WO2022211508A1 - 인간 cldn18.2에 대한 항체를 포함하는 항체 약물 접합체 및 이의 용도 - Google Patents
인간 cldn18.2에 대한 항체를 포함하는 항체 약물 접합체 및 이의 용도 Download PDFInfo
- Publication number
- WO2022211508A1 WO2022211508A1 PCT/KR2022/004552 KR2022004552W WO2022211508A1 WO 2022211508 A1 WO2022211508 A1 WO 2022211508A1 KR 2022004552 W KR2022004552 W KR 2022004552W WO 2022211508 A1 WO2022211508 A1 WO 2022211508A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- conjugate
- acceptable salt
- solvate
- pharmaceutically acceptable
- independently
- Prior art date
Links
- 229940049595 antibody-drug conjugate Drugs 0.000 title abstract description 51
- 239000000611 antibody drug conjugate Substances 0.000 title abstract description 41
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 37
- 238000009739 binding Methods 0.000 claims abstract description 35
- 201000011510 cancer Diseases 0.000 claims abstract description 33
- 239000012634 fragment Substances 0.000 claims abstract description 32
- 239000000427 antigen Substances 0.000 claims abstract description 27
- 108091007433 antigens Proteins 0.000 claims abstract description 27
- 102000036639 antigens Human genes 0.000 claims abstract description 27
- 102000002038 Claudin-18 Human genes 0.000 claims abstract description 15
- 108050009324 Claudin-18 Proteins 0.000 claims abstract description 15
- 108010029485 Protein Isoforms Proteins 0.000 claims abstract description 13
- 102000001708 Protein Isoforms Human genes 0.000 claims abstract description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 5
- 230000002491 angiogenic effect Effects 0.000 claims abstract description 4
- 125000005647 linker group Chemical group 0.000 claims description 127
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 107
- 125000000217 alkyl group Chemical group 0.000 claims description 105
- 229910052739 hydrogen Inorganic materials 0.000 claims description 85
- 239000001257 hydrogen Substances 0.000 claims description 74
- 125000001072 heteroaryl group Chemical group 0.000 claims description 61
- 239000013543 active substance Substances 0.000 claims description 60
- 150000003839 salts Chemical class 0.000 claims description 56
- 239000012453 solvate Substances 0.000 claims description 55
- 125000003118 aryl group Chemical group 0.000 claims description 54
- -1 isoprenyl Chemical class 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 54
- 210000004027 cell Anatomy 0.000 claims description 49
- 125000002947 alkylene group Chemical group 0.000 claims description 46
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 45
- 229940024606 amino acid Drugs 0.000 claims description 42
- 235000001014 amino acid Nutrition 0.000 claims description 42
- 125000003545 alkoxy group Chemical group 0.000 claims description 39
- 150000001413 amino acids Chemical class 0.000 claims description 39
- 150000002431 hydrogen Chemical class 0.000 claims description 29
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 25
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 24
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 24
- 125000005843 halogen group Chemical group 0.000 claims description 24
- 125000004474 heteroalkylene group Chemical group 0.000 claims description 24
- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical compound C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 20
- 150000002923 oximes Chemical class 0.000 claims description 20
- 125000004414 alkyl thio group Chemical group 0.000 claims description 19
- 125000003282 alkyl amino group Chemical group 0.000 claims description 18
- 102000004357 Transferases Human genes 0.000 claims description 17
- 108090000992 Transferases Proteins 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 238000003776 cleavage reaction Methods 0.000 claims description 17
- 235000018417 cysteine Nutrition 0.000 claims description 17
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 17
- 230000007017 scission Effects 0.000 claims description 17
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 16
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 15
- 239000002202 Polyethylene glycol Substances 0.000 claims description 15
- 229920001223 polyethylene glycol Polymers 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 12
- 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 12
- 239000004471 Glycine Substances 0.000 claims description 12
- 239000002246 antineoplastic agent Substances 0.000 claims description 12
- 125000004429 atom Chemical group 0.000 claims description 12
- 239000003053 toxin Substances 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000004434 sulfur atom Chemical group 0.000 claims description 11
- 231100000765 toxin Toxicity 0.000 claims description 11
- 108700012359 toxins Proteins 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 11
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 10
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 10
- 235000004400 serine Nutrition 0.000 claims description 10
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 9
- 125000000539 amino acid group Chemical group 0.000 claims description 9
- 108010044540 auristatin Proteins 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 229960004679 doxorubicin Drugs 0.000 claims description 9
- 229930195712 glutamate Natural products 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 239000012190 activator Substances 0.000 claims description 8
- 125000003827 glycol group Chemical group 0.000 claims description 8
- 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 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
- 108090000623 proteins and genes Proteins 0.000 claims description 8
- 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 8
- 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 7
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 7
- 229930012538 Paclitaxel Natural products 0.000 claims description 7
- 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 7
- 229940127089 cytotoxic agent Drugs 0.000 claims description 7
- 125000005549 heteroarylene group Chemical group 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 229960001592 paclitaxel Drugs 0.000 claims description 7
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 7
- 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 7
- 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 6
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 6
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 6
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 6
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 6
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims description 6
- 235000004279 alanine Nutrition 0.000 claims description 6
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical group O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 claims description 6
- 125000004450 alkenylene group Chemical group 0.000 claims description 6
- 150000001408 amides Chemical group 0.000 claims description 6
- 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 6
- 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 6
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 6
- 235000005772 leucine Nutrition 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 229930182817 methionine Natural products 0.000 claims description 6
- 235000006109 methionine Nutrition 0.000 claims description 6
- 229960001156 mitoxantrone Drugs 0.000 claims description 6
- 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 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- UOWVMDUEMSNCAV-WYENRQIDSA-N rachelmycin Chemical compound C1([C@]23C[C@@H]2CN1C(=O)C=1NC=2C(OC)=C(O)C4=C(C=2C=1)CCN4C(=O)C1=CC=2C=4CCN(C=4C(O)=C(C=2N1)OC)C(N)=O)=CC(=O)C1=C3C(C)=CN1 UOWVMDUEMSNCAV-WYENRQIDSA-N 0.000 claims description 6
- 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 6
- 229930189413 Esperamicin Natural products 0.000 claims description 5
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 5
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 5
- PSNOPSMXOBPNNV-VVCTWANISA-N cryptophycin 1 Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 claims description 5
- PSNOPSMXOBPNNV-UHFFFAOYSA-N cryptophycin-327 Natural products C1=C(Cl)C(OC)=CC=C1CC1C(=O)NCC(C)C(=O)OC(CC(C)C)C(=O)OC(C(C)C2C(O2)C=2C=CC=CC=2)CC=CC(=O)N1 PSNOPSMXOBPNNV-UHFFFAOYSA-N 0.000 claims description 5
- 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 5
- 238000009472 formulation Methods 0.000 claims description 5
- 230000002519 immonomodulatory effect Effects 0.000 claims description 5
- 229910052698 phosphorus Inorganic materials 0.000 claims description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 4
- 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 4
- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8s,11r,13r,14s,17s)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-N 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 4
- 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 4
- 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 4
- 229960005538 6-diazo-5-oxo-L-norleucine Drugs 0.000 claims description 4
- 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 4
- 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
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims description 4
- 102000007644 Colony-Stimulating Factors Human genes 0.000 claims description 4
- 108010071942 Colony-Stimulating Factors Proteins 0.000 claims description 4
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 4
- 108010092160 Dactinomycin Proteins 0.000 claims description 4
- 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 4
- 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 4
- 102000004190 Enzymes Human genes 0.000 claims description 4
- 108090000790 Enzymes Proteins 0.000 claims description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 4
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 claims description 4
- 108010063738 Interleukins Proteins 0.000 claims description 4
- 102000015696 Interleukins 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
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 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
- 102000003946 Prolactin Human genes 0.000 claims description 4
- 108010057464 Prolactin Proteins 0.000 claims description 4
- 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 4
- 108010039491 Ricin Proteins 0.000 claims description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 4
- 101150117115 V gene Proteins 0.000 claims description 4
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 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
- 150000001345 alkine derivatives Chemical class 0.000 claims description 4
- 229960003437 aminoglutethimide Drugs 0.000 claims description 4
- 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 4
- 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 4
- 229950000242 ancitabine Drugs 0.000 claims description 4
- 239000003242 anti bacterial agent Substances 0.000 claims description 4
- 239000003429 antifungal agent Substances 0.000 claims description 4
- 229940121375 antifungal agent Drugs 0.000 claims description 4
- 239000003096 antiparasitic agent Substances 0.000 claims description 4
- 229940125687 antiparasitic agent Drugs 0.000 claims description 4
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 150000001540 azides Chemical class 0.000 claims description 4
- 229930188356 brevetoxin Natural products 0.000 claims description 4
- 229930195731 calicheamicin Natural products 0.000 claims description 4
- 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 4
- 229940127093 camptothecin Drugs 0.000 claims description 4
- 229960005243 carmustine Drugs 0.000 claims description 4
- WTXGTTBOKVQBGS-ZOTXBKINSA-N chembl1077122 Chemical compound C(/[C@H]1O[C@H]2C[C@H]3O[C@H](CC(=C)C=O)C[C@H](O)[C@]3(C)O[C@@H]2C[C@@H]1O[C@@H]1C2)=C/C[C@@H]1O[C@H]1[C@@]2(C)O[C@]2(C)CC[C@@H]3O[C@@H]4C[C@]5(C)O[C@@H]6C(C)=CC(=O)O[C@H]6C[C@H]5O[C@H]4C[C@@H](C)[C@H]3O[C@H]2C1 WTXGTTBOKVQBGS-ZOTXBKINSA-N 0.000 claims description 4
- 229960004630 chlorambucil Drugs 0.000 claims description 4
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 4
- VYVRIXWNTVOIRD-UHFFFAOYSA-N ciguatoxin Natural products O1C(C(C(C)C2OC3CC(C)CC4OC5(C)C(O)CC6OC7C=CC8OC9CC%10C(C(C%11OC(C=CCC%11O%10)C=CC(O)CO)O)OC9C=CC8OC7CC=CCC6OC5CC4OC3CC2O2)O)C2C(C)C(C)C21CC(O)CO2 VYVRIXWNTVOIRD-UHFFFAOYSA-N 0.000 claims description 4
- 229960004397 cyclophosphamide Drugs 0.000 claims description 4
- 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 4
- 229930188854 dolastatin Natural products 0.000 claims description 4
- 229960005501 duocarmycin Drugs 0.000 claims description 4
- 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 4
- 229930184221 duocarmycin Natural products 0.000 claims description 4
- 239000000839 emulsion Substances 0.000 claims description 4
- 229950011487 enocitabine Drugs 0.000 claims description 4
- 229960000390 fludarabine Drugs 0.000 claims description 4
- 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 4
- 229960002949 fluorouracil Drugs 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
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 claims description 4
- 210000004602 germ cell Anatomy 0.000 claims description 4
- 229960001101 ifosfamide Drugs 0.000 claims description 4
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 4
- 229960003881 letrozole Drugs 0.000 claims description 4
- 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 4
- 229960001691 leucovorin Drugs 0.000 claims description 4
- 229960000485 methotrexate Drugs 0.000 claims description 4
- 229950011093 onapristone Drugs 0.000 claims description 4
- 229960001756 oxaliplatin Drugs 0.000 claims description 4
- 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 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- 229940097325 prolactin Drugs 0.000 claims description 4
- 235000018102 proteins Nutrition 0.000 claims description 4
- 102000004169 proteins and genes Human genes 0.000 claims description 4
- 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 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
- 230000002285 radioactive effect Effects 0.000 claims description 4
- 229960004622 raloxifene Drugs 0.000 claims description 4
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 claims description 4
- 229960001196 thiotepa Drugs 0.000 claims description 4
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 claims description 4
- 229950011457 tiamiprine Drugs 0.000 claims description 4
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- 229960001099 trimetrexate Drugs 0.000 claims description 4
- 229930184737 tubulysin Natural products 0.000 claims description 4
- 239000004474 valine Substances 0.000 claims description 4
- 235000014393 valine Nutrition 0.000 claims description 4
- 229960004355 vindesine Drugs 0.000 claims description 4
- 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 4
- 229950009268 zinostatin Drugs 0.000 claims description 4
- 229930188224 Cryptophycin Natural products 0.000 claims description 3
- 102100020880 Kit ligand Human genes 0.000 claims description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 3
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010039491 Sarcoma Diseases 0.000 claims description 3
- 108010039445 Stem Cell Factor Proteins 0.000 claims description 3
- 150000001299 aldehydes Chemical class 0.000 claims description 3
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 108010006226 cryptophycin Proteins 0.000 claims description 3
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 229960000310 isoleucine Drugs 0.000 claims description 3
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 3
- 235000014705 isoleucine Nutrition 0.000 claims description 3
- 125000000468 ketone group Chemical group 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 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
- 108010059074 monomethylauristatin F Proteins 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- 239000000829 suppository Substances 0.000 claims description 3
- 239000000725 suspension Substances 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
- 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
- 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
- TVIRNGFXQVMMGB-OFWIHYRESA-N (3s,6r,10r,13e,16s)-16-[(2r,3r,4s)-4-chloro-3-hydroxy-4-phenylbutan-2-yl]-10-[(3-chloro-4-methoxyphenyl)methyl]-6-methyl-3-(2-methylpropyl)-1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12-tetrone Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H](O)[C@@H](Cl)C=2C=CC=CC=2)C/C=C/C(=O)N1 TVIRNGFXQVMMGB-OFWIHYRESA-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
- 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 claims description 2
- NOPNWHSMQOXAEI-PUCKCBAPSA-N (7s,9s)-7-[(2r,4s,5s,6s)-4-(2,3-dihydropyrrol-1-yl)-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione 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)CCC=C1 NOPNWHSMQOXAEI-PUCKCBAPSA-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
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 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
- 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 claims description 2
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 claims description 2
- CJHKJXZMFZKGHI-UHFFFAOYSA-N 1h-pyrido[2,3-i][1,2]benzodiazepine Chemical compound N1N=CC=CC2=CC=C(N=CC=C3)C3=C12 CJHKJXZMFZKGHI-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
- 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 claims description 2
- KWYLVDGOCQSPDM-UHFFFAOYSA-N 3,7-dihydropurine-6-thione Chemical compound SC1=NC=NC2=C1NC=N2.S=C1N=CNC2=C1NC=N2 KWYLVDGOCQSPDM-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
- DODQJNMQWMSYGS-QPLCGJKRSA-N 4-[(z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-phenylbut-1-en-2-yl]phenol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 DODQJNMQWMSYGS-QPLCGJKRSA-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
- 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 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
- 108010059616 Activins Proteins 0.000 claims description 2
- 102000005606 Activins Human genes 0.000 claims description 2
- 101800002638 Alpha-amanitin 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
- 108010027164 Amanitins Proteins 0.000 claims description 2
- 108010005853 Anti-Mullerian Hormone Proteins 0.000 claims description 2
- 108020000948 Antisense Oligonucleotides Proteins 0.000 claims description 2
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 claims description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 2
- 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 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
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 108010006654 Bleomycin Proteins 0.000 claims description 2
- 108030001720 Bontoxilysin Proteins 0.000 claims description 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 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 claims description 2
- 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 claims description 2
- 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 claims description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-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
- 102000053642 Catalytic RNA Human genes 0.000 claims description 2
- 108090000994 Catalytic RNA Proteins 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
- 108010049048 Cholera Toxin Proteins 0.000 claims description 2
- 102000009016 Cholera Toxin Human genes 0.000 claims description 2
- 102100021809 Chorionic somatomammotropin hormone 1 Human genes 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 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 2
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-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
- 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 claims description 2
- AUGQEEXBDZWUJY-UHFFFAOYSA-N Diacetoxyscirpenol Natural products CC(=O)OCC12CCC(C)=CC1OC1C(O)C(OC(C)=O)C2(C)C11CO1 AUGQEEXBDZWUJY-UHFFFAOYSA-N 0.000 claims description 2
- 102000016607 Diphtheria Toxin Human genes 0.000 claims description 2
- 108010053187 Diphtheria Toxin Proteins 0.000 claims description 2
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 claims description 2
- 229930193152 Dynemicin Natural products 0.000 claims description 2
- AFMYMMXSQGUCBK-UHFFFAOYSA-N Endynamicin A Natural products C1#CC=CC#CC2NC(C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C3)=C3C34OC32C(C)C(C(O)=O)=C(OC)C41 AFMYMMXSQGUCBK-UHFFFAOYSA-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
- 108090000394 Erythropoietin Proteins 0.000 claims description 2
- 102000003951 Erythropoietin Human genes 0.000 claims description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 claims description 2
- 108050007372 Fibroblast Growth Factor Proteins 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
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 claims description 2
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 claims description 2
- 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 2
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 claims description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 2
- 102000003886 Glycoproteins Human genes 0.000 claims description 2
- 108090000288 Glycoproteins Proteins 0.000 claims description 2
- 102000006771 Gonadotropins Human genes 0.000 claims description 2
- 108010086677 Gonadotropins Proteins 0.000 claims description 2
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 claims description 2
- 108010069236 Goserelin Proteins 0.000 claims description 2
- 101001037140 Homo sapiens Immunoglobulin heavy variable 3-23 Proteins 0.000 claims description 2
- 101001047617 Homo sapiens Immunoglobulin kappa variable 3-11 Proteins 0.000 claims description 2
- 101001047618 Homo sapiens Immunoglobulin kappa variable 3-15 Proteins 0.000 claims description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-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
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 claims description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 claims description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 claims description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 claims description 2
- 102100040220 Immunoglobulin heavy variable 3-23 Human genes 0.000 claims description 2
- 102100022955 Immunoglobulin kappa variable 3-11 Human genes 0.000 claims description 2
- 102100022965 Immunoglobulin kappa variable 3-15 Human genes 0.000 claims description 2
- 102000002746 Inhibins Human genes 0.000 claims description 2
- 108010004250 Inhibins Proteins 0.000 claims description 2
- 102000006992 Interferon-alpha Human genes 0.000 claims description 2
- 108010047761 Interferon-alpha Proteins 0.000 claims description 2
- 102000003996 Interferon-beta Human genes 0.000 claims description 2
- 108090000467 Interferon-beta Proteins 0.000 claims description 2
- 102000008070 Interferon-gamma Human genes 0.000 claims description 2
- 108010074328 Interferon-gamma Proteins 0.000 claims description 2
- 102000014150 Interferons Human genes 0.000 claims description 2
- 108010050904 Interferons Proteins 0.000 claims description 2
- 108010002352 Interleukin-1 Proteins 0.000 claims description 2
- 108090000174 Interleukin-10 Proteins 0.000 claims description 2
- 102000013462 Interleukin-12 Human genes 0.000 claims description 2
- 108010065805 Interleukin-12 Proteins 0.000 claims description 2
- 108010002350 Interleukin-2 Proteins 0.000 claims description 2
- 108010002386 Interleukin-3 Proteins 0.000 claims description 2
- 108090000978 Interleukin-4 Proteins 0.000 claims description 2
- 108010002616 Interleukin-5 Proteins 0.000 claims description 2
- 108090001005 Interleukin-6 Proteins 0.000 claims description 2
- 108010002586 Interleukin-7 Proteins 0.000 claims description 2
- 108090001007 Interleukin-8 Proteins 0.000 claims description 2
- 108010002335 Interleukin-9 Proteins 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 2
- JLERVPBPJHKRBJ-UHFFFAOYSA-N LY 117018 Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCC3)=CC=2)C2=CC=C(O)C=C2S1 JLERVPBPJHKRBJ-UHFFFAOYSA-N 0.000 claims description 2
- 229920001491 Lentinan Polymers 0.000 claims description 2
- 108010000817 Leuprolide Proteins 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
- 102000009151 Luteinizing Hormone Human genes 0.000 claims description 2
- 108010073521 Luteinizing Hormone Proteins 0.000 claims description 2
- 108090000542 Lymphotoxin-alpha Proteins 0.000 claims description 2
- 102000004083 Lymphotoxin-alpha Human genes 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
- 229930126263 Maytansine Natural products 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
- 102100026632 Mimecan Human genes 0.000 claims description 2
- 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 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 2
- 101710204212 Neocarzinostatin Proteins 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
- 229930187135 Olivomycin Natural products 0.000 claims description 2
- 101800002327 Osteoinductive factor Proteins 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
- 102000003982 Parathyroid hormone Human genes 0.000 claims description 2
- 108090000445 Parathyroid hormone Proteins 0.000 claims description 2
- 108010057150 Peplomycin Proteins 0.000 claims description 2
- 102000015731 Peptide Hormones Human genes 0.000 claims description 2
- 108010038988 Peptide Hormones 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
- 108010003044 Placental Lactogen Proteins 0.000 claims description 2
- 239000000381 Placental Lactogen Substances 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
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 108090000103 Relaxin Proteins 0.000 claims description 2
- 102000003743 Relaxin Human genes 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 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 claims description 2
- 206010039509 Scab Diseases 0.000 claims description 2
- 108010003723 Single-Domain Antibodies Proteins 0.000 claims description 2
- 229920000519 Sizofiran Polymers 0.000 claims description 2
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 2
- 108010090804 Streptavidin Proteins 0.000 claims description 2
- 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 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
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 2
- 206010057644 Testis cancer Diseases 0.000 claims description 2
- 108010055044 Tetanus Toxin Proteins 0.000 claims description 2
- 108010041111 Thrombopoietin Proteins 0.000 claims description 2
- 102000036693 Thrombopoietin Human genes 0.000 claims description 2
- 102000011923 Thyrotropin Human genes 0.000 claims description 2
- 108010061174 Thyrotropin Proteins 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
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 claims description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 2
- ZYVSOIYQKUDENJ-ASUJBHBQSA-N [(2R,3R,4R,6R)-6-[[(6S,7S)-6-[(2S,4R,5R,6R)-4-[(2R,4R,5R,6R)-4-[(2S,4S,5S,6S)-5-acetyloxy-4-hydroxy-4,6-dimethyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-7-[(3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-4,10-dihydroxy-3-methyl-5-oxo-7,8-dihydro-6H-anthracen-2-yl]oxy]-4-[(2R,4R,5R,6R)-4-hydroxy-5-methoxy-6-methyloxan-2-yl]oxy-2-methyloxan-3-yl] acetate Chemical class COC([C@@H]1Cc2cc3cc(O[C@@H]4C[C@@H](O[C@@H]5C[C@@H](O)[C@@H](OC)[C@@H](C)O5)[C@H](OC(C)=O)[C@@H](C)O4)c(C)c(O)c3c(O)c2C(=O)[C@H]1O[C@H]1C[C@@H](O[C@@H]2C[C@@H](O[C@H]3C[C@](C)(O)[C@@H](OC(C)=O)[C@H](C)O3)[C@H](O)[C@@H](C)O2)[C@H](O)[C@@H](C)O1)C(=O)[C@@H](O)[C@@H](C)O ZYVSOIYQKUDENJ-ASUJBHBQSA-N 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
- IHGLINDYFMDHJG-UHFFFAOYSA-N [2-(4-methoxyphenyl)-3,4-dihydronaphthalen-1-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(OC)=CC=C1C(CCC1=CC=CC=C11)=C1C(=O)C(C=C1)=CC=C1OCCN1CCCC1 IHGLINDYFMDHJG-UHFFFAOYSA-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
- 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
- 239000000488 activin Substances 0.000 claims description 2
- 229950004955 adozelesin Drugs 0.000 claims description 2
- 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 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
- CIORWBWIBBPXCG-SXZCQOKQSA-N alpha-amanitin Chemical compound O=C1N[C@@H](CC(N)=O)C(=O)N2C[C@H](O)C[C@H]2C(=O)N[C@@H]([C@@H](C)[C@@H](O)CO)C(=O)N[C@@H](C2)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@H]1C[S@@](=O)C1=C2C2=CC=C(O)C=C2N1 CIORWBWIBBPXCG-SXZCQOKQSA-N 0.000 claims description 2
- 229960000473 altretamine Drugs 0.000 claims description 2
- CIORWBWIBBPXCG-JZTFPUPKSA-N amanitin Chemical compound O=C1N[C@@H](CC(N)=O)C(=O)N2CC(O)C[C@H]2C(=O)N[C@@H](C(C)[C@@H](O)CO)C(=O)N[C@@H](C2)C(=O)NCC(=O)N[C@@H](C(C)CC)C(=O)NCC(=O)N[C@H]1CS(=O)C1=C2C2=CC=C(O)C=C2N1 CIORWBWIBBPXCG-JZTFPUPKSA-N 0.000 claims description 2
- 229960002749 aminolevulinic acid Drugs 0.000 claims description 2
- 229960003896 aminopterin 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
- 229960001220 amsacrine Drugs 0.000 claims description 2
- 229960002932 anastrozole Drugs 0.000 claims description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 2
- 239000000868 anti-mullerian hormone Substances 0.000 claims description 2
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 claims description 2
- 239000000074 antisense oligonucleotide Substances 0.000 claims description 2
- 238000012230 antisense oligonucleotides Methods 0.000 claims description 2
- 150000008209 arabinosides Chemical class 0.000 claims description 2
- 239000003886 aromatase inhibitor Substances 0.000 claims description 2
- 229940046844 aromatase inhibitors Drugs 0.000 claims description 2
- 229960002756 azacitidine Drugs 0.000 claims description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 2
- 229950011321 azaserine Drugs 0.000 claims description 2
- 229960000997 bicalutamide Drugs 0.000 claims description 2
- 230000003115 biocidal effect Effects 0.000 claims description 2
- 229960002685 biotin Drugs 0.000 claims description 2
- 235000020958 biotin Nutrition 0.000 claims description 2
- 239000011616 biotin Substances 0.000 claims description 2
- 229950008548 bisantrene Drugs 0.000 claims description 2
- 229950006844 bizelesin Drugs 0.000 claims description 2
- 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 2
- 229960001467 bortezomib Drugs 0.000 claims description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 claims description 2
- 229940053031 botulinum toxin 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
- 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 claims description 2
- 229960002092 busulfan Drugs 0.000 claims description 2
- 108700002839 cactinomycin Proteins 0.000 claims description 2
- 229950009908 cactinomycin 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
- 229950009823 calusterone Drugs 0.000 claims description 2
- 230000000711 cancerogenic effect Effects 0.000 claims description 2
- 229960004117 capecitabine Drugs 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 229960004562 carboplatin Drugs 0.000 claims description 2
- 229960002115 carboquone Drugs 0.000 claims description 2
- 229960003261 carmofur Drugs 0.000 claims description 2
- 229950007509 carzelesin Drugs 0.000 claims description 2
- 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 claims description 2
- 108010047060 carzinophilin Proteins 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 229950008249 chlornaphazine Drugs 0.000 claims description 2
- 229960001480 chlorozotocin 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
- 229960004316 cisplatin Drugs 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
- 230000000295 complement effect Effects 0.000 claims description 2
- 108010089438 cryptophycin 1 Proteins 0.000 claims description 2
- 108010090203 cryptophycin 8 Proteins 0.000 claims description 2
- 229960000684 cytarabine 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
- 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
- 239000003534 dna topoisomerase inhibitor Substances 0.000 claims description 2
- 229960003668 docetaxel Drugs 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
- 229950004203 droloxifene Drugs 0.000 claims description 2
- 229940017825 dromostanolone Drugs 0.000 claims description 2
- 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 2
- AFMYMMXSQGUCBK-AKMKHHNQSA-N dynemicin a Chemical compound C1#C\C=C/C#C[C@@H]2NC(C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C3)=C3[C@@]34O[C@]32[C@@H](C)C(C(O)=O)=C(OC)[C@H]41 AFMYMMXSQGUCBK-AKMKHHNQSA-N 0.000 claims description 2
- 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 2
- 229950006700 edatrexate Drugs 0.000 claims description 2
- 229960002759 eflornithine Drugs 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
- 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
- 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 2
- 229940105423 erythropoietin 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
- 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
- 229960005420 etoposide Drugs 0.000 claims description 2
- 229960000255 exemestane Drugs 0.000 claims description 2
- 125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 229940126864 fibroblast growth factor Drugs 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
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 claims description 2
- 229960002074 flutamide Drugs 0.000 claims description 2
- 229940028334 follicle stimulating hormone Drugs 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
- 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 2
- 229960002584 gefitinib Drugs 0.000 claims description 2
- 229960005277 gemcitabine Drugs 0.000 claims description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 2
- 125000002686 geranylgeranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 229930182470 glycoside Natural products 0.000 claims description 2
- 239000002622 gonadotropin Substances 0.000 claims description 2
- 229960002913 goserelin Drugs 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000003102 growth factor Substances 0.000 claims description 2
- 230000002440 hepatic effect Effects 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
- 229940088597 hormone Drugs 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229940015872 ibandronate Drugs 0.000 claims description 2
- 229960003685 imatinib mesylate Drugs 0.000 claims description 2
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.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 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 claims description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 2
- 230000002163 immunogen Effects 0.000 claims description 2
- 229950008097 improsulfan 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
- 239000000893 inhibin Substances 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 229940079322 interferon Drugs 0.000 claims description 2
- 229960003130 interferon gamma Drugs 0.000 claims description 2
- 229960001388 interferon-beta Drugs 0.000 claims description 2
- 201000002313 intestinal cancer Diseases 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
- 229940043355 kinase inhibitor Drugs 0.000 claims description 2
- 229960004891 lapatinib Drugs 0.000 claims description 2
- 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 2
- 229940115286 lentinan Drugs 0.000 claims description 2
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 claims description 2
- 229960004338 leuprorelin Drugs 0.000 claims description 2
- 150000002632 lipids Chemical class 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 229960002247 lomustine Drugs 0.000 claims description 2
- 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 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
- 229940040129 luteinizing hormone Drugs 0.000 claims description 2
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims description 2
- 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 2
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 claims description 2
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 claims description 2
- 229960004296 megestrol acetate Drugs 0.000 claims description 2
- 201000001441 melanoma Diseases 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
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 2
- 229960001428 mercaptopurine Drugs 0.000 claims description 2
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 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
- 229960005485 mitobronitol Drugs 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
- 108010093470 monomethyl auristatin E Proteins 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
- 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 claims description 2
- 239000002105 nanoparticle Substances 0.000 claims description 2
- 239000002858 neurotransmitter agent Substances 0.000 claims description 2
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 claims description 2
- 229960002653 nilutamide Drugs 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
- 108020004707 nucleic acids Proteins 0.000 claims description 2
- 102000039446 nucleic acids Human genes 0.000 claims description 2
- 150000007523 nucleic acids Chemical class 0.000 claims description 2
- 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 claims description 2
- 201000008968 osteosarcoma 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
- 239000000199 parathyroid hormone Substances 0.000 claims description 2
- 229960001319 parathyroid hormone Drugs 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
- 239000000813 peptide hormone Substances 0.000 claims description 2
- RLZZZVKAURTHCP-UHFFFAOYSA-N phenanthrene-3,4-diol Chemical compound C1=CC=C2C3=C(O)C(O)=CC=C3C=CC2=C1 RLZZZVKAURTHCP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003757 phosphotransferase inhibitor Substances 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
- 229960000952 pipobroman Drugs 0.000 claims description 2
- 229950001100 piposulfan Drugs 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
- 229960001221 pirarubicin Drugs 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 229920001184 polypeptide Polymers 0.000 claims description 2
- 108010001062 polysaccharide-K Proteins 0.000 claims description 2
- 229940034049 polysaccharide-k Drugs 0.000 claims description 2
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000843 powder 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
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 2
- 108010087851 prorelaxin Proteins 0.000 claims description 2
- 239000003909 protein kinase inhibitor Substances 0.000 claims description 2
- 229950010131 puromycin Drugs 0.000 claims description 2
- 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 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
- 229930002330 retinoic acid Natural products 0.000 claims description 2
- 108091092562 ribozyme Proteins 0.000 claims description 2
- 229950004892 rodorubicin Drugs 0.000 claims description 2
- 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 claims description 2
- 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 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
- 229930182947 sarcodictyin Natural products 0.000 claims description 2
- 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 2
- 229960002930 sirolimus Drugs 0.000 claims description 2
- 229950001403 sizofiran Drugs 0.000 claims description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 2
- 229960003787 sorafenib Drugs 0.000 claims description 2
- 229950006315 spirogermanium Drugs 0.000 claims description 2
- 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 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
- 229940034785 sutent Drugs 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 229960001603 tamoxifen Drugs 0.000 claims description 2
- 201000003120 testicular cancer Diseases 0.000 claims description 2
- 229960005353 testolactone Drugs 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
- 229940118376 tetanus toxin Drugs 0.000 claims description 2
- CFMYXEVWODSLAX-QOZOJKKESA-N tetrodotoxin Chemical compound O([C@@]([C@H]1O)(O)O[C@H]2[C@@]3(O)CO)[C@H]3[C@@H](O)[C@]11[C@H]2[C@@H](O)N=C(N)N1 CFMYXEVWODSLAX-QOZOJKKESA-N 0.000 claims description 2
- 229950010357 tetrodotoxin Drugs 0.000 claims description 2
- CFMYXEVWODSLAX-UHFFFAOYSA-N tetrodotoxin Natural products C12C(O)NC(=N)NC2(C2O)C(O)C3C(CO)(O)C1OC2(O)O3 CFMYXEVWODSLAX-UHFFFAOYSA-N 0.000 claims description 2
- 229940034208 thyroxine Drugs 0.000 claims description 2
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 claims description 2
- 229960003087 tioguanine Drugs 0.000 claims description 2
- 229940044693 topoisomerase inhibitor Drugs 0.000 claims description 2
- 229960000303 topotecan Drugs 0.000 claims description 2
- 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 claims description 2
- 229960005026 toremifene Drugs 0.000 claims description 2
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 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
- 229950001353 tretamine Drugs 0.000 claims description 2
- 229960001727 tretinoin Drugs 0.000 claims description 2
- 229960004560 triaziquone Drugs 0.000 claims description 2
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 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
- 229960001670 trilostane Drugs 0.000 claims description 2
- 229950000212 trioxifene 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
- 229950010147 troxacitabine Drugs 0.000 claims description 2
- RXRGZNYSEHTMHC-BQBZGAKWSA-N troxacitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)OC1 RXRGZNYSEHTMHC-BQBZGAKWSA-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
- 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
- 229960005088 urethane Drugs 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 229960005486 vaccine Drugs 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
- 229960003048 vinblastine Drugs 0.000 claims description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 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
- 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 description 2
- 229940053867 xeloda 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
- 229940127121 immunoconjugate Drugs 0.000 claims 4
- 208000007766 Kaposi sarcoma Diseases 0.000 claims 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 claims 1
- 244000046052 Phaseolus vulgaris Species 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000004108 freeze drying Methods 0.000 claims 1
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 claims 1
- 239000006187 pill Substances 0.000 claims 1
- 239000003826 tablet Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 46
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000008685 targeting Effects 0.000 abstract description 5
- 239000002207 metabolite Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 description 37
- 239000000562 conjugate Substances 0.000 description 16
- 229960002433 cysteine Drugs 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 239000004475 Arginine Substances 0.000 description 10
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 10
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 10
- 229940125644 antibody drug Drugs 0.000 description 10
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 10
- 229960003121 arginine Drugs 0.000 description 10
- 230000003013 cytotoxicity Effects 0.000 description 10
- 231100000135 cytotoxicity Toxicity 0.000 description 10
- 239000002243 precursor Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 229960001153 serine Drugs 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 8
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 8
- 239000004472 Lysine Substances 0.000 description 8
- 229940049906 glutamate Drugs 0.000 description 8
- 230000003834 intracellular effect Effects 0.000 description 8
- 229960003646 lysine Drugs 0.000 description 8
- 108091005804 Peptidases Proteins 0.000 description 7
- 101100434411 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) ADH1 gene Proteins 0.000 description 7
- 101150102866 adc1 gene Proteins 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 6
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 6
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 6
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 6
- 229940009098 aspartate Drugs 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 229960003104 ornithine Drugs 0.000 description 6
- 239000004365 Protease Substances 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 238000012650 click reaction Methods 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 229960002743 glutamine Drugs 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 235000019419 proteases Nutrition 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 101150042711 adc2 gene Proteins 0.000 description 4
- 229960003767 alanine Drugs 0.000 description 4
- 235000003704 aspartic acid Nutrition 0.000 description 4
- 229960005261 aspartic acid Drugs 0.000 description 4
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 229960002449 glycine Drugs 0.000 description 4
- 229960003136 leucine Drugs 0.000 description 4
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical group O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- 102000002029 Claudin Human genes 0.000 description 3
- 108050009302 Claudin Proteins 0.000 description 3
- 108010016626 Dipeptides Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229960001230 asparagine Drugs 0.000 description 3
- 235000009582 asparagine Nutrition 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 229960002885 histidine Drugs 0.000 description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
- 210000003712 lysosome Anatomy 0.000 description 3
- 230000001868 lysosomic effect Effects 0.000 description 3
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 229960002429 proline Drugs 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 150000003568 thioethers Chemical class 0.000 description 3
- 229960002898 threonine Drugs 0.000 description 3
- 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 2
- 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
- IOOMXAQUNPWDLL-UHFFFAOYSA-N 2-[6-(diethylamino)-3-(diethyliminiumyl)-3h-xanthen-9-yl]-5-sulfobenzene-1-sulfonate Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(O)(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- 101100028791 Caenorhabditis elegans pbs-5 gene Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- 238000011230 antibody-based therapy Methods 0.000 description 2
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000006664 bond formation reaction Methods 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 229960002173 citrulline Drugs 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229960004452 methionine Drugs 0.000 description 2
- 239000012457 nonaqueous media Substances 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- 210000001578 tight junction Anatomy 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- FAAUXWHHCHVODE-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-(1-phenylethylsulfanyl)-2H-pyridine-1-carboxylate Chemical compound CC(C1=CC=CC=C1)SC2C=CC=CN2C(=O)ON3C(=O)CCC3=O FAAUXWHHCHVODE-UHFFFAOYSA-N 0.000 description 1
- OMRPLUKQNWNZAV-CONSDPRKSA-N (6as)-3-[3-[[(6as)-2-methoxy-8-(4-methoxyphenyl)-11-oxo-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-8-(4-aminophenyl)-2-methoxy-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C1=CC(OC)=CC=C1C1=CN2C(=O)C3=CC(OC)=C(OCCCOC=4C(=CC=5C(=O)N6C=C(C[C@H]6C=NC=5C=4)C=4C=CC(N)=CC=4)OC)C=C3N=C[C@@H]2C1 OMRPLUKQNWNZAV-CONSDPRKSA-N 0.000 description 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- ZDBUBSTWFUQTKJ-UHFFFAOYSA-N 3-(pyridin-2-yldisulfanyl)butanoic acid Chemical compound OC(=O)CC(C)SSC1=CC=CC=N1 ZDBUBSTWFUQTKJ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 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
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 108010009504 Gly-Phe-Leu-Gly Chemical group 0.000 description 1
- 101000749329 Homo sapiens Claudin-18 Proteins 0.000 description 1
- 102000009490 IgG Receptors Human genes 0.000 description 1
- 108010073807 IgG Receptors Proteins 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
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 206010064912 Malignant transformation Diseases 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010063916 Metastatic gastric cancer Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 208000012868 Overgrowth 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
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000005262 alkoxyamine group Chemical group 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 102000005936 beta-Galactosidase Human genes 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000003118 drug derivative Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000006077 hetero Diels-Alder cycloaddition reaction Methods 0.000 description 1
- 125000004404 heteroalkyl group Chemical group 0.000 description 1
- 102000048350 human CLDN18 Human genes 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
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000000879 imine group Chemical group 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- VMPHSYLJUKZBJJ-UHFFFAOYSA-N lauric acid triglyceride Natural products CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000036212 malign transformation Effects 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 108010073101 phenylalanylleucine Proteins 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 230000013823 prenylation Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 230000000722 protumoral effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 150000007659 semicarbazones Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- 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
- A61K47/54—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 organic compound
- A61K47/545—Heterocyclic compounds
-
- 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
- A61K47/54—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 organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- 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
- A61K47/68035—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a pyrrolobenzodiazepine
-
- 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
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
Definitions
- the present invention provides a novel antibody-drug conjugate (ADC) targeting claudin 18 isoform 2 (claudin 18 isoform 2, CLDN18.2), active metabolites of these ADCs, methods for preparing these ADCs, and disease to the use of these ADCs for treatment and/or prophylaxis, and also to the use of these ADCs for the production of medicaments for the treatment and/or prophylaxis of diseases, more particularly hyperproliferative and/or angiogenic diseases such as cancer diseases. and, more particularly, to an antibody-drug conjugate comprising a novel antibody or antigen-binding fragment thereof that binds to CLDN18.2, and a pharmaceutical composition comprising the same.
- ADC antibody-drug conjugate
- Cancer refers to a disease caused by an abnormally grown mass caused by the autonomous overgrowth of body tissues, and is the result of uncontrolled cell growth in various tissues. Early stage tumors can be removed by surgery and radiation therapy, and metastases are usually treated with chemotherapy for palliative care.
- chemotherapeutic agents can induce serious effects of unwanted side effects and even toxicity as a result of systemic administration, thus enabling improved and selective application of these chemotherapeutic agents in tumor cells or immediately adjacent tissues.
- the focus has been on the development of novel chemotherapeutic agents to simultaneously achieve increased efficacy and minimized toxicity/side effects.
- Antibody-drug conjugates are target-directed new technologies that bind to an antigen-binding antibody with a toxin or drug and then release a toxic substance from the inside of the cell, leading to apoptosis of cancer cells, etc. It is a technology that delivers drugs accurately to target cancer cells with minimal effect on healthy cells and releases them only under specific conditions, so it is more effective than the antibody treatment itself and can significantly lower the risk of side effects compared to existing anticancer drugs.
- the basic structure of such an antibody-drug conjugate is composed of "antibody-linker-small molecule drug (toxin)".
- the linker not only plays a functional role of simply linking the antibody and the drug, but also stably reaches the target cell when circulating in the body, and then the antibody-drug conjugate enters the cell and dissociates between the antibody and the drug (e.g., for enzyme hydrolysis). result), the drug should fall off well and show the drug effect on the target cancer cells. That is, depending on the stability of the linker, the linker plays a very important role in terms of safety such as efficacy and systemic toxicity of the antibody-drug conjugate (Discovery Medicine 2010, 10(53): 329-39). 85-8 2018-08-14)
- the inventors of the present invention have developed a linker containing an effective self-immolative group that is more stable in plasma, stable even when circulating in the body, and that the drug is easily released in cancer cells to show drug efficacy.
- a patent has been secured (Korea Patent No. 1,628,872).
- monoclonal antibodies for the treatment of cancer has achieved considerable success.
- Monoclonal antibodies are suitable for target-directed addressing of tumor tissues and tumor cells.
- Antibody drug conjugates have become a powerful and new therapeutic option for the treatment of lymphoma and solid cancers, and immunomodulatory antibodies have recently achieved considerable clinical success.
- the development of therapeutic antibodies is based on a deep understanding of cancer serology, protein engineering techniques and their actions, mechanisms of resistance, and interactions between the immune system and cancer cells.
- an antigen expressed on the cell surface of human cancer refers to a wide range of targets that are overexpressed or mutated and selectively expressed compared to normal tissues.
- a key challenge is to identify antigens suitable for antibody-based therapies. These therapeutics mediate changes in antigen or receptor function (i.e., function as stimulants or antagonists), modulate the immune system through Fc and T cell activation, and deliver specific drugs that bind to specific antigen-targeting antibodies. exert its effectiveness.
- Molecular technologies that can change antibody pharmacokinetics, function, size and immune stimulation are emerging as key factors in the development of novel antibody-based therapies.
- Evidence obtained from clinical trials of therapeutic antibodies in cancer patients shows that the affinity and binding of the antibodies to the target antigen, the selection of antibody structures, and the optimization of antibodies, including therapeutic approaches (blocking signal transduction or immune function), Emphasizes the importance of approaches to choice.
- Human claudin 18 subtype 2 (claudin 18 isoform 2, CLDN18.2) is a transmembrane type membrane protein consisting of 261 amino acids in full length, 2 extracellular loops and 4 transmembrane domains. It differs from CLDN18.1, which is expressed in some normal tissues, in part of the amino acid sequence up to the extracellular domain loop 1.
- CLDN18.2 belongs to the claudin family, which is an important component of tight junctions.
- the claudin protein is expressed in various cancer tissues and is known as a potential target for diagnostic and therapeutic modalities. It is also known to play an important role in tumorigenesis and inflammatory response, and changes in claudin protein expression cause dysfunction of tight junctions, affect signal transduction pathways, and are known to have a tumor-promoting action in some epithelial cancers. .
- CLDN18.2 is specifically expressed in primary and metastatic gastric cancer, except for expression in the apical region of some gastric mucosa, and is known as a cancer-specific antigen that is also associated with malignant transformation, pancreatic cancer , ectopic activation has been reported in esophageal cancer, ovarian cancer, and lung cancer.
- An object of the present invention is to provide a novel antibody-linker drug conjugate targeting claudin 18 isoform 2 (CLDN18.2) or a salt or solvate thereof.
- An object of the present invention is to provide an antibody-drug conjugate comprising an antibody that specifically binds to CLDN18.2 and a drug that binds thereto, and a pharmaceutical composition comprising the same.
- An object of the present invention is to provide an antibody-linker-drug (toxin) system that can stably reach cells and effectively exhibit drug effects while significantly lowering toxicity.
- Ab is an antibody or antigen-binding fragment that specifically binds to claudin 18 isoform 2 (CLDN18.2) comprising a heavy chain variable region and a light chain variable region,
- the heavy chain variable region comprises a heavy chain CDR1 consisting of the amino acid sequence shown in SEQ ID NO: 2, a heavy chain CDR2 consisting of the amino acid sequence shown in SEQ ID NO: 4, and a heavy chain CDR3 consisting of the amino acid sequence shown in SEQ ID NO: 6,
- the light chain variable region includes a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 9, a light chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 11, and a light chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 13,
- LINKER is a linker
- l and m are each independently an integer selected from 1 to 20,
- B may be the same as or different from each other.
- the antibody or antigen-binding fragment that specifically binds to CLDN18.2 comprises a heavy chain variable region and a light chain variable region,
- the heavy chain variable region comprises a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 2, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and a heavy chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 6,
- the light chain variable region includes a light chain CDR1 comprising the amino acid sequence shown in SEQ ID NO: 9, a light chain CDR2 comprising the amino acid sequence shown in SEQ ID NO: 11, and a light chain CDR3 comprising the amino acid sequence shown in SEQ ID NO: 13.
- the heavy chain variable region may include the heavy chain FR of a human antibody, and the gene encoding the heavy chain FR may be derived from the germline V gene IGHV3-23.
- the heavy chain FR is a heavy chain FR1 consisting of the amino acid sequence shown in SEQ ID NO: 1, heavy chain FR2 consisting of the amino acid sequence shown in SEQ ID NO: 3, heavy chain FR3 consisting of the amino acid sequence shown in SEQ ID NO: 5, SEQ ID NO: 7 and a heavy chain FR4 consisting of the indicated amino acid sequence.
- the light chain variable region includes the light chain FR of a human antibody, and the gene encoding the light chain FR may be derived from the germline V gene IGKV3-11 or IGKV3-15.
- the light chain FR is a light chain FR1 consisting of the amino acid sequence shown in SEQ ID NO: 8, light chain FR2 consisting of the amino acid sequence shown in SEQ ID NO: 10, light chain FR3 consisting of the amino acid sequence shown in SEQ ID NO: 12, SEQ ID NO: 14 and a light chain FR4 consisting of the indicated amino acid sequence.
- the light chain FR4 may include a moiety consisting of the amino acid sequence shown in SEQ ID NO: 19 at the C-terminus for binding to the linker.
- the antibody or antigen-binding fragment that specifically binds to CLDN18.2 comprises an amino acid sequence represented by SEQ ID NO: 15; Or a heavy chain variable region consisting of an amino acid sequence having at least 80% homology thereto and an amino acid sequence represented by SEQ ID NO: 16; or a light chain variable region consisting of an amino acid sequence having at least 80% homology thereto.
- the antibody or antigen-binding fragment that specifically binds to CLDN18.2 includes an amino acid sequence represented by SEQ ID NO: 15; Or a heavy chain variable region consisting of an amino acid sequence having at least 80% or more, 85% or more, 90% or more, 95% or more homology thereto and the amino acid sequence represented by SEQ ID NO: 16; Or it includes a light chain variable region consisting of an amino acid sequence having at least 80% or more, 85% or more, 90% or more, 95% or more homology thereto, and specifically binds to CLDN18.2.
- the antibody or antigen-binding fragment that specifically binds to CLDN18.2 includes an amino acid sequence represented by SEQ ID NO: 15; or at least 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more.
- a heavy chain variable region and sequence comprising an amino acid sequence having at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% homology.
- the antibody or antigen-binding fragment that specifically binds to CLDN18.2 comprises an amino acid sequence represented by SEQ ID NO: 17; or a heavy chain consisting of an amino acid sequence having at least 80% homology thereto and an amino acid sequence represented by SEQ ID NO: 18; or a light chain consisting of an amino acid sequence having at least 80% homology thereto.
- the antibody or antigen-binding fragment that specifically binds to CLDN18.2 includes an amino acid sequence represented by SEQ ID NO: 17; or an amino acid sequence represented by SEQ ID NO: 18 and a heavy chain consisting of an amino acid sequence having at least 80% or more, 85% or more, 90% or more, 95% or more homology thereto; or a light chain consisting of an amino acid sequence having at least 80% or more, 85% or more, 90% or more, 95% or more homology thereto, and specifically binds to CLDN18.2.
- the antibody or antigen-binding fragment that specifically binds to CLDN18.2 includes an amino acid sequence represented by SEQ ID NO: 17; or at least 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more.
- a heavy chain consisting of an amino acid sequence having at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% homology and SEQ ID NO: 18 amino acid sequence represented by; or at least 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more. at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% homology, It binds specifically to CLDN18.2.
- the heavy chain consisting of an amino acid sequence having at least 80% homology to the amino acid sequence represented by SEQ ID NO: 17 includes L237A and L238A mutations.
- the antibody or antigen-binding fragment thereof is a monoclonal antibody, a domain antibody (dAb), a single chain antibody (scAb), a Fab fragment, a Fab' fragment, F(ab')2 fragment, scFab fragment, Fv fragment, dsFv fragment, single chain variable fragment (scFv), scFv-Fc fragment, single domain heavy chain antibody, single domain light chain
- dAb domain antibody
- scAb single chain antibody
- Fab fragment fragment
- Fab' fragment F(ab')2 fragment
- scFab fragment Fv fragment
- dsFv fragment single chain variable fragment
- scFv-Fc fragment single domain heavy chain antibody
- linker refers to a compound that covalently binds a cytotoxic compound to a ligand.
- linkers described herein may be cleavable, non-cleavable, hydrophilic or hydrophobic.
- the cleavable linker is cleavable under intracellular conditions such that cleavage of the linker releases the active agent from the antibody construct-activator conjugate in the intracellular environment.
- a cleavable linker is cleavable by a cleaving agent present in the intracellular environment (eg, in a lysosome or endosome or caveolea).
- the cleavable linker may be, for example, a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme including, but not limited to, a lysosomal or endosomal protease.
- the peptidyl linker is at least 2 amino acids in length or at least 3 amino acids in length.
- Cleavage agents may include cathepsins B and D and plasmin, all of which are known to hydrolyze dipeptide drug derivatives to release the active drug in target cells (eg, Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123).
- Peptidyl linkers cleavable by enzymes present in antigen-expressing cells are most common.
- a peptidyl linker cleavable by the thiol-dependent protease cathepsin-B which is highly expressed in cancer tissues, can be used (eg, a Phe-Leu or Gly-Phe-Leu-Gly linker).
- Other such linkers are described, for example, in US Pat. No. 6,214,345.
- peptidyl linker cleavable by an intracellular protease is described in, for example, a Val-Cit linker, a Phe-Lys linker (eg, U.S. Patent No. 6,214,345, which describes the synthesis of doxorubicin using a Val-Cit linker). see) or a Val-Ala linker.
- the Val-Cit linker or Val-Ala linker may contain a pentafluorophenyl group and may contain a succinimide group or a maleimide group.
- it may contain a PABA group and a pentafluorophenyl group, and may contain a 4-aminobenzoic acid (PABA) group and a maleimide group, and may contain a PABA group and a succinimide group.
- PABA 4-aminobenzoic acid
- intracellularly cleaved and intracellular cleavage refer to a metabolic process or response inside a cell to an antibody construct-activator conjugate, whereby an active agent ( B) and the covalent attachment between the antibody construct (Ab), eg the linker is disrupted, resulting in free drug or other metabolites of the conjugate separated from the intracellular antibody.
- the cleavable linker is pH-sensitive, i.e., can be readily hydrolyzed at certain pH values.
- the pH-sensitive linker can be hydrolyzed under acidic conditions.
- acid-labile linkers capable of being hydrolyzed in lysosomes (e.g., hydrazone, semicarbazone, thiosemicarbazone, cis-aconic amide (cis) -aconitic amide), orthoesters, acetals, ketals, etc.) can be used (e.g., U.S. Patent Nos. 5,122,368; 5,824,805; 5,622,929; Dubowchik and Walker, 1999, Pharm. Therapeutics 83).
- linkers are relatively stable at neutral pH conditions, such as blood, but are unstable below pH 5.5 or 5.0, the approximate pH of lysosomes.
- hydrolysable linkers include thioether linkers (eg, thioethers attached to a therapeutic agent via an acylhydrazone bond (see, eg, US Pat. No. 5,622,929)).
- the linker is cleavable under reducing conditions (eg, a disulfide linker).
- a disulfide linker For example, SATA (N-succinimidyl-5-acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB (N-succinimidyl- Formed using 3-(2-pyridyldithio)butyrate) and SMPT (N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-thio)toluene)-, SPDB and SMPT
- SATA N-succinimidyl-5-acetylthioacetate
- SPDP N-succinimidyl-3-(2-pyridyldithio)propionate
- SPDB N-succinimidyl- Formed using 3-(2-pyrid
- linkers include malonate linkers (Johnson et al., 1995, Anticancer Res. 15:1387-93), maleimidobenzoyl linkers (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1299- 1304), 3'-N-amide analogs (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1305-12), beta-glucuronide linker (Jeffery et al) ., 2006, Bioconjug Chem. 17(3):832-40), or beta-galactosidase linker (Kolodych et al., 2017, Eur J Med Chem. Dec 15;142:376- 382) may be.
- the non-cleavable linker may be a maleimidocaproyl linker.
- the maleimidocaproyl linker may comprise N-maleimidomethylcyclohexane-1-carboxylate.
- the maleimidocaproyl linker may contain a succinimide group.
- the maleimidocaproyl linker may contain a pentafluorophenyl group.
- the linker may be a combination of a maleimide group and one or more polyethylene glycol molecules.
- the linker may be a combination of a maleimidocaproyl group and one or more polyethylene glycol molecules.
- the linker may be a maleimide-PEG4 linker.
- the linker may be a combination of a maleimidocaproyl linker containing a succinimide group and one or more polyethylene glycol molecules.
- the linker may be a combination of a maleimidocaproyl linker containing a pentafluorophenyl group and one or more polyethylene glycol molecules.
- the linker may contain a maleimide linked to a polyethylene glycol molecule, wherein the polyethylene glycol allows for more linker flexibility or may use a longer linker.
- the linker may be a (maleimidocaproyl)-(valine-citrulline)-(para-aminobenzyloxycarbonyl) linker.
- the linker may be a cleavable linker.
- the linker is a protease cleavable linker, an acid-cleavable linker, a disulfide linker, a self-immolative linker or a self-stabilizing linker, a malonate linker, maleimidobenzoyl linker, 3'-N-amide analog, beta-glucuronide linker, or beta-galactoside linker.
- the protease cleavable linker may include a thiol-reactive spacer or a dipeptide, and more specifically, the protease cleavable linker is a thiol-reactive maleimidocaproyl spacer, valine -citrulline dipeptide or p-amino-benzyloxycarbonyl spacer.
- the acid-cleavable linker may be a hydrazine linker or a quaternary ammonium linker.
- the linker may have a structure of Formula II.
- the tilde indicates a site linked to an antibody or antigen-binding fragment that specifically binds to CLDN18.2, * indicates a site linked to an active agent;
- G is a glucuronic acid moiety or ego
- R 3 is hydrogen or a carboxyl protecting group, and each R 4 is independently hydrogen or a hydroxyl protecting group;
- R 1 and R 2 are each independently hydrogen, C 1-8 alkyl or C 3-8 cycloalkyl
- W is -C(O)-, -C(O)NR'-, -C(O)O-, -SO 2 NR'-, -P(O)R''NR'-, -SONR'- or -PO 2 NR'-, wherein C, S or P is directly bonded to a phenyl ring, and R' and R'' are each independently hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di- C 1-8 alkylamino, C 3-20 heteroaryl or C 6-20 aryl;
- Z is independently hydrogen, C 1-8 alkyl, halogen, cyano or nitro;
- n is an integer from 0 to 3;
- L is any one of the following A) or B):
- L is 1 to 50 membered heteroalkylene
- said alkylene is substituted with one or more C 1-20 alkyl
- the conjugate may have a structure of the following general formula IIa.
- Ab is an antibody or antigen-binding fragment that specifically binds to CLDN18.2 comprising a heavy chain variable region and a light chain variable region,
- B' are each independently the same or different active agents
- G is each independently a glucuronic acid moiety or ego;
- R 3 is hydrogen or a carboxyl protecting group, and each R 4 is independently hydrogen or a hydroxyl protecting group;
- R 1 and R 2 are each independently hydrogen, C 1-8 alkyl or C 3-8 cycloalkyl
- W is each independently -C(O)-, -C(O)NR'-, -C(O)O-, -SO 2 NR'-, -P(O)R''NR'-, -SONR '- or -PO 2 NR'-, wherein C, S or P is directly bonded to a phenyl ring, wherein NR' is bonded to L, and R' and R'' are each independently hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl or C 6- 20 is aryl;
- each Z is independently hydrogen, C 1-8 alkyl, halogen, cyano or nitro;
- n is an integer from 0 to 3, and when n is an integer of 2 or more, each Z may be the same as or different from each other;
- Each L is independently any one of the following A) or B):
- L is 1 to 50 membered heteroalkylene
- said alkylene is further substituted with one or more C 1-20 alkyl
- n is an integer selected from 1 to 20.
- the present invention relates to a conjugate represented by the following general formula IIa or a pharmaceutically acceptable salt or solvate thereof.
- Ab is an antibody or antigen-binding fragment that specifically binds to claudin 18 isoform 2 (CLDN18.2),
- G is each independently a glucuronic acid moiety or ego;
- R 3 is hydrogen or a carboxyl protecting group, and each R 4 is independently hydrogen or a hydroxyl protecting group;
- R 1 and R 2 are each independently hydrogen, C 1-8 alkyl or C 3-8 cycloalkyl
- W is each independently -C(O)-, -C(O)NR'-, -C(O)O-, -SO 2 NR'-, -P(O)R''NR'-, -SONR '- or -PO 2 NR'-, wherein C, S or P is directly bonded to a phenyl ring, wherein NR' is bonded to L, and R' and R'' are each independently hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl or C 6- 20 is aryl;
- each Z is independently hydrogen, C 1-8 alkyl, halogen, cyano or nitro;
- n is an integer from 0 to 3;
- Each L is independently any one of the following A) or B):
- L is 1 to 50 membered heteroalkylene
- said alkylene is substituted with one or more C 1-20 alkyl
- B' is an active agent
- l and m are each independently an integer selected from 1 to 20,
- the active agents may each be the same or different.
- G is a glucuronic acid moiety or a compound of formula (IIIa):
- R 3 is hydrogen or a carboxyl protecting group
- each R 4 is each independently hydrogen or a hydroxyl protecting group.
- each G is independently ego
- R 3 is hydrogen or a carboxyl protecting group
- Each of said R 4 is independently hydrogen or a hydroxyl protecting group.
- R 3 is hydrogen, and each R 4 is hydrogen.
- R 1 and R 2 are each hydrogen.
- each Z is independently hydrogen, C 1-8 alkyl, halogen, cyano or nitro.
- W is -C(O)-, -C(O)NR'- or -C(O)O-, and more specifically, W is -C(O)NR'-, wherein C( O) is connected to a phenyl ring, and NR' is connected to L.
- R' is hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di- C 1-8 alkylamino, C 3 20 heteroaryl or C 6-20 aryl.
- n 0, 1, 2 or 3, more specifically 0, 1 or 2, and even more specifically 0.
- G is a compound of formula (IIIa):
- R 3 is hydrogen or a carboxyl protecting group
- each R 4 is each independently hydrogen or a hydroxyl protecting group
- W is -C(O)NR'-, wherein C(O) is connected to a phenyl ring and NR' is bonded to L, each Z is C 1-8 alkyl, halogen, cyano or nitro, n is 0, m is 1, and R 1 and R 2 are each hydrogen.
- At least one L is alkylene having 1 to 100 carbon atoms, wherein the carbon atoms of the alkylene are one or more heteroatoms selected from the group consisting of N, O and S. may be substituted, and the alkylene may be further substituted with one or more alkyl having 1 to 20 carbon atoms.
- At least one L is C 1-50 alkylene or 1-50 membered heteroalkylene, and may satisfy one or more of the following:
- L is 1 to 50 membered heteroalkylene
- said alkylene is substituted with one or more C 1-20 alkyl.
- the at least one L is a nitrogen-containing 1-50 membered heteroalkylene
- the linker includes two or more atoms of a hydrophilic amino acid
- the nitrogen is capable of forming a peptide bond with a carbonyl of the hydrophilic amino acid.
- L is C 2-50 alkylene, C 2-50 heteroalkylene, hydrophilic amino acid, -C(O)-, -C(O)NR''-, -C(O)O -, -(CH 2 ) s -NHC(O)-(CH 2 ) t -, -(CH 2 ) u -C(O)NH-(CH 2 ) v -, -(CH 2 ) s -NHC( O)-(CH 2 ) t -C(O)-, -(CH 2 ) u -C(O)NH-(CH 2 ) v -C(O)-, -S(O) 2 NR''- , -P(O)R'''NR''-, -S(O)NR''-, or -PO 2 NR''-,
- R'' and R''' are each independently hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1 -8 alkylamino, C 3-20 heteroaryl or C 5-20 aryl, and s, t, u and v are each independently an integer from 0 to 10.
- L is a nitrogen-containing 1-5 membered heteroalkylene
- the linker includes two or more atoms of a hydrophilic amino acid, and the nitrogen forms a peptide bond with the carbonyl of the hydrophilic amino acid.
- L is covalently bonded to the antibody through a thioether bond, and the thioether bond includes a sulfur atom of cysteine of the antibody.
- At least one L is a hydrophilic amino acid.
- the hydrophilic amino acid may be arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine, or threonine.
- the hydrophilic amino acid may be an amino acid comprising a side chain having a residue having a charge at neutral pH in aqueous solution.
- the hydrophilic amino acid is aspartate or glutamate.
- the hydrophilic amino acid is ornithine or lysine.
- the hydrophilic amino acid is arginine.
- At least one L is -C(O)-, -C(O)NR''-, -C(O)O-, -S(O) 2 NR''-, -P (O)R'''NR''-, -S(O)NR''-, or -PO 2 NR''-, wherein R'' and R'' are each independently hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl, or C 6-20 aryl.
- At least one L is -C(O)NR''-, -(CH 2 ) s -NHC(O)-(CH 2 ) t -, -(CH 2 ) u -C( O)NH-(CH 2 ) v -, -(CH 2 ) s -NHC(O)-(CH 2 ) t -C(O)-, or -(CH 2 ) u -C(O)NH-( CH 2 ) v —C(O)—, wherein R′′ is hydrogen, C 1-5 alkyl, C 3-8 cycloalkyl, C 1-5 alkoxy, C 3-20 heteroaryl, or C 6 -20 aryl, and s, tu and v are each independently an integer from 0 to 10.
- At least one L is -C(O)NR''- and R'' is hydrogen.
- At least one L is -(CH 2 ) s -NHCO-, and s is an integer from 1 to 5.
- At least one L is -(CH 2 ) u -C(O)NH-(CH 2 ) v -C(O)-, u is an integer from 1 to 5, and v is 1 to an integer of 5.
- L is,
- L 1 is a direct bond or alkylene having 1 to 30 carbon atoms
- R 11 is hydrogen or alkyl having 1 to 10 carbon atoms
- L 2 is alkylene having 1 to 30 carbon atoms.
- L further comprises a second unit represented by the general formula VIII or IX.
- the at least one second unit is represented by the general formula VIII or IX:
- V is a single bond, -O-, -S-, -NR 21 -, -C(O)NR 22 -, -NR 23 C(O)-, -NR 24 SO 2 - or -SO 2 NR 25 - ego;
- X is —O—, C 1-8 alkylene or —NR 21 —;
- R 21 to R 25 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkyl C 6-20 aryl or C 1-6 alkyl C 3-20 heteroaryl;
- r is an integer from 0 to 10;
- p is an integer from 0 to 10;
- q is an integer from 1 to 20;
- w is an integer from 1 to 20;
- q may be 4 to 20, more specifically 5 to 20. Also, q may be 1 to 10, or 2 to 12, and more specifically 2, 4, 5, or 11. Also, r may be 1 or 2. Also, p may be 1 or 2. Also, V may be -O-.
- r may be 2
- p may be 2
- q may be 2
- 4 5 or 11
- V may be -O-.
- X may be -O-.
- w may be an integer from 4 to 20.
- X is -O-, and w may be 1 to 10, or 4 to 20.
- the at least one second unit is at least one polyethylene glycol unit, or has the structure of
- n 1 to 12.
- the at least one second unit is 1 to 12 -OCH 2 CH 2 -units, or 3 to 12 -OCH 2 CH 2 -units, or 5 to 12 -OCH 2 CH 2 -units, or 6 to 12 -OCH 2 CH 2 -unit, or 3 -OCH 2 CH 2 -unit.
- the at least one second unit is -(CH 2 CH 2 X) w -,
- X is a single bond, —O—, C 1-8 alkylene, or —NR 21 —;
- R 21 is hydrogen, C 1-6 alkyl, C 1-6 alkyl-C 6-20 aryl, or C 1-6 alkyl-C 3-20 heteroaryl, w is an integer from 1 to 20, specifically 1, 3, 6, or 12.
- X is -O-, and w is an integer from 6 to 20.
- L comprises an oxime, and at least one polyethylene glycol unit covalently bonds the oxime to the active agent.
- the linker is 1,3-dipolar cycloaddition reactions, hetero-Diels-Alder reactions, nucleophilic substitutions formed by reactions, non-aldol type carbonyl reactions, addition to carbon-carbon multiple bond, oxidation reactions or click reactions a third unit.
- the third unit is formed by a reaction between an alkyne and an azide, or between an aldehyde or ketone group and a hydrazine or alkoxyamine.
- L further includes a third unit represented by the following general formula IVa, IVb, IVc, IVd, or IVe.
- L 1 is a single bond or alkylene having 1 to 30 carbon atoms
- R 11 is hydrogen or C 1-10 alkyl.
- the third unit comprises:
- L 1 is a single bond or alkylene having 1 to 30 carbon atoms, preferably alkylene having 10, 11, 12, 13, 14, 15 or 16 carbon atoms;
- R 11 is hydrogen or alkyl having 1 to 10 carbon atoms, specifically methyl
- L 2 is alkylene having 1 to 30 carbon atoms.
- L 1 and L 2 are each independently a single bond or C 1-30 alkylene; R 11 is hydrogen or C 1-10 alkyl.
- L 1 is a single bond, or alkylene having 11 carbon atoms, or alkylene having 12 carbon atoms.
- the third unit or including,
- V is a single bond , -O-, -S-, -NR 21 -, -C(O)NR 22 -, -NR 23 C(O)-, -NR 24 SO 2 -, or -SO 2 NR 25 - is;
- R 21 to R 25 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkyl C 6-20 aryl, or C 1-6 alkyl C 3-20 heteroaryl;
- r is an integer from 1 to 10;
- p is an integer from 0 to 10;
- q is an integer from 1 to 20;
- L 1 is a single bond.
- r may be 2 or 3. Also, p may be 1 or 2. Also, q may be 1 to 6.
- r is 2 or 3; p is 1 or 2; q may be 1 to 6.
- the linker comprising the third unit is
- tilde indicates a site connected to the antibody construct
- * indicates a site connected to the active agent
- n is an integer from 0 to 20.
- the third unit comprises: or includes
- the linker is in a precursor state
- the third unit may be formed by a reaction between an alkyne and an azide in the above structure, specifically, a click reaction.
- the linker is in the precursor state.
- Including, through the structure can form a third unit, the third unit
- L is 3 to 50 heteroalkylene including oxime
- the oxygen atom of the oxime is on the side of L linked to W and the carbon atom of the oxime is on the side of L linked with Ab;
- the carbon atom of the oxime is on the side of L linked to W, and the oxygen atom of the oxime is on the side of L linked to Ab.
- L comprises an oxime, and at least one isoprenyl unit is to covalently bond the oxime to Ab.
- the linker is It may further contain at least one isoprenyl unit having the structure of , wherein n is at least 2 or more.
- the at least one isoprenyl unit is a substrate of an isoprenoid transferase or a product of an isoprenoid transferase.
- the isoprenyl unit of the linker is covalently bound to the antibody by a thioether bond, the thioether bond comprising the sulfur atom of the cysteine of the antibody construct.
- the isoprenyl unit can covalently bond the oxime included in the linker to the antibody construct.
- the antibody construct comprises an amino acid motif recognized by an isoprenoid transferase and the thioether bond comprises a sulfur atom of a cysteine of the amino acid motif.
- the antibody construct comprises an amino acid motif recognized by an isoprenoid transferase and the thioether bond comprises a sulfur atom of a cysteine of the amino acid motif.
- the amino acid motif is a sequence selected from the group consisting of CXX, CXC, XCXC, XXCC, and CYYX, wherein C represents cysteine; Y at each occurrence independently represents an aliphatic amino acid; X independently for each occurrence represents glutamine, glutamate, serine, cysteine, methionine, alanine, or leucine; The thioether linkage contains the sulfur atom of the cysteine of the amino acid motif.
- the amino acid motif is the sequence CYYX, and Y for each occurrence is independently alanine, isoleucine, leucine, methionine or valine.
- the amino acid motif is a CVIM or CVLL sequence.
- At least one of 1 to 20 amino acids preceding the amino acid motif may be independently selected from glycine, arginine, aspartic acid and serine.
- At least one of 1 to 20 amino acids preceding the amino acid motif is glycine.
- one or more of the 1 to 10 amino acids preceding the amino acid motif may each be independently selected from glycine, arginine, aspartic acid and serine.
- at least one of the seven amino acids preceding the amino acid motif is glycine.
- at least three of the seven amino acids preceding the amino acid motif are each independently selected from glycine, arginine, aspartic acid and serine.
- 1 to 10 amino acids preceding the amino acid motif are glycine, specifically, at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids preceding the amino acid motif are glycine.
- the antibody may comprise the amino acid sequence of GGGGGGGCVIM.
- L may include the amino acid sequence GGGGGGGCVIM at the C-terminus.
- the second unit connects L and the third unit, L and the fourth unit, or the third unit and the fourth unit,
- the one or more fourth units are capable of releasing one or more drugs or toxins
- L is for connecting the second unit and the fourth unit, the second unit and the third unit, or the second unit with another second unit.
- the fourth unit has the structure of formula (IIb):
- G is a sugar, sugar acid, or sugar derivatives
- W is -C(O)-, -C(O)NR'-, -C(O)O-, -S(O) 2 NR'-, -P(O)R''NR'-, -S (O)NR'-, or -PO 2 NR'-,
- R' and R'' are each independently hydrogen, (C 1-8 )alkyl, (C 3-8 )cycloalkyl, (C 1 - 8 )alkoxy, (C 1-8 )alkylthio, mono- or di-(C 1-8 )alkylamino, (C 3-20 )heteroaryl, or (C 6-20 )aryl, W is L or connected to the second unit,
- each Z is independently hydrogen, (C 1-8 )alkyl, halogen, cyano or nitro;
- n is an integer from 1 to 3
- n 0 or 1
- R 1 and R 2 are each independently hydrogen, (C 1-8 )alkyl or (C 3-8 )cycloalkyl, or R 1 and R 2 together with the carbon atom to which they are attached are (C 3-8 )cycloalkyl. form an alkyl ring.
- the sugar or sugar acid is a monosaccharide.
- G is a compound of the structure (IIIa):
- R 3 is hydrogen or a carboxyl protecting group
- each R 4 is each independently hydrogen or a hydroxyl protecting group.
- R 3 is hydrogen and each R 4 is hydrogen.
- W is -C(O)NR'-, wherein C(O) is connected to a phenyl ring and NR' is connected to L or a second unit.
- Z is hydrogen
- R 1 and R 2 are each hydrogen.
- the second unit is -(CH 2 ) r (V(CH 2 ) p ) q -, -((CH 2 ) p V) q -, -(CH 2 ) r (V(CH ) 2 ) p ) q Y-, -((CH 2 ) p V) q (CH 2 ) r -, -Y((CH 2 ) p V) q - or -(CH 2 ) r (V(CH 2 ) p ) represented by q YCH 2 -,
- r is an integer from 0 to 10;
- p is an integer from 1 to 10;
- q is an integer from 1 to 20,
- V and Y are each independently a single bond, -O-, -S-, -NR 21 -, -C(O)NR 22 -, -NR 23 C(O)-, -NR 24 SO 2 -, or - SO 2 NR 25 -,
- R 21 to R 25 are each independently hydrogen, (C 1-6 )alkyl, (C 1-6 )alkyl(C 6-20 )aryl or (C 1-6 )alkyl(C 3-20 )heteroaryl .
- r is 2.
- p is 2.
- q is an integer from 6 to 20.
- q is 2, 5, or 11.
- V and Y are each independently -O-.
- L or the third unit is , , or including,
- L 1 is a direct bond or alkylene having 1 to 30 carbon atoms
- R 11 is hydrogen or alkyl having 1 to 10 carbon atoms, specifically methyl
- L 2 is alkyl having 1 to 30 carbon atoms it's ren
- L 1 is alkylene having 12 carbon atoms.
- R 11 is methyl
- L 2 is alkylene having 11 carbon atoms.
- the Binding Unit is covalently bound to the antibody by a thioether bond, the thioether bond comprising the sulfur atom of a cysteine of the antibody.
- the antibody comprises an amino acid motif recognized by an isoprenoid transferase, and the thioether bond comprises a sulfur atom of a cysteine of the amino acid motif.
- the amino acid motif is a sequence selected from the group consisting of CXX, CXC, XCXC, XXCC, and CYYX, wherein C represents cysteine; Y at each occurrence independently represents an aliphatic amino acid; X independently for each occurrence represents glutamine, glutamate, serine, cysteine, methionine, alanine, or leucine; The thioether linkage contains the sulfur atom of the cysteine of the amino acid motif.
- the amino acid motif is the sequence CYYX, and Y for each occurrence is independently alanine, isoleucine, leucine, methionine or valine.
- the amino acid motif is a CVIM or CVLL sequence.
- At least one of the 1 to 20 amino acids preceding the amino acid motif is glycine.
- one or more of the 1 to 20 amino acids preceding the amino acid motif may each be independently selected from glycine, arginine, aspartic acid and serine.
- 1 to 20 amino acids preceding the amino acid motif are glycine, in particular at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids are glycine.
- the antibody may comprise the amino acid sequence of GGGGGGGCVIM.
- the isoprenoid transferase is farnesyl protein transferase (FTase) or geranylgeranyl transferase (GGTase).
- FTase farnesyl protein transferase
- GTTase geranylgeranyl transferase
- L comprises one or more branched linkers covalently bonded to Ab
- each branched linker comprises a fifth unit covalently linked to the Ab by a first linker (PL);
- each branched linker comprises a first branch (B1) wherein the first active agent is covalently linked to the fifth unit by a second linker (SL) and a cleavage group (CG); and
- each branched linker comprises: a) a second branch (B2) wherein the second active agent is covalently linked to the fifth unit by a second linker (SL) and a cleavage group (CG); or b) a second branch (B2) wherein the polyethylene glycol moiety is covalently bound to the fifth unit,
- Each of the cleavage groups may be hydrolyzed to release the active agent from the antibody construct-active agent conjugate.
- the branched linker comprises a fifth unit (BR) covalently bonded to the reactive moiety by a first linker (PL);
- the fifth unit comprises a first active agent covalently bonded to the first branch (B1) and covalently bonded to a second linker (SL) and a cleavage group (CG);
- the fifth unit comprises a second active agent covalently linked to a second branch (B2) and covalently linked to a second linker (SL) and a cleavage group (CG) or b) a polyethylene glycol moiety, wherein Each cleavage group can be hydrolyzed to release the active agent.
- the cleavage group is as shown in Formula II.
- the second linker (eg, connecting the active agent to the fifth unit) is a 1,3-dipolar cycloaddition reaction, a hetero-Diels-Elder reaction (hetero) -Diels-Alder reaction, nucleophilic substitution reaction, non-aldol type carbonyl reaction, addition to a carbon-carbon multiple bond ), an oxidation reaction or a click reaction may include a third unit formed.
- the third unit may be formed by a reaction of an alkyne with an azide as above, or a non-aldol-type carbonyl reaction, such as a reaction of an aldehyde or ketone group with a hydrazine or hydroxylamine, which is an active agent and/or to allow mild coupling of the cleavage group and L.
- a non-aldol-type carbonyl reaction such as a reaction of an aldehyde or ketone group with a hydrazine or hydroxylamine, which is an active agent and/or to allow mild coupling of the cleavage group and L.
- the fifth unit , , , , or ego the fifth unit , or ego,
- the L 2 , L 3 , L 4 are each independently a direct bond or -C n H 2n -, wherein n is an integer from 1 to 30,
- the G 1 , G 2 , G 3 are independently a direct bond, ,
- R 30 is hydrogen or C 1-30 alkyl
- R 40 is hydrogen, C 1-10 alkyl or -L 5 -COOR 50 , wherein L 5 is a direct bond or -C n H 2n -,
- n is an integer from 1 to 10
- R 50 is hydrogen or C 1-30 alkyl.
- the fifth unit , , or ego the fifth unit , or ego
- L 2 , L 3 , L 4 , G 1 , G 2 , G 3 , R 30 , R 40 , and L 5 may be the same as described above.
- the cleavage group is cleavable in a target cell.
- the cleavage group is capable of releasing one or more active agents.
- the conjugate comprises Ab;
- each branched linker is associated with one or two or more active agents
- active agents are each the same or different.
- each of said active agents is bound to a branched linker by a cleavable bond.
- L is a linker comprising at least one fifth unit and a first linker (PL).
- the first linker of the antibody-drug conjugate comprises an alkylene having 1 to 100, preferably 1 to 50 carbon atoms, or:
- alkylene contains at least one unsaturated bond
- alkylene includes at least one heteroarylene
- a carbon atom of the alkylene is replaced by one or more heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S); or
- Alkylene is further substituted with one or more alkyl having 1 to 20 carbon atoms.
- each of said branched linkers comprises a fifth unit, each active agent binds to the fifth unit via a secondary linker, said fifth unit being an antibody by a primary linker is coupled to
- the fifth unit is an amide and the primary linker comprises a carbonyl of the amide.
- the fifth unit is a lysine unit.
- At least one carbon atom of the alkylene is replaced with a nitrogen
- the first linker comprises at least two atoms of a hydrophilic amino acid
- the nitrogen forms a peptide bond with the backbone carbonyl of the hydrophilic amino acid.
- the hydrophilic amino acid may be, for example, arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine or threonine.
- the branched linker of the antibody-active agent comprises an amino acid having a side chain with a charged moiety at neutral pH in aqueous solution, preferably arginine, aspartate, glutamate, lysine or ornithine.
- the amino acid may be located anywhere in the branched linker.
- the oxime of the branched linker can be covalently bonded to the polyethylene glycol unit of the branched linker.
- such amino acids may be present in a second linker, optionally in each second linker.
- the linker-activator comprises a compound of the following structural formula.
- B' and B'' represent active agents, which may be the same or different;
- n1 to n3 each independently represent an integer of 0 to 30;
- AA represents an amino acid group
- AA represents an amino acid group
- the amino acid group refers to a form in which one or more amino acids are bound.
- the linker comprises a peptide sequence of a plurality of amino acids; ii) at least two active agents are covalently linked with the side chain of the amino acid.
- the amino acid group is linked to a main chain of 1 to 20 amino acids; or a side chain bond.
- the amino acid group comprises 1 to 20 main chain bonds of arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine or threonine; or a group by a side chain bond.
- the amino acid group comprises 1 to 20 main chain bonds of arginine, aspartate, glutamate, lysine or ornithine; or a group by a side chain bond.
- the amino acid group comprises at least one lysine of 1 to 20 amino acids.
- amino acid group includes main chain and side chain bonds of lysine.
- the branched linker comprising the fifth unit is
- activator moiety refers to a compound covalently bonded to a linker or a portion of the linker, including an active agent.
- an activator moiety may be directly bonded to the linker, and one or more, specifically, two or more, three or more, four or more, activator moieties to the linker may be directly bonded to the linker.
- the active agent moiety in the present invention may include a compound unit for directly bonding the active agent to the linker.
- a portion of the active agent moiety is cleavable and the portion can be cleaved to release the active agent in the intracellular environment.
- the active moiety and the linker can determine the number of bonds in consideration of the DAR, pharmacological activity, etc. of the conjugate.
- the active agent moiety may refer to the whole including the following structure and the active agent, through which the active agent and the linker may be directly bonded. However, this is illustrative and not limited thereto.
- the active agents are each independently selected from a chemotherapeutic agent and a toxin.
- the active agent may be an immunomodulatory compound, an anticancer agent, an antiviral agent, an antibacterial agent, an antifungal agent, an antiparasitic agent, or a combination thereof, and may optionally be used among the active agents listed below:
- affinity ligand is a substrate, an inhibitor, an activator, a neurotransmitter, a radioactive isotope, or a combination thereof;
- radioactive label 32P, 35S, fluorescent die, electron dense reagent, enzyme, biotin, streptavidin, dioxigenin, hapten, an immunogenic protein, a nucleic acid molecule with a sequence complementary to a target, or a combination thereof;
- immunomodulatory compounds anticancer agents, anti-viral agents, anti-bacterial agents, anti-fungal agents , and an anti-parasitic agent, or a combination thereof;
- the active agent is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-oxidedoxedoxedoxedoxethyl
- y is an integer from 1 to 10.
- the active agent is a pyrrolobenzodiazepine dimer
- the linker and the antibody are connected through the N10 or N10' position of the pyrrolobenzodiazepine dimer.
- -C(O)O-*, -S(O)O-*, -C(O)-*, -C(O)NR-*, - at the N10 and N10' positions of the pyrrolobenzodiazepine dimer each independently any one selected from the group consisting of S(O) 2 NR-*, -(P(O)R')NR-*, -S(O)NR-*, and -PO 2 NR-* groups is attached,
- R and R' are each independently H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted substituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-8 alkoxy, substituted or unsubstituted C 1-8 alkylthio, substituted or unsubstituted C 3-20 heteroaryl, substituted or unsubstituted C 5-20 aryl or mono- or di-C 1-8 alkylamino;
- C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl are substituted, H, OH, N substituted with a substituent selected from the group consisting of 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NNH 2 , halo, C 1-6 alkyl, C 1-6 alkoxy and C 6-12 aryl;
- a pyrrolobenzodiazepine dimer prodrug, a pharmaceutically acceptable salt or solvate thereof may be used as the active agent.
- the N10 position of the pyrrolobenzodiazepine dimer is substituted with X at the N'10 position or X' at the N'10 position, wherein X or X' connects the pyrrolobenzodiazepine dimer to the linker;
- X and X' are each independently -C(O)O*, -S(O)O-*, -C(O)-*, -C(O)NR X -*, -S(O) 2 NR X -*, -P(O)R'NR X -*, -S(O)NR X -*, or -PO 2 NR X -*;
- R X and R X ' are independently H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1 - 8 alkoxy, C 1-8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di(di)-C 1-8 alkylamino.
- a pyrrolobenzodiazepine dimer precursor is provided as the active agent.
- a pyrrolobenzodiazepine dimer precursor is provided as the active agent.
- the antibody-drug conjugate prepared by the conventional method in the case of the antibody-drug conjugate prepared by the conventional method, the content of impurities is high and the exposed imine group is attacked by nucleophiles, which may result in the production of a drug having an unwanted structure.
- the antibody-drug conjugate prepared by the method according to the present invention has the advantage of easy separation due to high purity, and it has been shown that the physical properties are more improved compared to the existing PBD or PBD dimer.
- the pyrrolobenzodiazepine dimer precursor is a pyrrolobenzodiazepine dimer precursor, a pharmaceutically acceptable salt or solvate thereof, characterized in that it has the structure of Formula X or Formula XI:
- the dotted line indicates the optional presence of a double bond between C1 and C2, between C2 and C3, between C'1 and C'2, or between C'2 and C'3;
- R m ′ is selected from R m , CO 2 R m , COR m , CHO, CO 2 H, and halo;
- each R m is independently C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 cycloalkyl, 3-7 - selected from the group consisting of -membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7-membered heteroaryl;
- R X2 , R X2 ' R X3 , R X3 ', R X5 , and R X5 ' are independently H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m 2 , NO 2 , and halo;
- R X4 and R X4 ′ are independently H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m 2 , NO 2 , halo, C 1-6 alkyl C 1-6 alkoxy; C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 5-12 aryl, 5-7 membered heteroaryl, -CN, -NCO, -OR n , -OC(O)R n , -OC(O)NR n R n ', -OS(O)R n , -OS(O) 2 R n , -SR n , -S(O)R n , -S(O) 2 R n , -S(O)NR n R n ', -S(O) 2 NR n R n
- X and X' are independently -C(O)O*, -S(O)O-*, -C(O)-*, -C(O)NR X -*, -S(O) 2 NR X -*, -P(O)R'NR X -*, -S(O)NR X -*, or -PO 2 NR X -*;
- R X and R X ' are independently H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1 - 8 alkoxy, C 1-8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di(di)-C 1-8 alkylamino;
- Y and Y' are independently selected from O, S, and N(H);
- R X6 is independently selected from C 3-12 alkylene, C 3-12 alkenylene, or C 3-12 heteroalkylene;
- R X7 and R X7 ' are independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 6- 10 aryl, 5-7 membered heteroaryl, -OR r , -OC(O)R r , -OC(O)NR r R r ', -OS(O)R r , -OS(O) 2 R r , -SR r , -S(O)R r , -S(O) 2 R r , -S(O)NR r R r ', -S(O) 2 NR r R r ', -OS(O) NR r R r ', -OS(O) NR r R r ', -OS(O) 2 NR r R r ', -OS(O) NR r
- each R r , R r ', R s , and R s ' is independently H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5-10 aryl, and 5 to 7-membered heteroaryl;
- each R X8 and R X8 ′ is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 heteroalkyl, 3-7 membered heterocycloalkyl, C 5 -10 aryl, 5-7 membered heteroaryl, -S(O)R m , -S(O) 2 R m , -S(O)NR m R m ', -S(O) 2 NR m R m ', -NR m R m ', -NR m C(O)R m , -NR m C(O)OR n , -NR m C(O)NR n R n ', -NR m S(O)R n , -NR m S(O) 2 R n , -NR m S(O)NR n R n ', -NR m S(O) 2 NR n , -
- Z a is selected from OR X12a , NR X12a R X12a , or SR X12a ;
- Z b is selected from OR X13a , NR X13a R X13a , or SR X13a ;
- Z a ' is selected from OR X12a ', NR X12a 'R X12a ', or SR X12a ';
- Z b ' is selected from OR X13a ', NR X13 'R X13a ' or SR X13a ';
- each R X12a , R X12a ', R X13a ' and R X13a ' is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 - membered heterocycloalkyl, C 5-10 aryl, 5-7 membered heteroaryl, -C(O)R X15a , -C(O)OR X15a and -C(O)NR X15a R X15a '; and
- each R X15a and R X15a ′ is independently C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 cycloalkyl , 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7-membered heteroaryl;
- Z a and Z b are optionally taken together with the atoms to which they are attached to form a 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, or 3 to 7-membered heteroaryl, and Z a ' and Z b ' are optionally taken together with the atom to which they are attached to form a 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, or 3 to 7-membered heteroaryl; and
- each of R n , R n ', R o , R o ', R p , and R p ' is independently H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5-10 aryl, and 5 to 7-membered heteroaryl.
- R m is independently C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 selected from the group consisting of cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7-membered heteroaryl,
- R m is additionally C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 cycloalkyl , 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, or 5 to 7-membered heteroaryl.
- R X4 and R X4 ' are independently H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m R m ', NO 2 , halo, C 1-6 alkyl C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 5-12 aryl, 5-7- membered heteroaryl, -CN, -NCO, -OR n , -OC(O)R n , -OC(O)NR n R n ', -OS(O)R n , -OS(O) 2 R n , -SR n , -S(O)R n , -S(O) 2 R n , -S(O)NR n R n ', -S
- R X4 or R X4 ' is C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 5-12 aryl or 5-7 membered heteroaryl, additionally one or more C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl , 3-7-membered heterocycloalkyl, C 5-10 aryl, 5-7-membered heteroaryl, -OR p , -OC(O)R p , -OC(O)NR p R p ', -OS( O)R p , -OS(O) 2 R p , -SR p , -S(O)R p , -S(O) 2 R p , -S(O)NR p R
- R X7 and R X7 ' are independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7- membered heterocycloalkyl, C 6-10 aryl, 5-7 membered heteroaryl, -OR r , -OC(O)R r , -OC(O)NR r R R r ', -OS(O)R r , -OS(O) 2 R r , -SR r , -S(O)R r , -S(O) 2 R r , -S(O)NR r R r ', -S(O) 2 NR r R r ', -OS(O)NR r R r ', -OS(O) 2 NR r R r ', -OS(O)NR r R r ', -OS(O) 2 NR
- R X7 or R X7 ' is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6-10 aryl, 5 to 7-membered heteroaryl, additionally C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6-10 aryl, 5-7 membered heteroaryl, -OR t , -OC(O)R t , -OC(O)NR t R t ', -OS(O)R t , -OS(O) 2 R t , -SR t , -S(O)R t , -S(O) 2 R t , -S(O)NR t R t ', -S(O) 2 NR
- R r , R r ', R s , R s ', R t , R t ', R u and R u ' are independently H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3-7 membered heterocycloalkyl, C 5-10 aryl, and 5-7 membered heteroaryl.
- R X1 and R X1 ' are independently selected from R m ;
- R m is selected from C 1-6 alkyl, C 2-6 alkenyl, C 5-7 aryl and C 3-6 heteroaryl.
- R X2 , R X2 ′, R X3 , R X3 ′, R X5 , and R X5 ′ are independently selected from H or OH.
- R X4 and R X4 ′ are independently selected from R m ;
- R m is C 1-6 alkoxy.
- R X4 and R X4 ' are independently any one selected from the group consisting of methoxy, ethoxy and butoxy.
- Y and Y' are O.
- R X6 is C 3-12 alkylene, C 3-12 alkenylene or C 3-12 heteroalkylene, and R X6 is -NH 2 , -NHR m , -NHC(O )R m , —NHC(O)CH 2 —[OCH 2 CH 2 ] n —R XX , or —[CH 2 CH 2 O] n —R XX substituted;
- R XX is H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1 -8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di-C 1-8 alkyl amino; and
- n is an integer from 1 to 6.
- the pyrrolobenzodiazepine dimer is represented by the following general formula X.
- the dotted line indicates the optional presence of a double bond between C1 and C2, between C2 and C3, between C'1 and C'2, or between C'2 and C'3;
- R X2 , R X2 ′ R X3 , and R X3 ′ are each independently selected from H, R m , OH, OR m , NR m 2 , NO 2 , and halo;
- R X4 and R X4′ are each independently selected from H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m 2 , halo, and C 1-6 alkyl;
- R X5 and R X5' are each independently H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m 2 , -NR m R m ', NO 2 , -NR m C( O)R m' , -NR m C(O)OR m' , -NR m C(O)NR m R m' , -S(O)R m , -S(O) 2 R m , -S( O)NR m R m ', -S(O) 2 NR m R m ', -NR m S(O)R m ', -NR m S(O) 2 R m ', -P(O)R m , -P(O)NR m R m ', -P(O) 2 NR m R m ', -P(O) 2
- Y and Y' are each independently O, S, or N(H);
- R X6 is independently C 3-12 alkylene, C 3-12 alkenylene, or C 3-12 heteroalkylene; R X6 is -NH 2 , -NHR m , -NHC(O)R m , -NHC(O)CH 2 -[OCH 2 CH 2 ] n -R XX , or -[CH 2 CH 2 O] n -R XX is substituted or unsubstituted;
- R XX is H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1 -8 alkyl thio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di-C 1-8 alkylamino, wherein n is an integer from 1 to 6;
- R X7 and R X7 ' are each independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)R r , -C(O)OR s or -C (O)NR r R r ';
- R r , R r ', and R s are each independently H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3-7 membered heterocyclo alkyl, C 5-10 aryl or 5 to 7 membered heteroaryl;
- each R m' is independently selected from R m , CO 2 R m , COR m , CHO, CO 2 H, and halo;
- R X2 , R X2 ′, R X3 , and R X3 ′ are each independently selected from H or OH.
- the R X5 , and R X5 ' are each independently H, OH, -S(O)R m , S(O) 2 R m , -P(O)R m , and -P (O) 2 R m is selected from the group consisting of, wherein R m is H, OH, C 1-12 alkyl, C 1-12 alkoxy, C 2-12 alkenyl, or C 2-12 alkynyl.
- R X4 and R X4 ' are each independently C 1-6 alkoxy.
- R X4 and R X4 ' are independently any one selected from the group consisting of methoxy, ethoxy and butoxy.
- Y and Y' are O.
- R X6 is C 3-12 alkylene, C 3-12 alkenylene or C 3-12 heteroalkylene, and R X6 is -NH 2 , -NHR m , -NHC(O )R m , -NHC(O)CH 2 -[OCH 2 CH 2 ] n -R XX , or -[CH 2 CH 2 O] n -R XX ;
- R XX is H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1 -8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di-C 1-8 alkyl amino; and
- n is an integer from 1 to 6.
- the active agent is a pyrrolobenzodiazepine dimer represented by the general formula XII or XIII:
- X a and X a ' are independently selected from a bond or C 1-6 alkylene;
- Z X ' and Z X are independently hydrogen, C 1-8 alkyl, halogen, cyano, nitro, , or -(CH 2 ) m -OCH 3 ;
- n is an integer from 0 to 12;
- Z X ' and Z X are independently hydrogen, , And -(CH 2 ) m -OCH 3 Any one selected from the group consisting of,
- R 80 , R 90 and R 100 is any one selected from the group consisting of hydrogen, C 1-3 alkyl and C 1-3 alkoxy,
- n 1 to 6.
- the [LINKER-(B) l ] precursor is
- the [LINKER-(B) l ] precursor is
- MMAE is monomethyl auristatin E
- MMAF is monomethyl auristatin F.
- the [LINKER-(B) l ] precursor comprises the following structure.
- B' and B'' represent an active agent, which may be the same or different;
- n and n each independently represent an integer of 0-30.
- the present invention relates to a pharmaceutical composition for the prevention or treatment of hyperproliferative, cancer, or angiogenic diseases comprising the conjugate.
- the pharmaceutical composition further comprises a pharmaceutically effective amount of a chemotherapeutic agent.
- the cancer is lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, bowel cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi Any one selected from the group consisting of sarcoma and melanoma.
- the present invention also relates to a pharmaceutical formulation comprising the conjugate.
- parenteral means an administration route in a broad sense, for example, transdermal, intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, intranasal, sublingual, intrathecal (intrathecal), inhalation, ocular, rectal, vaginal, ventricular administration, and the like.
- composition When formulating the composition, it is usually prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant.
- a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant.
- Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, and such solid preparations include at least one compound according to the present invention and at least one excipient, for example, starch, calcium carbonate, It is prepared by mixing sucrose or lactose or gelatin.
- excipients for example, starch, calcium carbonate, It is prepared by mixing sucrose or lactose or gelatin.
- lubricants such as magnesium stearate talc are also used.
- Liquid formulations for oral administration include suspensions, solutions, emulsions, or syrups.
- various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, injections, freeze-dried formulations, suppositories, and the like.
- propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solutions and suspensions.
- injectable esters such as ethyl oleate
- witepsol, macrogol, tween 61, cacao butter, laurin fat, glycerol, gelatin, etc. may be used as the base of the suppository.
- the conjugate according to the present invention is administered in a pharmaceutically effective amount.
- pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type, severity, and drug activity of the patient. , sensitivity to the drug, administration time, administration route and excretion rate, duration of treatment, factors including concurrent drugs, and other factors well known in the medical field.
- the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
- the effective amount of the conjugate according to the present invention may vary depending on the age, sex, and weight of the patient, and is generally 0.01 mg to 150 mg per kg body weight, more specifically 0.1 mg to 100 mg per kg body weight. It can be administered daily or every other day, or divided into 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, severity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.
- the antibody-drug conjugate according to the present invention contains an anti-CLDN18.2 antibody that specifically binds to claudin 18 isoform 2 (CLDN18.2) expressing cells and is internalized into the cells, thereby effectively and specific for the drug. It can be delivered selectively and selectively, and the drug is stably bound to the antibody to exhibit the desired cytotoxicity while maintaining in vivo stability.
- grafting linker technology that includes a self-immolative group that is more stable in plasma and is stable even in circulation in the body, and the drug is easily released within cancer cells to maximize drug efficacy, drugs and/or toxins are transferred to target cells. It has the effect of providing a drug-linker-ligand system that can stably reach and effectively exhibit drug effects while significantly lowering toxicity.
- FIGS. 2 and 3 are diagrams showing the in vivo experimental results of ADC samples.
- FIGS 4 to 7 are schematic diagrams of the manufacturing process of the ADC according to the present invention.
- the present invention is an antibody or antigen-binding fragment, wherein the antibody specifically binds to claudin 18 isoform 2 (CLDN18.2) comprising a heavy chain variable region and a light chain variable region, and the heavy chain variable region is SEQ ID NO: 2 a heavy chain CDR1 consisting of the amino acid sequence shown in SEQ ID NO: 4, a heavy chain CDR2 consisting of the amino acid sequence shown in SEQ ID NO: 4, and a heavy chain CDR3 consisting of the amino acid sequence shown in SEQ ID NO: 6, wherein the light chain variable region has an amino acid sequence shown in SEQ ID NO: 9 It relates to a conjugate comprising a light chain CDR1 consisting of, a light chain CDR2 consisting of the amino acid sequence shown in SEQ ID NO: 11, and a light chain CDR3 consisting of the amino acid sequence shown in SEQ ID NO: 13.
- PR002726-heavy chain SEQ ID NO: FR1 EVQLLESGGGLVQPGGSLRLSCAAS One CDR1 GFTFSSFVMS 2 FR2 WVRQAPGKGLEWVS 3 CDR2 TISGSGRSTYYADSVKG 4 FR3 RFTISRDNSKNTLHLQMNSLRAEDTAVYYCAK 5 CDR3 DAAAAGTKFDY 6 FR4 WGQGTLVTVSS 7 V H EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFVMSWVRQAPGKGLEWVSTISGSGRSTYYADSVKGRFTISRDNSKNTLHLQMNSLRAEDTAVYYCAKDAAAAGTKFDYWGQGTLVTVSS 15 HC EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFVMSWVRQAPGKGLEWVSTISGSGRSTYYADSVKGRFTISRDNSKNTLHLQMNSLRAEDTAVYYCAKDAAAAGTKFDYWGQGTLVTV
- the light chain FR4 (SEQ ID NO: 14) C-terminus of the antibody of Table 1 (PR002726) was fused with a CaaX peptide moiety (GGGGGGGCVIM; SEQ ID NO: 19) to prepare an antibody clone PR301839, and CHO cell-based Antibodies were produced through transient expression.
- the produced PR301839 antibody was used for the next ADC synthesis.
- the compounds 1 and 2 were prepared by the method described in Korean Patent Application Laid-Open No. 10-2018-0110645.
- the compound 3 was prepared by the method described in International Patent Publication No. WO2017-089895.
- the compound 4 and compound 5 were prepared by the method described in patent WO2017-089890.
- ADC was prepared through the following two steps, and LCB14-0606 and LCB14-0512, which were commonly used, were prepared by the method described in Korean Patent Application Laid-Open No. 10-2014-0035393.
- the structural formulas of LCB14-0606 and LCB14-0512 are as follows:
- a prenylation reaction mixture of the antibody prepared in Example 1 was prepared and reacted at 30° C. for 16 hours.
- the reaction mixture was prepared in a buffer containing 24 ⁇ M antibody, 400 nM FTase (Calbiochem #344145) and 0.25 mM LCB14-0511 or LCB14-0606 (50 mM Tris-HCl (pH 7.4), 5 mM MgCl 2 , 10 ⁇ M ZnCl 2 ) , 0.25 mM DTT).
- the prenylated antibody was decontaminated with a G25 Sepharose column (AKTA purifier, GE healthcare) equilibrated with PBS buffer.
- Step 2 Drug-conjugation method
- the oxime bond generation reaction mixture between the prenylated antibody and the linker-drug was prepared in 100 mM Na-acetate buffer pH 5.2, 10% DMSO, 20 ⁇ M antibody and 200 ⁇ M linker-drug (in house, the compounds of Examples 1 and 2) 1, 2, 3, 4, 5, 7, and 8) were mixed and stirred gently at 30°C. After 6 hours or 24 hours of reaction, excess low molecular weight compounds were removed through FPLC (AKTA purifier, GE healthcare) process, and protein fractions were collected and concentrated.
- FPLC AKTA purifier, GE healthcare
- ADC using a copper-free click binding reaction between prenylated antibody and linker-drug was performed in PBS buffer (pH 7.4), 1% DMSO, 10 ⁇ M prenylated antibody and 100 ⁇ M linker-drug (in house, carried out)
- Compound No. 2 of Example 1 was mixed to prepare a reaction mixture, and after reaction at 25 ° C for 6 hours, FPLC (AKTA purifier, GE healthcare) or G25 Sepharose column process was performed to remove excess low molecular weight compounds. concentrated.
- the cancer cell binding ability of the Anti-CLDN18.2 antibody (PR002726) and the antibody (PR301839) used to prepare the ADC in the form of a CaaX peptide fused to the light chain FR4 C-terminus was confirmed by a cell binding experiment using a flow cytometer (FACS).
- gastric cancer cell lines SNU-601 and SNU-620 known to express CLDN18.2, and pancreatic cancer cell line PATU-8988s were used as cancer cells.
- a group treated with human IgG as a control antibody and a group treated with only a secondary antibody were used. .
- PR002726 and PR301839 in SNU-601 were 22.95 times and 17.5 times stronger than the IgG control group, respectively.
- PR002726 and PR301839 were confirmed to bind 15.09 times and 11.21 times stronger than the control group.
- PATU-8988s PR301839 was confirmed to bind 16.21 times stronger than the control.
- the two antibodies PR002726 and PR301839 were capable of binding to cancer cells expressing CLDN18.2. (See Fig. 1)
- the cell proliferation inhibitory activity of the drugs and ADCs shown in Table 4 below was measured against cancer cell lines.
- cancer cell lines commercially available human gastric cancer cell lines NUGC-4, SNU-601 SNU-602 and pancreatic cancer cell line PATU-8988s were used, and normal cell lines HaCaT, Fa2N-4, HK-2, and HS738.st/Int were used.
- drugs MMAE and SG2057 were used as ADCs, and the ADCs in Table 3 were used.
- Each cancer cell line was inoculated in a 96-well plate for 144 hours in a 144-hour treatment group, and 2,500 to 10,000 per well were seeded and cultured for 24 hours.
- the auristatin-based antibody-drug complex (ADC3) showed equivalent or higher cytotoxicity than the pyrrolobenzodiazepine-based antibody-drug complex (ADC1, ADC2) in the cytotoxicity test with the same time response.
- the pyrrolobenzodiazepine-based antibody-drug complex (ADC3, ADC4, ADC5) was compared to the auristatin-based antibody-drug complex (ADC3, ADC4, ADC5) in the same time response cytotoxicity test. of the antibody-drug complex (ADC1, ADC2) was confirmed to show strong cytotoxicity.
- both 0.2 and 0.4 mg/kg of the pyrrolobenzodiazepine-based antibody-drug complex ADC1 confirmed the tumor growth inhibitory efficacy compared to the control group.
- the tumor growth inhibitory efficacy was confirmed in a dose-dependent manner compared to the control group.
- the experimental results (primary) of the in vivo efficacy of the ADC samples are shown in FIG. 2.
- the secondary experimental results it was confirmed that the tumor growth inhibitory efficacy of the ADC3 1 mg/kg group was similar to the results of the primary experiment.
- all doses of ADC4 and ADC5 the tumor growth inhibitory efficacy was confirmed in a dose-dependent manner.
- the in vivo efficacy comparison experiment results (secondary) of ADC samples are as shown in FIG. 3 .
- Fc ⁇ RI and Fc ⁇ RII interact with distinct but overlapping sites on human
- the present invention can be usefully used in the pharmaceutical field through novel antibody-drug conjugates targeting claudin 18 subtype 2, active metabolites thereof, methods for preparing the same, uses thereof, and pharmaceutical compositions comprising the same.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Cell Biology (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
PR002726-heavy chain | 서열번호 | |
FR1 | EVQLLESGGGLVQPGGSLRLSCAAS | 1 |
CDR1 | GFTFSSFVMS | 2 |
FR2 | WVRQAPGKGLEWVS | 3 |
CDR2 | TISGSGRSTYYADSVKG | 4 |
FR3 | RFTISRDNSKNTLHLQMNSLRAEDTAVYYCAK | 5 |
CDR3 | DAAAAGTKFDY | 6 |
FR4 | WGQGTLVTVSS | 7 |
VH | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFVMSWVRQAPGKGLEWVSTISGSGRSTYYADSVKGRFTISRDNSKNTLHLQMNSLRAEDTAVYYCAKDAAAAGTKFDYWGQGTLVTVSS | 15 |
HC | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFVMSWVRQAPGKGLEWVSTISGSGRSTYYADSVKGRFTISRDNSKNTLHLQMNSLRAEDTAVYYCAKDAAAAGTKFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK | 17 |
PR002726-light chain | 서열번호 | |
FR1 | EIVLTQSPATLSLSPGERATLSC | 8 |
CDR1 | RASQSVSSYLA | 9 |
FR2 | WYQQKPGQAPRLLIY | 10 |
CDR2 | DASNRAT | 11 |
FR3 | GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC | 12 |
CDR3 | QQRSNWPLT | 13 |
FR4 | FGGGTKVEIK | 14 |
VL | EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK | 16 |
LC | EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 18 |
클론 | FR1 | CDR1 | FR2 | CDR2 | FR3 | CDR3 | FR4 | VH/VL |
PR301839-VH | EVQLLESGGGLVQPGGSLRLSCAAS | GFTFSSFVMS | WVRQAPGKGLEWVS | TISGSGRSTYYADSVKG | RFTISRDNSKNTLHLQMNSLRAEDTAVYYCAK | DAAAAGTKFDY | WGQGTLVTVSS | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFVMSWVRQAPGKGLEWVSTISGSGRSTYYADSVKGRFTISRDNSKNTLHLQMNSLRAEDTAVYYCAKDAAAAGTKFDYWGQGTLVTVSS |
서열번호 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 15 |
PR301839-VL | EIVLTQSPATLSLSPGERATLSC | RASQSVSSYLA | WYQQKPGQAPRLLIY | DASNRAT | GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC | QQRSNWPLT | FGGGTKVEIKGGGGGGGCVIM | EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIKGGGGGGGCVIM |
서열번호 | 8 | 9 | 10 | 11 | 12 | 13 | 20 | 21 |
ADCs | Antibody | linker-toxin |
ADC1 | PR301839 | 화합물1 |
ADC2 | 화합물2 | |
ADC3 | 화합물3 | |
ADC4 | 화합물4 | |
ADC5 | 화합물5 |
Test samples | IC50 (nM) | |||||||
NUGC-4 | SNU-601 | SNU-620 | PATU-8988s | HaCaT | Fa2N-4 | HK-2 | Hs738.st/Int | |
MMAE | 0.29 | 0.51 | 0.71 | 0.145 | 0.14 | 3.0 | 21.9 | N/D |
SG2057 | 0.03 | 0.003 | 0.097 | - | - | - | - | - |
ADC1 | 17.11 | 0.028 | 20.2 | - | - | - | - | - |
ADC2 | 9.73 | 0.022 | 20.55 | - | - | - | - | - |
ADC3 | 6.72 | 0.81 | 18.14 | 2.073 | 32.7 | 365.7 | >1,000 | >1,000 |
ADC4 | - | 4.122 | - | 9.297 | 420.7 | - | - | - |
ADC5 | - | 2.278 | - | 27.26 | 562.5 | - | - | - |
Test sample | 개체수 | Dose (mg/kg) | Dose interval |
PBS | 5 | - | qdx1 |
ADC1 | 5 | 0.2 | |
5 | 0.4 | ||
ADC3 | 5 | 0.5 | |
5 | 1 | ||
5 | 2 |
Test sample | 개체수 | Dose (mg/kg) | Dose interval |
PBS | 5 | - | qdx1 |
ADC3 | 5 | 1 | |
ADC4 | 5 | 2 | |
5 | 4 | ||
ADC5 | 5 | 2 | |
5 | 4 |
Claims (54)
- 하기 일반식 I로 표시되는 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물:[일반식 I]Ab-[LINKER-(B)l]m상기 식에서,Ab는 중쇄 가변영역 및 경쇄 가변영역을 포함하는 클라우딘 18 아형 2(claudin 18 isoform 2, CLDN18.2)에 특이적으로 결합하는 항체 또는 항원 결합단편이고,중쇄 가변영역은 서열번호 2로 표시되는 아미노산 서열로 이루어진 중쇄 CDR1, 서열번호 4로 표시되는 아미노산 서열로 이루어진 중쇄 CDR2, 서열번호 6으로 표시되는 아미노산 서열로 이루어진 중쇄 CDR3을 포함하고,경쇄 가변영역은 서열번호 9로 표시되는 아미노산 서열로 이루어진 경쇄 CDR1, 서열번호 11로 표시되는 아미노산 서열로 이루어진 경쇄 CDR2, 서열번호 13으로 표시되는 아미노산 서열로 이루어진 경쇄 CDR3을 포함하며,LINKER는 링커이고,B는 활성제 모이어티이며,l 및 m은 각각 독립적으로 1 내지 20 중에서 선택되는 정수이며,l이 2 이상의 정수인 경우, B는 각각 서로 동일하거나 상이할 수 있다.
- 제1항에 있어서,중쇄 가변영역은 인간 항체의 중쇄 FR을 포함하고, 상기 중쇄 FR을 암호화하는 유전자는 배선 V 유전자 IGHV3-23(germline V gene IGHV3-23)으로부터 유래된, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제2항에 있어서,중쇄 FR은 서열번호 1로 표시되는 아미노산 서열로 이루어진 중쇄 FR1, 서열번호 3으로 표시되는 아미노산 서열로 이루어진 중쇄 FR2, 서열번호 5로 표시되는 아미노산 서열로 이루어진 중쇄 FR3, 서열번호 7로 표시되는 아미노산 서열로 이루어진 중쇄 FR4를 포함하는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제1항에 있어서,경쇄 가변영역은 인간 항체의 경쇄 FR을 포함하고, 상기 경쇄 FR을 암호화하는 유전자는 배선 V 유전자 IGKV3-11 또는 IGKV3-15로부터 유래된, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제4항에 있어서,경쇄 FR은 서열번호 8로 표시되는 아미노산 서열로 이루어진 경쇄 FR1;서열번호 10으로 표시되는 아미노산 서열로 이루어진 경쇄 FR2;서열번호 12로 표시되는 아미노산 서열로 이루어진 경쇄 FR3;서열번호 14로 표시되는 아미노산 서열로 이루어진 경쇄 FR4, 또는 서열번호 20으로 표시되는 아미노산 서열로 이루어진 경쇄 FR4를 포함하는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제1항에 있어서,CLDN18.2에 특이적으로 결합하는 항체 또는 항원 결합단편은 서열번호 15 로 표시되는 아미노산 서열; 또는 이에 대해 80%의 상동성을 갖는 아미노산 서열로 이루어진 중쇄 가변영역; 및서열번호 16으로 표시되는 아미노산 서열; 또는 이에 대해 80%의 상동성을 갖는 아미노산 서열로 이루어진 경쇄 가변영역을 포함하는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제1항에 있어서,상기 항체 또는 이의 항원 결합 단편은 단일클론 항체(monoclonal antibody), 도메인 항체(domain antibody; dAb), 단일 사슬 항체(single chain antibody; scAb), Fab 단편, Fab'단편, F(ab')2 단편, scFab 단편, Fv 단편, dsFv 단편, 단일 사슬 가변 항체(single chain variable fragment; scFv), scFv-Fc 단편, 단일 도메인 중쇄 항체(single domain heavy chain antibody), 단일 도메인 경쇄 항체(single domain light chain antibody), 항체 변이체(variant antibody), 다중 결합 항체(multimeric antibody), 미니바디, 다이아바디, 이중 특이적 항체(bispecific antibody) 및 다중 특이적 항체로 이루어진 군으로부터 선택되는 어느 하나인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제1항에 있어서,상기 항체와 활성제 사이의 링커는 절단 가능한 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제1항에 있어서,상기 접합체는 하기 일반식 IIa의 구조를 갖는 것인, 항체 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물:[일반식 IIa]상기 식에서,Ab는 중쇄 가변영역 및 경쇄 가변영역을 포함하는 CLDN18.2에 특이적으로 결합하는 항체 또는 항원 결합단편이고,B‘은 각각 독립적으로 동일하거나 상이한 활성제이며,상기 R3은 수소 또는 카복실 보호기이며, 상기 각각의 R4는 독립적으로 수소 또는 하이드록실 보호기이고;R1 및 R2은 각각 독립적으로 수소, C1-8 알킬 또는 C3-8 사이클로알킬이며;W은 각각 독립적으로 -C(O)-, -C(O)NR'-, -C(O)O-, -SO2NR'-, -P(O)R''NR'-, -SONR'- 또는 -PO2NR'-이고, 상기 C, S 또는 P는 직접적으로 페닐링(phenyl ring)에 결합하며, 상기 NR'은 L에 결합하고, 상기 R' 및 R''는 각각 독립적으로 수소, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, 모노- 또는 다이-C1-8 알킬아미노, C3-20 헤테로아릴 또는 C6-20아릴이며;.Z는 각각 독립적으로 수소, C1-8 알킬, 할로겐, 시아노 또는 나이트로이고;n은 0 내지 3의 정수이며, n이 2 이상의 정수인 경우 각각의 Z는 서로 동일하거나 상이할 수 있고;L은 각각 독립적으로, 하기 A) 또는 B) 중 어느 하나이고:A) C1-50 알킬렌 또는 1-50 원자 헤테로알킬렌이며, 하기 중 하나 이상을 만족한다:(i) L은 하나 이상의 불포화 결합을 포함하고;(ii) L 내의 2개의 원자가 치환체와 같은 2가 치환체로 치환되고; 이는 헤테로아릴렌(heteroarylene)을 완성시키며;(iii) L은 1 내지 50 원자 헤테로알킬렌이고;(iv) 상기 알킬렌은 하나 이상의 C1-20 알킬로 더 치환된다;B) 이소프레노이드 트랜스퍼라제에 의하여 인식될 수 있는 하기 일반식 Ⅲ의 이소프레닐 유도체 유닛을 하나 이상 포함한다:[일반식 Ⅲ]m은 1 내지 20 중에서 선택되는 정수이다.
- 하기 일반식 IIa로 표시되는 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물:[일반식 IIa]상기 식에서,Ab는 클라우딘 18 아형 2(claudin 18 isoform 2, CLDN18.2)에 특이적으로 결합하는 항체 또는 항원 결합단편이고,상기 R3은 수소 또는 카복실 보호기이며, 상기 각각의 R4는 독립적으로 수소 또는 하이드록실 보호기이고;R1 및 R2은 각각 독립적으로 수소, C1-8 알킬 또는 C3-8 사이클로알킬이며;W은 각각 독립적으로 -C(O)-, -C(O)NR'-, -C(O)O-, -SO2NR'-, -P(O)R''NR'-, -SONR'- 또는 -PO2NR'-이고, 상기 C, S 또는 P는 직접적으로 페닐링(phenyl ring)에 결합하며, 상기 NR'은 L에 결합하고, 상기 R' 및 R''는 각각 독립적으로 수소, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, 모노- 또는 다이-C1-8 알킬아미노, C3-20 헤테로아릴 또는 C6-20아릴이며;.Z는 각각 독립적으로 수소, C1-8 알킬, 할로겐, 시아노 또는 나이트로이고;n은 0 내지 3의 정수이며;L은 각각 독립적으로, 하기 A) 또는 B) 중 어느 하나이고:A) C1-50 알킬렌 또는 1-50 원자 헤테로알킬렌이며, 하기 중 하나 이상을 만족한다:(i) L은 하나 이상의 불포화 결합을 포함하고;(ii) L 내의 2개의 원자가 치환체와 같은 2가 치환체로 치환되고; 이는 헤테로아릴렌(heteroarylene)을 완성시키며;(iii) L은 1 내지 50 원자 헤테로알킬렌이고;(iv) 상기 알킬렌은 하나 이상의 C1-20 알킬로 치환된다;B) 이소프레노이드 트랜스퍼라제에 의하여 인식될 수 있는 하기 일반식 Ⅲ의 이소프레닐 유도체 유닛을 하나 이상 포함한다:[일반식 Ⅲ]B’는 활성제이고,Ab는 물결표시된 부분에 결합되고;l 및 m은 각각 독립적으로 1 내지 20 중에서 선택되는 정수이고,l이 2 이상인 경우, 활성제는 각각 동일하거나 상이할 수 있다.
- 제9항 또는 제10항에 있어서,상기 R1 및 R2은 모두 수소이고;n은 0이며;상기 W는 각각 독립적으로 -C(O)NR'-이고, 상기 C는 직접적으로 페닐링(phenyl ring)에 결합하며, 상기 R'은 수소, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, 모노- 또는 다이- C1-8 알킬아미노, C3-20 헤테로아릴 또는 C6-20아릴이며, NR'은 L에 결합하는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제9항 또는 제10항에 있어서,상기 L은 질소 함유 1-5 원자 헤테로 알킬렌이고,상기 링커는 친수성 아미노산의 2 이상의 원자를 포함하며,상기 질소는 친수성 아미노산의 카르보닐과 펩타이드 결합을 형성하는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제9항 또는 제10항에 있어서,상기 L은 티오에테르 결합에 의해 항체와 공유결합하고,상기 티오에테르 결합은 항체의 시스테인의 황원자를 포함하는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제14항에 있어서,상기 항체는 이소프레노이드 트랜스퍼라제에 의하여 인식될 수 있는 아미노산 모티프를 항체의 C-말단에 포함하고,상기 티오에테르 결합은 상기 아미노산 모티프의 시스테인의 황원자를 포함하는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제15항에 있어서,상기 아미노산 모티프는 CYYX 서열이고, C가 시스테인이고, Y가 지방족 아미노산이며, X가 글루타민, 글루타메이트, 세린, 시스테인, 메티오닌, 알라닌 및 루신으로 이루어진 군으로부터 선택되는 어느 하나이며; 및상기 티오에테르 결합은 상기 아미노산 모티프의 시스테인의 황원자를 포함하는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제15항에 있어서,상기 아미노산 모티프는 CYYX 서열이고, Y가 알라닌, 이소루이신, 류신, 메티오닌 및 발린으로 이루어진 군으로부터 선택되는 어느 하나이거나; 또는CVIM 또는 CVLL 서열인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제15항에 있어서,아미노산 모티프에 선행하는 1 내지 20 개의 아미노산 중 적어도 하나가 글리신인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제9항 또는 제10항에 있어서,상기 L은 C-말단에 아미노산 서열 GGGGGGGCVIM을 포함하는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제9항 또는 제10항에 있어서,상기 L은 옥심을 포함하는 3 내지 50 헤테로알킬렌이고,상기 옥심의 산소 원자는 W와 연결된 L의 측면에 있으며,옥심의 탄소 원자는 Ab에 연결된 L의 측면에 있거나; 또는상기 옥심의 탄소 원자는 W에 연결된 L의 측면에 있으며,옥심의 산소 원자는 Ab에 연결된 L의 측면에 있는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제9항 또는 제10항에 있어서,상기 L은 옥심을 포함하고, 하나 이상의 이소프레닐 유닛은 옥심을 Ab에 공유 결합시키는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제9항 또는 제10항에 있어서,상기 L은 일반식 VIII 또는 일반식 IX로 표시되는 제2 유닛을 더 포함하는 것인, 항체 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물:[일반식 VIII]-(CH2)r(V(CH2)p)q-[일반식 IX]-(CH2CH2X)w-상기 V는 단일결합, -O-, -S-, -NR21-, -C(O)NR22-, -NR23C(O)-, -NR24SO2- 또는 -SO2NR25-이고;X는 -O-, C1-8 알킬렌 또는 -NR21-이고;R21 내지 R25는 각각 독립적으로 수소, C1-6 알킬, C1-6 알킬 C6-20 아릴 또는 C1-6 알킬 C3-20 헤테로아릴이고;r은 0 내지 10의 정수이고;p는 0 내지 10의 정수이고;q는 1 내지 20의 정수이고; 및w는 1 내지 20의 정수이다.
- 제22항에 있어서,상기 q는 1 내지 10의 정수이고;r 및 p는 각각 1 또는 2이며;V는 -O-인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제22항에 있어서,상기 X는 -O-이고;w는 1 내지 10의 정수인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제21항에 있어서,상기 L은 옥심을 포함하고,적어도 하나의 폴리에틸렌 글리콜 유닛은 옥심을 활성제에 공유 결합시키는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제9항 또는 제10항에 있어서,상기 L은 알카인과 아지드와의 반응, 또는 알데히드 또는 케톤 그룹과 하이드라진 또는 하이드록실아민과의 반응으로 형성되는 제3 유닛을 더 포함하는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제28항에 있어서,상기 L1 및 L2는 각각 독립적으로 단일결합; 또는 C11의 알킬렌; 또는 C12의 알킬렌인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제9항 또는 제10항에 있어서,이소프레노이드 트랜스퍼라제는 파네실 단백질 트랜스퍼라아제(FTase) 또는 게라닐게라닐 트랜스퍼라제(GGTase)인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제9항 또는 제10항에 있어서,L은 Ab에 공유 결합된 하나 이상의 분지형 링커를 포함하고,i) 각각의 분지형 링커는 제1 링커(PL)에 의해 Ab에 공유 결합된 제5 유닛을 포함하고;ii) 각각의 분지형 링커는 제1 활성제가 제2 링커 (SL) 및 절단 그룹(CG)에 의해 제5 유닛에 공유결합된 제1 분지(B1)를 포함하며; 및iii) 각각의 분지형 링커는 a) 제2 활성제가 제2 링커 (SL) 및 절단 그룹(CG)에 의해 제5 유닛에 공유 결합된 제2 분지 (B2); 또는 b) 폴리에틸렌 글리콜 모이어티(moiety)가 제5 유닛에 공유 결합되어 있는 제2 분지를 포함하고,상기 각각의 절단 그룹은 접합체부터 활성제를 방출하기 위해 가수분해되는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제31항에 있어서,상기 L2, L3, 및 L4는 각각 독립적으로 직접 결합 또는 -CnH2n-이며, 상기 n은 1 내지 30의 정수이고,상기 G1, G2, 및 G3은 각각 독립적으로 직접 결합,상기 R30은 수소 또는 C1-30 알킬이고;상기 R40은 수소 또는 L5-COOR6이며;상기 L5는 직접 결합 또는 -Cn‘H2n’-이고, 여기에서 n‘은 1 내지 10의 정수이고, R6는 수소 또는 C1-30 알킬인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제31항에 있어서,상기 절단 그룹은 표적 세포 내에서 절단가능하거나; 또는 하나 이상의 활성제를 방출시킬 수 있는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제33항에 있어서,접합체는 Ab를 포함하고;Ab에 공유 결합 된 1, 2, 3 또는 4개 이상의 분지형 링커를 포함하며;각 분지형 링커가 1 또는 2개 이상의 활성제와 결합하고;여기에서 활성제는 각각 동일하거나, 상이한 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제32항에 있어서,각각의 분지형 링커는 제5 유닛을 포함하고, 각각의 활성제는 2차 링커를 통해 제5 유닛에 결합하고, 상기 제5 유닛은 1차 링커에 의해 항체에 결합되는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제35항에 있어서,상기 제5 유닛은 아미드이고, 1차 링커는 아미드의 카르보닐을 포함하는 것이거나; 또는리신 유닛인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제9항 또는 제10항에 있어서,상기 활성제는 화학요법제 또는 톡신인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제9항 또는 제10항에 있어서,상기 활성제는 면역 조절 화합물, 항암제, 항바이러스제, 항균제, 항진균제, 항기생충제 또는 이들의 조합인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제9항 또는 제10항에 있어서,상기 활성제는 하기로부터 선택되는 어느 하나인, 항체 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물:(a) 엘로티닙(erlotinib), 보르테조밉(bortezomib), 풀베스트란트(fulvestrant), 수텐트(sutent), 레트로졸(letrozole), 이마티닙 메실레이트(imatinib mesylate), PTK787/ZK 222584, 옥살리플라틴(oxaliplatin), 5-플루오로우라실(5-fluorouracil), 루코보린(leucovorin), 라파마이신(rapamycin), 라파티닙(lapatinib), 로나파르닙(lonafarnib), 소라페닙(sorafenib), 제피티닙(gefitinib), AG1478, AG1571, 티오테파(thiotepa), 사이클로포스파마이드(cyclophosphamide), 부술판(busulfan), 임프로술판(improsulfan), 피포술판(piposulfan), 벤조도파(benzodopa), 카르보콘(carboquone), 메츄도파(meturedopa), 유레도파(uredopa), 에틸렌이민(ethylenimine), 알트레타민(altretamine), 트리에틸렌멜라민(triethylenemelamine), 트리에틸렌포스포라미드(trietylenephosphoramide), 트리에틸렌티오포스포라미드(triethiylenethiophosphoramide), 트리메틸롤로멜라민(trimethylolomelamine), 불라타신(bullatacin), 불라타시논(bullatacinone), 캄토테신(camptothecin), 토포테칸(topotecan), 브리오스타틴(bryostatin), 칼리스타틴(callystatin), CC-1065, 아도젤레신(adozelesin), 카르젤레신(carzelesin), 비젤레신(bizelesin), 크립토피신 1(cryptophycin 1), 크립토피신 8(cryptophycin 8), 돌라스타틴(dolastatin), 듀오카마이신(duocarmycin), KW-2189, CB1-TM1, 엘루테로빈(eleutherobin), 판크라티스타틴(pancratistatin), 사르코딕티인(sarcodictyin), 스폰지스타틴(spongistatin), 클로람부실(chlorambucil), 클로르나파진(chlornaphazine), 클로로포스파미드(cholophosphamide), 에스트라무스틴(estramustine), 이포스파미드(ifosfamide), 메클로르에타민(mechlorethamine), 멜팔란(melphalan), 노벰비킨(novembichin), 페네스테린(phenesterine), 프레드니무스틴(prednimustine), 트로포스파미드(trofosfamide), 우라실 머스타드(uracil mustard), 카르무스틴(carmustine), 클로로코토신(chlorozotocin), 포테쿠스틴(fotemustine), 로무스틴(lomustine), 니무스틴(nimustine), 라니무스틴(ranimnustine), 칼리키아미신(calicheamicin), 칼리키아미신 감마 1(calicheamicin gamma 1), 칼리키아미신 오메가 1(calicheamicin omega 1), 디네미신(dynemicin), 디네미신 A(dynemicin A), 클로드로네이트(clodronate), 에스페르아미신(esperamicin), 네오카르지노스타틴크로모포어(neocarzinostatin chromophore), 아클라시노마이신(aclacinomysins), 악티노마이신(actinomycin), 안트르마이신(antrmycin), 아자세린(azaserine), 블레오마이신(bleomycins), 칵티노마이신(cactinomycin), 카라비신(carabicin), 카르니노마이신(carninomycin), 카르지노필린(carzinophilin), 크로모마이신(chromomycins), 닥티노마이신(dactinomycin), 다우노루비신(daunorubicin), 데토루부신(detorubucin), 6-디아조-5-옥소-L-노르루신(6-diazo-5-oxo-L-norleucine), 독소루비신(doxorubicin), 모르폴리노-독소루비신(morpholino-doxorubicin), 시아노모르폴리노-독소루비신(cyanomorpholino-doxorubicin), 2-피롤리노-독소루비신(2-pyrrolino-doxorubucin), 리포소말 독소루비신(liposomal doxorubicin), 데옥시독소루비신(deoxydoxorubicin), 에피루비신(epirubicin), 에소루비신(esorubicin), 마르셀로마이신(marcellomycin), 미토마이신 C(mitomycin C), 미코페놀산(mycophenolic acid), 노갈라마이신(nogalamycin), 올리보마이신(olivomycins), 페플로마이신(peplomycin), 포트피로마이신(potfiromycin), 퓨로마이신(puromycin), 쿠엘라마이신(quelamycin), 로도루비신(rodorubicin), 스트렙토미그린(streptomigrin), 스트렙토조신(streptozocin), 투베르시딘(tubercidin), 우베니멕스(ubenimex), 지노스타틴(zinostatin), 조루비신(zorubicin), 5-플루오로우라신(5-fluorouracil), 데노프테린(denopterin), 메토트렉세이트(methotrexate), 프테로프테린(pteropterin), 트리메트렉세이트(trimetrexate), 플루다라빈(fludarabine), 6-머캅토퓨린(6-mercaptopurine), 티아미프린(thiamiprine), 티구아닌(thiguanine), 안시타빈(ancitabine), 아자시티딘(azacitidine), 6-아자유리딘(6-azauridine), 카르모푸르(carmofur), 시타라빈(cytarabine), 디데옥시유리딘(dideoxyuridine), 독시플루리딘(doxifluridine), 에노시타빈(enocitabine), 플록수리딘(floxuridine), 칼루스테론(calusterone), 드로모스타놀론(dromostanolone),프로피오네이트(propionate), 에피티오스타놀(epitiostanol), 메피티오스테인(mepitiostane), 테스토락톤(testolactone), 아미노글루테티미드(aminoglutethimide), 미토테인(mitotane), 트릴로스테인(trilostane), 폴린산(folinic acid), 아세글라톤(aceglatone), 알도포스파미드 글리코사이드(aldophosphamide glycoside), 아미노레불린산(aminolevulinic acid), 에닐우라실(eniluracil), 암사크린(amsacrine), 베스트라부실(bestrabucil), 비산트렌(bisantrene), 에다트락세이트(edatraxate), 데포파민(defofamine), 데메콜신(demecolcine), 디아지콘(diaziquone), 엘포르니틴(elfornithine), 엘립티니움 아세테이트(elliptinium acetate), 에토글루시드(etoglucid), 갈리움 나이트레이트(gallium nitrate), 하이드록시우레아(hydroxyurea), 렌티난(lentinan), 로니다이닌(lonidainine), 메이탄신(maytansine), 안사미토신(ansamitocins), 미토구아존(mitoguazone), 미토잔트론(mitoxantrone), 모피단몰(mopidanmol), 니트라에린(nitraerine), 펜토스타틴(pentostatin), 페나메트(phenamet), 피라루비신(pirarubicin), 로소잔트론(losoxantrone), 2-에틸하이드라지드(2-ethylhydrazide), 프로카르바진(procarbazine), 폴리사카라이드-k(polysaccharidek), 라족세인(razoxane), 리조신(rhizoxin), 시조피란(sizofiran), 스피로게르마늄(spirogermanium), 테누아존산(tenuazonic acid), 트리아지콘(triaziquone),2,2',2''-트리클로로트리에틸아민(2,2',2''-trichlorotriethylamine), T-2 톡신, 베라큐린 A(verracurin A), 로리딘 A(roridin A), 안구이딘(anguidine), 우레탄(urethane), 빈데신(vindesine), 다카르바진(dacarbazine), 만노무스틴(mannomustine), 미토브로니톨(mitobronitol), 미토락톨(mitolactol), 피포브로만(pipobroman), 가시토신(gacytosine), 아라비노사이드(arabinoside), 사이클로포스파미드(cyclophosphamide), 티오테파(thiotepa), 파클리탁셀(paclitaxel), 파클리탁셀, 파클리탁셀의 알부민-엔지니어드 나노파티클(albumin-engineered nanoparticle formulation of paclitaxel), 도세탁셀, 클로람부실, 젬시타빈, 6-티오구아닌, 머캅토퓨린, 시스플라틴, 카보플라틴(carboplatin), 빈블라스틴(vinblastine), 플래티늄(platinum), 에토포사이드(etoposide), 이포스파미드(ifosfamide), 미톡산트론(mitoxantrone), 빈크리스틴, 비노렐빈(vinorelbine), 노반트론(novantrone), 테니포사이드(teniposide), 에다트렉세이트(edatrexate), 다우노마이신(daunomycin), 아미노프테린(aminopterin), 젤로다(xeloda), 이반드로네이트(ibandronate), CPT-11, 토포이소머라아제 저해제 RFS 2000, 디플루오로메틸오르니틴(difluoromethylornithine), 레티노산(retinoic acid), 카페시타빈(capecitabine), 또는 이의 약학적으로 허용되는 염, 용매화물 또는 산;(b) 모노카인(monokine), 림포카인(lympokine), 폴리펩타이드 호르몬(traditional polypeptide hormone), 부갑상선 호르몬(parathyroid hormone), 티록신(thyroxine), 릴렉신(relaxin), 프로릴렉신(prorelaxin), 당단백 호르몬(glycoprotein hormone), 여포자극호르몬(follicle stimulating hormone), 갑상샘자극호르몬(thyroid stimulating hormone), 황체형성호르몬(luteinizing hormone), 간 성장인자 섬유모세포성장인자(hepatic growth factor fibroblast growth factor), 프롤락틴(prolactin), 태반성 락토젠(placental lactogen), 종양괴사인자 (tumor necrosis factor), 종양괴사인자-α, 종양괴사인자-β, 뮐러관 억제물질(mullerian inhibiting substance), 마우스 고나도트로핀-연관 펩타이드(mouse gonadotropin associated peptide), 인히빈(inhibin), 액티빈(activin), 혈관내피증식인자(vascular endothelial growth factor), 트롬보포이에틴(thrombopoietin), 에리스로포이에틴(erythropoietin), 골유도 인자(osteoinductive factor), 인터페론, 인터페론-α, 인터페론-β, 인터페론-γ, 콜로니자극인자(colony stimulating factor, CSF), 마크로파지-CSF, 과립구-마크로파지-CSF(granulocyte-macrophage-CSF), 과립구-CSF, 인터루킨(IL), IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, 폴리펩타이드 인자, LIF, 키트 리간드(kit ligand), 또는 이들의 배합물;(c) 디프테리아 톡신, 보툴리눔 톡신, 테타누스 톡신, 디센터리 톡신, 콜레라 톡신, 아마니틴, α-아마니틴, 피롤로벤조디아제핀, 피롤로벤조디아제핀 유도체, 인돌리노벤조디아제핀, 피리디노벤조디아제핀, 테트로도톡신, 브레베톡신(brevetoxin), 시구아톡신(ciguatoxin), 리신(ricin), AM 톡신, 오리스타틴(auristatin), 투불리신(tubulysin), 겔다나마이신(geldanamycin), 메이탄시노이드(maytansinoid), 칼리케아마이신(calicheamycin), 다우노마이신(daunomycin), 독소루비신(doxorubicin), 메토트렉세이트(methotrexate), 빈데신(vindesine), SG2285, 돌라스타틴(dolastatin), 돌라스타틴유사체(dolastatin analog), 크립토피신(cryptophycin), 캄토테신(camptothecin), 리족신(rhizoxin), 리족신 유도체(rhizoxin derivatives), CC-1065, CC-1065 유사체 또는 유도체, 듀오카마이신(duocarmycin), 에네다인 항생제(enediyne antibiotic), 에스페라마이신(esperamicin), 에포틸론(epothilone), 톡소이드(toxoid), 또는 이들의 배합물;(d) 친화성 리간드(affinity ligand), 여기에서 친화성 리간드는 기질, 저해제, 활성화제, 신경전달물질, 방사성 동위원소, 또는 이들의 배합물;(e) 방사능표지(radioactive label), 32P, 35S, 형광다이, 전자밀도 반응제(electron dense reagent), 효소, 비오틴, 스트렙타비딘(streptavidin), 디옥시제닌(dioxigenin), 햅텐(hapten), 면역성 단백질(immunogenic protein), 타겟에 컴플러멘터리한 서열을 갖는 핵산 분자(nucleic acid molecule with a sequence complementary to a target) 또는 이들의 배합물;(f) 면역조절 화합물(immunomodulatory compound), 항-암제(anti-cancer agent), 항-바이러스제(anti-viral agent), 항-박테리아제(anti-bacterial agent), 항-곰팡이제(anti-fungal agent), 및 항-기생충제(anti-parasitic agent), 또는 이들의 배합물;(g) 타목시펜(tamoxifen), 랄록시펜(raloxifene), 드롤록시펜(droloxifene), 4-하이드록시타목시펜(4-hydroxytamoxifen), 트리옥시펜(trioxifene), 케옥시펜(keoxifene), LY117018, 오나프리스톤(onapristone) 또는 토레미펜(toremifene);(h) 4(5)-이미다졸, 아미노글루테티미드(aminoglutethimide), 메제스톨 아세테이트(megestrol acetate), 엑스메스탄(exemestane), 레트로졸(letrozole), 또는 아나스트로졸(anastrozole)(i) 플루타미드(flutamide), 닐루타미드(nilutamide), 비칼루타미드(bicalutamide), 리우프롤라이드(leuprolide), 고세렐린(goserelin), 또는 트록사시타빈(troxacitabine);(j) 아로마타아제 저해제;(k) 단백질 키나아제 저해제;(l) 리피드 키나아제 저해제;(m) 안티센스 올리고뉴클레오티드;(n) 리보자임;(o) 백신; 및(p) 항-맥관형성제(anti-angiogenic agent).
- 제1항에 있어서,상기 활성제는 피롤로벤조디아제핀 다이머이고;상기 피롤로벤조디아제핀 다이머는 N10 위치에서 X 또는 N'10 위치에서 X '로 치환되고, 여기서 X 또는 X'는 피롤로벤조디아제핀 다이머를 링커에 연결하며;X 및 X'는 각각 독립적으로 -C(O)O-*, -또는 -C(O)-*이고;*는 피롤로벤조디아제핀 다이머와 링커 사이의 결합 지점인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제42항에 있어서,상기 피롤로벤조디아제핀 다이머는 하기 일반식 X 또는 일반식 XI로 표현되는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물:[일반식 X]상기 식에서,상기 점선은 C1과 C2 사이, C2와 C3 사이, C'1과 C'2 사이, 또는 C'2과 C'3 사이의 이중 결합의 선택적 존재를 나타내며;RX1 및 RX1'는 각각 독립적으로 H, OH, =O, =CH2, CN, Rm, ORm, =CH-Rm, =C(Rm')2, OSO2-Rm, CO2Rm, CORm, 할로 또는 디할로로부터 선택되고;RX2, RX2' RX3, 및 RX3'는 각각 독립적으로 H, Rm, OH, ORm, NRm 2, NO2, 및 할로로부터 선택되며;RX4 및 RX4'는 각각 독립적으로 H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRm 2, 할로, 및 C1-6 알킬로부터 선택되고;RX5 및 RX5'는 각각 독립적으로 H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRm 2, -NRmRm', NO2, -NRmC(O)Rm‘, -NRmC(O)ORm‘, -NRmC(O)NRmRm‘, -S(O)Rm, -S(O)2Rm, -S(O)NRmRm', -S(O)2NRmRm', -NRmS(O)Rm', -NRmS(O)2Rm', -P(O)Rm, -P(O)2Rm, -P(O)NRmRm', -P(O)2NRmRm', -NRmP(O)Rm', -NRmP(O)2Rm', 및 할로로부터 선택되며;Y 및 Y'는 각각 독립적으로 O, S, 또는 N(H)이고;RX6는 독립적으로 C3-12 알킬렌, C3-12 알케닐렌, 또는 C3-12 헤테로알킬렌이며; RX6은 -NH2, -NHRm, -NHC(O)Rm, -NHC(O)CH2-[OCH2CH2]n-RXX, 또는 -[CH2CH2O]n-RXX로 치환되거나 비치환되고;상기 RXX는 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, C1-8 알킬, C3-8 시클로알킬, C1-8 알콕시, C1-8 알킬 티오, C3-20 헤테로아릴, C5-20 아릴 또는 모노- 또는 디-C1-8 알킬아미노이고, 여기에서 n은 1 내지 6의 정수이며;RX7 및 RX7'는 각각 독립적으로 H, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, -C(O)Rr, -C(O)ORs 또는 -C(O)NRrRr'이고;Rr, Rr', 및 Rs는 각각 독립적으로 H, C1-7 알킬, C2-7 알케닐, C2-7 알키닐, C3-13 사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10 아릴 또는 5 내지 7-원 헤테로아릴로이며;각 Rm'는 독립적으로 Rm, CO2Rm, CORm, CHO, CO2H, 및 할로로부터 선택되며,각 Rm은 독립적으로 H, OH, C1-12 알킬, C1-12 알콕시, C2-12 알케닐, C2-12 알키닐, C5-20 아릴, C5-20 헤테로아릴, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 및 5 내지 7-원 헤테로아릴로 이루어진 군으로부터 선택되고, 여기에서 C5-20 아릴, C5-20 헤테로아릴, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 및 5 내지 7-원 헤테로아릴의 하나 이상의 수소원자는 OH, =O, C1-12 알킬, 또는 C1-12 알콕시로 치환될 수 있다.
- 제43항에 있어서,상기 RX1 및 RX1'는 각각 독립적으로 =CH2; C1-6 알킬; C1-6 알콕시; C2-6 알케닐; C5-7 아릴; C3-6 헤테로아릴; 또는 C1-6 알킬, 또는 C1-6 알콕시로 치환된 C5-7 아릴로부터 선택되는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제43항에 있어서,상기 RX2, RX2', RX3, 및 RX3'은 각각 독립적으로 H 또는 OH로부터 선택되는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제43항에 있어서,RX5, 및 RX5'은 각각 독립적으로 H, OH, -S(O)Rm, S(O)2Rm, -P(O)Rm, 및 -P(O)2Rm로 이루어진 군에서 선택되고, 여기에서 Rm은 H, OH, C1-12 알킬, C1-12 알콕시, C2-12 알케닐, 또는 C2-12 알키닐인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제43항에 있어서,상기 RX4 및 RX4'는 각각 독립적으로 C1-6 알콕시인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제43항에 있어서,상기 Y 및 Y'는 O인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제43항에 있어서,RX6는 C3-12 알킬렌, C3-12 알케닐렌 또는 C3-12 헤테로알킬렌이고, 상기 RX6은 -NH2, -NHRm, -NHC(O)Rm, -NHC(O)CH2-[OCH2CH2]n-RXX, 또는 -[CH2CH2O]n-RXX로 치환되며;상기 RXX는 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, C3-20 헤테로아릴, C5-20 아릴 또는 모노- 또는 디-C1-8 알킬 아미노이고; 및n은 1 내지 6의 정수인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
- 제1항 또는 제10항의 접합체를 포함하는 과증식, 암 또는 혈관신생질환의 예방 또는 치료용 약학적 조성물.
- 제51항에 있어서,추가적으로 약학적으로 유효한 양의 화학 치료제(chemotherapeutic agent)를 포함하는, 약학적 조성물.
- 제51항에 있어서,상기 암은 폐암, 소세포성 폐암, 위장관암, 대장암, 장암, 유방암, 난소암, 전립선암, 고환암, 간암, 신장암, 방광암, 췌장암, 뇌암, 육종, 골육종, 카포시 육종 및 흑색종으로 이루어진 군으로부터 선택되는 어느 하나인, 약학적 조성물.
- 제1항 또는 제10항의 접합체, 및 약제학적으로 허용되는 담체를 포함하는, 주사제, 정제, 환제, 산제, 과립제, 캡슐제, 트로키제, 현탁제, 내용액제, 유제, 시럽제, 유제, 동결건조제제, 및 좌제로 이루어진 군으로부터 선택되는, 약학 제제.
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA3213985A CA3213985A1 (en) | 2021-03-30 | 2022-03-30 | Antibody-drug conjugate including antibody against human cldn18.2, and use thereof |
EP22781627.9A EP4321180A1 (en) | 2021-03-30 | 2022-03-30 | Antibody-drug conjugate including antibody against human cldn18.2, and use thereof |
JP2023555736A JP2024515934A (ja) | 2021-03-30 | 2022-03-30 | ヒトcldn18.2に対する抗体を含む抗体-薬物コンジュゲートおよびその使用 |
AU2022250810A AU2022250810A1 (en) | 2021-03-30 | 2022-03-30 | Antibody-drug conjugate including antibody against human cldn18.2, and use thereof |
US18/285,194 US20240131178A1 (en) | 2021-03-30 | 2022-03-30 | Antibody-drug conjugate including antibody against human cldn18.2, and use thereof |
IL307301A IL307301A (en) | 2021-03-30 | 2022-03-30 | An antibody-drug conjugate including an antibody against human CLDN18.2 and its use |
BR112023020093A BR112023020093A2 (pt) | 2021-03-30 | 2022-03-30 | Conjugado anticorpo-fármaco, incluindo anticorpo contra cldn18.2 humano, e uso do mesmo |
CN202280026360.1A CN117279663A (zh) | 2021-03-30 | 2022-03-30 | 一种包括针对人cldn18.2的抗体的抗体药物偶联物及其用途 |
MX2023011507A MX2023011507A (es) | 2021-03-30 | 2022-03-30 | Conjugado anticuerpo- farmaco que incluye un anticuerpo contra la cldn18.2 humana y uso del mismo. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2021-0041447 | 2021-03-30 | ||
KR20210041447 | 2021-03-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022211508A1 true WO2022211508A1 (ko) | 2022-10-06 |
Family
ID=83459705
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2022/004552 WO2022211508A1 (ko) | 2021-03-30 | 2022-03-30 | 인간 cldn18.2에 대한 항체를 포함하는 항체 약물 접합체 및 이의 용도 |
Country Status (11)
Country | Link |
---|---|
US (1) | US20240131178A1 (ko) |
EP (1) | EP4321180A1 (ko) |
JP (1) | JP2024515934A (ko) |
KR (1) | KR20220136267A (ko) |
CN (1) | CN117279663A (ko) |
AU (1) | AU2022250810A1 (ko) |
BR (1) | BR112023020093A2 (ko) |
CA (1) | CA3213985A1 (ko) |
IL (1) | IL307301A (ko) |
MX (1) | MX2023011507A (ko) |
WO (1) | WO2022211508A1 (ko) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023194800A1 (en) * | 2022-04-06 | 2023-10-12 | Legochem Biosciences, Inc. | Antibody-drug conjugate comprising antibody against human trop2 and use thereof |
WO2024140670A1 (en) * | 2022-12-26 | 2024-07-04 | Full-Life Technologies Hk Limited | Conjugate and uses thereof |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024189428A1 (en) * | 2023-03-10 | 2024-09-19 | Ligachem Biosciences Inc. | Antibody-drug conjugate comprising antibodies against human l1cam and uses thereof |
Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4880935A (en) | 1986-07-11 | 1989-11-14 | Icrf (Patents) Limited | Heterobifunctional linking agents derived from N-succinimido-dithio-alpha methyl-methylene-benzoates |
US5122368A (en) | 1988-02-11 | 1992-06-16 | Bristol-Myers Squibb Company | Anthracycline conjugates having a novel linker and methods for their production |
US5622929A (en) | 1992-01-23 | 1997-04-22 | Bristol-Myers Squibb Company | Thioether conjugates |
US5824805A (en) | 1995-12-22 | 1998-10-20 | King; Dalton | Branched hydrazone linkers |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
KR20140035393A (ko) | 2011-05-08 | 2014-03-21 | 주식회사 레고켐 바이오사이언스 | 단백질-활성제 접합체 및 이의 제조 방법 |
KR101628872B1 (ko) | 2014-05-28 | 2016-06-09 | 주식회사 레고켐 바이오사이언스 | 자가-희생 기를 포함하는 화합물 |
WO2017089890A1 (en) | 2015-11-25 | 2017-06-01 | Legochem Biosciences, Inc. | Conjugates comprising self-immolative groups and methods related thereto |
WO2017089895A1 (en) | 2015-11-25 | 2017-06-01 | Legochem Biosciences, Inc. | Antibody-drug conjugates comprising branched linkers and methods related thereto |
KR20180110649A (ko) * | 2017-03-29 | 2018-10-10 | 주식회사 레고켐 바이오사이언스 | 피롤로벤조디아제핀 이량체 전구체 및 이의 리간드-링커 접합체 화합물 |
WO2019242505A1 (zh) * | 2018-06-17 | 2019-12-26 | 上海健信生物医药科技有限公司 | 靶向cldn18.2的抗体、双特异性抗体、adc和car及其应用 |
-
2022
- 2022-03-30 IL IL307301A patent/IL307301A/en unknown
- 2022-03-30 WO PCT/KR2022/004552 patent/WO2022211508A1/ko active Application Filing
- 2022-03-30 KR KR1020220039969A patent/KR20220136267A/ko unknown
- 2022-03-30 CN CN202280026360.1A patent/CN117279663A/zh active Pending
- 2022-03-30 JP JP2023555736A patent/JP2024515934A/ja active Pending
- 2022-03-30 US US18/285,194 patent/US20240131178A1/en active Pending
- 2022-03-30 BR BR112023020093A patent/BR112023020093A2/pt unknown
- 2022-03-30 MX MX2023011507A patent/MX2023011507A/es unknown
- 2022-03-30 EP EP22781627.9A patent/EP4321180A1/en active Pending
- 2022-03-30 CA CA3213985A patent/CA3213985A1/en active Pending
- 2022-03-30 AU AU2022250810A patent/AU2022250810A1/en active Pending
Patent Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4880935A (en) | 1986-07-11 | 1989-11-14 | Icrf (Patents) Limited | Heterobifunctional linking agents derived from N-succinimido-dithio-alpha methyl-methylene-benzoates |
US5122368A (en) | 1988-02-11 | 1992-06-16 | Bristol-Myers Squibb Company | Anthracycline conjugates having a novel linker and methods for their production |
US5622929A (en) | 1992-01-23 | 1997-04-22 | Bristol-Myers Squibb Company | Thioether conjugates |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
US5824805A (en) | 1995-12-22 | 1998-10-20 | King; Dalton | Branched hydrazone linkers |
KR20140035393A (ko) | 2011-05-08 | 2014-03-21 | 주식회사 레고켐 바이오사이언스 | 단백질-활성제 접합체 및 이의 제조 방법 |
KR101628872B1 (ko) | 2014-05-28 | 2016-06-09 | 주식회사 레고켐 바이오사이언스 | 자가-희생 기를 포함하는 화합물 |
WO2017089890A1 (en) | 2015-11-25 | 2017-06-01 | Legochem Biosciences, Inc. | Conjugates comprising self-immolative groups and methods related thereto |
WO2017089895A1 (en) | 2015-11-25 | 2017-06-01 | Legochem Biosciences, Inc. | Antibody-drug conjugates comprising branched linkers and methods related thereto |
KR20180079452A (ko) * | 2015-11-25 | 2018-07-10 | 주식회사 레고켐 바이오사이언스 | 자기-희생기를 포함하는 접합체 및 이의 제조방법 |
KR20180110649A (ko) * | 2017-03-29 | 2018-10-10 | 주식회사 레고켐 바이오사이언스 | 피롤로벤조디아제핀 이량체 전구체 및 이의 리간드-링커 접합체 화합물 |
KR20180110645A (ko) | 2017-03-29 | 2018-10-10 | 주식회사 레고켐 바이오사이언스 | 피롤로벤조디아제핀 이량체 전구체 및 이의 리간드-링커 접합체 화합물 |
WO2019242505A1 (zh) * | 2018-06-17 | 2019-12-26 | 上海健信生物医药科技有限公司 | 靶向cldn18.2的抗体、双特异性抗体、adc和car及其应用 |
Non-Patent Citations (13)
Title |
---|
DISCOVERY MEDICINE, vol. 10, no. 53, 2010, pages 329 - 39 |
DUBOWCHIKWALKER, PHARM. THERAPEUTICS, vol. 83, 1999, pages 67 - 123 |
DUNCAN, A. R.J. M. WOOFL. J. PARTRIDGED. R. BURTONG. WINTER: "Localisation of the binding site for the human high-affinity Fc receptoron IgG", NATURE, vol. 332, 1988, pages 563 - 564 |
GUOYUN ZHU, FOLETTI DAVIDE, LIU XIAOHUI, DING SHENG, MELTON WITT JODY, HASA-MORENO ADELA, RICKERT MATHIAS, HOLZ CHARLES, ASCHENBRE: "Targeting CLDN18.2 by CD3 Bispecific and ADC Modalities for the Treatments of Gastric and Pancreatic Cancer", SCIENTIFIC REPORTS, vol. 9, no. 1, 1 January 2019 (2019-01-01), pages 1 - 11, XP055630964, DOI: 10.1038/s41598-019-44874-0 * |
JEFFERY ET AL., BIOCONJUG CHEM., vol. 17, no. 3, 2006, pages 832 - 40 |
JOHNSON ET AL., ANTICANCER RES, vol. 15, 1995, pages 1387 - 93 |
JOONG-JAE LEE, HYO-JUNG CHOI, MISUN YUN, YINGJIN KANG, JI-EUN JUNG, YISEUL RYU, TAE YOON KIM, YOUNG-JE CHA, HYUN-SOO CHO, JUNG-JOO: "Enzymatic Prenylation and Oxime Ligation for the Synthesis of Stable and Homogeneous Protein-Drug Conjugates for Targeted Therapy", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, VERLAG CHEMIE, vol. 54, no. 41, 5 October 2015 (2015-10-05), pages 12020 - 12024, XP055385290, ISSN: 1433-7851, DOI: 10.1002/anie.201505964 * |
KOLODYCH ET AL., EUR J MED CHEM., vol. 142, 15 December 2017 (2017-12-15), pages 376 - 382 |
LAU ET AL., BIOORG-MED-CHEM., vol. 3, no. 10, 1995, pages 1305 - 1304 |
LUND, J.G. WINTERP. T. JONESJ. D. POUNDT. TANAKAM. R. WALKERP. J. ARTYMIUKY. ARATAD. R. BURTONR. JEFFERIS: "Human FcγRl and FcγRll interact with distinct but overlapping sites on human IgG", J. IMMUNOL., vol. 147, 1991, pages 2657 - 2662 |
NEVILLE ET AL., BIOL. CHEM., vol. 264, 1989, pages 14653 - 14661 |
SARMAY, G.J. LUNDZ. ROZSNAYAYJ. GERGELEYR. JEFFERIS: "Mapping and comparison of the interaction sites on the Fc region of IgG responsible for triggering antibody dependent cellular cytotoxicity (ADCC) through different types of human Fc receptor", MOL. IMMUNOL., vol. 29, 1992, pages 633 - 639, XP023683016, DOI: 10.1016/0161-5890(92)90200-H |
THORPE ET AL., CANCER RES, vol. 47, 1987, pages 5924 - 5931 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023194800A1 (en) * | 2022-04-06 | 2023-10-12 | Legochem Biosciences, Inc. | Antibody-drug conjugate comprising antibody against human trop2 and use thereof |
WO2024140670A1 (en) * | 2022-12-26 | 2024-07-04 | Full-Life Technologies Hk Limited | Conjugate and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
BR112023020093A2 (pt) | 2023-11-14 |
MX2023011507A (es) | 2023-10-04 |
AU2022250810A1 (en) | 2023-11-09 |
EP4321180A1 (en) | 2024-02-14 |
CN117279663A (zh) | 2023-12-22 |
JP2024515934A (ja) | 2024-04-11 |
KR20220136267A (ko) | 2022-10-07 |
CA3213985A1 (en) | 2022-10-06 |
US20240131178A1 (en) | 2024-04-25 |
IL307301A (en) | 2023-11-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2022211508A1 (ko) | 인간 cldn18.2에 대한 항체를 포함하는 항체 약물 접합체 및 이의 용도 | |
WO2015182984A1 (ko) | 자가-희생 기를 포함하는 화합물 | |
WO2020180121A1 (ko) | 인간 dlk1에 대한 항체를 포함하는 항체 약물 접합체 및 이의 용도 | |
WO2018182341A1 (ko) | 피롤로벤조디아제핀 이량체 전구체 및 이의 리간드-링커 접합체 화합물 | |
EP3423104B1 (en) | Amanitin conjugates | |
JP6021963B2 (ja) | クロスリンカーおよびそれらの使用 | |
US6214345B1 (en) | Lysosomal enzyme-cleavable antitumor drug conjugates | |
WO2013125891A1 (ko) | 시스테인 잔기를 포함하는 모티프가 결합된 변형항체, 상기 변형항체를 포함하는 변형항체-약물 접합체 및 그 제조방법 | |
WO2010126178A1 (ko) | 신규한 클로린 e6-엽산 결합 화합물, 이의 제조방법 및 이를 함유하는 암 치료용 약학적 조성물 | |
WO2020184944A1 (ko) | 위치특이적 항체 콘쥬게이션 및 이의 구체예로서의 항체-약물 콘쥬게이트 | |
WO2022245186A1 (ko) | Ror1 및 b7-h3에 결합하는 항체-약물 접합체 및 그 용도 | |
WO2021137646A1 (ko) | 피롤로벤조디아제핀 유도체 및 이의 리간드-링커 접합체 | |
WO2018174544A2 (ko) | Muc1에 특이적으로 결합하는 항체 및 그의 용도 | |
WO2020153774A1 (ko) | 항체-페이로드 컨쥬게이트 제조용 화합물, 이의 용도 | |
WO2020222573A1 (ko) | 트리스 구조를 가지는 링커를 포함하는 리간드-약물 접합체 | |
WO2020141923A9 (ko) | 안전성이 향상된 피롤로벤조디아제핀 이량체 화합물 및 이의 용도 | |
WO2018124758A2 (ko) | 베타-갈락토사이드가 도입된 자가-희생 기를 포함하는 화합물 | |
WO2022149837A1 (ko) | 항-fgfr3 항체 및 이의 용도 | |
WO2021201654A1 (ko) | Glp-2 유도체 또는 이의 지속형 결합체를 포함하는 방사선요법, 화학요법, 또는 이들의 조합으로 유발된 점막염의 예방 또는 치료용 약학적 조성물 | |
WO2021194298A1 (ko) | 약물 이합체를 포함하는 나노입자 및 이의 용도 | |
WO2024025396A1 (ko) | 신규 오리스타틴 전구약물 | |
WO2024012569A9 (en) | Linkers, conjugates and applications thereof | |
WO2022031150A1 (ko) | 데옥시사이티딘계 항암제 및 실릴 에테르 함유 링커를 포함하는 접합체 및 이의 용도 | |
WO2010126179A1 (ko) | 클로린 e6-엽산 결합 화합물 및 키토산을 함유하는 암 치료용 약학적 조성물 | |
WO2024225837A1 (ko) | 말레이미드 함유 링커-페이로드 접합체 및 이를 포함하는 신규한 항체-약물 중합체 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
DPE2 | Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22781627 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2023555736 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 307301 Country of ref document: IL |
|
ENP | Entry into the national phase |
Ref document number: 3213985 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 202280026360.1 Country of ref document: CN Ref document number: MX/A/2023/011507 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 18285194 Country of ref document: US |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112023020093 Country of ref document: BR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 202317070198 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 804952 Country of ref document: NZ Ref document number: AU2022250810 Country of ref document: AU Ref document number: 2022250810 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2023127619 Country of ref document: RU Ref document number: 2022781627 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2022250810 Country of ref document: AU Date of ref document: 20220330 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2022781627 Country of ref document: EP Effective date: 20231030 |
|
ENP | Entry into the national phase |
Ref document number: 112023020093 Country of ref document: BR Kind code of ref document: A2 Effective date: 20231002 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 11202307439S Country of ref document: SG |