetrakis:肆(三苯基膦)鈀。
實施例
1.
抗
ENO-1
抗體之製備
根據本發明之具體實施例,用於產生抗ENO-1抗體的一般方法包括獲得產生針對ENO-1的單株抗體的雜交瘤。用於生產單株抗體之方法為本領域已知的,並且在此將不再闡述。簡言之,小鼠以抗原(ENO-1)及合適的佐劑攻毒。然後,收穫免疫小鼠的脾臟細胞並與雜交瘤融合。陽性選殖株可使用任何已知方法,例如ELISA,來鑑定用於結合ENO-1抗原的能力。於一具體實施例中,該抗ENO-1抗體為HuL001。示例性抗體HuL001如美國專利公開第US2019/0322762號中所述,其內容透過引用整體併入。
請求保護的發明之抗體-藥物共軛物(ADCs)可特異性地以ENO-1為標靶。這些ADCs可使用任何與ENO-1特異性結合的抗體。例如,請求保護的發明的ADCs可使用小鼠或人源化的抗ENO-1抗體,或其一scFv或Fab片段。示例性抗ENO-1抗體,例如, HuL001,可包括具有三個互補區域的重鏈可變結構域,包括HCDR1(GYTFTSCVMN;SEQ ID NO: 1)、HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO: 2)以及HCDR3(EGFYYGNFDN;SEQ ID NO: 3),以及具有三個互補區域的輕鏈可變結構域,包括LCDR1(RASENIYSYLT;SEQ ID NO: 4)、LCDR2(NAKTLPE;SEQ ID NO: 5)以及LCDR3(QHHYGTPYT;SEQ ID NO: 6)。另一示例性抗ENO-1抗體可包含具有三個互補區域的重鏈可變結構域,包括HCDR1(GYTFTSXVMN,其中X為半胱胺酸以外的任何胺基酸;SEQ ID NO: 7)、HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO: 2)以及HCDR3(EGFYYGNFDN;SEQ ID NO: 3),以及具有三個互補區域的輕鏈可變結構域,包括LCDR1(RASENIYSYLT;SEQ ID NO: 4 ),LCDR2(NAKTLPE;SEQ ID NO: 5)以及LCDR3(QHHYGTPYT;SEQ ID NO: 6)。
根據本發明之具體實施例,該抗體可為小鼠抗體。或者,該抗體可為嵌合抗體(例如,與小鼠可變區耦合的人類恆定區域)或人源化抗體(例如,嫁接在人類免疫球蛋白的框架區域的小鼠CDRs)或完全人類抗體。
可透過從雜交瘤獲得CDR序列並將該CDR序列選殖到人類框架序列中以產生人源化抗體來使單株抗體人源化。可使用本領域已知的用於識別CDR序列的任何常用方法。本發明中的CDR區域以Kabat編號方法識別。首先,產生抗ENO-1的雜交瘤(例如,小鼠雜交瘤)。可以標準方法產生這種雜交瘤,用於生產單株抗體。然後分離雜交瘤的總RNA,例如使用TRIzol®
試劑。然後,自該總RNA合成cDNA,例如使用第一鏈cDNA合成套組(Superscript III)以及寡核苷酸(dT20
)引子或Ig-3’恆定區引子。
然後從cDNA中選殖免疫球蛋白基因的重鏈及輕鏈可變區。例如,使用小鼠Ig-5’引子組(Novagen公司),透過PCR從小鼠雜交瘤cDNA擴增抗ENO-1 mAb的VH及VL可變區。可使用CloneJetTM
PCR選殖套組(Ferments)將PCR產物直接選殖到合適的載體(例如,pJET1.2載體)中。該pJET1.2載體含有致死插入片段,只有在將所需基因選殖到該致死區域時,才能在選擇條件下生存。這有助於選擇重組菌落。最後,篩選重組菌落,選出所需的選殖株,分離並定序這些選殖株的DNAs。免疫球蛋白(Ig)核苷酸序列可在國際免疫原性資訊系統(IGMT)網站上分析。
抗體表現及純化
針對抗體生產,分離的選殖株可在任何合適的細胞中表現。舉例而言,將F293細胞(Life technologies公司)以表現抗ENO-1 mAb的質體轉染並培養7天。使用蛋白質A親和管柱(GE公司)從培養基中純化抗ENO-1抗體。蛋白質濃度可以Bio-rad蛋白質分析套組測定並以12% SDS-PAGE分析,使用本領域已知的方法或根據製造商的說明書進行分析。
根據本發明之具體實施例,任何這些抗ENO-1抗體可用於製備抗體-藥物共軛物(ADCs),如以下實施例所示。
於本實施例中,ADCs含有DM1,其係用於癌症治療的一種美登木素生物鹼(maytansinoid)。美登素(maytansine),一種苯並金剛大環內酯(benzoansamacrolide),為一種高效的以微管為標靶的化合物,其在次奈米莫耳的濃度下可誘導有絲分裂抑制並殺腫瘤細胞。DM1在微管的尖端結合以抑制微管的動態,即抑制微管的組裝。DM1為一種美登木素生物鹼(maytansinoid),其系統性毒性少於美登素(maytansine)。於本實施例中,使用SMCC-DM1,其為具有反應性連接子SMCC的DM1,與抗體反應以製備抗體藥物共軛物。SMCC-DM1可從商業來源獲得,如Medkoo Biosciences公司或ALB Technology公司。
例如,將HuL001(70 mg)的緩衝液交換為pH6.5 檸檬酸鈉緩衝液,並調節至5 mg/mL。將SMCC-DM1(5 mM,溶於DMA中,16當量)的溶液緩慢加入到HuL001溶液中。將反應混合物於37℃下在振盪培養箱(150 rpm)中培養18小時。具有30 kDa NMW1的Amicon Ultra-15離心過濾器以及25 mM 檸檬酸鈉pH 6.5用於HuL001-SMCC-DM1的濃縮以及除去SMCC-DM1。ADC濃度:5.478 mg/ml,ADC產率:16.5 mg(23.5%),平均DAR:3.87。
於本實施例中,ADC包含DM4,這是另一個美登素(maytansine)類似物。DM4也是一種有效的以微管為標靶的化合物,可在有絲分裂階段抑制細胞增殖。本發明之某些具體實施例可使用DM4。
於本實施例中,將HuL001(70 mg)的緩衝液交換為pH 6.5檸檬酸鈉緩衝液,並調節至5 mg/mL。將SPP-DM4(10 mM溶於DMA中,15當量)的溶液中緩慢加入到HuL001溶液中。將反應混合物於37℃下在振盪培養箱(150 rpm)中培養18小時。具有30 kDa NMWL的Amicon Ultra-15離心過濾器以及25 mM 檸檬酸鈉pH 6.5用於HuL001-SMCC-DM4的濃縮以及除去SPP-DM4。ADC濃度:3.65 mg/mL,ADC產量:34.3 mg(49%),平均DAR:3.18。
單甲基澳瑞他汀E(MMAE)為一種抗腫瘤劑,其透過阻斷微管蛋白的聚合來抑制細胞分裂。其係源自海洋無殼軟體動物(尾海兔素(dolastatin)類藥物)中產生的胜肽。MMAE已被證明為ADCs的有用有效負載。
ADCs中的連接子可能對生物活性產生重大影響。例如,體內研究顯示,胜肽連接的共軛物可誘導已建立的腫瘤異種移植物的消退及治癒,治療指數高達60倍。這些共軛物說明了連接子技術、藥物效力以及共軛方法在製定用於癌症治療的安全以及有效的mAb藥物共軛物中的重要性。
本發明之某些具體實施例涉及透過溶酶體上可切割的二胜肽,纈胺酸-瓜胺酸(valine-citrulline,vc)與抗體連接的MMAEs,vc已經顯現出改善ADC效率。於本實施例中,將HuL001(1 mg)的緩衝液交換為pH 7.4 PBS/EDTA緩衝液,並調節至5 mg/mL。將TCEP(10 mM,3當量)的水溶液緩慢加入到HuL001溶液中。透過於37℃下培養2小時,減少抗體中的二硫鍵。然後將mal-PEG2-vc-PAB-MMAE(10 mM溶於DMA,10當量)的溶液緩慢加入蛋白質溶液中。將反應混合物於25℃下在振盪培養箱(150 rpm)培養2小時。然後使用100 mM NAC(20當量)來淬滅過量的mal-vc-類固醇。使用具有10 kDa NMWL的Amicon Ultra-15離心過濾器以及緩衝液(pH6.0 PBS以及137 mM NaCl)用於HuL001-mal-vc-MMAE的濃縮以及去除mal-PEG2-vc-PAB-MMAE。ADC濃度:3.7 mg/ml,ADC產率:0.481 mg(48.1%),平均DAR:3.64。
本發明之某些具體實施例涉及含有單甲基澳瑞他汀F(MMAF)的ADCs,MMAF為MMAE的類似物。將HuL001(37 mg)的緩衝液交換為pH 7.4 PBS緩衝液,並調節至5 mg/mL。將OSu-ph-MMAF(5 mM溶於DMA,5當量)的溶液緩慢加入蛋白質溶液中。將反應混合物於37℃下在振盪培養箱(150 rpm)中培養1小時。具有30kDa NMWL的Amicon Ultra-15離心機過濾器以及25 mM 檸檬酸鈉pH 6.5用於HuL001-ph-MMAF的濃縮以及去除OSu-ph-MMAF。ADC濃度:7.8 mg/ml,ADC產率:34.1 mg(92.1%),平均DAR:3.09。
於本實施例中,將HuL001(1 mg)的緩衝液交換為pH 7.4 PBS/EDTA緩衝液,並調節至10 mg/ml。將TCEP的水溶液(10 mM,4當量)緩慢加入蛋白質溶液中。透過於37 ℃下培養1.5小時,減少抗體中的二硫鍵。然後將mal-vc-類固醇(10 mM溶於DMSO,10當量)的溶液緩慢加入蛋白質溶液中。將反應混合物於0℃下在振盪培養箱(150 rpm)中培養18小時。然後使用100 mM NAC(20當量)來淬滅過量的mal-vc-類固醇。具有30kDa NMWL的Amicon Ultra-15離心機過濾器以及緩衝液(pH 6.0 PBS以及137 mM NaCl)用於HuL001-mal-vc-類固醇的濃縮以及去除mal-vc-類固醇。ADC濃度:2.2 mg/ml,ADC產率:0.33 mg(33%),平均DAR:5.2。
實施例
7. PLRP-HPLC
或
HIC
分析
透過PLRP-HPLC或HIC分析根據請求保護的發明具體實施例的各種ADCs。圖1-5所示為共軛反應基本上完成,且僅留下抗ENO-1抗體以及ADCs的殘留量。
實施例
8.
完整或降低的
LC/MS
分析
評估藥物-抗體比(drug-to-antibody ratio,DAR)對於監測目標抗體的有效負載共軛效率是重要的。藥物-抗體比可能影響抗ENO-1 ADC產品的治療效果。完整的液相色層分析-質譜(LC-MS)是測定離胺酸連接抗體-藥物共軛物(ADCs)的藥物-抗體比(DAR)以及藥物負荷分佈的選擇方法。降低的LC-MS為測定半胱胺酸連接ADCs的DAR以及藥物負荷分佈的選擇方法。峰的面積百分比表示特定藥物載體ADCs物種的相對分佈。然後使用百分比峰面積資訊以及藥物負載數來計算加權平均DAR。
圖5-10說明根據請求保護的發明的具體實施例的ADCs的LC-MS分析的實例(抗ENO-1 ADCs),這表示附著在抗體上的各種藥物的分佈,其中最豐富的物種有1~12種附著在抗體上的藥物。這些實施例中平均藥物-抗體比(DAR)的範圍為3.18-5.2。 具有附著於一抗體的多個相同藥物將確保該藥物更有效地將被遞送至細胞中。
實施例
9.
細胞毒性分析
抗ENO-1 ADC產物的細胞激素誘導的細胞毒性作用已在ENO-1依賴性細胞株中展示,該細胞株衍生自不同的人類癌症,包括淋巴瘤、肺癌、乳腺癌、胰臟癌以及瀰漫性大B細胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)。各種細胞株,例如U937、A549、MDA-MB-231、MCF-7、MBA-MD-453、MBA-MD-175、PANC-1、Raji、Su-DHL-4、Toledo、GA-10或HT,分別以細胞激素TGF-β、MCP-1,或IL-6活化4小時以模擬發炎性腫瘤微環境,並與連續稀釋抗體溶液再作用72小時。透過使用細胞計數(CCK-8)套組測量細胞存活率,並計算IC50
的值。測試的細胞HuL001的IC50
高於測試的最高濃度(1000 nM)。結果表示,抗ENO-1 ADC產品特異性地抑制各種細胞株的細胞激素誘導的(20 ng/ml TGF-β,100 ng/mL MCP-1,50 ng/ml IL-6)促發炎表面ENO-1。表1及表2顯示,在大多數細胞株中,HuL001-SMCC-DM1以及HuL001-mal-vc-MMAE的IC50
在活化後顯著降低到個位數含量以反映細胞毒性效應。圖11表示DLBCL細胞株DHL-4中HuL001-SPP-DM4的IC50
的個位數含量。圖12及圖13表示在存在或不存在LPS刺激的情況下,在分離的正常人類B細胞中沒有可檢測的HuL001或HuL001-SMCC-DM1以及HuL001-mal-vc-MMAE的體外細胞毒性。總之,根據本發明之ADC有效地殺死癌細胞,尤其是在細胞激素模擬時,而不影響正常細胞的活力。它被認為是針對性癌症治療的潛在候選者。
表1 在細胞激素刺激的癌細胞株中HuL001-SMCC-DM1的體外細胞毒性結果
HuL001-SMCC-DM1誘導的細胞毒性的IC50 (nM) | HuL001的IC50 > 1000 nM | ||||
未處理 | TGF-β | MCP-1 | IL-6 | ||
單核細胞 | U937 | 71±5.65 | 7.5 | 9.7 | 7.1 |
肺癌 | A549 | 56±4.38 | 8.2 | 12.1 | 11.2 |
乳癌 | MDA-MB-231 | 68.95±7.71 | 24.2 | 22.4 | 34.6 |
MCF-7 | 74.9 | 53.5 | 36.2 | 38.6 | |
MDA-MB-453 | 39.8 | 16.6 | 24.7 | 22.8 | |
MDA-MB-175 | 76.4 | 38.3 | 40.5 | 45.1 | |
胰臟癌 | PANC-1 | 174 | 116 | 109.6 | 134.3 |
瀰漫性大B細胞淋巴瘤 | Raji | 32.2±3.39 | 18.6 | 21.7 | 17.1 |
SU-DHL-4 | 7.65±0.91 | 7.4 | 7.6 | 8.3 | |
Toledo | 8 | 9.8 | 8.1 | 11.4 | |
DB | 5.5 | 5.1 | 4.1 | 5.8 | |
GA-10 | 37.8 | 22.8 | 25.6 | 26.6 | |
HT | 7.3 | 6.1 | 7.6 | 6.6 |
表2 在細胞激素刺激的癌細胞株中HuL001-mal-vc-MMAE的體外細胞毒性結果
HuL001-mal-vc-MMAE誘導的細胞毒性的IC50 (nM) | HuL001的IC50 > 1000 nM | ||||
未處理 | TGF-β | MCP-1 | IL-6 | ||
單核細胞 | U937 | 29.2 | 5.3 | 6.7 | 3.7 |
肺癌 | A549 | 32.9 | 7.3 | 8.3 | 7.8 |
乳癌 | MDA-MB-231 | 75.3 | 32.4 | 45.1 | 35.8 |
MDA-MB-453 | 95.2 | 40.5 | 38.3 | 31.8 | |
瀰漫性大B細胞淋巴瘤 | Rai | 32.4 | - | - | - |
SU-DHL-4 | 4.5 | - | - | - | |
Toledo | 9.7 | - | - | - | |
DB | 5.3 | - | - | - | |
GA-10 | 37.1 | - | - | - | |
HT | 6.9 | 7.5 | 7.5 | 7.7 |
實施例
10.
細胞激素分析
在人類單核細胞細胞株THP-1中證明了抗ENO-1-類固醇ADC的抗發炎作用。以LPS刺激THP-1細胞以誘導ENO-1表面表現以及促發炎細胞激素TNF-α以及CCL2的分泌。圖14表示,相較於抗ENO-1抗體,抗ENO-1-類固醇ADC的卓越抗發炎作用。
實施例
11.
抗
ENO-1 ADC
的前列腺癌模型
在實驗去勢抵抗性前列腺癌模型中評估了HuL001-SMCC-DM1。使用雄性4~6週齡裸(nu/nu
)小鼠(Lasco有限公司,台灣)。在接種之前,以PBS洗滌去勢抵抗性人類前列腺癌細胞株PC-3細胞,以PBS及Matrigel以1:1重新懸浮該細胞至107
個細胞/ml的終濃度。將細胞(106
個/100 µl)皮下植入小鼠的右側。在平均腫瘤體積達到100 mm3
(植入後6天)後,將小鼠隨機分配至對照組及處理組,其分別以PBS(5 ml/kg)作為載劑對照或HuL001-SMCC-DM1(1或9 mg/kg)施用。HuL001-SMCC-DM1透過腹膜內注射一次每6天給予一次,總共2個劑量,直至研究結束。每天進行體重以及腫瘤體積測量。根據以下公式測定皮下腫瘤的體積:腫瘤體積 = 較短的直徑2
x 較長的直徑/2,透過腹膜內注射劑量。圖15表示HuL001-SMCC-DM1抑制腫瘤生長而不造成體重的減損。
實施例
12.
抗
ENO-1 ADC
的
EAE
疾病模型
在C57BL/6小鼠中,在實驗性自體免疫腦脊髓炎(experimental autoimmune encephalomyelitis,EAE)中評估HuL001-SMCC-DM1,這是人類發炎脫髓疾病、多發性硬化症的最常用的實驗模型。向10至12週齡的雌性C57BL/6小鼠皮下注射100微克在弗氏完全佐劑中的MOG p35-55,然後腹膜內注射100 ng百日咳毒素。於第二天,給與另一劑量的100 ng百日咳毒素。每天觀察動物,臨床症狀評估如下:0,沒有跡象;1,尾巴活性下降;2,輕度單肢輕癱或不完全麻痺;3,嚴重的後軀輕癱;4,截癱及/或四肢輕癱;5,瀕臨死亡或死亡。將小鼠隨機分為3組,其中10隻小鼠在對照組以及COPAXONE®
組(Teva製藥公司),以及5隻小鼠在HuL001-SMCC-DM1組中。疾病發病(疾病評分 ≥ 1)的日期被設定為第1天。HuL001-SMCC-DM1組的EAE小鼠在第1、8以及15天皮下注射。COPAXONE組的 EAE小鼠自第1天至第18天每天皮下注射。圖16所示為相較於PBS對照組甚至COPAXONE®
組,HuL001-SMCC-DM1的治療能夠減緩EAE小鼠的疾病症狀的進展。
實施例
13.
抗
ENO-1 ADC
的
IPF
疾病模型
以在C57BL/6小鼠中薄萊黴素誘導的肺纖維化評估HuL001-SMCC-DM1,這是人類纖維化疾病,特發性肺纖維化最常用的實驗模型。氣管內給予單一劑量的薄萊黴素(3 mg/kg)至7至9週齡雄性C57BL/6小鼠。將小鼠隨機分為3組,其中3隻小鼠在假手術組,6隻小鼠分別在博萊黴素組以及HuL001-SMCC-DM1組。以博萊黴素攻毒的日期被設定為第0天。HuL001-SMCC-DM1組小鼠在第1、8以及15天皮下注射。圖17說明相較於博萊黴素組,以HuL001-SMCC-DM1治療能夠減少體重的損失以及肺重量的增加。透過HuL001-SMCC-DM1處理減少了支氣管肺泡灌洗液(bronchial alveolar lavage fluid,BALF)中的肺羥脯胺酸含量以及TGF-β含量。
除非另外定義,否則所有技術以及科學術語以及本文所用之任何首字母縮略詞都具有本發明領域中普通技術人員通常理解的相同含義。雖然可以使用與本文所述之那些相似或相當的任何組合物、方法、套組以及用於傳達訊息的裝置實施本發明,但是本文描述本發明之較佳組合物、方法、套組以及用於傳達訊息的裝置。
本文引用之所有參考文獻在此透過引用透過法律允許的全部程度併入本文。這些參考文獻的討論僅僅是總結其作者所作的主張。不承認任何參考文獻(或任何參考文獻的一部分)為相關的現有技術。申請人保留質疑任何引用文獻的準確性及相關性的權利。
無
圖 1
所示為HuL001-SMCC-DM1的PLRP-HPLC結果。實施例7描述共軛反應基本上完成,且僅留下抗ENO-1抗體以及ADCs的殘留量。
圖 2
所示為HuL001-SPP-DM4的PLRP-HPLC結果。實施例7描述共軛反應基本上完成,且僅留下抗ENO-1抗體以及ADCs的殘留量。
圖 3
所示為HuL001-mal-vc-MMAE的HIC結果。實施例7描述共軛反應基本上完成,且僅留下抗ENO-1抗體以及ADCs的殘留量。
圖 4
所示為HuL001-Ph-MMAF的PLRP-HPLC結果。實施例7描述共軛反應基本上完成,且僅留下抗ENO-1抗體以及ADCs的殘留量。
圖 5
所示為HuL001-mal-vc-類固醇的HIC結果。實施例7描述共軛反應基本上完成,且僅留下抗ENO-1抗體以及ADCs的殘留量。
圖 6
所示為HuL001-SMCC-DM1的LC/MS結果。細節描述於實施例8中。
圖 7
所示為HuL001-SPP-DM4的LC/MS結果。細節描述於實施例8中。
圖 8
所示為HuL001-mal-vc-MMAE的降低的LC/MS結果。細節描述於實施例8中。
圖 9
所示為HuL001-Ph-MMAF的LC/MS結果。細節描述於實施例8中。
圖 10
所示為HuL001-mal-vc-類固醇的降低的LC/MS結果。細節描述於實施例8中。
圖 11
所示為在LPS刺激的B細胞癌細胞株DHL-4中的HuL001-SPP-DM4的體外細胞毒性結果。細節描述於實施例9中。
圖 12
所示為無論LPS的刺激如何,在分離的正常人類B細胞中的HuL001-SMCC-DM1沒有可偵測的體外細胞毒性。細節描述於實施例9中。
圖 13
所示為無論LPS的刺激如何,在分離的正常人類B細胞中的HuL001-mal-vc-MMAE沒有可偵測的體外細胞毒性。細節描述於實施例9中。
圖 14
所示為,相較於HuL001,HuL001-mal-vc-類固醇對於在LPS處理的人類單核細胞株THP-1中的TNF-α以及CCL2分泌物具有優異的抗發炎作用。細節描述於實施例10。
圖 15
所示為在PC-3異種移植前列腺癌模型中的HuL001-SMCC-DM1體內療效。相較於載劑對照組,以HuL001-SMCC-DM1處理能夠抑制腫瘤生長。如實施例11中所述進行詳細的程序。
圖 16
所示為在C57BL/6 EAE疾病模型中HuL001-SMCC-DM1的體內療效。相較於PBS對照組甚至COPAXONE®
組,以HuL001-SMCC-DM1處理能夠減緩EAE小鼠的疾病症狀的進展。如實施例12中所述進行詳細的程序。
圖 17
所示為在C57BL/6博萊黴素誘導的肺纖維化疾病模型中HuL001-SMCC-DM1的體內療效。相較於以博萊黴素處理的組別,以HuL001-SMCC-DM1處理能夠弱化肺纖維化小鼠體重的減輕以及肺重量的增加。如實施例13中所述進行詳細的程序。
無
Claims (16)
- 一種對ENO-1專一結合的免疫共軛物,包括: Ab-(L-D)m (I)的通式, 其中Ab為抗ENO-1抗體或其結合片段,L為連接子或直接鍵,D為治療劑或標記物,m為1至12的整數。
- 如請求項1所述之免疫共軛物,其中該抗體為單株抗體。
- 如請求項1所述之免疫共軛物,其中該抗體為小鼠抗體、人類抗體、嵌合抗體、人源化抗體或其抗體片段。
- 如請求項1所述之免疫共軛物,其中該治療劑包含細胞毒劑、免疫調節劑、放射性同位素,以及毒素。
- 如請求項1所述之免疫共軛物,其中該細胞毒性劑包含美登木素生物鹼1(maytansinoids 1,DM1)、美登木素生物鹼4(DM4)、單甲基澳瑞他汀E(Monomethyl auristatin E,MMAE),單甲基澳瑞他汀F(MMAF)、蒽環素、吡咯洛唑二氮雜,α-蠅蕈素、微管溶素(tubulysin)、苯二氮平類藥物、厄洛替尼(erlotinib)、硼替佐米(Bortezomib)、氟維司群(Fulvestrant)、舒尼替尼(Sunitinib)、來曲唑(letrozole)、甲磺酸伊馬替尼(imatinib)、PTK787/ZK 222584、奧沙利鉑(Oxaliplatin)、菊白葉酸(leucovorin)、雷帕黴素(rapamycin)、拉帕替尼(lapatinib)、洛那法尼(lonafarnib)、索拉非尼(sorafenib),以及吉非替尼(gefitinib)、AG1478、AG1571,烷基化試劑,包括噻替哌(thiotepa)或環膦醯胺;亞烷基磺酸鹽,包括白消安(busulfan)、英丙舒凡(improsulfan)或哌泊舒凡(piposulfan);氮丙啶類,包括苯唑多巴(benzodopa)、卡波醌(carboquone)、米得哌(meturedopa),或烏得哌(uredopa);吖環丙烷(ethylenimines)以及甲基蜜胺類(methylamelamines),包括六甲蜜胺(altretamine)、三乙烯三聚氰胺(triethylenemelamine)、三亞乙基磷醯胺(triethylenephosphoramide)、三亞乙基硫代磷醯胺(triethylenethiophosphoramide)以及三甲基蜜胺(trimethylomelamine);內酯(acetogenins);喜樹鹼(camptothecin);苔蘚蟲素(bryostatin);卡利斯他汀(callystatin);CC-1065;念珠藻素(cryptophycins);尾海兔素(dolastatin);杜卡黴素(duocarmycin);艾榴塞洛素(eleutherobin);胰抑素(pancratistatin);珊瑚素(sarcodictyin);海綿素(spongistatin);氮芥劑包括氯芥苯丁酸(chlorambucil)、萘氮芥(chlornaphazine)、氯萘嗪(cholophosphamide)、環磷醯胺(cholophosphamide)、雌莫司汀(estramustine)、異環磷醯胺(ifosfamide)、甲氯乙胺(mechlorethamine)、鹽酸甲乙胺鹽酸鹽(mechlorethamine oxide hydrochloride)、美法侖(melphalan)、新氮芥(novembichin)、苯芥膽甾醇(phenesterine)、潑尼氮芥(prednimustine)、曲磷胺(trofosfamide),或尿嘧啶氮芥(uracil mustard);亞硝基脲(nitrosureas),包括卡莫司汀(carmustine)、氯脲霉素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine),或雷諾氮芥(ranimustine);抗生素,如烯二炔抗生素,包括卡奇黴素(calicheamicin),尤其是卡奇黴素γ1以及卡奇黴素ω1;達尼黴素(dynemicin),包括達尼黴素A;雙磷酸鹽類,包括氯磷酸鹽(clodronate);埃司帕黴素(esperamicin);以及新卡他汀發色團(neocarzinostatin chromophore)以及相關的色素蛋白烯二炔抗生素發色團、阿克拉黴素(aclacinomysins)、放線菌黴素(actinomycin)、安麯黴素(authramycin)、茜素(azaserine)、博萊黴素(bleomycins)、放線菌素(cactinomycin)、卡拉黴素(carabicin)、洋紅黴素(caminomycin)、嗜癌菌素(carzinophilin)、色黴素(chromomycinis)、放線菌素(dactinomycin)、道諾黴素(daunorubicin)、艾黴素(detorubicin)、6-重氮-5-氧代-L-正白胺酸、阿黴素(doxorubicin)、泛艾黴素(epirubicin)、表阿黴素(esorubicin)、艾達黴素(idarubicin)、麻西羅黴素(marcellomycin),絲裂黴素(mitomycins),包括絲裂黴素C、黴酚酸(mycophenolic acid)、諾加黴素(nogalamycin)、橄欖黴素(olivomycins)、培洛黴素(peplomycin)、泊非黴素(potfiromycin)、嘌呤黴素(puromycin)、喹納黴素(quelamycin)、羅黴素(rodorubicin)、鏈黑菌素(streptonigrin)、鏈脲佐菌素(streptozocin)、結核菌素(tubercidin)、苯丁抑制素(ubenimex)、新制癌菌素(zinostatin)、紅柔黴素(zorubicin);抗代謝物,包括氨甲蝶呤(methotrexate)以及5-氟尿嘧啶(5-fluorouracil,5-FU);葉酸類似物,包括二甲葉酸(denopterin)、蝶羅呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤類似物,包括氟達拉濱(fludarabine)、6-巰基嘌呤(6-mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鳥嘌呤(thioguanine);嘧啶類似物,包括安西他濱(ancitabine)、阿扎胞苷(azacitidine)、6-硫唑脲嘧啶(6-azauridine)、卡莫呋(carmofur)、阿糖胞苷(cytarabine)、雙去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、伊諾他濱(enocitabine)、氟尿苷(floxuridine);雄激素,包括鈣雌酮(calusterone)、屈他雄酮丙酸酯(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄酮(mepitiostane)、睾內酯酮(testolactone);抗腎上腺劑,包括胺魯米特(aminoglutethimide)、米托坦(mitotane)、三矽烷(trilostane);葉酸補充劑,包括醛葉酸(folinic acid);乙醯格雷酮(aceglatone);醛磷醯胺糖苷(aldophosphamide glycoside);胺乙醯丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);阿莫司汀(bestrabucil);比生群(bisantrene);依達曲沙(edatraxate);地磷醯胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);艾福米辛(elformithine);依利醋銨(elliptinium acetate);埃博黴素(epothilone);依託格魯(etoglucid);硝酸鎵;羥基脲;香菇多醣(lentinan);氯尼達明(lonidainine);美登木素生物鹼(maytansinoids),包括美登素(maytansine)以及安絲菌素(ansamitocins);米托脲腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidanmol);硝拉維林(nitraerine);噴司他丁(pentostatin);蛋胺氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基醯肼(ethylhydrazide);甲基芐肼(procarbazine);多醣複合物;雷佐生(razoxane);根黴素(rhizoxin);西佐喃(sizofiran);鍺螺胺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);三亞胺醌(Triaziquone);2,2’,2’’-三氯三乙胺(trichlorotriethylamine);新月毒素(trichothecenes);烏拉坦(urethan);長春地辛(vindesine);達卡巴仁(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);溴丙哌嗪(pipobroman);甲托辛(gacytosine);阿糖胞苷(arabinoside);環磷醯胺(cyclophosphamide);噻替哌(thiotepa);類紫杉醇(taxoids),紫杉醇(paclitaxel),紫杉醇的白蛋白工程化奈米粒子製劑,以及歐洲紫杉醇(docetaxel);苯丁酸氮芥(chloranbucil);吉西他濱(gemcitabine);6-硫鳥嘌呤(6-thioguanine);巰基嘌呤(mercaptopurine);氨甲蝶呤(methotrexate);鉑類似物,包括順鉑(cisplatin)以及卡鉑(carboplatin);長春花鹼(vinblastine);鉑;依託泊苷(etoposide)(VP-16);異環磷醯胺(ifosfamide);米托蔥醌(mitoxantrone);長春新鹼(vincristine);溫諾平(vinorelbine);米托蔥醌(novantrone);替尼泊苷(teniposide);依達曲沙(edatrexate);道諾黴素(daunomycin);胺基蝶呤(aminopterin;);截瘤達(xeloda);伊班膦酸(ibandronate);CPT-11;拓撲異構酶抑制劑RFS 2000;二氟甲基鳥胺酸(difluoromethylornithine,DMFO);維他命A酸類(retinoids),包括視黃酸(retinoic acid);卡培他濱(capecitabine);以及上述任何一種的醫藥上可接受的鹽類、酸類或衍生物。
- 如請求項1所述之免疫共軛物,其中該標記物包括診斷或成像試劑。
- 如請求項1所述之免疫共軛物,其中該抗體包含 一重鏈可變結構域,其具有三個互補區域,包括 HCDR1(GYTFTSCVMN;SEQ ID NO: 1), HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO: 2),以及 HCDR3(EGFYYGNFDN;SEQ ID NO: 3);以及 一輕鏈可變結構域,其具有三個互補區域,包括 LCDR1(RASENIYSYLT;SEQ ID NO: 4), LCDR2(NAKTLPE;SEQ ID NO: 5),以及 LCDR3(QHHYGTPYT;SEQ ID NO: 6)。
- 如請求項1所述之免疫共軛物,其中該抗體包含 一重鏈可變結構域,其具有三個互補區域,包括 HCDR1(GYTFTSXVMN,其中X為除了半胱胺酸之外的任何胺基酸;SEQ ID NO: 7), HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO: 2),以及 HCDR3(EGFYYGNFDN;SEQ ID NO: 3);以及 一輕鏈可變結構域,其具有三個互補區域,包括 LCDR1(RASENIYSYLT;SEQ ID NO: 4), LCDR2(NAKTLPE;SEQ ID NO: 5),以及 LCDR3(QHHYGTPYT;SEQ ID NO: 6)。
- 一種用於診斷或使表現ENO-1的細胞或組織成像之組合物,包含如請求項6所述之免疫共軛物。
- 一種用於治療發炎性疾病、免疫疾病,或表現ENO-1的癌症之醫藥組合物,包含如請求項1~5所述之免疫共軛物。
- 如請求項10所述之醫藥組合物,其中該抗體包含 一重鏈可變結構域,其具有三個互補區域,包括 HCDR1(GYTFTSCVMN;SEQ ID NO: 1), HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO: 2),以及 HCDR3(EGFYYGNFDN;SEQ ID NO: 3);以及 一輕鏈可變結構域,其具有三個互補區域,包括 LCDR1(RASENIYSYLT;SEQ ID NO: 4), LCDR2(NAKTLPE;SEQ ID NO: 5),以及 LCDR3(QHHYGTPYT;SEQ ID NO: 6)。
- 如請求項10所述之醫藥組合物,其中該抗體包含 一重鏈可變結構域,其具有三個互補區域,包括 HCDR1(GYTFTSXVMN,其中X為除了半胱胺酸之外的任何胺基酸;SEQ ID NO: 7), HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO: 2),以及 HCDR3(EGFYYGNFDN;SEQ ID NO: 3);以及 一輕鏈可變結構域,其具有三個互補區域,包括 LCDR1(RASENIYSYLT;SEQ ID NO: 4), LCDR2(NAKTLPE;SEQ ID NO: 5),以及 LCDR3(QHHYGTPYT;SEQ ID NO: 6)。
- 如請求項10所述之醫藥組合物,其中該發炎性疾病或該免疫病症包含多發性硬化症、類風濕性關節炎、克羅恩氏病、潰瘍性結腸炎、全身性紅斑性狼瘡、慢性阻塞性肺病(COPD)、異位性皮膚炎、特發性肺纖維化、非酒精性脂肪肝炎、氣喘、過敏、牛皮癬、牛皮癬性關節炎、第1型糖尿病、動脈粥樣硬化、骨質疏鬆症、系統性硬化、病毒誘導肺炎,或巨噬細胞活化症候群。
- 如請求項10所述之醫藥組合物,其中該癌症包含血癌、多發性骨髓瘤、胃癌、皮膚癌、肺癌、黑色素瘤、腎癌、肝癌、骨髓瘤、前列腺癌、乳腺癌、直腸癌、胃癌、胰臟癌、甲狀腺癌、血液性癌症、淋巴瘤、血癌,皮膚癌、卵巢癌、膀胱癌、尿路上皮癌、頭頸癌,或該癌症的轉移性病變。
- 一種治療發炎性疾病、免疫疾病或癌症之方法,包含對一有此需要的受試者施用有效量的如請求項1至8中任一項所述之免疫共軛物,或如請求項10至14中任一項所述之醫藥組合物。
- 一種如請求項1至8中任一項所述之免疫共軛物或如請求項10至14中任一項所述之醫藥組合物用於製備治療發炎性疾病、免疫疾病或表現ENO-1的癌症之藥物之用途。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202063022702P | 2020-05-11 | 2020-05-11 | |
US63/022,702 | 2020-05-11 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW202207990A true TW202207990A (zh) | 2022-03-01 |
TWI807320B TWI807320B (zh) | 2023-07-01 |
Family
ID=78525301
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW110116808A TWI807320B (zh) | 2020-05-11 | 2021-05-10 | 含有α-烯醇酶抗體之藥物共軛物及其用途 |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP4149546A4 (zh) |
JP (1) | JP2023525965A (zh) |
KR (1) | KR20230026983A (zh) |
CN (1) | CN115666642A (zh) |
AU (1) | AU2021271383A1 (zh) |
BR (1) | BR112022019853A2 (zh) |
CA (1) | CA3171288A1 (zh) |
TW (1) | TWI807320B (zh) |
WO (1) | WO2021228044A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023093822A1 (en) * | 2021-11-26 | 2023-06-01 | Hunilife Biotechnology, Inc. | Methods to regulate glycolysis via targeting extracellular alpha-enolase for treating human diseases |
KR20230085578A (ko) * | 2021-12-07 | 2023-06-14 | 한국과학기술연구원 | 암 예방 또는 치료를 위한 알부민 결합 전구약물, 이를 포함하는 약학 조성물 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100910962B1 (ko) * | 2008-09-22 | 2009-08-05 | 한국생명공학연구원 | Eno1―특이적인 인간항체 |
TWI572358B (zh) * | 2013-12-20 | 2017-03-01 | 財團法人生物技術開發中心 | α-烯醇化酶特異性抗體及其使用在免疫疾病之方法 |
AU2013408259B2 (en) * | 2013-12-20 | 2020-05-21 | Development Center For Biotechnology | Alpha-enolase specific antibodies and methods of uses in cancer therapy |
US9382331B2 (en) * | 2013-12-27 | 2016-07-05 | Development Center For Biotechnology | Alpha-enolase specific antibodies and methods of uses in cancer therapy |
JP6585721B2 (ja) * | 2014-12-31 | 2019-10-02 | ディヴェロップメント センター フォー バイオテクノロジー | ヒト化α−エノラーゼ特異的抗体及びがん治療におけるその使用方法 |
TWI637966B (zh) * | 2015-11-30 | 2018-10-11 | 輝瑞股份有限公司 | 用於部位專一性接合之抗體和抗體片段 |
TWI726217B (zh) * | 2017-06-15 | 2021-05-01 | 財團法人生物技術開發中心 | 含有抗globo h抗體之抗體-藥物共軛物及其用途 |
JP6544669B1 (ja) * | 2018-03-16 | 2019-07-17 | ディヴェロップメント センター フォー バイオテクノロジー | アルファエノラーゼに特異的な抗体及びその使用 |
CN109651510B (zh) * | 2018-12-04 | 2023-03-24 | 上海长征医院 | 抗Eno1抗体及其用途 |
CN110376378B (zh) * | 2019-07-05 | 2022-07-26 | 中国医学科学院肿瘤医院 | 可用于肺癌诊断的标志物联合检测模型 |
-
2021
- 2021-05-10 BR BR112022019853A patent/BR112022019853A2/pt unknown
- 2021-05-10 CN CN202180034808.XA patent/CN115666642A/zh active Pending
- 2021-05-10 TW TW110116808A patent/TWI807320B/zh active
- 2021-05-10 EP EP21803290.2A patent/EP4149546A4/en active Pending
- 2021-05-10 WO PCT/CN2021/092811 patent/WO2021228044A1/en unknown
- 2021-05-10 JP JP2022563173A patent/JP2023525965A/ja active Pending
- 2021-05-10 KR KR1020227032477A patent/KR20230026983A/ko active Search and Examination
- 2021-05-10 CA CA3171288A patent/CA3171288A1/en active Pending
- 2021-05-10 AU AU2021271383A patent/AU2021271383A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
AU2021271383A1 (en) | 2022-09-22 |
WO2021228044A1 (en) | 2021-11-18 |
EP4149546A4 (en) | 2024-02-07 |
BR112022019853A2 (pt) | 2022-11-22 |
CA3171288A1 (en) | 2021-11-18 |
KR20230026983A (ko) | 2023-02-27 |
TWI807320B (zh) | 2023-07-01 |
CN115666642A (zh) | 2023-01-31 |
EP4149546A1 (en) | 2023-03-22 |
JP2023525965A (ja) | 2023-06-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI804499B (zh) | Ror1抗體免疫接合物 | |
JP7423513B2 (ja) | 抗葉酸受容体α抗体コンジュゲート及びその使用 | |
TW201116300A (en) | DR5 Ligand Drug Conjugates | |
JP7337824B2 (ja) | 抗cd33および抗cd7併用療法 | |
CA2979895A1 (en) | Conjugates for the treatment of cancer targeted at intracellular tumor-associated antigens | |
TWI807320B (zh) | 含有α-烯醇酶抗體之藥物共軛物及其用途 | |
WO2022136888A1 (en) | Bispecific antibodies binding to cd7 and cd33 | |
EP4321180A1 (en) | Antibody-drug conjugate including antibody against human cldn18.2, and use thereof | |
JP2024501380A (ja) | 新しい治療法 | |
US20240091372A1 (en) | Anti-doppel antibody drug conjugates | |
US20240131178A1 (en) | Antibody-drug conjugate including antibody against human cldn18.2, and use thereof | |
US20240058467A1 (en) | Anti-ror1 antibody conjugates, compositions comprising anti ror1 antibody conjugates, and methods of making and using anti-ror1 antibody conjugates | |
WO2022179570A1 (en) | Targeting conjugates comprising effector molecules and uses thereof | |
TW202313122A (zh) | 與ror1和b7-h3結合抗體-藥物偶聯物及其用途 | |
TW202344271A (zh) | 包含針對人cldn18.2的抗體的抗體藥物偶聯物及其用途 | |
KR20230143869A (ko) | 인간 trop2에 대한 항체를 포함하는 항체-약물 접합체 및 이의 용도 | |
BR112019027448B1 (pt) | Imunoconjugado compreendendo um anticorpo conjugado a uma porção de fármaco citotóxica, composição farmacêutica e uso dos mesmos |